Clinical Pharmacy Pocket Companion 2nbsped 9780857112552 9780857111579 Compress

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Clinical Pharmacy
Pocket Companion
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Clinical Pharmacy
Pocket Companion
SECOND EDITION
Alistair Howard Gray

BSc (Hons), Dip Clin Pharm, MRPharmS
Clinical Services Lead Pharmacist
East Lancashire Hospitals NHS Trust
Jane Wright
BSc (Hons), Dip Clin Pharm, IPresc, MRPharmS
Specialist Clinical Pharmacist
Lancashire Care NHS Foundation Trust
Lynn Bruce
BSc, Dip Clin Pharm, IPresc, MRPharmS
Medical Assessment Unit Lead Pharmacist
k Jennifer Oakley k
MPharm, Dip Clin Pharm, IPresc, MRPharmS
Antimicrobial and Critical Care Pharmacist
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Published by Pharmaceutical Press
66–68 East Smithfield, London E1W 1AW, UK
© The Royal Pharmaceutical Society 2016
is a trade mark of Pharmaceutical Press
Pharmaceutical Press is the publishing division of the Royal Pharmaceutical Society
First edition published 2006

Reprinted 2008, 2010, 2011, 2012, 2014
Second edition published 2016
Typeset by SPi Global, Chennai, India
Printed in Great Britain by TJ International, Padstow, Cornwall
ISBN 978 0 85711 157 9 (print)

ISBN 978 0 85711 255 2 (ePDF)
ISBN 978 0 85711 256 9 (ePub)
ISBN 978 0 85711 257 6 (mobi)
All rights reserved. No part of this publication may be reproduced, stored in a retrieval
system, or transmitted in any form or by any means, without the prior written
permission of the copyright holder.
The publisher makes no representation, express or implied, with regard to the accuracy
of the information contained in this book and cannot accept any legal responsibility or
k liability for any errors or omissions that may be made. k
The right of Alistair Howard Gray, Jane Wright, Lynn Bruce and Jennifer Oakley to be
identified as the authors of this work has been asserted by them in accordance with the
Copyright, Designs and Patents Act 1988.
A catalogue record for this book is available from the British Library.
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Acknowledgements
We would like to thank everyone at the Pharmaceutical Press who has

been involved in producing this second edition and for their patience
during the writing process. A special thanks to all the contributors
whose experience and dedication have been distilled into these pages;
and to contributors of the first edition who were small in number but
‘got it’. Finally we should mention Vince Goodey, co-author of the first
edition, who gracefully bowed out to spend more time on his
allotment.
Alistair would like to thank Rachel for all of her support and Amelia
and Imogen for providing distraction.
Jane would like to thank Steve for his support during the writing
process.
Jenny would like to thank Simon for his support.

Lynn thanks John for scraping her off the ceiling during moments of
stress.
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Contents
Preface xiii
▼
About the authors xvii

▼
Contributors xix
▼
ABCD2 scoring system 1

▼
ACE inhibitor-induced cough 2

▼
Acetylcysteine for nebulisation 3

▼
Acute kidney injury 4

▼
Addison’s disease 7
▼
Adrenaline: nebulised 9
▼
Adverse drug reactions 10

▼
Anaemias 20
▼
Angioedema: drug causes and treatment 25

▼
Antibiotic choice 27
▼
Antimicrobial allergy management 28

▼
k Antiphospholipid syndrome 30 k
▼
Antipsychotics: equivalent doses 32

▼
Apomorphine 33
▼
Appetite stimulation 36
▼
Arterial blood gases and acid–base balance 38

▼
Artificial saliva 39
▼
Asthma 41
▼
Atrial fibrillation 47
▼
Bariatric surgery 54
▼
Benzodiazepines and ‘z’ hypnotics 57

▼
Bicarbonate 59
▼
Body surface area calculation 61

▼
Bronchiectasis (non-cystic fibrosis) 65

▼
Calcium 68
▼
Carbamazepine 71
▼
Chemotherapy-induced nausea and vomiting 74

▼
Child–Pugh score 75
▼
Chloramphenicol (systemic) 76
▼
Chronic obstructive pulmonary disease 79

▼
vii
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Ciclosporin: management and monitoring 83
▼
Cigarette smoking: calculation of pack-years 86
▼
Cigarette smoking –drug interactions 87
▼
Clozapine 88
▼
Cognitive assessment tools 90
▼
Constipation 92
▼
Corticosteroid oral/intravenous equivalence 94
▼
Corticosteroids (topical) 96
▼
CosmoFer 98
▼
C-reactive protein 100

▼
CURB-65 101
▼
Cushing’s syndrome 102

▼
Cytotoxic chemotherapy waste 104

▼
D-dimer 107
▼
Delirium 108
▼
Depression 112
▼
Diabetes insipidus (cranial) 116

▼
Diabetes mellitus 117

▼
Diabetes mellitus: management of hypoglycaemia

k (‘hypo’) in adults 119 k
▼
Diabetes mellitus: management of acute illness

(‘sick-day rules’) 122
▼
Diabetes mellitus: monitoring and tests 123

▼
Diabetic ketoacidosis 127

▼
Digoxin 131
▼
Dobutamine 137
▼
Dopamine 138
▼
DVLA: advice concerning medication and medical conditions 140

▼
Early warning score 142

▼
Emollients 143
▼
Endocarditis 147
▼
Enoxaparin dosing in unstable angina 150

▼
Enteral feeding systems and drug administration 151

▼
Epidural analgesia in the postoperative period 156

▼
Epilepsy: therapeutic drug monitoring of antiepileptics in

adults 158
▼
Erythrocyte sedimentation rate 167

▼
Eye drops: use and care 168

▼
Eye ointments: use and care 170

▼
viii CONTENTS
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Falls: pharmaceutical care 173
▼
Ferinject 176
▼
Fluid balance 177
▼
Food–drug interactions 182
▼
Gastrointestinal bleeding risk management 184
▼
Gentamicin 185
▼
Glasgow Coma Scale 190

▼
Glucosamine 192
▼
Grapefruit juice –drug interactions 194

Human immunodeficiency virus treatment ▼ 197
▼
Hyperosmolar hyperglycaemic state 208
▼
Hypodermoclysis 211
▼
Hypopituitarism 213
▼
Ideal body weight 216

▼
Immunoglobulin (normal) for intravenous administration 216
▼
Inflammatory bowel disease 219
▼
Inhaler devices in respiratory disease 223

▼
Insulins 224
▼
Insulin: variable-rate intravenous insulin infusion 231

▼
k Interstitial lung disease 233 k

▼
Iron: guidance on parenteral dosing and administration 238

▼
Kidney stones (renal calculi) 241

▼
Lactose-free medicines 243

▼
Learning disability: caring for people with learning disability and

other vulnerable patients 244
▼
LipidRescue 248
▼
Lithium: management and monitoring 249

▼
Liver disease (chronic) 253

▼
Liver function tests 259

▼
Low-molecular-weight heparin 262

▼
Magnesium 264
▼
Medicines reconciliation 268

▼
Methotrexate: calcium folinate rescue regimen 270

▼
Monofer 272
▼
Mouth ulcers and sore mouth 273

▼
Multiple sclerosis: symptomatic management 274

▼
Nausea and vomiting 278

▼
Neuroleptic malignant syndrome 279

▼
Neutropenic sepsis 280

▼
CONTENTS ix
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Nicotine replacement therapy 282
▼
‘Nil-by-mouth’: management of long-term medicines during
surgery ▼ 284
Nutraceuticals for eye health 289
▼
Omeprazole: parenteral administration 292
▼
Oncological emergencies 296
▼
Opioid comparative doses 297
Opioid misuse management ▼ 298
▼
Opioid partial agonists 303
▼
Osteoporosis 303
▼
Oxygen 308
▼
Pain management 311

▼
Palliative and end-of-life care 318

▼
Pancreatitis 327
▼
Parenteral nutrition: a practical overview 331

▼
Patient consultation 334

▼
Patient-controlled analgesia 339

▼
Phaeochromocytoma 341
▼
Pharmacocultural issues 343

▼
k Phenytoin: management and monitoring 345 k

▼
Phosphate 349
▼
Postoperative nausea and vomiting 352

▼
Potassium 355
▼
Prescription charge exemptions and prepayment certificates 360

▼
Protamine 361
▼
Prothrombin complex concentrates 362

▼
Pulmonary function tests 363

▼
Pulmonary hypertension and pulmonary arterial

hypertension 368
▼
Quinine for muscle cramps 373

▼
Rapid tranquillisation 375

▼
Renal disease: assessment of renal function 379

▼
Renal disease: dosing in renal impairment and renal replacement

therapy 382
▼
Renal disease: chronic kidney disease 386

▼
Renal replacement therapy: haemodialysis 393

▼
Renal replacement therapy: haemofiltration 396

▼
Renal replacement therapy: peritoneal dialysis 398

▼
Rheumatoid arthritis: drugs suppressing the disease process 400

▼
x CONTENTS
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Rockall score for gastrointestinal bleed 411
▼
Sarcoidosis 412
▼
Sclerosants for the management of malignant pleural
effusions 415
▼
Serotonin syndrome 416

▼
Systemic inflammatory response syndrome due to sepsis scoring
system 418
▼
Sodium 420
▼
Sterile larvae 422

▼
Stroke and transient ischaemic attack 424

Suppositories 433 ▼
▼
Surgical pharmacy 434

▼
Synacthen (tetracosactide) tests 440

▼
Syndrome of inappropriate secretion of antidiuretic hormone 442
▼
Syringe pumps 443
▼
Theophylline 447
▼
Thunderclap headache 450

▼
Thyroid function 450

▼
Tinzaparin dosing in pulmonary embolism and deep-vein

thrombosis 454
▼
k k
Tobramycin: monitoring and management 455
▼
Travel recommendations 458

▼
Tuberculosis 459
▼
Vancomycin 470
▼
Venofer 474
▼
Vitamins and minerals 474

▼
von Willebrand disease 484

▼
Warfarin treatment and monitoring 486

▼
Wells score for deep-vein thrombosis 494

▼
Wells score for pulmonary embolism 495

▼
Yellow Card scheme 497

▼
Zinc 502
▼
APPENDICES 505
1 Glossary of terms 505
▼
2 Laboratory reference ranges 509

▼
3 Imperial –metric height conversion 512

▼
4 Imperial –metric weight conversion 513

▼
Index 515
▼
CONTENTS xi
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Preface
Welcome to the second edition of the Clinical Pharmacy Pocket

Companion. It is a measure of the support and demand from users of
the first edition that a second edition (and hopefully future editions)
of this book exists. Feedback and suggestions from people using the
book have informed how this edition is laid out, what new entries
have been included and what has been removed. Please continue to
let us know what you think at [email protected].
The aim of the Clinical Pharmacy Pocket Companion is to provide
the user with a range of tools, suggestions and advice to assist in the
provision of effective pharmaceutical care. The book has three main
purposes.
Firstly as an aide-mémoire, the Companion helps to resolve routine
queries arising from therapeutic drug monitoring, electrolyte
disturbances, management of disease states and perioperative drug
administration as well as more obscure problems. It complements
existing literature, bridging the gap between the patient’s bedside and
the dispensary library. It brings together useful information not easily
k found in other reference sources, and previously not available in k
one text.
Secondly, there are prompts to seek out local information, for
instance laboratory ranges and various drug policies. The action of
actively seeking out this information supplements the user’s
continuing professional development. The references also provide
further reading suggestions to explore a subject further.
Finally, space is provided at the end of each entry and section to
record personal information, for example, passwords, websites and
prompts from one’s own experience of clinical practice.
The second edition

The way each entry has been created has changed. The first edition
was written mainly by the authors with support from five
contributors; for the second edition entries have been written or
reviewed by many different people. Our contributors were
approached because they are experts in a particular clinical field and
include various professors, doctors and even a couple of presidents;
and they aren’t all pharmacists – a dietician and a clinical
psychologist have contributed. What they all have in common was a
desire to share their expertise with other healthcare professionals
who have an interest in clinical pharmacy to benefit patients.
Where practical all non-essential, less clinical entries have
been removed, including the hotly debated Regimen or regime?
(For the record, a regimen (pronounced like ‘regiment’ without the ‘t’)
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is a prescribed course of action, e.g. exercise, diet or pharmacological

intervention, with a desired outcome. A regime is a method of
government. The terms are commonly mixed up in the vernacular, in
professional journals and in presentations!).
Refer-to-Pharmacy
The book is aimed at anyone associated with delivering
pharmaceutical care (or medicines optimisation) in both a hospital
setting and in community pharmacy. Some entries lend themselves
more to secondary care by their very nature; however most apply to
both disciplines. With the advent of various commissioned services in
primary care to improve medicines adherence, e.g. New Medicine
Service, Discharge Medication Review, Medicines Use Review, the
clinical aspect and consultation skills of a community pharmacist’s
role are rightly becoming even more crucial.
With the advent of schemes such as Refer-to-Pharmacy
(www.elht.nhs.uk/refer), which actively facilitates the referral of
patients from the hospital pharmacy team to their community
pharmacy for postdischarge pharmaceutical care, this book provides
essential tips, knowledge and skills to community pharmacists
consulting with patients referred to them. At the time of writing such
referral schemes are in their infancy, and for more information visit
www.rpharms.com/referraltoolkit to read the Royal Pharmaceutical
Society’s Hospital referral to community pharmacy toolkit to see how a
k referral scheme can be implemented in your health economy. k
How to use the Clinical Pharmacy Pocket Companion
In the print edition the thumbnail cut-outs allow quick access to any
letter of the alphabet. Subjects have been sited intuitively, e.g.
treatment of hyperkalaemia is under ‘P’ for potassium. There is some
cross-referencing and some information is repeated for ease of use;
for example, the calculation of ideal body weight is included
wherever it is needed and as an entry in its own right.
The list of contents is displayed alphabetically as laid out in the
book, and there is also a full index at the back of the book.
Where doses appear, unless otherwise stated, they relate to adults.
The Injectable Drugs Guide
This is the sister publication of the Clinical Pharmacy Pocket
Companion by these authors, available in print form or via
www.MedicinesComplete.com. The Injectable Drugs Guide was
published between editions of the Clinical Pharmacy Pocket
Companion and rather went under the radar.
The Injectable Drugs Guide is an A–Z of approximately 300
injectable drugs in monograph format, each covering the following
topics:
● pretreatment checks
● dosing regimens
xiv PREFACE
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● preparation and administration

● compatibility and stability information
● monitoring requirements during treatment
● side effects, interactions and pharmacokinetic information.
The Injectable Drugs Guide is designed to support the National

Patient Safety Agency risk assessment process and each drug has a
risk rating.
The book provides a holistic approach to injectable medicines to
meet the needs of the many disciplines involved in the clinical use of
injectables, and to those providing advice about injectable drug use.
Some sample entries can be viewed at www.pharmpress.com
(search for Injectable Drugs Guide) and we have included the
omeprazole monograph in this book to illustrate the benefit this
one-stop shop of a book can bring to doctors, nurses and pharmacists.
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About the authors
Alistair Gray is from Sunderland. He studied pharmacy at

Sunderland Polytechnic, graduating in 1988 with first-class honours,
and then completed his pre-registration year with Boots in
Newcastle-upon-Tyne. He continued working for Boots in a variety of
pharmacy and store management positions in the north-west of
England. In 2002 he changed disciplines and became Community
Services Pharmacist at Queens Park Hospital in Blackburn. He
completed a Diploma in Clinical and Health Services Pharmacy at the
University of Manchester in 2008 and subsequently became Clinical
Services Lead Pharmacist for East Lancashire Hospitals NHS Trust in
2009, based at the now renamed Royal Blackburn Hospital. In 2012
he received the Royal Pharmaceutical Society’s Medicines Safety
Award for work in Transfer of Care. His interest in this area has
continued, resulting in him conceiving what has become the
Refer-to-Pharmacy scheme.
Alistair is married with two children and loves spending time with
his family. He follows Formula One motor racing closely and enjoys
reading, eating out, going to the movies, playing the guitar and song
k writing (best bits at https://soundcloud.com/Al Chemist).
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Jane Wright, after working for 18 years in the Civil Service,
attended the University of Manchester to study pharmacy. Jane
graduated in 1994 and did her pre-registration year at the Royal
Preston Hospital. For the next 10 years Jane worked in Blackburn
hospitals in a variety of clinical roles, her last being Clinical Services
Manager with responsibility for education and training. In 1999 she
obtained a Diploma in Clinical and Health Services Pharmacy at the
University of Manchester. She moved to Lancashire Care NHS
Foundation Trust in April 2005 where she was employed as Lead
Pharmacist for East Lancashire until retirement in October 2014.
Since then she has returned to work part-time as a non-medical
prescriber in the Memory Assessment Service at Lancashire Care NHS
Foundation Trust.
Jane is married and in her spare time enjoys playing with Molly
and Polly (two very lively dogs).
Lynn Bruce studied pharmacy at Aston University. The first 20 years
of her working life were based in secondary care variously as
medicines information pharmacist, clinical pharmacy lead, clinical
economist and latterly in various management positions. She
migrated across the divide to primary care in 1997, becoming
primary care group and then primary care trust prescribing advisor.
Hospital clinical pharmacy beckoned her back to secondary care in
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2002: she is now Pharmacy Team Leader on the Medical Assessment

Unit at the Royal Blackburn Hospital.
Lynn is married and, when she’s not writing pharmacy books, loves
studying wild life and travelling and is addicted to puzzles of all types.
Jennifer Oakley is from the Wirral, Merseyside. She studied

pharmacy at Liverpool John Moore’s University, graduating in 2007
with a first-class honours degree, and was jointly awarded the local
Royal Pharmaceutical Society of Great Britain branch prize in 2007.
She then went on to complete her Postgraduate Clinical Diploma
whilst undertaking a residency at Wirral University Teaching
Hospitals. Meeting her future husband led her to Lancashire where
she has worked in several roles, currently as an Antimicrobial and
Critical Care Pharmacist at East Lancashire Hospitals.
Jenny is recently married and enjoys travelling the world and
visiting exotic places.
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xviii ABOUT THE AUTHORS
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Contributors
James Andrews
MPharm, MRPharmS
Practice Pharmacist, The Guildowns Group Practice
Lead Pharmacist for the West, Virgin Care
Sotiris Antoniou
MSc, Dip Mgt, IPresc, MRPharmS, FFRPS
Consultant Pharmacist
Cardiovascular Medicine, Barts Health NHS Trust
Nina Barnett
MSc, IPresc, FRPharmS, FFRPS, JP
Consultant Pharmacist, Care of Older People
NHS Specialist Pharmacy Service and
London North West London Hospitals NHS Trust
Victoria Bithell
BSc, MPsychol, CPsychol, AFBPsS
k Registered Clinical Psychologist k
Wirral Hospice St John’s
Mark Borthwick
BPharm (Hons), MSc, FRPharmS, FFRPS
Consultant Pharmacist: Critical Care
Oxford University Hospitals NHS Trust
Annette Clarkson
MPharm, Dip Clin Pharm, MRPharmS
Specialist Clinical Pharmacist Antimicrobials and Infection Control
Nottingham University Hospitals NHS Trust, Nottingham, UK
Ailsing Considine
Senior Clinical Pharmacist Liver and Private Patient Services
Kings College Hospital NHS Foundation Trust
Sian Davison
Specialist Clinical Pharmacist, Medical Admissions Unit
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Peter Foxon
Senior Clinical Pharmacist Antibiotics
Nottingham University Hospitals
Patricia Ging
BPharm, MPSI, MSc, MRPharmS
Transplant/Pulmonary Hypertension Pharmacist
Pharmacy Department, Mater Misericordiae University Hospital,
Dublin, Republic of Ireland
Niamh Gormley
MPharm
Clinical Pharmacist
UHND Pharmacy Department, University Hospital of North Durham
Jill Gray
Specialist Pharmacist
Dan Greer
BPharm, MSc, Dip Clin Pharm
Pharmacist Lecturer/Practitioner
University of Leeds/Leeds Teaching Hospitals
k Susan Holgate k
Nikki Holmes
MPharm, PGDipPsychPharm, IPresc, MCMHP, MRPharmS,
RegPharmNZ
Head of Pharmacy – Forensic Directorate
Nottinghamshire Healthcare NHS Foundation Trust
Sally James
BSc (Hons), MSc, MRPharmS
Divisional Pharmacist for Medicine
Royal Liverpool Hospital
Kevin Johnson
MPharm, Dip Clin Pharm, IPresc
Senior Clinical Pharmacist
Emergency Assessment Unit
Salford Royal Hospitals Foundation Trust
xx CONTRIBUTORS
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Shelley Jones
MSc, MPharm, IPresc, MRPharmS
Clinical Pharmacy Team Leader, Neurosciences
Kings College Hospital NHS Foundation Trust
Roger Knaggs
BSc (Hons), BMedSci, PhD, MRPharmS
Associate Professor in Clinical Pharmacy Practice
School of Pharmacy, University of Nottingham
Advanced Pharmacy Practitioner – Pain Management
Nottingham University Hospitals NHS Trust
Hannah Macfarlane
MPharm (Hons), PGDipPsychPharm, MCMHP, MRPharmS
Senior Clinical Pharmacist and Clinical Tutor
Birmingham and Solihull MHFT and Aston University
Lloyd Mayers
MPharm, Clin Dip Pharm, MRPharmS
Specialist Pharmacist Respiratory Medicine and Interstitial Lung
Disease
North Bristol NHS Trust
Catherine McKenzie
BSc, PhD, FFRPS, FRPharmS
k Consultant Pharmacist in Critical Care k
Guy’s and St Thomas’ NHS Foundation Trust
Debra Morris
BPharm, MRPharmS
Senior Clinical Pharmacist and Clinical Tutor
Salford Royal Foundation Trust/University of Manchester
Anna Murphy
MSc, DPharm, IPresc, MRPharmS
Honorary Visiting Professor, Department of Pharmacy, DeMontfort
University
Consultant Respiratory Pharmacist
University Hospitals of Leicester NHS Trust
Anne Neary
Senior Pharmacist for Antimicrobials and Infectious Diseases
Royal Liverpool University Hospital
Lelly Oboh
BPharm, Dip Clin Pharm, IP, FRPharmS
Consultant Pharmacist, Care of Older People
Guy’s and St Thomas’ NHS Foundation Trust
CONTRIBUTORS xxi
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Smita Ojha
BPharm (Hons), Dip Clin Pharm, IPresc, MRPharmS
Directorate Pharmacist for Stroke, Care of Elderly and Rehabilitation
Simon Purcell
Lead Pharmacist, Haematology and Aseptic Services
Wirral University Teaching Hospital NHS Foundation Trust
Christine Randall
BPharm, MRPharmS
Senior Medicines Information Pharmacist
North West Medicines Information Centre/Yellow Card Centre
North West
Viki Richards
Advanced Primary Care Pharmacist
East Lancashire Clinical Commissioning Group
Victoria Ruszala
MPharm, Clin Dip Pharm
Specialist Pharmacist, Diabetes and Endocrinology
k Christine Sluman k
Highly Specialised Renal Pharmacist
Victoria Smith
Lynsey Stephenson
MPharm, DipClinPharm, IP, PGCCE
Senior Clinical Trials Pharmacist
UHND Pharmacy Department, University Hospital of North Durham
Katherine Stirling
BPharm (Hons), Dip Clin Pharm, IPresc, MRPharmS
Consultant Pharmacist Anticoagulation and Thrombosis
Leeds Teaching Hospitals NHS Trust
Dave Thornton
Principal Pharmacist, Clinical Services
University Hospital Aintree
xxii CONTRIBUTORS
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Alan Timmins
MSc, FFRPS, MRPharmS
Principal Pharmacist – Clinical Services
Victoria Hospital, Kirkcaldy
Mark Tomlin
BPharm, MSc (Biopharmacy), PhD, IPresc, FRPharmS, FFRPS
Consultant Pharmacist: Critical Care
Southampton General Hospital
Steve Wanklyn
MSc, IPresc, MRPharmS
Consultant Pharmacist in Palliative and End of Life Care; Joint Chair
London Opioid Safety and Improvement Group; Member PallE8
London Cancer North and East
Guy’s and St Thomas’ NHS Foundation Trust; Trinity Hospice;
St Joseph’s Hospice; Richard House Children’s Hospice
Jennifer Wilding
BSc (Hons) Applied Human Nutrition (Dietetics)
Nutrition Support Lead Dietitian
Rachel M Wilson
k Specialist Clinical Pharmacist k
Verity Woodhall
Lead Clinical Pharmacist for Musculoskeletal and Dermatology
Newcastle upon Tyne Hospitals NHS Foundation Trust
Antony Zorzi
BPharm, MSc, Dip Clin Pharm, IPresc
Lead Pharmacist, Antimicrobials and Respiratory
Pharmacy Department, Musgrove Park Hospital
Taunton and Somerset NHS Foundation Trust
CONTRIBUTORS xxiii
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ABCD2 scoring system 1
A
A
ABCD2 scoring system

Background
The ABCD2 score is a validated risk assessment tool designed to identify individuals at high
early risk of subsequent stroke after a transient ischaemic attack (TIA). Assessing people
rapidly can minimise the chances of a full stroke occurring, as there is a 20% risk of a full
stroke within the first 4 weeks after a TIA.1,2
SCORING SYSTEM
Clinical feature Score
A – Age (≥60 years) 1
B – Blood pressure at presentation (≥140/90 mmHg) 1
C – Clinical features: unilateral weakness 2
speech disturbance without weakness 1
D – Duration of symptoms: ≥60 minutes 2
10–59 minutes 1
k D – Diabetes mellitus 1 k
Total ABCD2 score 0–7
Interpretation3,4
Early risk of stroke after TIA: 2-day risk of stroke:
Scores 0–3: low risk, 1%
Scores 4–5: moderate risk, 4.1%
Scores 6–7: high risk, 8.1%
● People with a score of ≥4 are regarded as being at a higher risk of early stroke. Aspirin
300 mg daily should be started immediately and specialist assessment (exclusion of
stroke mimics, identification of vascular treatment, identification of likely causes) and
investigation should happen (in a TIA clinic) within 24 hours of onset of symptoms.
● People with a score of ≤3 are considered at lower risk but should also start aspirin
300 mg daily and have specialist assessment and investigation within a maximum of
7 days of onset of symptoms
REFERENCES
1 Intercollegiate Stroke Working Party. Royal College of Physicians (2012). National
Clinical Guideline for Stroke, 4th edn. https://www.rcplondon.ac.uk/sites/default/
files/national-clinical-guidelines-for-stroke-fourth-edition.pdf (accessed 13
December 2014).
2 NICE (2008). Clinical guideline 68. Stroke: Diagnosis and initial management
of acute stroke and transient ischaemic attack (TIA). https://www.nice.org.uk/
guidance/cg68 (accessed 13 December 2014).
k
k
2 ACE inhibitor-induced cough
3 Rothwell PM et al. (2007). Effect of urgent treatment of transient ischaemic

A attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective
population-based sequential comparison. Lancet 370: 1432–1442.
4 Coull A et al. (2004). Early risk of stroke after a TIA or minor stroke in a population-
based incidence study. BMJ 328: 326–328.
ACE inhibitor-induced cough

Chronic cough is a well-described class effect of angiotensin-
converting enzyme (ACE) inhibitors.1 The cough is typically dry and
is associated with a tickling or scratching sensation in the throat.
Reports vary; 5 –35% of patients who receive ACE inhibitors develop
a dry cough, sometimes severe enough to require discontinuation of
the drug.1,2
ACE inhibitor cough is considered a class effect that may occur
with any ACE inhibitors and is not dose-dependent. Cough may occur
within hours of the first dose of medication, or its onset can be delayed
for weeks to months after the initiation of therapy. Treatment with
ACE inhibitors may sensitise the cough reflex, thereby potentiating
other causes of chronic cough.3 Although cough usually resolves
within 1 –4 weeks of cessation of therapy with the offending drug, in
a subgroup of individuals cough may linger for up to 3 months.
Women and those of black or Asian ethnicity have been reported to
k be at increased risk of ACE inhibitor cough. k
Mechanisms of cough from ACE inhibitors
The inhibition of ACE prevents the conversion of angiotensin I to
angiotensin II, with consequent salutary benefits via the renin–
angiotensin system in pathological states. ACE inhibitor cough is
thought to be linked to the suppression of ACE, which is proposed to
result in an accumulation of substances normally metabolised by ACE:
bradykinin and substance P. However, the development of cough may
result from a more complex cascade of events than originally believed.
Bradykinin has been shown to induce the production of arachidonic
acid metabolites and nitric oxide, and there is some evidence that
these products, which are subject to regulation by other pathways,
may promote cough through proinflammatory mechanisms.3,4
Can angiotensin II receptor blockers be used in patients
with a history of ACE inhibitor cough?
Theoretically, angiotensin II receptor blockers (ARBs) should not
induce cough as they do not directly inhibit ACE activity or inhibit the
breakdown of bradykinin. Indeed, ARBs have been associated with a
low incidence of cough in patients with a history of ACE inhibitor
cough, e.g. the frequency of cough with losartan was lower than with
lisinopril (29 versus 72%, P < 0.01), and similar to
hydrochlorothiazide (34%).5
k
k
Acetylcysteine for nebulisation 3
Treatment of ACE inhibitor cough A

The only uniformly effective intervention for ACE inhibitor-induced
cough is the cessation of therapy with the offending agent. In cases in
which the continuation of an ACE inhibitor is necessary despite
cough, cromoglicate, baclofen, theophylline and local anaesthetics
have been reported to be of some benefit, although none has been
subjected to large-scale trials.6,7
Since the use of ACE inhibitors is now widespread, it is vitally
important that practitioners consider identifying cases of ACE
inhibitor-induced cough. Available studies indicate that, in the great
majority of patients, those who develop these adverse reactions from
ACE inhibitors can tolerate ARBs. The cardiovascular benefits and
potential reduction in mortality from use of these drug classes are
important and significant. Therefore, in a risk–benefit assessment,
consideration should be given to the cautious alternative use of ARBs
in the management of patients who develop cough from ACE
inhibitors.
REFERENCES
1 Visser LE et al. (1995). Angiotensin converting enzyme inhibitor associated cough:
a population-based case-control study. J Clin Epidemiol 48: 851–857.
2 Elliott WJ (1996). Higher incidence of discontinuation of angiotensin converting
enzyme inhibitors due to cough in black subjects. Clin Pharmacol Ther 60: 582–588.
3 Dicpinigaitis PV (2006). Angiotensin-converting enzyme inhibitor-induced cough:
ACCP evidence-based clinical practice guidelines. Chest 129(1 Suppl): 169S–173S.
4 Trifilieff A et al. (1993). Kinins and respiratory tract diseases. Eur Respir J 6:
k 576–587. k
5 Lacourciere Y et al. (1994). Effects of modulators of the renin– angiotensin–
aldosterone system on cough. Losartan Cough Study Group. J Hypertens 12:
1387–1393.
6 Allen TL, Gora-Harper ML (1997). Cromolyn sodium for ACE inhibitor-induced
cough. Ann Pharmacother 31: 773–775.
7 Luque CA, Vazquez Ortiz M (1999). Treatment of ACE inhibitor-induced cough.
Pharmacotherapy 19: 804–810.
Acetylcysteine for nebulisation

Acetylcysteine injection is sometimes used in an unlicensed capacity
as a mucolytic.1
The adult dose is 3 –5 mL of acetylcysteine 20% injection, or
6 –10 mL of a 10% solution through a face mask or mouthpiece,
nebulised three or four times daily with air (use of concentrated
oxygen causes degradation).
Acetylcysteine reacts with some materials, e.g. rubber, iron, copper
and nickel, so ensure the nebuliser does not contain these.
Nebulisation equipment should be cleaned immediately after use with
hot water and left to air dry.
Acetylcysteine may induce bronchospasm. As a precaution this can
be avoided by either administration of a lower dose, diluting 1 mL of
k
k
4 Acute kidney injury
A acetylcysteine 20% injection in 5 mL sodium chloride 0.9% and

nebulising 3 –4 mL, or preadministering a nebulised bronchodilator.
Alternatively 1 –10 mL of a 20% solution or 2 –20 mL of a 10%
solution may be given by nebulisation every 2 –6 hours.
REFERENCE
1 Martindale: The Complete Drug Reference (2014). www.medicinescomplete.com
(accessed 27 January 2015).
Acute kidney injury

Overview
Definition Clinically acute kidney injury (AKI) is characterised by a rapid reduction in
kidney function over hours or days, resulting in a failure to maintain
fluid, electrolyte and acid–base homeostasis. Untreated this can lead to
pulmonary oedema, hyperkalaemia and metabolic acidosis.
AKI is defined when one of the following criteria is met.1
● Increase in serum creatinine of ≥26 micromol/L within 48 hours
● Increase in serum creatinine of ≥50% from baseline (the lowest
serum creatinine value recorded within 3 months of the event), which
is known or presumed to have occurred within the past 7 days
● Fall in urine output to <0.5 mL/kg/hour for >6 consecutive hours in
adults and >8 hours in children
k Causes Prerenal AKI (≈80% of cases)

k
Blood flow to the kidney is reduced which, if left untreated, can lead to
ischaemic injury to the kidney (known as acute tubular necrosis or ATN).
Common causes of prerenal AKI include:
● hypotension
● dehydration
● sepsis
● significant blood loss, e.g. gastrointestinal bleeding
● cardiac or liver failure
● severe burns
Some medications may cause prerenal AKI, such as NSAIDs, ACE
inhibitors, ARBs and diuretics (see ‘Further reading’ for more detailed
information).
Postrenal AKI (≈10% of cases)
Obstruction to urine outflow from the kidneys occurs.
Common causes of postrenal AKI include:
● benign prostatic hypertrophy
● bladder or prostate cancer
● abdominal tumours compressing the urinary tract
● renal stones
Some medications may cause postrenal AKI, either through deposition of
crystals (e.g. aciclovir or cytotoxic agents) or through blood clots after
bleeding (e.g. antiplatelet or anticoagulant therapy)
k
k
Acute kidney injury 5
Intrinsic AKI (≈10% of cases) A

Damage occurs to the kidney itself, often immunological in origin.
Common causes of intrinsic AKI include:
● acute interstitial nephritis (AIN) – a hypersensitivity reaction that
may often be drug-related, e.g. proton pump inhibitors (PPIs) and
pencillins
● myeloma – through deposition of light chains in the kidney
● autoimmune renal disease, including lupus and vasculitis
● rhabdomyolysis – due to the renal toxicity of myoglobin from muscle
breakdown
Risk factors ● Age >75 years
● Chronic kidney disease
● Cardiac failure
● Peripheral vascular disease
● Liver disease
● Diabetes mellitus
● Nephrotoxic medications, including iodinated radiological contrast
media
● Hypovolaemia
● Sepsis
● Surgical procedures
Diagnostic ● Drug history

tests ● Vital signs (temperature, heart rate, blood pressure)
● Biochemistry (urea and electrolytes)
● Full blood count
k ● Urine dipstick ± microscopy k
● Microbiology:
● Urine culture
● Blood culture
● Urine output
● Hydration status, including jugular venous pressure
More specific renal investigations are dependent upon the clinical
presentation and may include:
● renal immunology
● urinary biochemistry (electrolytes, osmolality)
● renal tract ultrasound within 24 hours (if renal tract obstruction is
suspected)
● kidney biopsy
Staging The severity of AKI can be classified into three stages.2

Stage 1: serum creatinine increase of ≥26 micromol/L within 48 hours
or increase to ≥1.5–1.9 times baseline; urine output <0.5 mL/kg/hour
for >6 consecutive hours
Stage 2: serum creatinine increased to ≥2–2.9 times baseline; urine
output <0.5 mL/kg/hour for >12 hours
Stage 3: serum creatinine increased to ≥3 times baseline or increased
to ≥354 micromol/L or commenced on renal replacement therapy,
irrespective of stage; urine output <0.3 mL/kg/hour for >24 hours or
anuria for 12 hours
k
k
6 Acute kidney injury
A Treatment AKI has a poor prognosis, with the mortality ranging from 10% to 80%.
goals depending upon the patient population studied. Even small increases in
serum creatinine are associated with worse patient outcomes, including
prolonged hospital stay and increased morbidity and mortality.3
The goals of AKI treatment are:
● Prevention
● Early identification and assessment
● Appropriate hydration
● Avoid hypotension (systolic blood pressure <110 mmHg)
● Prompt treatment of infection and other medical conditions
● Stop nephrotoxic drugs
● Adjust doses of renally excreted drugs
Treatment ● Identify and treat potential causes, e.g. underlying sepsis

options ● Assess volume status and give appropriate intravenous fluid therapy
● Use potassium-containing solutions (e.g. Hartmann’s) cautiously due
to the risk of exacerbating hyperkalaemia
● Daily observations, fluid balance, body weight and urine output
should be monitored to ensure appropriate fluid therapy and avoid
overload
● Medication review:
● Discontinue/avoid all nephrotoxic medications
● Discontinue antihypertensive medications if patient is hypotensive
● Adjust medication doses as necessary
● Administer vasopressors and/or inotropes to increase blood pressure
where appropriate
Manage biochemical complications, e.g. treatment of hyperkalaemia
k k
●
and/or metabolic acidosis

● Give renal replacement therapy
Pharmaceutical care and counselling

Assess ● Ensure a detailed drug history is taken, including OTC, herbal and
recently stopped medications
● Fluid status
● Medication review
Essential Many drugs can precipitate AKI and all nephrotoxic medications or
intervention medications that may affect renal haemodynamics should be stopped or
avoided, e.g. NSAIDs, ACE inhibitors and diuretics.
Advise on suitable alternatives where appropriate
Essential Review the side-effect profile of all medicines to identify potential causes
intervention of ATN or interstitial nephritis, e.g. amphotericin, PPIs
Essential Discontinue non-essential medications where appropriate until AKI has
intervention resolved, e.g. statins
Essential Advise on appropriate drug dosing in AKI.
intervention Many pharmacokinetic parameters, including volume of distribution,
clearance and protein binding, are altered in AKI.
Drug doses need to be adjusted appropriately with the correct
assessment of kidney function to reduce toxicity. Examples include dose
reduction of renally excreted drugs such as digoxin or gabapentin, or use
of alternative agents that are less renally excreted, e.g. switching from
morphine to fentanyl
k
k
Addison’s disease 7
Secondary Advise on the appropriate use of intravenous fluids (see Fluid balance A
intervention entry).
Provide recommendations around fluid restriction and minimum infusion
volumes for drugs used in fluid-overloaded patients
Continued Daily assessment of renal function and review of medication doses as
monitoring renal function improves.
Consider reintroduction of non-causative medications once AKI has
resolved
Counselling Counsel a patient regarding any medication changes prior to discharge,
in particular any causative agents that have now been stopped.
Advise patients about any medications to be avoided in future (e.g. OTC
NSAIDs).
Advise patients receiving medications that put them at risk of AKI to seek
medical advice if they become acutely unwell or think they might be
dehydrated.
Provide accurate discharge information to general practitioners,
including changes to medication, medicines to be restarted after
discharge (and when this should occur) and any counselling provided
Further Shaw S et al . (2012). Acute kidney injury – diagnosis, staging and
reading prevention. Clin Pharmacist 4: 98–102.
Shaw S et al . (2012). Acute kidney injury – management.
Clin Pharmacist 4: 103–106.
k REFERENCES
k
1 NICE (2013). Acute Kidney Injury: Prevention, detection and management up to
the point of renal replacement therapy. NICE guidelines CG169. www.nice.org.uk/
guidance/CG169 (accessed 7 September 2014).
2 Kidney Disease: Improving Global Outcomes (2012). Clinical Practice Guideline
for Acute Kidney Injury www.kdigo.org/clinical practice guidelines/pdf/KDIGO%
20AKI%20Guideline.pdf (accessed 7 September 2014).
3 UK Renal Association (2011). Clinical Practice Guidelines: Acute Kidney Injury,
5th edn. http://www.renal.org/docs/default-source/guidelines-resources/
Acute Kidney Injury - Final Version 08 March 2011.pdf?sfvrsn=0 (accessed
7 September 2014).
Addison’s disease
Overview
Definition Addison’s disease occurs when the adrenal glands do not produce
enough cortisol and, in some cases, aldosterone. There are two types of
adrenal insufficiency: primary and secondary.
Primary adrenal insufficiency (Addison’s disease) is caused by
adrenal gland malfunction.
Secondary adrenal insufficiency is much more common than primary
adrenal insufficiency and is due to pituitary malfunction and a lack of
adrenocorticotrophic hormone (ACTH)1
k
k
8 Addison’s disease
A Risk factors Addison’s disease has a prevalence of 93–140 per million people and
annual incidence of 4.7–6.2 per million people in western populations
Differential The onset of Addison’s disease is often insidious. Its usual symptoms
diagnosis (such as fatigue, lethargy, weakness and low mood) are non-specific and
highly prevalent in the general population, and overlap with many other
common conditions, including:
● depression
● chronic fatigue syndrome
● anorexia nervosa
● type 1 diabetes
● gastrointestinal disorders
Diagnostic About half of patients with Addison’s disease are diagnosed only after an
tests acute adrenal crisis. A diagnosis of Addison’s disease is made by
laboratory tests, firstly to determine whether levels of cortisol are
insufficient and then to establish the cause. A short Synacthen test is the
investigation of choice to confirm or exclude Addison’s disease.
250 micrograms of tetracosactide (an analogue of corticotropin) is
administered by intramuscular or intravenous injection and three blood
samples for serum cortisol are taken immediately, at 30 minutes and at
60 minutes. A normal response is a rise in serum cortisol level to above
500 nmol/L at 30 minutes or 60 minutes. A level less than 100 nmol/L
indicates a high likelihood of adrenal insufficiency. A plasma ACTH
concentration should be measured, as a raised concentration will
distinguish Addison’s disease from secondary adrenal insufficiency. Once
the diagnosis of Addison’s disease is made, further investigations are
needed to determine the underlying cause
k k
Treatment Replacing or substituting the adrenal hormones
goals
Treatment ● Hydrocortisone
options ● Prednisolone
● Fludrocortisone
Pharmaceutical care and counselling1,2
Essential Cortisol is replaced orally with hydrocortisone tablets, usually given once
intervention or twice daily. If aldosterone is also deficient, it is replaced with oral
doses of fludrocortisone acetate taken once a day. Patients receiving
aldosterone replacement therapy are usually advised to increase their
salt intake. The doses of each of these medications are adjusted to meet
the needs of individual patients
Essential The usual replacement dose of hydrocortisone is 15–25 mg/day, given in
intervention two or three divided doses. Fludrocortisone is given in a single dose of
50–200 micrograms a day. Doses do not have to be matched to meals so
patients can take to suit their lifestyle
Secondary Medication may need to be increased (doubled or tripled) during times of
intervention stress, infection or injury. This should be given parenterally if a patient
cannot tolerate the drug orally. A patient with an acute adrenal crisis
needs urgent hospital admission for intravenous fluid, parenteral
hydrocortisone and treatment of the precipitating cause
k
k
Adrenaline: nebulised 9
Continued There are no objective measures for assessing the effectiveness of A

monitoring treatment. Monitor for signs of:
● Overreplacement: hypertension, thin skin, striae, easy bruising,
glucose intolerance, hyperglycaemia, electrolyte abnormalities
● Underreplacement: symptoms of Addison’s disease, including fatigue,
postural hypotension, nausea, weight loss and salt craving
Further NICE (2010). Clinical Knowledge Summaries: Addison’s Disease.

reading http://cks.nice.org.uk/addisons-disease#!topicsummary (accessed 10
October 2014).
REFERENCES
1 Vaidya B, Chakera AJ (2009). Addison’s disease. BMJ 339: b2385.
2 Baker AJK, Wass AJH (2009). A patient’s journey. Addison’s disease. BMJ 339:
b2384.
Adrenaline: nebulised
Adrenaline has a sympathomimetic action at alpha- and
beta-adrenoceptors. It causes increased cardiac contraction, blood
flow to skeletal muscle, hyperglycaemia, oxygen consumption and
relaxation of bronchial smooth muscle.1
In patients with severe croup, nebulised adrenaline may be used
for rapid relief alongside corticosteroid treatment. Croup is an
k inflammation of the respiratory tract that usually occurs in childhood. k
Method of administration for children
1 month –12 years1,2,3,4
1 Use 400 microgram/kg (max. 5 mg) of 1:1000 (1 mg/mL)
adrenaline solution.
2 Dilute with sterile sodium chloride 0.9% solution.
3 Rinse the mouth with water to prevent ingestion.
4 Monitor closely.
5 Repeat after 30 minutes if necessary.
6 The effects will last for 2 –3 hours.
7 Monitor for recurrence of obstruction.
REFERENCES
1 Martindale (2014). The Complete Drug Reference. Medicines Complete: Martindale.
www.medicinescomplete.com (accessed 30 July 2014).
2 NHS Greater Glasgow and Clyde (2008). Croup. NHS Greater Glasgow and
Clyde: Emergency department, The Royal Hospital for Sick Children. http://
www.clinicalguidelines.scot.nhs.uk/Emergency%20Medicine/YOR-AE-
008%20Croup.pdf (accessed 30 August 2014).
3 National Institute for Health Research (2006). The Safety of Nebulization with 3 to
5 ml of Adrenaline (1:1000) in Children: An evidence based review. NHS: University of
York. http://www.crd.york.ac.uk/CRDWeb/ShowRecord.asp?ID=12006003026#
.U CSUWOGe20 (accessed 30 August 2014).
4 BMJ group. British National Formulary for Children. London: Pharmaceutical Press;
2014.
k
k
10 Adverse drug reactions
A Adverse drug reactions

Definition of ADRs
An adverse drug reaction (ADR) is a response to a drug that is noxious
and unintended and which occurs at doses normally used in humans
for the prophylaxis, diagnosis or therapy of disease or for the
modification of a physiological function.1
This definition was introduced by the WHO in the 1970s and
excludes events such as errors in drug administration and instances of
intentional and unintentional poisoning or overdose, which other
definitions may include.
In July 2012, new pharmacovigilance legislation came into effect
across the EU and was transposed into UK law in the Human
Medicines Regulations 2012.2 The legislation3 defines adverse
reactions as being noxious and unintended effects resulting not only
from the authorised use of a medicinal product at normal doses, but
also from medication errors and uses outside the terms of the
marketing authorisation, including the misuse and abuse of the
medicinal product.
The terms ‘adverse effect’ and ‘adverse reaction’ tend to be used
interchangeably and the term ‘side effect’ tends to be used for minor,
predictable ADRs. In practice, use of the word ‘effect’ describes the
problem from the drug perspective, whereas ‘reaction’ describes the
patient perspective. ‘Adverse events’, however, are not necessarily
k related to drug therapy but, in terms of a medicine’s use, they k
describe any adverse effect that occurred during drug therapy. For
example, if a patient slipped on ice and fractured a hip, this could be
perceived as an adverse event.
Classification of ADRs
Traditionally ADRs have been classified into two distinct categories.
Type A reactions may be predicted from the pharmacological actions
of the drug and are usually dose-dependent. They tend to be classified
as mild (although important from the patient’s perspective), have low
mortality and may be alleviated by a reduction in dose. Examples of
type A reactions include bradycardia with beta-blockers,
hypoglycaemia with a sulphonylurea, dry mouth with antimuscarinics
and drowsiness with benzodiazepines. In some instances, patients
will become tolerant to these ADRs once their bodily systems have
adjusted to the effects of the drug, e.g. drowsiness with gabapentin is
usually transient. Type A reactions may be precipitated by factors
leading to increased plasma concentrations of drug, for example,
hepatic or renal impairment, drug –drug interactions or dosage form
design. The ageing process may also contribute to the development of
type A reactions because of important effects on the metabolism and
excretion of drugs, increasing sensitivity to drug stimulation of
receptors and altered homeostatic mechanisms.
Conversely, type B reactions tend to be more bizarre in nature as
they are idiosyncratic, unpredictable and unrelated to the
k
k
pharmacological action of a drug. Type B reactions appear to affect A

only susceptible individuals and, because they may be less common,
can lead to drug withdrawals after marketing. These reactions are not
dose-dependent and have a higher mortality rate than type A
reactions. Anaphylactic reactions to penicillin, hepatotoxicity with
sulfasalazine and malignant hyperthermia after anaesthetics are
examples of type B reactions.
It is also important to consider the effect of dosage form with
regard to ADRs. Almost all medicinal products contain excipients that
may precipitate type B reactions.
This classification is frequently under review, primarily because
the two groups are somewhat restrictive. Further subtypes for ADR
classification have been suggested, including categories for ADRs
caused by long-term use of a drug, drug –drug interactions, or
overdose and those resulting in carcinogenicity or teratogenicity.
The timing of type B reactions cannot always be predicted either.
Angioedema associated with ACE inhibitors and anaphylactic
reactions with infliximab may not always occur at the start of
treatment.
ADRs affect the public’s confidence in medicines

The press love bad news; unfortunately, medicines provide plenty of
subject matter. Over the last decade the ADRs of a number of
medicines have made it into the national press. Following the
k withdrawal of rofecoxib in 2004, the debate over cyclooxygenase 2 k
(COX-2) inhibitors made repeated national headlines. Other
medicines to hit the headlines include adverse effects of ketamine
abuse, muscle adverse effects of statins, cardiac ADRs with NSAIDs,
fatalities associated with tramadol, and the MMR vaccine debate,
which continues to have real impact on public health.
Information sources on ADRs

The BNF is a useful starting point, but to explore the likelihood of an
ADR, further information is readily available. A first option would be
the SPC, which contains information about adverse effects, and where
available, how commonly the ADR in question occurs. Commonly
used and useful reference sources include:
● Martindale4
● American Hospital Formulary Service5
● Adverse Drug Reactions6
● Meyler’s Side Effects of Drugs7
● Davies’s Textbook of Adverse Drug Reactions.8
Periodical publications such as Drug Safety Update from the MHRA
are also useful for bringing current issues about the adverse effects of
drugs to healthcare professionals’ attention. For more detailed
k
k
A medicines information, your local UK Medicines Information centre

will provide you with a high level of expert knowledge in this area.
Information sources on adverse drug –drug interactions
Vigilance for potential adverse drug –drug interactions of clinical
significance is a key role for the pharmacist. As with ADRs, the BNF is
limited but is a useful starting point for checking and investigating the
effects of individual drug interactions. The commonly used specialist
references are Stockley’s Drug Interactions9 and Hansten and Horn’s
Drug Interactions: Analysis and Management.10
Adverse drug –food interactions
There are a number of well-documented drug –food interactions, such
as those with grapefruit juice (see Grapefruit juice–drug interactions).
Patients taking warfarin should be advised to avoid cranberry
products since there are several documented reports of the effects of
warfarin being enhanced by cranberry. Patients taking MAOIs should
be advised to avoid foods containing significant amounts of tyramine,
e.g. mature cheese or yeast extracts, since MAOIs can potentiate the
pressor effect of tyramine, causing a dangerous increase in blood
pressure. See Food–drug interactions for further information.
ADRs to complementary medicines
Significant numbers of patients take herbal or homeopathic
medicines. Since these medicines are not regulated in the same way
k as licensed medicines, there is less information regarding their quality k
assurance, safety or efficacy. The content of complementary
medicines may vary significantly in terms of potency, content of active
ingredient and the range of excipients. Furthermore, herbal
medicines can be adulterated with heavy metals, corticosteroids,
sildenafil and many other things. There can also be significant
interactions between standard therapies and herbal medicines,
e.g. St John’s wort interacts with digoxin, warfarin and oral
contraceptives. Other significant interactions include gingko biloba,
vitamin E and ginger interacting with warfarin, and devil’s claw
interacting with digoxin.
It is difficult to ascertain the significance or incidence of adverse
effects with complementary medicines because the majority of
reactions go unreported, few clinical trials have collected data in a
structured manner and patients often actively or passively choose not
to disclose use of complementary medicines when consulting their
doctor. There is a perception that complementary medicines are safe
because of their ‘natural origin’, which creates a false sense of security.
As few patients volunteer information about herbal medicines during
medication history taking, it is important to ask about their use.
Information sources for complementary medicines-related ADRs
include Herbal Medicines11 and the Natural Medicines Comprehensive
Database.12
k
k
Identifying ADRs A
Timing
Many ADRs occur soon after a medicine is started; however, not all
reactions occur instantly, e.g. angioedema with ACE inhibitors can
occur at any time during treatment and recur at infrequent intervals;
gum hyperplasia with phenytoin occurs after a long period of
treatment; and drug-induced parkinsonism can develop after months
of treatment. Oculogyric reactions associated with metoclopramide
can occur very soon after administration, as can seizures with
ciprofloxacin.
Some ADRs develop after a patient has stopped taking the drug
responsible, so identification of the culprit should not be limited to
the medicines that the patient is currently taking. A classic example is
cholestatic jaundice and hepatitis associated with flucloxacillin, which
can occur up to several weeks after completion of treatment. Patients
can be exposed to unnecessary investigations and treatment because
of a failure to consider recent therapies. When assessing causality, the
suspect drug’s half-life should be considered; for example, the
half-lives of amiodarone and leflunomide are very long, and
significant plasma concentrations persist for long periods after
cessation of therapy.
Dose
It is important to understand the pharmacology of a drug suspected of
causing an ADR in order to differentiate between type A and type B
k reactions. Type A reactions are dose-related and may well respond to
k
a reduction in dose. Of particular concern are medicines that have a
narrow therapeutic window, where a small change in drug concen-
tration separates lack of efficacy and toxicity, e.g. gentamicin, digoxin,
theophylline, lithium, phenytoin and ciclosporin. The risk of type A
reactions should be considered for elderly patients who, due to
reduced metabolic and excretory pathways, may accumulate high
concentrations of some drugs.
The dose of a medicine is not important for type B reactions;
withdrawal of the drug is usually required for resolution of these
reactions.
De-challenge and re-challenge
If symptoms improve when a drug is withdrawn or dose reduced, it is
suggestive that the drug was responsible. A drug re-challenge may
confirm or deny the association. Clearly, it is not safe to do this in all
circumstances and the risks to the patient associated with re-exposure
should be carefully balanced against the importance of identifying the
true cause of the reaction.
Other medical conditions
When attempting to ascertain the cause of a new symptom, consider
other non-drug possibilities, in particular the patient’s concurrent
disease state. For example, syndrome of inappropriate secretion of
k
k
A antidiuretic hormone (SIADH) in a patient taking an antidepressant

could be due to a lung tumour secreting antidiuretic hormone.
Similarly, jaundice in a patient taking cyproterone could be related to
gallstones or hepatitis.
The placebo effect has a significant impact on ADRs. In clinical
trials, where adverse events are recorded for all patients, reactions to
the placebo are often similar to those for the active drug.
Documentation and communication
When a patient suffers an ADR, it is important that the drug and its
specific effect are documented in the patient’s case notes and
communicated to the general practitioner, community pharmacist
and to the patient. This is vital to prevent inadvertent re-exposure to
the drug. If a patient is intolerant to a drug but has not suffered a
severe ADR, this should be fully documented to avoid life-saving
therapy being withheld should the need arise. For example, many
patients who consider themselves to be allergic to penicillin are
merely intolerant to the drug, e.g. suffer unpleasant
gastrointestinal effects.
At-risk patients
Elderly patients are vulnerable to ADRs. The complex effects of the
ageing process alter drug metabolism and excretion as well as altering
organ sensitivity to drugs such as benzodiazepines. Elderly patients
often have multiple pathologies with multiple drug therapies and are
k therefore at significantly increased risk of a drug –drug or k
drug –disease interaction.
Since the elderly have decreased functional and homeostatic
reserve, they are more susceptible to the effects of many drugs, for
example, antihypertensives. One method of avoiding or reducing this
problem in the elderly is to use a lower starting dose and increase the
dose gradually.
It is not only elderly patients who may suffer from polypharmacy:
as evidence-based medicine grows, more and more patients will be
taking complex medication regimens for diseases including congestive
cardiac failure, post myocardial infarction and HIV infection.
Neonates and infants are at risk of ADRs because of the immaturity
of their metabolic systems. In particular, neonates should not be
prescribed chloramphenicol as it reaches toxic levels sooner and less
predictably than in older children, causing cardiovascular collapse.
This is referred to as the grey-baby syndrome.
Population genetic variation (polymorphism) is one reason for the
wide variability in response to drugs between individuals. Some
polymorphisms increase the risk of ADRs: cytochrome P450
isoenzymes, e.g. CYP2D6, dictate codeine metaboliser status with
ultrarapid metabolisers at risk of opioid adverse effect; human
leukocyte antigens, e.g. presence of the HLA-B*1502 allele, increases
the risk of Stevens–Johnson syndrome with carbamazepine in
individuals of Han Chinese or Thai origin; non-cytochrome P450
metabolising enzymes, e.g. thiopurine S-methyl transferases (TPMT)
catalyses metabolism of azathioprine and 6-mercaptopurine; TPMT
k
k
status is used as a predictor of drug toxicity, particularly myelotoxicity. A

Ethnicity may have a bearing on risk of ADRs, with some medications,
for example rosuvastatin, requiring lower doses in patients of Asian
origin. Few drugs are dosed on a gender basis, although alcohol
intoxication, the neuropsychiatric effects of mefloquine and ACE
inhibitor-induced cough all have increased incidence in women.
Patients with a history of ADRs/allergies also have a higher risk of
experiencing a further ADR. Hepatic disorders, thyroid dysfunction
and renal disorders all contribute to alterations in pharmacokinetic
handling of medicines and the risks of accumulation or increases in
blood concentrations should be monitored.
Preventing and managing ADRs
The basic principles are:
● Is the patient’s drug therapy appropriate?
● Do the benefits of therapy outweigh the possible risks?
● Is a safer alternative available?
● Is there a potential for drug –drug or drug –disease interactions?
● Is the patient particularly vulnerable?
● Does the drug have a narrow therapeutic window?
● Is the patient on the lowest effective dose?
Fringe benefits of ADRs

In a number of instances, ADRs aren’t necessarily bad news. Table A1
k gives some examples of this. k
TABLE A1
Fringe benefits of adverse drug reactions
Drug ADR Fringe benefit
Codeine Causes constipation in many Is sometimes used ‘off-label’ to treat
patients diarrhoea
Erythromycin Stimulates motilin receptors In the intensive care setting, where a
in the gut, which can cause patient’s gut motility may be
diarrhoea in some patients significantly impaired following
prolonged intravenous feeding,
intravenous erythromycin can be used
‘off-label’ to stimulate gut motility
Hyoscine Can cause dry mouth In patients with drooling hyoscine can
be used to dry up secretions
Minoxidil As an antihypertensive it can It has been marketed as an
cause excess hair growth in over-the-counter medicine for
patients male-pattern baldness
Nifedipine Causes postural hypotension Used to help relieve the symptoms of
due to its vasodilatory effects Raynaud’s phenomenon
Phenytoin Causes gum hyperplasia Has been investigated in the healing
of wounds
Sildenafil Originally tested as a drug Used to treat erectile dysfunction
for cardiovascular disease;
however, interesting side
effects became apparent
k
k
A In practice
Be proactive in looking for ADRs: make your interest known to
medical and nursing staff. Patients and their carers are a vastly
underused source of information about medicines and this aspect of
care should be actively discussed with them. Monitor the high-risk
drugs closely; these drugs are the ones that put patients’ health
at risk.
‘Black-triangle’ drugs are those most recently marketed and their
use must be closely observed for adverse reactions and even
‘expected’ ADRs should be reported (see Yellow Card scheme entry).
Education is a key factor in monitoring adverse reactions and
it is important that both the patient and the pharmacist are aware
of the adverse effects of the medicines they are using. Finally, if we
are ever to learn and keep learning about ADRs: report, report
and report.
ADRs and drugs that cause them
Table A2 gives an indication of some ADRs and their causative agents.
TABLE A2
Examples of adverse drug reactions and drugs that
cause them
ADRs Drugs causing the ADR
k Central nervous system disorders k
Agitation, excitation Antihistamines, caffeine, omeprazole, SSRIs, theophylline,
and irritability vigabatrin
Confusion Antimuscarinics, benzodiazepines, cimetidine, levodopa,
quinolone antibiotics, tramadol, tricyclic antidepressants
Drowsiness Antiepileptic drugs, antihistamines, MAOIs, opioids, tricyclic
antidepressants
Headache Glyceryl trinitrate/nitrates, nifedipine, proton pump inhibitors,
nicorandil, tramadol, leukotriene receptor antagonists,
COX-2-selective inhibitors
Insomnia Caffeine, theophylline, flupentixol, ephedrine, nicotine
patches, levodopa, bupropion, statins, corticosteroids
Sleep disturbances Beta-blockers, nicotine patches, levodopa, varenicline
Mood disturbances Isotretinoin, bupropion, COX-2-selective inhibitors, ACE
inhibitors, progestogens
Convulsions Amphotericin, baclofen, bupivacaine, clozapine, ciclosporin,
fluoxetine, foscarnet, ganciclovir, beta-lactam antibiotics,
mefloquine, methylphenidate, mianserin, opioids,
theophylline, tramadol
Eye disorders
Cataracts Corticosteroids
Retinal disorders Hydroxychloroquine
Visual disturbances Tricyclic antidepressants, digoxin, vigabatrin
k
k
TABLE A2
(Continued)
A
Nose disorders
Disturbances of smell Nifedipine, diltiazem
Disorders of the mouth and throat
Dry mouth Tricyclic antidepressants, hyoscine, antipsychotics, opioids,
alpha-blockers, SSRIs, oxybutynin
Gingival hyperplasia Phenytoin, calcium-channel blockers, ciclosporin,
ethosuximide
Oral thrush Antibiotics, inhaled steroids
Taste disturbances Metronidazole, ACE inhibitors, penicillamine, terbinafine,
quinolone antibiotics, allopurinol
Sore throat/mouth NSAIDs, carbimazole, nicorandil, ACE inhibitors, methotrexate
ulcers
Cough ACE inhibitors, gabapentin, mycophenolate, nitrofurantoin
Disorders of the ear
Vertigo Bupropion, opioids, benzodiazepines, amiodarone
Deafness Aminoglycosides, furosemide, macrolide antibiotics
Tinnitus NSAIDs, mefloquine, COX-2-selective inhibitors,
aminoglycosides
Disorders of the heart
k Hypertension Ciclosporin, corticosteroids, erythropoietin, fludrocortisone, k
MAOIs, NSAIDs, sevoflurane, tramadol, etoricoxib
Hypotension Beta-blockers, amiodarone, baclofen, benzodiazepines,
calcium-channel blockers, cannabinoids, desmopressin,
disopyramide, diuretics, enoximone, flecainide, iloprost,
interleukins, lidocaine, MAOIs, opioids, phenytoin,
procainamide, quinidine, sildenafil, teicoplanin, tricyclic
antidepressants, vasodilators
Bradycardia Amiodarone, beta-blockers, digoxin, opioids, sumatriptan
Tachycardia Beta-2 agonists, digoxin, tricyclic antidepressants,
theophylline, mirabegron
Irregular heart beat Terfenadine, amiodarone, digoxin, quinine, SSRIs, mefloquine,
opioids, calcium-channel blockers
Disorders of the muscles and joints
Joint disease Beta-blockers, quinolone antibiotics, SSRIs, omeprazole,
cephalosporins
Cold extremities Beta-blockers
Muscle cramps/pains Beta-2 agonists, ACE inhibitors, cholesterol-lowering agents,
terbinafine, corticosteroids, quinolone antibiotics
Tendon rupture Quinolone antibiotics, corticosteroids
Limb oedema NSAIDs, calcium-channel blockers, corticosteroids
(continued )
k
k
TABLE A2
A (Continued)
Breathing disorders
Shortness of breath/ Beta-blockers (including eye drops), NSAIDs, ACE inhibitors,
worsening of asthma tramadol, omeprazole, amiodarone, methotrexate
Disorders of skin
Hair loss Cytotoxics, lithium, anticoagulants, proton pump inhibitors,
leflunomide, vigabatrin, mefloquine, ACE inhibitors
Facial or excessive hair Danazol, phenytoin, tibolone, corticosteroids, minoxidil
growth
Flushing Nitrates, calcium-channel blockers, nicorandil, vancomycin,
opioids, ACE inhibitors
Oedema Corticosteroids, NSAIDs
Pigmentation/ Oral contraceptives, antimalarials, minocycline, amiodarone,
discoloration phenothiazines
Acne-like eruptions Steroids, danazol, isoniazid, progestogens, phenytoin
Photosensitivity Chlorpromazine, tetracyclines, amiodarone, proton pump
inhibitors, NSAIDs, quinolone antibiotics
Exacerbation of Beta-blockers, NSAIDs, antimalarials, lithium
psoriasis
Urticaria Aspirin, opioids, penicillins
Disorders of the gastrointestinal tract
k Anorexia/weight loss Tricyclic antidepressants, digoxin, sulfasalazine, k
metronidazole, SSRIs, ciprofloxacin, leflunomide, donepezil
Weight increase Gabapentin, danazol, finasteride, mirtazapine, tricyclic
antidepressants, oestrogens/progestogens, corticosteroids,
varenicline
Heartburn/dyspepsia NSAIDs, ACE inhibitors, corticosteroids, alendronate,
risedronate, SSRIs
Nausea and vomiting Antibiotics, levodopa, methotrexate, opioids, SSRIs
Flatulence Lactulose, acarbose, statins, captopril, bulk-forming laxatives
Gastrointestinal upset NSAIDs, prednisolone, SSRIs
Abdominal pain Clofibrate (gallstones), macrolide antibiotics, cephalosporins,
mefloquine, stimulant laxatives, dabigatran
Constipation Aluminium-containing antacids, antipsychotics, iron salts,
opioids, tricyclic antidepressants, verapamil
Diarrhoea Acarbose, antibiotics, leukotriene receptor antagonists,
magnesium-containing antacids, misoprostol, mefloquine
Jaundice/abnormal liver Statins, SSRIs, antipsychotics, tricyclic antidepressants,
function tests cyproterone, methotrexate, co-amoxiclav, flucloxacillin
Disorders of hormonal regulation
Gynaecomastia Oestrogens, spironolactone, H2 -receptor antagonists, tricyclic
antidepressants, calcium-channel blockers
Period problems Oral contraceptives, danazol, medroxyprogesterone,
spironolactone, tamoxifen, antipsychotics
k
k
TABLE A2
(Continued)
A
Disorders of the urinary tract
Impotence Beta-blockers, antiepileptic drugs, cimetidine, spironolactone,
ACE inhibitors
Urinary retention Tricyclic antidepressants, trihexyphenidyl, antihistamines,
benzodiazepines
Urinary frequency Diuretics, levodopa, alpha-blockers, lithium
Urine discoloration Dantron, levodopa, senna, rifampicin, imipenem, sulfasalazine
Cystitis Tiaprofenic acid, cyclophosphamide
Biochemical disorders
Hypercalcaemia Calcipotriol, calcium, ciclosporin, danazol, diuretics,
oestrogens, lithium, tamoxifen, vitamin D
Hyperkalaemia Ciclosporin, heparins, fluconazole, indometacin, penicillins,
potassium-sparing diuretics, trimethoprim
Hypocalcaemia Antiepileptic drugs, corticosteroids
Hypokalaemia Amphotericin, beta-lactam antibiotics, diuretics, levodopa
Hyponatraemia Amiloride, antiepileptic drugs, antidepressants, cisplatin,
cyclophosphamide, diuretics
Blood disorders
Agranulocytosis Aspirin and NSAIDs, allopurinol, beta-lactam antibiotics,
cephalosporins, cocaine, colchicine, co-trimoxazole, dapsone,
k fluconazole, metronidazole, mianserin, nitrofurantoin, k
penicillamine, ranitidine, rifampicin, sertraline, sulfasalazine,
thiazide diuretics, tricyclic antidepressants
Anaemias Amphotericin, auranofin, azathioprine, cisplatin,
co-trimoxazole, cyclophosphamide, flucytosine, ganciclovir,
corticosteroids, NSAIDs, lamivudine, levodopa, losartan,
penicillamine, phenindione, sulphonamides, dabigatran
Leukopenia Allopurinol, amphotericin, antiepileptic drugs, azathioprine,
beta-lactam antibiotics, carbamazepine, cimetidine,
chloramphenicol, colchicine, co-trimoxazole, flucytosine, gold
salts, griseofulvin, mesalazine, methotrexate, mianserin,
mycophenolate, phenelzine, quinolone antibiotics, rifampicin,
tamoxifen
Thrombocytopenia Abciximab, aspirin and NSAIDs, aminophylline, antiepileptic
drugs, azathioprine, beta-lactam antibiotics, chloramphenicol,
co-trimoxazole, ethambutol, ganciclovir, gold salts, heparin,
mesalazine, methotrexate, mianserin, nitrofurantoin,
omeprazole, quinidine, quinine, rifampicin, sulphonamides,
teicoplanin, terbinafine, trimethoprim, valproic acid
Infections and infestations
Upper respiratory tract Infliximab, etanercept
infections
Sinusitis Infliximab
Conjunctivitis Infliximab
k
k
20 Anaemias
REFERENCES
A 1 WHO (1970). International drug monitoring – the role of the hospital – a WHO
report. Drug Intell Clin Pharm 4: 101–110.
2 Human Medicines Regulations (2012). http://www.legislation.gov.uk/uksi/2012/
1916/contents/made (accessed 12 October 2014).
3 Directive 2010/84/EU of the European Parliament and of the Council of 15
December 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC
on the Community code relating to medicinal products for human use.
http://ec.europa.eu/health/files/eudralex/vol-1/dir 2010 84/dir 2010 84 en.pdf
(accessed 12 October 2014).
4 Brayfield A (ed.) (2014) Martindale: The Complete Drug Reference, 38th edn.
London: Pharmaceutical Press.
5 McEvoy GK et al. (eds) (2014). American Hospital Formulary Service. Bethesda,
MD: American Society of Health-System Pharmacist.
6 Lee A (2005). Adverse Drug Reactions, 2nd edn. London: Pharmaceutical Press.
7 Aronson JK (ed.) (2006). Meyler’s Side Effects of Drugs, 15th edn. London: Elsevier.
8 Davies DM et al. (eds) (1999). Davies’s Textbook of Adverse Drug Reactions,
5th edn. London: Chapman and Hall.
9 Baxter K, Preston C (eds) (2013). Stockley’s Drug Interactions, 10th edn. London:
Pharmaceutical Press.
10 Hansten PD, Horn JT (eds) (2014). Drug Interactions: Analysis and management.
St Louis, MO: Wolters Kluwer Health.
11 Barnes J (2013). Herbal Medicines. 4th edn. London: Pharmaceutical Press.
12 Natural Medicines Comprehensive Database. http://naturaldatabase
.therapeuticresearch.com/ (accessed 12 October 2014).
k k
Anaemias
Anaemia is a reduction in the red blood cell (RBC) mass1 and is one of
the most common conditions in the world.2 It is not a diagnosis – it is
a symptom that can arise from many different pathologies. Therefore,
it is important to determine the cause of the anaemia to ensure
appropriate therapy is given.1
The WHO has defined anaemia in adults as being when
haemoglobin is less than 130 g/L for males and less than 120 g/L for
non-pregnant females.3 Low haemoglobin can be a result of increased
haemoglobin loss or a reduction in haemoglobin synthesis.
Anaemia can be subdivided into the following categories:
microcytic anaemia, megaloblastic anaemia and haemolytic anaemia.
Microcytic anaemia includes: iron-deficiency anaemia, anaemia of
chronic disease and sideroblastic anaemia. Megaloblastic anaemia
includes: folate deficiency and vitamin B12 deficiency. Haemolytic
anaemia includes sickle cell disease, thalassaemia and autoimmune
haemolytic anaemia.2
Investigations
It is important to establish the cause of the anaemia to ensure
appropriate treatment is commenced. Investigations will include a
full blood count, which will show the haemoglobin concentration and
k
k
Anaemias 21
the RBC count. The size, shape and colour of the RBCs may be A
assessed as well as the mean corpuscular volume (MCV) that is used
to determine the type of anaemia. The ‘normal’ laboratory results for
various anaemias are shown in Table A3.
TABLE A3
Laboratory results for different anaemias1
Type of anaemia Consistent laboratory tests
Iron-deficiency (microcytic) Reduced serum iron
Reduced haematocrit
Reduced haemoglobin
Reduced ferritin
Reduced mean cell volume
Reduced mean cell haemoglobin concentration
Increased total iron-binding capacity (TIBC)
Pernicious (megaloblastic) Reduced haematocrit
Reduced haemoglobin
Normal serum iron
Increased mean cell volume
Reduced RBC count
Reduced serum vitamin B12 (N.B. antibiotics can
give a ‘false low’)
Folate deficiency (megaloblastic) Reduced haematocrit
k Reduced haemoglobin k
Normal serum iron
Increased mean cell volume
Reduced RBC count
Reduced serum folate
Anaemia of renal failure or chronic Reduced haematocrit
disease Reduced haemoglobin
Reduced reticulocyte count
Iron-deficiency anaemia
Iron deficiency is the most common cause of anaemia and may arise
from:
● inadequate iron absorption, e.g. malabsorption or inadequate

intake
● increased physiological demand
● blood loss (the most common cause in the western world).
Signs and symptoms
These will vary with the degree of anaemia, as well as the time over
which the anaemia developed. They include tiredness, pallor,
fainting, palpitations, tachycardia and worsening or precipitation of
angina and/or cardiac failure.
k
k
22 Anaemias
Food containing iron

A
These include red meat, fish, eggs, baked beans, pulses such as kidney
beans and lentils, dried apricots and fortified cereals. In healthy
adults, 10% of dietary iron intake is absorbed from the duodenum
and the jejunum.2
Treatment
Treatment involves the appropriate management of the underlying
cause and iron replacement therapy to correct the anaemia and
replenish body stores.4 The oral dose of elemental iron for iron-
deficiency anaemia should be 100 –200 mg daily. Therefore, the
cost-effective treatment of choice is oral administration of ferrous
sulphate 200 mg three times a day. For prophylaxis 200 mg once or
twice a day may be given. Although other iron compounds are
available, haemoglobin regeneration rate is little affected by the type
of ferrous salt used provided sufficient iron is given; however, there is
little evidence to suggest other ferrous salts offer important
advantages.
Modified-release preparations are not recommended because they
tend to release the iron in the lower gut, where absorption is poor.5
Ascorbic acid (250 –500 mg with the iron preparation) is
sometimes prescribed to aid the absorption of iron.4
The amount of elemental iron contained in different oral
preparations is shown in Table A4.
k TABLE A4
k
Iron content of proprietary preparations5
Preparation Amount Amount of ferrous iron
Ferrous fumarate 210 mg 68 mg
Ferrous gluconate 300 mg 35 mg
Ferrous sulfate 300 mg 60 mg
Ferrous sulfate, dried 200 mg 65 mg
Ferrous sulfate, dried 325 mg 105 mg
Sodium feredetate 190 mg/5 mL 27.5 mg/5 mL
Polysaccharide–iron complex 100 mg/5 mL
For people intolerant or not responding to oral iron, there are

parenteral iron therapies available (see Iron: guidance on parenteral
dosing and administration entry).
Timing of dose
Oral iron should ideally be taken on an empty stomach to achieve
maximum absorption; however, many patients experience
gastrointestinal side effects, in which case the dose may be given after
food.5
Adverse reactions
Iron preparations are associated with unpleasant side effects,
including nausea, epigastric pain, constipation and diarrhoea, which
can lead to poor adherence. If side effects occur the iron dose could be
k
k
Anaemias 23
reduced or an alternative preparation trialled with a lower dose of A

elemental iron.5
Patients should be counselled that accidental ingestion of iron can
be very dangerous or fatal, especially in children, and they should
seek immediate medical advice if this occurs.
Duration of treatment
When a patient has been started on iron replacement therapy, the
haemoglobin level should be expected to rise by about 20 g/L every
3 weeks, although this varies from patient to patient.5 Oral iron
should be continued for 3 months after the iron deficiency has been
corrected so that stores are replenished; the patient’s full blood count
should be checked after this time.4,5
Megaloblastic anaemias
These are macrocytic anaemias and the major causes are vitamin B12
deficiency and/or folate deficiency.2
Vitamin B12 deficiency
This may arise from decreased supply (reduced intake or absorption)
or increased demand (greater metabolic consumption, destruction or
excretion).1 Causes include veganism, poor-quality diet or a
congenital or acquired lack of intrinsic factor, e.g. gastrectomy.
Treatment
Vitamin B12 deficiency is treated by giving intramuscular injections of
k hydroxocobalamin. At the start of treatment 1 mg is given three times
k
a week for 2 weeks and then 1 mg every 3 months. If there is
neurological involvement, 1 mg is given on alternate days until no
further improvement, and then every 2 months.5 In the majority of
patients the duration of treatment is normally lifelong.2
Folate-deficiency anaemia
Folate requirements vary with age and are increased in conditions
with high metabolic rates and/or an increased rate of cell division.
Folate is abundant in virtually all food sources, especially fresh green
vegetables, yeast and liver. For this reason most people in Britain have
an adequate intake. A daily intake of 200 micrograms is
recommended. The body stores about 5 –10 mg of folate and
deficiency can occur within 3 –4 months of reduced intake.1
Causes
Folic acid deficiency can be caused by inadequate dietary intake or
malabsorption, alcoholism and rapid cell turnover. During pregnancy
deficiency can occur, partly due to inadequate diet, partly due to the
transfer of folate to the fetus, and partly due to increased folate
degradation.
Some drugs, such as antiepileptic drugs, sulfasalazine,
trimethoprim and methotrexate, may alter folate metabolism,
resulting in folate deficiency.1
k
k
24 Anaemias
Treatment
A
Before commencing treatment with folic acid as monotherapy,
vitamin B12 deficiency must be excluded, as folic acid treatment may
correct the anaemia but allow neurological disease to develop.
Folic acid 5 mg daily is given for 4 months to replenish body stores.
In the case of malabsorption it may be necessary to increase the dose
to 15 mg daily. Long-term folate supplementation is rarely necessary
because most causes of folate deficiency are self-limiting or will yield
to a short course of treatment.5
In pregnancy, for prevention of neural tube defects, women at low
risk should take 400 micrograms daily of folic acid. This should be
taken before conception and until week 12 of pregnancy. Pregnancies
at high risk of neural tube defects include: couples where either
partner has a neural tube defect (or has a family history of neural tube
defects), or a previous pregnancy has been affected by a neural tube
defect in women with malabsorption states, e.g. coeliac disease,
diabetes mellitus, sickle cell anaemia or taking antiepileptic drugs. In
this group women should be advised to take folic acid 5 mg daily if
they wish to become pregnant (or are at risk of becoming pregnant)
and continue until week 12 of pregnancy. Women with sickle cell
disease should continue taking their normal dose of folic acid 5 mg
daily (or increase the dose to 5 mg daily) and continue this
throughout pregnancy.5
Anaemia of chronic disease
k This includes anaemia associated with inflammatory diseases, e.g. k
arthritis, malignancy and inflammatory bowel disease, and anaemia
associated with chronic kidney disease and heart failure. As the
anaemia accompanies many different diseases, symptoms are
non-specific and can vary from person to person. The patient will
display symptoms of the chronic condition and general symptoms of
anaemia.2
Treatment
Treatment is dependent upon the underlying cause of anaemia. Oral
iron tends to be ineffective as patients have a functional iron
deficiency rather than an actual iron deficiency.2 Erythropoietins are
used in the treatment of symptomatic anaemia associated with
erythropoietin deficiency in chronic renal failure.5
REFERENCES
1 Alldredge BK et al. (eds) (2012). Koda-Kimble & Young’s Applied Therapeutics: The
Clinical Use of Drugs,10th edn. London: Lippincott, Williams and Wilkins.
2 Walker R, Whittlesea C (eds) (2012). Clinical Pharmacy and Therapeutics, 5th edn.
Edinburgh: Churchill Livingstone.
3 WHO (2008). Worldwide Prevalence of Anaemia 1993–2005. http://www.who.int/
vmnis/publications/anaemia prevalence/en/ (accessed 30 October 2014).
4 Goddard AF et al. (2011). Guidelines for the management of iron deficiency
anaemia. Gut 60: 1309–1316.
5 Joint Formulary Committee (2014). British National Formulary (68th edn). London:
BMJ Group and Pharmaceutical Press.
k
k
Angioedema: drug causes and treatment 25
Angioedema: drug causes and treatment A

Angioedema is swelling in the deep dermal layers of the skin and is
seen as part of both allergic and non-allergic reactions. It can affect
any part of the body but most commonly affects the eyes, lips,
genitals, hands and feet. In severe cases, when the insides of the
mouth and throat are affected, it can be life-threatening. The swelling
is non-pitting and either erythematous or skin-coloured. Angioedema
has been associated with a wide range of drugs.1,2
Drug-induced angioedema can be split into three main categories:
1 immediate hypersensitivity (allergic)

2 NSAID/aspirin-induced (non-allergic, intolerance, pseudoallergy)
3 ACEI-related (non-allergic).
Immediate hypersensitivity
Immediate hypersensitivity angioedema is an IgE-mediated allergic
response that is characterised by angioedema and/or urticaria (raised
itchy erythematous swellings) with systemic symptoms (e.g.
hypotension) that can result in life-threatening anaphylaxis.3
Treatment
The treatment is antihistamines and corticosteroids either orally or
intravenously depending on the severity of the reaction.4,5
k NSAID/aspirin-induced k
NSAID/aspirin-induced angioedema is generally non-allergic, and is
often described as an ‘intolerance’ or ‘pseudoallergic’.
NSAID intolerance has a prevalence of 0.3 –0.9% in the general
population. It occurs in 2 –23% of patients with asthma and can
induce or aggravate clinical symptoms in 20 –40% of patients with
chronic idiopathic urticarial angioedema.
Clinical features of NSAID-induced angioedema (rhinitis,
bronchospasm, urticaria and angioedema) are similar to those of
immediate hypersensitivity angioedema and generally occur within
minutes to a few hours of NSAID exposure.
Non-selective NSAIDs interfere with arachidonic acid metabolism
by inhibiting COX-1 and 2 pathways, resulting in overproduction of
leukotrienes and reduction of prostaglandin E2 . Consequences
include increased microvascular permeability, oedema and
degranulation of mast cells. This mechanism is pharmacological
rather than immunological, meaning that individuals with
NSAID-induced angioedema are likely to react to multiple structurally
and chemically unrelated NSAIDs, often on first exposure.
NSAIDs displaying strong COX-1 inhibition are more likely to cause
intolerance than those displaying preferential COX-2 inhibition (e.g.
meloxicam), selective COX-2 inhibition (e.g. celecoxib) or very weak
COX-1/COX-2 inhibition (e.g. paracetamol). However, the small
k
k
26 Angioedema: drug causes and treatment
A percentage of individuals cross-intolerant to NSAIDs and paracetamol

are more likely to be intolerant to COX-2-selective NSAIDs.
The only reliable test for NSAID sensitivity is oral challenge.
Treatment
Treatment is antihistamines and corticosteroids. Patients should be
warned to avoid NSAIDs as a class until safe alternatives can be
confirmed.
ACEI-related angioedema
This is usually localised to the head and neck. Onset is often sudden
and may be associated with pain or heat, but rarely with urticaria or
erythema. Swelling lasts for 1 –3 days, leaving no visible signs.
It occurs in up to 0.7% of patients taking an ACEI and is fatal in
approximately 0.1% of these cases.
Risk factors include black race (increased three- or four-fold),
female gender, past history of angioedema, previous drug rash,
smoking, age >65 years, seasonal allergies, recent initiation of an
ACEI (first week of therapy), obesity, upper-airway surgery or trauma,
sleep apnoea and immunosuppression in cardiac and renal transplant
recipients.
About one in four cases occurs during the first month of taking an
ACEI. The remaining cases develop many months or even years after
treatment begins; this often leads to ACEIs being overlooked as a
cause. Continuing administration tends to lead to more severe attacks.
k Episodes may recur for up to 3 months after an ACEI is stopped. k
ACE inhibition decreases bradykinin degradation. Increased
bradykinin levels dilate blood vessels, mediate inflammation, increase
vascular permeability and activate nociceptors. High plasma levels of
bradykinin are found in individuals taking ACEIs during acute
episodes of angioedema. However, impaired bradykinin degradation
by ACEIs is not the only factor involved, as angioedema appears
inconsistently and in just a small percentage of patients. These
additional factors are yet to be established.
ACEI-related angioedema is usually diagnosed after exclusion of
other causes. No reliable tests can differentiate ACEI-related
angioedema from angioedema due to other causes.
Treatment
Basic symptomatic emergency treatment is required. Although
antihistamines and steroids are often used, evidence suggests that
they are not very effective. In acute life-threatening situations, use of
fresh frozen plasma has been tried. ACEIs must be stopped following
an episode of angioedema and are contraindicated in patients with a
history of chronic angioedema of any aetiology. Referral is only
indicated if symptoms recur 3 months after stopping treatment.
Icatibant, a bradykinin inhibitor, is licensed for acute attacks of
hereditary angioedema in patients with C1-esterase inhibitor
deficiency but in 2014 failed to be granted a licence in the EU for
ACEI-related angioedema.
k
k
Antibiotic choice 27
REFERENCES
1 NHS Choices (2014). Angioedema. http://www.nhs.uk/conditions/Angioedema/ A
Pages/Introduction.aspx (accessed 7 October 2014).
2 Clinical Knowledge Summaries (2012). Angio-oedema and Anaphylaxis.
http://cks.nice.org.uk/angio-oedema-and-anaphylaxis (accessed 7 October 2014).
3 British Association of Dermatologists (2012). Urticaria and Angioedema. Patient
Information. http://www.bad.org.uk/library-media/documents/Urticaria%20and%
20Angioedema%20Update%20Sept%202012%20-%20lay%20reviewed%20May%
202012.pdf (accessed 7 October 2014).
4 Powell RJ et al. (2007). BSACI guidelines for the management of chronic urticaria
and angio-oedema. Clin Exp Allergy 37: 631–650.
5 Inomata N (2012). Recent advances in drug-induced angioedema. Allergol Int 61:
545–557.
Antibiotic choice
Ultimately the initial choice of antibiotic is dependent on the severity
of the infection and the type of bacteria likely to be causing the
infection. Antibiotic choice can be driven by laboratory culture
results; however, it is often necessary to initiate antibiotic therapy
before the results of cultures are known. The information here aims to
aid in decision making but bacterial resistance rates vary by locality
and therefore it is important to consult local guidelines.
Severity of infection
k When treating a severe systemic infection it is essential antibiotics are k
given via the intravenous route; in sepsis this should be within the
first hour of diagnosis.1 For many mild and moderate infections the
oral route is preferred. Many antibiotics do not have an oral and
intravenous equivalent and therefore this can restrict choice, even
when laboratory cultures are available.
Disease factors
Certain bacteria will colonise particular body areas, e.g. abdominal
infections are more likely to be caused by Gram-negative aerobic or
anaerobic bacteria, whereas skin infections are more likely to be
caused by Gram-positive bacteria. The antibiotic choice should
reflect this.
If the patient is currently, or has previously been, a carrier of
MRSA, then this should affect your antibiotic choice. If a Gram-
positive infection is suspected, the empirical antibiotic choice should
cover MRSA, e.g. vancomycin. Certain antibiotics, such as quinolones,
which will select for MRSA, should be avoided in MRSA carriers.
If the patient is currently, or has previously tested, positive for
Clostridium difficile (polymerase chain reaction or toxin), certain
antibiotics should be avoided if possible. Examples include
co-amoxiclav, cephalosporins, clindamycin and quinolones, which
will all select for Clostridium difficile.2
k
k
28 Antimicrobial allergy management
A Previous history
It is important to know the medical history of the patient being
treated. If the patient has had recent hospital admissions then the
antibiotic history should be reviewed. If the person has had multiple
infections within the past year with repeated courses of antibiotics, he
or she is at risk of multiresistant infections. Review the patient notes
and previous cultures before deciding on the antibiotic.
Site of infection
Antibiotics, like any drug, have variable rates of absorption and
distribution. It is important that the antibiotic reaches therapeutic
levels in the desired tissues. Many antibiotics cannot penetrate the
blood–brain barrier, even when it is inflamed. Therefore, even when
guided by culture results, the distribution of individual antibiotics
should be taken into account. Summary of Product Characteristics
will give information on antibiotic distribution.
Renal function
Many antibiotics are renally excreted and therefore dosage reductions
are needed in renal impairment. Certain antibiotics, like the
aminoglycosides, are nephrotoxic and for patients in acute kidney
injury should be avoided where possible, or given with appropriate
dose reductions and monitoring.
Reviewing
k Regular reviewing of an antibiotic prescription is essential. If the k
patient is clinically improving and infective markers are returning to
normal, switching to oral antibiotics may be appropriate. The use of
broad-spectrum antibiotics increases the risk of resistance developing
and therefore, if culture results are now available, the one with the
narrowest spectrum of activity should be used.
REFERENCES
1 Bochud PY et al. (2004). Antimicrobial therapy for patients with severe sepsis and
septic shock: an evidence-based review. Crit Care Med 3211(Suppl): S495–S512.
Antimicrobial allergy management

Allergy is an essential factor to consider when deciding upon the most
appropriate antimicrobial for a patient. Obtaining a detailed accurate
history from the patient is crucial to determine the exact nature of the
allergic reaction. The main aim is to establish whether the patient
describes any symptoms that are highly suggestive of an IgE-mediated
allergic reaction. IgE-mediated reactions (also referred to as
immediate-onset reactions) usually occur within 1 hour of
administration and are life-threatening.
k
k
Antimicrobial allergy management 29
Clinical signs and symptoms include diffuse urticarial rash, pruritus, A

bronchospasm, angioedema, hypotension and anaphylaxis. The choice
of antimicrobial can often be limited by a doubtful or unconfirmed
allergy history. As the most commonly reported allergic reactions
are to beta-lactam antibiotics, the focus of this section will be on
the appropriate management of those patients with penicillin allergy.
About 10% of the general population will claim to have a penicillin
allergy; of these, only 10% will have a genuine allergy.1 True
anaphylaxis to penicillin occurs in less than 0.05% of patients
receiving treatment.2 A number of studies have shown that patients
allergic to penicillin are more likely to receive alternatives that are
more costly and broader-spectrum and can therefore select for
C. difficile and the induction of antimicrobial resistance.3
Those patients with a clear history suggestive of anaphylaxis or a
severe reaction (e.g. angioedema, immediate-onset urticarial rash)
should not receive a penicillin. A patient with an immediate
hypersensitivity reaction may also react to cephalosporins and
carbapenems and these too should be avoided (see section below).2
Those patients reporting a history of minor rash (i.e. non-confluent,
non-pruritic rash restricted to one area of the body) or a rash
occurring more than 72 hours after administration of a penicillin are
most probably not allergic. In the event of serious infections, a
penicillin should not be unnecessarily withheld; however, the patient
should be closely monitored for signs of an allergic reaction.2 For
k those patients where the history is suggestive of side effects only, k
e.g. gastrointestinal upset, a penicillin can be given.
Cross-reactivity with cephalosporins
The reported cross-over risk between cephalosporins and penicillins is
0.5 –6.5%2 ; the true rate of cross-reaction is dependent upon the
generation of cephalosporin. The risk of cross-reactivity is higher with
first-generation cephalosporins (e.g. cefalexin, cefradine) compared
to second- and third-generation cephalosporins, which are less likely
to be associated with cross-reactivity due to differences in chemical
structure. If a cephalosporin is deemed essential in those patients with
an immediate hypersensitivity reaction to penicillin, then cefotaxime,
ceftazidime, cefuroxime or ceftriaxone can be used with caution and
cefaclor, cefadroxil, cefradine and cefalexin should be avoided.2
Cross-reactivity with carbapenems and monobactams
In a review, penicillin-allergic patients (identified by skin testing)
were then skin-tested for reaction to a carbapenem. The reported
cross-sensitivity was 1% between penicillins and a carbapenem.4
Aztreonam is a monobactam that may be administered to those with a
penicillin allergy; there have been no significant reports in the
literature of cross-reactivity. Aztreonam possesses a similar side chain
to ceftazidime; therefore, those patients with an IgE-mediated
reaction to ceftazidime should avoid aztreonam.
k
k
30 Antiphospholipid syndrome
A NICE guidelines recommend that those patients requiring

treatment for an infection, which can only be treated by beta-lactam
antibiotics (penicillins, cephalosporins, carbapenems) or have a high
likelihood for future need for beta-lactam antibiotics should be
referred to a specialist drug allergy service.5
It is recommended that a patient’s drug allergy status should be
determined before the prescription, dispensing or administration of
any drug. The name of the drug, nature of the reaction and date the
reaction occurred should be documented on patient records
(including general practitioner referral letters, hospital discharge
letters and on all prescriptions issued in any healthcare setting).5
REFERENCES
1 Yates AB (2008). Management of patients with a history of allergy to beta lactam
antibiotics. Am J Med 121: 572–576.
2 British National Formulary 67 (2014). London: BMA and Pharmaceutical Press.
3 MacLaughlin EJ (2000). Costs of beta-lactam allergies: Selection and costs of antibi-
otics for patients with a reported beta-lactam allergy. Arch Fam Med 9: 722–726.
4 Frumin J, Gallagher JC (2009). Allergic cross-sensitivity between penicillin, car-
bapenem, and monobactam antibiotics: what are the chances? Ann Pharmacother
43: 304–315.
5 NICE (2014). Drug Allergy: Diagnosis and Management of Drug Allergy in Adults,
Children and Young People. Draft for consultation.
k Antiphospholipid syndrome k
Antiphospholipid syndrome (APS) or antiphospholipid antibody
syndrome (APLS) is an acquired autoimmune condition. Patients
usually present with a venous thrombosis such as a deep-vein
thrombosis (DVT) or pulmonary embolism (PE) or arterial thrombosis
(transient ischaemic attack, stroke or, more rarely, myocardial
infarction). Another manifestation is pregnancy complications and
pregnancy failure, in the form of recurrent miscarriages, late
miscarriages, still or premature birth. Testing for APS should be done
in patients with an unprovoked DVT or PE, as recurrence is higher in
patients with APS. Patients under the age of 50 years who present
with a stroke should also be tested for APS, as should women who
have three or more miscarriages before 10 weeks.1 The laboratory
tests required are for anticardiolipin antibodies, anti-beta-2
glycoprotein antibodies and lupus anticoagulant. As these can all be
transiently raised by infections or antibiotics the tests, if positive,
must be repeated after 12 weeks to ensure the increases weren’t just
transient. If positive on both occasions, a diagnosis of APS can be
made.2 Note that lupus anticoagulant can give a false-positive result
in patients on anticoagulants, so this test should not be done until the
patient is off anticoagulation. In the case of warfarin, the test should
be done no less than 4 weeks after stopping warfarin but with other
anticoagulants 7 days is sufficient.3
k
k
Antiphospholipid syndrome 31
Patients with an incidental finding of APS but with no history of A

venous or arterial thrombosis should not receive treatment. Patients
who present with a stroke and are found to have APS should be
treated with aspirin. Warfarin is the anticoagulant of choice in
patients with previous venous thrombosis (DVT, PE). The INR should
be kept in the range 2 –3, with a target of 2.5. Bridging with some
form of heparin will be required if warfarin needs to be stopped for
surgery or procedures. For patients who have recurrent venous
thrombosis while the INR is therapeutic, an INR range of 3 –4
(target 3.5) is used. The NOACs have not been studied in APS, but
could be used in patients with a history of DVT or PE if warfarin isn’t
tolerated or there is poor control. For women with APS who have had
recurrent miscarriages, aspirin plus low-molecular-weight heparin
are recommended throughout pregnancy. Aspirin alone is
recommended in some women.4 Prepregnancy counselling is advised
and changing from warfarin to a low-molecular-weight heparin
should be done due to the teratogenic effects of warfarin.
Pharmaceutical interventions
● Ensure prothrombotic drugs such as oestrogens are stopped, with
counselling on appropriate contraception, such as progestogen
only.
● Ensure the INR is kept in the appropriate target range both as an
outpatient and inpatient.
k ● Advise on bridging therapies for patients undergoing surgery or k
procedures where there is a requirement for the INR to be below 2.
● Advise on restarting warfarin postoperatively and appropriate
monitoring and advice on when to stop heparin.
● Ensure young women starting on warfarin understand the dangers
around warfarin and pregnancy and information on prepregnancy
counselling is available. During pregnancy ensure appropriate
dosing of low-molecular-weight heparin, especially if there are
large weight changes, and ensure low-molecular-weight heparin is
extended postpartum.
Some patients with APS on warfarin, who have never had a DVT or
PE, often have a high INR range. It is important these individuals are
investigated to ensure they are on appropriate treatment and an
appropriate INR range and have confirmed positive results
for APS.
REFERENCES
1 Keeling D et al. (2012). Guidelines on the investigation and management of
antiphospholipid syndrome. Br J Haematol. 157: 47–58.
2 NHS Choices (2013). Antiphospholipid Syndrome (APS) – Causes.
http://www.nhs.uk/conditions/hughes-syndrome/pages/causes.aspx (accessed 24
January 2015).
3 NICE (2012). Venous Thromboembolic Diseases: The management of venous
thromboembolic diseases and the role of thrombophilia testing (CG144).
http://www.nice.org.uk/guidance/CG144 (accessed 24 January 2015).
k
k
32 Antipsychotics: equivalent doses
4 Royal College of Obstetricians and Gynaecologists (2011). Recurrent Miscar-

A riage, Investigation and Treatment of Couples (Green-top Guideline No. 17).
https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg17/
Antipsychotics: equivalent doses

Calculating antipsychotic equivalent doses can be important, most
often clinically when switching from one antipsychotic to another or
when antipsychotics are combined (Tables A5 and A6). Equivalent
doses are also important for clinical trials undertaking active
comparator studies in order to compare like with like.
TABLE A5
Oral antipsychotic dose equivalent
Approximate equivalent oral dose to 100 mg oral chlorpromazine1,2,3,4
Antipsychotic Equivalent dose
Amisulpride 100 mg (range 40–150 mg)
Aripiprazole 4 mg
Asenapine 4 mg
Clozapine 100 mg (range 30–150 mg)
Flupentixol 2–3 mg
Fluphenazine 2 mg (range 1.25–5 mg)
k Haloperidol 2–3 mg (range 1–5 mg) or 1.5 mg IM/IV for doses up to 20 mg k
Lurasidone 16 mg
Olanzapine 3 mg
Paliperidone 1.2 mg
Quetiapine 60 mg
Risperidone 0.5–1 mg (range 0.5–3 mg)
Sulpiride 200 mg (range 200–270 mg)
Trifluoperazine 5 mg (range 2–8 mg)
Zuclopenthixol 25 mg (range 25–60 mg)
Considerations
Antipsychotic equivalent dose calculations are inexact due to their
heterogeneity and the different calculation methods used and this is
reflected by the range of values quoted in the literature. Many authors
will not estimate dose equivalences for the ‘atypical’ or
‘second-generation’ antipsychotics, so all data for these agents should
be treated with additional caution. These equivalences solely concern
the dopaminergic effects of these agents. Adverse effects caused via
other neurotransmitter systems need to be considered separately
based on the propensity of each agent to cause them.
Calculations may be complicated by the half-lives of the different
agents, and the effect of first-pass metabolism on oral dose forms.
Calculated doses should always be checked against the SPC so
k
k
Apomorphine 33
TABLE A6
Depot and long-acting injection antipsychotic dose
A
equivalents
Approximate equivalent intramuscular dose to 100 mg oral chlorpromazine daily1,2,3
Antipsychotic Equivalent dose (mg/week)
Aripiprazole Only to be used for those responding to oral aripiprazole.
See the SPC for conversion details
Flupentixol decanoate 10 mg (range 8–20 mg)
Fluphenazine decanoate 5–10 mg (range 1–12.5 mg)
Haloperidol decanoate 15 mg (range 5–25 mg)
Olanzapine pamoate Only to be used for those responding to oral olanzapine.
See the SPC for conversion details
Paliperidone palmitate 12.5 mg (as roughly 50 mg every month)
Pipotiazine palmitate 10 mg (range 5–12.5 mg)
Risperidone 12.5 mg (as 25 mg every 2 weeks)
Zuclopenthixol decanoate 100 mg (range 40–100 mg)
unlicensed doses are not inadvertently used. Equivalent doses should

not be extrapolated beyond maximum licensed doses.
Clinical presentation should always be closely monitored, and
inform dose adjustments as indicated. Published equivalents may lag
behind licensing changes and also new agents becoming available.
k REFERENCES
k
2 Bazire S (2014). Psychotropic Drug Directory 2014: The professionals’ pocket hand-
book and aide memoire. Dorsington: Lloyd-Reinhold.
3 Taylor D (2012). The Maudsley Prescribing Guidelines in Psychiatry, 11th edn.
Chichester: Wiley-Blackwell.
4 Leucht S et al. (2014). Dose equivalents for second-generation antipsychotics: the
minimum effective dose method. Schizophr Bull 40: 314–326.
Apomorphine
Apomorphine is licensed for the treatment of motor fluctuations
(‘on-off’ phenomena) in patients with Parkinson’s disease, which are
not sufficiently controlled by oral anti-Parkinson medication. It is a
potent, non-selective, direct-acting dopamine receptor agonist.1,2
It may be used for long-term treatment in advanced disease or as a
palliative treatment near the end of life. It is also occasionally used in
the acute management of advanced Parkinson’s disease where no oral
access is available, e.g. in critical care.
The rapid and reliable response to apomorphine can be an
advantage when oral doses of levodopa combined with other
dopaminergic drugs become progressively less effective and less
predictable. These ‘on-off’ phenomena or dyskinesias can be
particularly problematic in younger-onset patients.
k
k
34 Apomorphine
A Apomorphine can be used as intermittent injections for use at the

onset of ‘off periods’ or via continuous infusion for patients whose
overall response is unsatisfactory despite use of intermittent
injections. The ‘off’ period is characterised by symptoms such as
dystonia, depression, pain, sleep dysfunction, bladder dysfunction
and swallowing difficulties. An ‘off’ period can occur suddenly and
unpredictably, with little indication to the patient of its approach.
Apomorphine initiation
Apomorphine should be initiated in the controlled environment of a
specialist clinic. The patient should be supervised by a physician
experienced in the treatment of Parkinson’s disease (e.g. neurologist).
Antiemetic treatment
Nausea and vomiting can be problematic in up to 10% of patients on
apomorphine, particularly at initiation. Domperidone, started at least
2 days before apomorphine therapy begins, has been shown to be
successful in controlling symptoms.1,2 Caution should be used when
prescribing domperidone and a full cardiac review is needed prior to
initiation. It is contraindicated in patients:3
● with conditions where cardiac conduction is, or could be, impaired

● with underlying cardiac diseases such as congestive heart failure
● receiving other medications known to prolong QT interval or
potent CYP3A4 inhibitors
k ● with severe hepatic impairment. k
It is usually possible to reduce and withdraw domperidone altogether
once apomorphine treatment has been established.
Apomorphine challenge
Apomorphine will not produce positive response in all patients.4 In
order to determine likely response to apomorphine treatment, the
patient should have an apomorphine challenge.
1 The patient is premedicated with domperidone, as above.

2 Normal anti-Parkinson medication should be withheld for
4 –6 hours to provide an ‘off’ period.
3 Record baseline ‘off’ state assessment. Record lying and standing
blood pressure; take Unified Parkinson’s Disease Rating Scale
(UPDRS) III to provide a baseline score. A 12-metre walk is
suggested, but not compulsory, and should not be done for
someone with postural hypotension.
4 A 1-mg dose of apomorphine is given by subcutaneous injection,
and the patient monitored for response and side effects for up to
30 minutes. The desired response is reversal of parkinsonian
symptoms within 5 –10 minutes following injection and for a
duration of 45 –60 minutes. A positive challenge is defined as a
UPDRS score of 20% above baseline, and where available, more
than a 25% improvement in walking time.
k
k
Apomorphine 35
5 If there is no response or a poor response, a further dose of 3 mg is A

given, and the patient assessed again, or specific symptoms,
e.g. pain, are alleviated.
6 This process is repeated if necessary, first with a 5-mg dose, then a
7-mg dose. If there is no response with a 7-mg dose, the patient is
classed as a non-responder, and apomorphine will not be suitable.
If the response at 7 mg is mild, then a maximum of 10 mg should
be tried.
The effective dose that is individually determined for the patient will
typically require no further adjustment once it has been established.
Administration
Apomorphine is given subcutaneously in one of two ways:
1 intermittent injection from a prefilled disposable pen
2 by continuous infusion using a syringe driver, or an APO-go pump.
Continuous infusions are considered for patients needing more than
10 injections per day, or who have shown a good ‘on’ period response
during the initiation stage of apomorphine therapy, but whose overall
control remains unsatisfactory using intermittent injections.
When given by continuous infusion via APO-go pump or syringe
driver, the 5 mg/mL prefilled syringes should be used, or the
10 mg/mL injection diluted with an equal volume of sodium chloride
0.9% to make the final concentration 5 mg/mL. If given more
k concentrated, apomorphine may provoke local inflammatory k
reactions. Water for injections should not be used as a diluent, as this
can increase the risk of nodule formation and ulceration.
Continuous infusions are normally given during the patient’s
waking hours, and unless severe nighttime problems are experienced,
24-hour infusions are not advised. The infusion site needs to be
changed every 12 hours.
Practical considerations for patients on apomorphine
therapy
Apomorphine injection is very irritant and stains clothes and bed
clothes on contact.
Skin nodules and ulcers are common with apomorphine use. It is
important to minimise the formation of nodules as it is thought they
may reduce the absorption of apomorphine and thus reduce the
efficacy of treatment.
Local reactions can be minimised by clean technique, daily rotation
of injection sites and using thumb tack needles. Gentle massage of the
injection sites can also be helpful. Silicone gel patches can also help to
reduce nodule formation and relieve itchiness.4
Monitoring
Haemolytic anaemia and thrombocytopenia have been reported in
patients taking apomorphine; therefore, regular full blood count
monitoring is advised.1,2
k
k
36 Appetite stimulation
A Impulse control disorders, e.g. pathological gambling, increased

libido, hypersexuality, compulsive spending/buying, binge eating and
compulsive eating, have also been reported with apomorphine;
therefore, counselling and regular monitoring are essential.
REFERENCES
1 SPC. APO-go Pre-filled Syringes 5 mg/mL. www.medicines.org.uk/emc (accessed 5
August 2014).
2 SPC. APO-go Pen 10 mg/mL. www.medicines.org.uk/
emc (accessed 5 August 2014).
3 Kings College Hospital NHS Trust (2002). The Use of Apomorphine in Parkinson’s
Disease. Shared Care Guidelines London: Kings College Hospital NHS Trust.
4 MHRA Drug Safety Update (2014). Domperidone: Risks of cardiac side effects –
indication restricted to nausea and vomiting, new contraindications and reduced
dose and duration of use. http://www.mhra.gov.uk/Safetyinformation/DrugSafety
Update/CON418518 (accessed 5 August 2014).
Appetite stimulation
Loss of appetite is a problem in many debilitating illnesses such as
HIV/AIDS and cancer. Stimulation of a patient’s appetite is important
to improve the patient’s nutritional status and sense of well-being. It is
important to identify any medical cause for weight loss. The reason
a patient may not be eating, or not maintaining weight, is often
k complex and there may be pathophysiological and psychological k
components.1
Dieticians and psychologists have an important role to play in
managing the cause of the weight loss in a patient; however,
prescribers will often seek advice on appetite-stimulating drug
treatment. It is useful to know what products exist, or have been tried,
for this purpose, even though the evidence base is weak.
Alcohol
Anecdotal evidence suggests that an alcoholic beverage may improve
appetite before meals. Alcohol is known to depress glycogenolysis,
and this may lead to a compensatory increase in appetite as the body
‘thinks’ it needs food. A 25-mL measure of sherry or whisky is
sometimes prescribed, equivalent to a single measure (one unit) of
alcohol. There is a major psychological benefit in serving alcohol in a
glass rather than in a medicine pot.
Cyproheptadine (Periactin)
Cyproheptadine was licensed as an appetite stimulant until 1994,
when this indication was removed from its product licence.2 The
previously licensed adult dose was 4 mg three to four times a day, and
in children over 3 years the dose was 2 mg three times a day.3,4
Although no longer licensed, and lacking strong evidence, it may still
be considered as an option.
k
k
Appetite stimulation 37
Bitters and tonics A

Traditionally mixtures containing simple and aromatic bitters are
remedies used for loss of appetite; however, there is no evidence to
support their use.5 In the case of the tonics the main ingredients are
various vitamins and minerals. The rationale for their possible effect
is that in patients deficient in these substances, loss of weight and
appetite does occur.
Progestogens (megestrol acetate and
medroxyprogesterone acetate)
Although licensed for use in the treatment of breast and endometrial
cancer in the UK, a coincidental increase in appetite and weight gain
has been observed in patients treated with the drug. In the USA, the
Food and Drug Administration has approved the use of megestrol
acetate for the treatment of anorexia, cachexia or an unexplained,
significant weight loss in patients with a diagnosis of AIDS. The usual
starting dose is 800 mg daily in divided doses, although clinical trials
found daily doses of 400 –800 mg to be effective.6 Progestogens have
been used in the treatment of weight loss associated with cancer
(the cancer anorexia cachexia syndrome). Megestrol at doses of
160 –320 mg each day and medroxyprogesterone at doses of 200 mg
three times a day have been used. It may take up to 2 weeks for the
benefit to be seen but, in comparison with corticosteroids, the
progestogens have fewer side effects.7
k Corticosteroids
k
In palliative care, corticosteroids have been used to improve appetite
and enhance a sense of well-being. Dexamethasone has been used in
the dose range 2 –4 mg daily.7
Mirtazapine
Mirtazapine is licensed as an antidepressant medication. When used
to treat depression in elderly patients, it has also been shown to
promote weight gain and increase appetite.8
REFERENCES
1 Yeh S-S, Shuster MW (1999). Geriatric cachexia: the role of cytokines. Am J Clin
Nutr 70: 183–197.
2 World Health Organization (WHO) (1994) Drug Information, volume 8 num-
ber 2. http://whqlibdoc.who.int/druginfo/DRUG INFO 8 2 1994.pdf (accessed
12 October 2014).
3 Rahimtoola RJ et al. (1970). Clinical experience with children on Periactin (cypro-
heptadine). Pak J Med Res 9: 15–19.
4 Halmi KA et al. (1982). Cyproheptadine for anorexia nervosa. Lancet 1(8285):
1357–1358.
6 US FDA. Product Label Megace Oral Suspension. http://www.accessdata.fda.gov/
drugsatfda docs/label/2012/020264s017lbl.pdf (accessed 12 October 2014).
k
k
38 Arterial blood gases and acid–base balance
7 Watson M et al. (2009). Oxford Handbook of Palliative Care (2nd edn.). Oxford:
A Oxford University Press.
8 Huffman GB (2002). Evaluating and treating intentional weight loss in the elderly.
Am Fam Physician 65: 640–651.
Arterial blood gases and acid–base balance

Overview
Definition Arterial blood is collected to measure for the partial pressure of O2 and
CO2 . Arterial blood gases (ABG) are also collected for the interpretation
of acid–base balance1
Risk ● Insertion of an arterial line can be painful
● Most commonly taken from the brachial artery
● In intensive care, continuous arterial lines are used routinely and can
be a source of infection if not changed regularly
Reference Partial pressure O2 : 11–13 kPa
values (all) Partial pressure CO2 : 4–6 kPa
pH: 7.35
Base excess/deficit: 0
Serum bicarbonate: 18–26 mmol/L
Serum lactate: <1.5 mmol/L
Common Hypercapnic respiratory drive: hypercapnia is where the CO2
k terms: ABG concentration is higher than the reference range. It is this raised CO2 that k
stimulates gas exchange in the alveoli.
Hypoxic respiratory drive: if one lives with a permanently high
concentration of CO2 then the hypercapnic respiratory drive is lost and
the patient is dependent on a hypoxic respiratory drive. This is typically a
patient with COPD. In this patient group it is the low O2 that stimulates
gas exchange.
O2 dissociation curve: free O2 (pO2 ) is bound to haemoglobin and
transferred from the lungs to the tissues in the form of
2,4-diphosphoglycerate. It then dissociates to pO2 and it is this partial
pressure of oxygen that is the free O2 , available for anaerobic
metabolism in the mitochondria
Common Metabolic acidosis: this literally means production of excess acid in the
terms: body. There are two acids: lactic (formed after anaerobic metabolism)
acid–base and hydroxybutyric acid (formed after diabetic ketoacidosis). There are
balance other forms of iatrogenic metabolic acidosis, e.g. hyperchloraemic
metabolic acidosis, which may occur after administration of excess
sodium chloride 0.9%.
Metabolic alkalosis: this is retention of excess bicarbonate and can
occur after overdose of tricyclic antidepressants. Compensation is
respiratory acidosis through retention of CO2 .
Respiratory acidosis: occurs due to the retention of CO2 in the form of
carbonic acid and due to the kidneys causing bicarbonate-compensatory
metabolic alkalosis. It commonly presents in opioid toxicity
k
k
Artificial saliva 39
Respiratory alkalosis: caused by exhaling an excess of CO2 and can A

occur in hyperventilation. Compensation is in the form of metabolic
acidosis (kidney excretes extra bicarbonate).
Base excess or deficit: this hypothetical figure describes the number of
moles of bicarbonate to be either added or removed from blood to attain
physiological pH 7.35; a negative base excess is indicative of metabolic
acidosis. It can be an early sign of sepsis.
Anion gap: this represents the concentration of unmeasured ions in
circulation. A large anion gap can signal the presence of metabolic
acidosis; it can help differentiate type (a larger anion gap signals organic
acidosis) and can be used to monitor the effect of treatment. A normal
anion gap is between 8 and 16 mmol/L
Clinical Type 1 respiratory failure
application ● Main presentation is hypoxia (pO2 <11 kPa)
(ABG) ● Occurs commonly in lower respiratory tract infection and asthma
Type 2 respiratory failure
● Main presentation is hypercapnia (pCO2 >6 kPa)
● Occurs commonly in COPD
Clinical ● Body pH is balanced at 7.35

application ● Enzymatic reactions only occur at specific pH
(acid–base ● Any drift of pH up or down from 7.35 can have grave consequences
balance) ● The two organs involved in maintaining pH are the lungs (for CO2
exchange) and the kidneys (for bicarbonate buffering)
Pharmaceutical care
k Assess ● Oxygen therapy: caution in COPD as patients may have lost their
k
hypercapnic respiratory drive
● Sodium bicarbonate 8.4% (given via a central line except in
emergencies) treatment for life-threatening metabolic acidosis when
kidneys cannot retain sufficient bicarbonate. Always administer over
30 minutes to prevent intracellular acidosis. Correction of acid–base
disturbance in the ICU is most commonly undertaken by renal
replacement therapy
● Arterial line: a common source of infection in the ICU: change every
10–14 days depending on local policy
REFERENCE
1 Warrell DA et al. (eds) (2012) Oxford Textbook of Medicine, 5th edn. Oxford: Oxford
University Press.
Artificial saliva
Dry mouth (xerostomia) can be managed by saliva stimulants or
substitutes. Saliva is made of 99% water and the remaining 1% is a
combination of electrolytes and molecules that are important for
saliva’s many functions: lubricating, cleansing, digestion, buffering,
mineralisation of teeth, taste and antimicrobial properties.1 Artificial
saliva is a poor substitute for natural saliva; saliva stimulants are
k
k
A
TABLE A7
Saliva substitutes and preparations to treat dry mouth4
Products available Formulation Prescribable on NHS? pH Contains Animal-derived ingredients? Gluten-free? Sugar-free?
(manufacturer) fluoride?
AS Saliva Orthana Oral spray 50 mL Yes Neutral Yes Yes Yes Yes
(AS Pharma) ACBS Porcine
Lozenges (30) Yes Neutral No Yes Yes Yes
ACBS Porcine Contains sorbitol
Biotene Oralbalance Saliva replacement Yes (dentist prescribing: Acidic No Yes (manufacturer did not provide Yes Yes
40 Artificial saliva
(GSK) gel 50 g may be prescribed as information on what these were) Contains glucose oxidase, an
artificial saliva gel) enzyme added to inhibit bacteria
growth. This is not a sugar
BioXtra products for dry Moisturising gel Yes Neutral No Yes Yes Yes
mouth (RIS Products) 40 mL ACBS Proteins extracted from cow’s milk
k
k
Gel mouth spray Yes Neutral Yes Yes Yes Yes

50 mL ACBS Proteins extracted from cow’s milk
Glandosane Aerosol spray 50 mL Yes Acidic No No Yes Yes
CPPC c01.tex
(Fresenius Kabi) (lemon, neutral, ACBS Contains sorbitol

peppermint)
Saliveze Oral spray 50 mL Yes Neutral No No Yes Yes
(Wyvern) ACBS
Saliva Stimulating Tablets (100) Yes Acidic No No Yes Yes
Tablets (SST) (Medac) Contains sorbitol
Xerotin (SpePharm) Oral spray 100 mL Yes Neutral No No Yes Yes
Dental prescribing Contains sorbitol
May be prescribed as
V2 - 11/18/2015 1:44 P.M.
artificial saliva spray

Page 40
k
k
Asthma 41
preferred unless a main salivary duct is blocked. Chewing gum A

stimulates saliva production and is as effective as, and preferred to,
mucin-based artificial saliva.2 Gum should be sugar-free and in
patients with dentures, low-tack, e.g. Orbit, Freedent.
The ideal artificial saliva should be easy to use, pleasant, effective
and well tolerated, have a neutral pH to prevent demineralisation of
teeth and contain fluoride to enhance remineralisation of teeth. Acidic
products should be avoided in patients with stomatitis/mucositis as
the acidity will increase pain; and in dentate patients due to the risk
of dental decay may cause oral candidosis. Mucin-based products are
generally better-tolerated and more effective than cellulose-based
ones; however, mucin is derived from the stomach of pigs and
therefore maybe an issue with certain groups, e.g. Muslims, Jews and
vegetarians (see Pharmacocultural issues entry).1
Artificial saliva products have a short duration of action due to
swallowing and evaporation, and therefore use may need to be
frequent: every 30 –60 minutes, before and during meals.1
Aquoral, Biotène Oralbalance Biotène gel or Xerotin can be used
for any condition giving rise to a dry mouth. BioXtra, Glandosane,
Saliva Orthana and Saliveze have ACBS approval for dry mouth
associated only with radiotherapy or sicca (Sjögren) syndrome.
Salivix pastilles, which act locally as salivary stimulants, are available
for any condition leading to a dry mouth. SST tablets may be
prescribed for dry mouth in patients with salivary gland impairment.3
k Table A7 summarises the saliva substitute products currently k
available in the UK.
REFERENCES
1 Twycross R, Wilcock A (2011). Artificial saliva and topical saliva stimulants. In: Pal-
liative Care Formulary (4th edn). Nottingham: Palliativedrugs.com, pp. 570–572.
2 Davies AN (2000). A comparison of artificial saliva and chewing gum in the man-
agement of xerostomia in patients with advanced cancer. Palliat Med 14: 197–203.
4 Henderson S (2013). UKMi Medicines Q&A 190.6. Saliva Substitutes: Choosing and
prescribing the right product. Liverpool: North West Medicines Information Centre.
Asthma
Overview
Definition Asthma is defined as ‘a chronic inflammatory disorder of the
airways in which many cells and cellular elements play a role; in
particular, mast cells, eosinophils, T lymphocytes, macrophages,
neutrophils, and epithelial cells’. The chronic inflammation causes
an associated increase in airway hyperresponsiveness that leads to
recurrent episodes of symptoms of asthma. These episodes are
usually associated with widespread but variable airflow obstruction
that is often reversible either spontaneously or with treatment
k
k
42 Asthma
A Causes There is no known single cause for asthma, but it is well recognised
that there are genetic and environmental factors that contribute to
developing the condition:
● Family history of asthma (especially a parent or sibling) or other
atopic conditions, e.g. eczema, hayfever
● Bronchiolitis as a child (40% of children exposed to respiratory
syncytial virus or parainfluenza virus will continue to wheeze or
have asthma into later childhood)
● Tobacco smoke, particularly if the mother smoked during
pregnancy
● Premature birth or low birth weight
● Occupational exposure (e.g. to plastics, agricultural substances
and volatile chemicals such as solvents)
● Obesity, especially if body mass index >30 kg/m2
● Bottle feeding: evidence shows that if an infant is breast-fed
there is a decreased risk of wheezing illness compared to infants
fed formula or soya-based milk feeds
Classification Asthma is classified in different ways depending on the level of
control and treatment. In the British Guideline on the Management
of Asthma,1 classification is based on the level of the treatment that
is needed to maintain asthma control, from step 1 increasing up to
step 5. Recently asthma research has introduced a new approach
to identify and classify asthma according to different subgroups
of asthma, such as eosinophilic asthma, atopic, late-onset
asthma
Signs and The classic signs of asthma are wheezing (especially expiratory
k symptoms wheeze), breathlessness, coughing (typically early-morning or k
nighttime) and chest tightness. The wheezing that occurs as a result
of airway bronchoconstriction and coughing is likely to be due to
stimulation of sensory nerves in the airways. These episodes are
usually reversible either spontaneously or with treatment. In a
severe exacerbation, wheeze may be absent and the chest may be
silent on auscultation due to such severe obstruction of the airway.
In these cases, often other signs will be present, such as cyanosis,
drowsiness and an inability to complete full sentences. These severe
cases are medical emergencies and require immediate medical
attention
Diagnostic tests There is no ‘gold standard’ test that can be used to diagnose
asthma. Therefore, asthma diagnosis is usually based on one or
more typical features, including: respiratory symptoms; evidence of
variable airflow obstruction using lung function tests; and the
person’s response to asthma medication. The diagnostic process is
different in adults and children and also varies among adults and
among children. Processes for diagnosis in adults and children are
described in the BTS/SIGN guidance1
k
k
Asthma 43
Treatment goals1 The goal of asthma management is control of the disease. Complete A
control of asthma is defined as:
● No daytime symptoms
● No nighttime awakening due to asthma
● No need for rescue medication
● No exacerbations
● No limitations on activity, including exercise
● Normal lung function (in practical terms: forced expiratory
volume in 1 second and/or peak expiratory flow rate (PEFR)
>80% predicted or best)
● Minimal side effects from medication
Treatment ● Avoidance of triggers (such as pollen, animal dander, aspirin or
options NSAIDs) is a key component of improving control and preventing
asthma exacerbations
● Medications used to treat asthma are divided into two general
classes: quick-relief medications (e.g. short-acting beta-2
agonists), used to treat acute symptoms; and long-term control
medications (e.g. inhaled corticosteroids), used to prevent
further exacerbation. The current BTS/SIGN algorithm for chronic
asthma can be found here:
BTS/SIGN Guideline Algorithm1

● Healthy lifestyle advice should be offered to patients, including
moderation of alcohol consumption, smoking cessation, regular
exercise, dietary advice to help manage weight, vaccinations
(annual influenza and one-off pneumococcal)
People with asthma should be provided with a written
k ●
personalised action plan given as part of structured education. k

Typically action plans contain specific advice as to how to
recognise loss of asthma control based on either symptoms or
PEFR and what action to take if asthma deteriorates (e.g. when
PEFR <50% it is best to seek emergency help). An asthma action
plan can be downloaded from the Asthma UK website
(www.asthma.org.uk)
● These plans can improve outcomes, giving self-efficacy,
knowledge and confidence for people with asthma to manage
their disease
k
k
44 Asthma
A Medicines Optimisation
The medication treatment options here are from BTS/SIGN guidance
Inhaled ● Most effective treatment to reduce inflammation in the lungs
corticosteroid and prevent exacerbations
(ICS) ● Start at a dose appropriate to the severity of the disease and
then titrate to the lowest dose at which effective control of
asthma is maintained
● Discuss the importance of regular inhaled corticosteroids use
even when feeling well. The risk of side effects from long-term
ICS to maintain adequate asthma control is minimal when
compared with repeated courses of oral corticosteroids for
asthma exacerbations and periods of poor control
● Optimise dose: most patients with asthma can achieve
well-controlled disease with relatively low doses of inhaled
corticosteroids (≤800 micrograms beclometasone
(non-extra-fine)/day or equivalent). The BTS/SIGN asthma
guideline contains a table showing dose comparisons between
inhaled corticosteroids
● Risk of systemic side effects is low with doses ≤800 micrograms
beclometasone (non-extra-fine)/day or equivalent
● Rinse mouth after use to reduce incidence of local side effects,
such as oral Candida and hoarseness
● Issue steroid warning card to all patients receiving high-dose
inhaled corticosteroids (>800 micrograms beclometasone
(non-extra-fine)/day or equivalent)
k Short-acting ● Most effective treatment to relieve acute symptoms of asthma k
beta-2 agonist ● Beta-2-agonists can mask symptoms and do not change the
(SABA) underlying inflammatory disease process
● Should always be prescribed ‘when required’ at all stages of the
disease
● Good control is associated with little to no need for SABA use.
Increased use is a marker of uncontrolled asthma
● Side effects such as tremor, cramps and ↓K (monitor) and
palpitations are dose-related
Long-acting ● Should always be prescribed in conjunction with an inhaled
beta-2 agonist corticosteroid in people with asthma due to the increased risk of
(LABA) death associated with use without an ICS (a combination inhaler
is recommended)
● Risk of ↓K, therefore monitor
Leukotriene ● LTRA may be of benefit in exercise-induced asthma,
antagonist (LTRA) aspirin-intolerant asthmatics and those with concomitant rhinitis
● Clinical response seen within 4 weeks, though not all patients
benefit
k
k
Asthma 45
Methylxanthine ● Narrow therapeutic window – appropriate dosing and A

(theophylline, monitoring are essential
aminophylline) ● Aim for a steady-state serum theophylline concentration of
10–20 micrograms/mL
● If the theophylline level is subtherapeutic, confirm the blood
sampling time was correct, assess adherence and check drug
interactions before considering increasing the dose. Recheck
levels after any dose increase
● Measure drug levels: when treatment starts, if side effects occur,
if expected therapeutic benefit is not achieved and if potential
drug interactions are suspected. Monitor levels daily if
intravenous aminophylline is prescribed (see Theophylline entry)
act on results
● Side effects occur commonly, such as tachycardia, palpitations,
headache, insomnia, nausea and other gastrointestinal
disturbances
● If intravenous aminophylline is prescribed to manage acute
severe exacerbations, ensure a loading dose is given only if the
person is not taking an oral methylxanthine
● Check for drug interactions with prescribed, herbal and OTC
medicines and withhold/adjust these medicines as appropriate
● Prescribe oral products by brand, as bioavailability may vary
from one brand to another
Oral ● Short courses (5–7 days) are prescribed to manage an asthma
corticosteroid exacerbation
● If long-term treatment is required to manage severe asthma, use
k the lowest dose possible to maintain control. To reduce the dose
or eliminate the steroid tablets, also prescribe maximum dose of
k
ICS
● For steroid courses longer than 3 weeks, provide a steroid
warning card
● Consider osteoporosis prophylaxis for people on ≥7.5 mg
prednisolone and/or more than four courses of oral steroids in a
year. Using a high-dose corticosteroid inhaler in the long term
may also be a risk. Epidemiological studies examining the
relationship between inhaled corticosteroids and osteoporosis
give conflicting results and are difficult to interpret due to
confounding factors. General measures to counteract
osteoporosis (such as regular exercise, smoking cessation,
adequate dietary calcium) are recommended in people who
require high doses of inhaled corticosteroids for prolonged
periods of time
Anti-IgE therapy ● Consider for people with documented allergic asthma and raised
(omalizumab) IgE
● NICE technology appraisal guides prescribing2
● Administered every 2 or 4 weeks by subcutaneous injection –
initially a 16-week trial to monitor response
Muscarinic ● If ipratropium is being nebulised, the mask must be fitted
antagonists carefully or ideally a mouthpiece used to avoid the aerosol
coming into contact with the eyes, as this could cause glaucoma.
Other antimuscarinic medication via an inhaled device should be
withheld whilst on nebulised ipratropium, due to increase in the
risk of adverse effects and no increased efficacy
k
k
46 Asthma
A Drug ● Give specific training and assessment on inhaler technique

administration before starting any new inhaler treatment. Ask patients to show
you how they use their inhalers; it is not sufficient just to ask
them if they know how to use them
● Make sure the patient’s spacer device is compatible with the
inhaler device and that patients know how to use the spacer
● The use of nebulisers in the day-to-day management of asthma
is rarely appropriate or necessary and can be dangerous. There is
a documented increased risk of dying associated with overuse of
SABAs during an exacerbation.3 Confirm that a nebuliser is
required and the patient has been allocated or has access to one
Essential ● Strongly advise patients not to smoke: smoking worsens asthma
interventions symptoms and reduces responsiveness to inhaled corticosteroids
in asthma patients
● Monitor asthma control (use a validated tool, such as RCP 3
questions4 ) and recommend stepping up or down treatments
appropriately
● Ensure the patient understands that asthma is a chronic
condition, even though the symptoms may vary
● Assess adherence to medicine (by asking patients, reviewing
repeat prescription frequency, examining dates on dispensing
labels)
● Ensure patients understand the differences between reliever and
preventer medication
● Ensure patients are offered an annual vaccination against
influenza and a one-off vaccination against pneumococcal
k disease k
Secondary ● Patient health beliefs – disarming myths, such as weight gain,
intervention dependence and intolerance, especially regarding inhaled
corticosteroids
● Make sure patients are aware how to follow their personalised
asthma action plan in response to their symptoms and/or peak
flow readings
● Provide health messages about avoidance of allergens
● Consider assessment and treatment of comorbidities
(e.g. allergic rhinitis, anxiety)
Monitoring on ● Assess severity of asthma exacerbation, observing respiratory
hospital rate, heart rate, blood pressure, state of consciousness and
admission whether the patient is able to speak in full sentences
● Assess airflow obstruction (peak expiratory flow measurement),
blood gas measurement, pulse oximetry, accessory muscle use
and chest sounds
● Review medication regimen, adherence, including need for
changes, and possible side effects
k
k
Further reading Asthma UK: http://www.asthma.org.uk/. A

Global Initiative for Asthma (GINA) (2014). Global Strategy for
Asthma Management and Prevention. http://www.ginasthma.org
(accessed 26 April 2015).
National Review of Asthma Deaths (NRAD) Why Asthma Still Kills.
https://www.rcplondon.ac.uk/sites/default/files/why-asthma-still-
kills-full-report.pdf (accessed 26 April 2015).
NICE (2013) Quality Standard for Asthma. http://www.nice.org.uk/
guidance/qs25/resources/guidance-quality-standard-for-asthma-pdf
Royal Pharmaceutical Society (RPS) (2015) Medicine Optimisation
Briefing – Asthma. http://www.rpharms.com/promoting-pharmacy-
pdfs/mo-briefing—asthma.pdf (accessed 26 April 2015).
REFERENCES
1 Joint British Thoracic Society/Scottish Intercollegiate Guidelines Network (2012).
British Guideline on the Management of Asthma. Clinical guideline 101 https://
www.brit-thoracic.org.uk/document-library/clinical-information/asthma/btssign-
guideline-on-the-management-of-asthma/ (accessed 4 May 2015).
2 NICE (2013). NICE Technology Appraisals (TA278). Omalizumab for treating severe
persistent allergic asthma. http://www.nice.org.uk/guidance/TA278/chapter/
1-guidance (accessed 1 October 2014).
3 Royal College of Physicians (2014). Why Asthma Still Kills: The National Review of
Asthma Deaths (NRAD); confidential enquiry report 2014. https://www.rcplondon
.ac.uk/sites/default/files/why-asthma-still-kills-full-report.pdf (accessed 27 January
k 2015). k
4 Royal College of Physicians (1999). Measuring Clinical Outcome in Asthma, A
patient-focused approach. https://www.rcplondon.ac.uk/publications/measuring
-clinical-outcome-asthma (accessed 27 January 2015).
Atrial fibrillation
Overview
Definition Atrial fibrillation (AF) is an arrhythmia caused by disorganised electrical
activity in the atria, usually leading to a rapid and irregular ventricular
rate. It is an important cause of morbidity and mortality due to heart
failure, stroke and thromboembolism, and is the most common
arrhythmia seen in clinical practice, with a prevalence approaching 2% of
the general population, rising to almost 10% in those over 80 years.
AF may be:
● Acute onset: started in the last 24–48 hours
● Paroxysmal: recurrent and usually self-limiting, usually lasting
<7 days
● Persistent: lasts longer than 48 hours and does not revert
spontaneously to sinus rhythm
● Permanent: long-standing and not amenable to cardioversion
k
k
48 Atrial fibrillation
A Causes ● Cardiac: ischaemic heart disease (IHD), hypertension, rheumatic heart

disease, cardiomyopathy, pericardial disease
● Non-cardiac: thyrotoxicosis, acute infection, pulmonary disease
(pneumonia, malignancy, effusion), excess alcohol (acute or chronic)
and the perioperative period
● Around 10% of cases have no obvious cause
Signs and Common presenting symptoms are those of heart failure (breathlessness,
symptoms fatigue, pulmonary or peripheral oedema), palpitations, stroke and
systemic thromboembolism. The left atrial appendage is a common site
for thrombus formation. Strokes associated with AF tend to be more
severe (higher mortality and more debilitating).
Some patients may be asymptomatic and AF is an incidental finding
Diagnostic ● ECG shows absent p-waves and irregular, narrow QRS complexes
tests ● Thyroid function tests to rule out thyrotoxicosis
● LFTs (including GGT). If elevated, alcohol may be the cause
● Chest X-ray for pulmonary oedema
● Transthoracic echocardiogram (TTE), particularly if rhythm control is
to be attempted or if there is a suspicion of structural or functional
heart disease (valve disease or heart failure)
● Transoesophageal echocardiogram (TOE) when TTE demonstrates an
abnormality that requires further assessment or is inconclusive or
when TOE-guided cardioversion is to be attempted (to rule out the
presence of atrial thrombus)
Treatment ● Reduce the risk of stroke
goals ● Control related symptoms, especially those of heart failure
k ● Control ventricular rate (rate control) in most patients k
● Cardiovert to (and maintain) sinus rhythm (rhythm control) in some
patients
Treatment ● Drug therapy is the commonest intervention to reduce stroke risk,
options reduce heart rate or maintain sinus rhythm
● In patients with a high stroke risk who are not suitable for
anticoagulants, left atrial appendage occlusion may be an option
● For patients with paroxysmal or persistent AF that has not been
controlled with drug treatment, left atrial catheter ablation (e.g.
pulmonary vein isolation) may be considered
● For patients with permanent AF whose symptoms persist due to a
high ventricular rate despite drug treatment, consider ventricular
pacing and AV node ablation
k
k
Medicines optimisation A
Assess1,2 Stroke risk: assess every patient with a history of AF using the
CHA2 DS2 VASc score:
Risk factor Score

Congestive heart failure (CHF) 1
Hypertension 1
Age >75 years 2
Age 65–74 years 1
Diabetes mellitus 1
Stroke, transient ischaemic attack or thromboembolism 2
Vascular disease (previous MI, peripheral artery disease, 1
aortic plaque)
Female 1
Use HAS-BLED score to identify any modifiable bleeding risks:
Risk factor Score

Uncontrolled hypertension (systolic blood pressure 1
>160 mmHg)
Abnormal liver function (cirrhosis or bilirubin >2 × normal or 1
k aspartate transaminase/alanine transaminase/alkaline k
phosphatase >3 × normal)
Abnormal renal function (dialysis, transplant, serum creatinine 1
>200 micromol/L)
Previous history of stroke 1
Prior major bleed or predisposition to bleeding 1
Labile INR 1
Elderly (over 65 years) 1
Antiplatelets or NSAIDs 1
Alcohol use (>8 drinks per week) 1
A HAS-BLED score of >3 indicates a high bleeding risk. Where possible,

address modifiable bleeding risks (hypertension, interacting drugs,
alcohol intake).
● Rate control versus rhythm control strategy: for most patients, an
initial rate control strategy will be appropriate. Patients presenting
with haemodynamic instability should be cardioverted urgently
● Lifestyle advice and modification, especially alcohol intake
● Treat underlying reversible causes, such as thyrotoxicosis, pneumonia
● Stop ivabradine if prescribed in patients with AF
k
k
A Stroke ● Offer oral anticoagulants to all patients with a CHA2 DS2 VASc score of
prevention1 >2, taking bleeding risk into account. Consider oral anticoagulants
for men with a CHA2 DS2 VASc score of 1, again taking bleeding risk
into account
● Continue anticoagulants in all patients with a history of AF, even if
they revert to sinus rhythm, taking bleeding risk into account
● Do not offer stroke prevention to men with a CHA2 DS2 VASc score of
0 or women with a CHA2 DS2 VASc score of 1 (very low stroke risk)
● Do not deny anticoagulants solely based on a history of falls
● Do not use aspirin monotherapy solely for stroke prevention in AF
Review all patients receiving suboptimal stroke prevention therapy and
address where appropriate:
● Replace aspirin monotherapy or no stroke prevention treatment with
an oral anticoagulant if indicated
● Replace warfarin with an NOAC if anticoagulation control is poor
(see below)
Choice of Treatment choice should be guided by local/national policies.
oral antico- NOACs are licensed for use in patients with non-valvular AF and at least
agulant one stroke risk factor; therefore in patients with valvular disease,
warfarin would be the appropriate oral anticoagulant.
NOACs are renally excreted and are contraindicated in patients with
significant renal impairment (creatinine clearance <30 mL/min for
dabigatran and <15 mL/min for apixaban and rivaroxaban).
In England, warfarin or an NOAC would be suitable first-line options in
most patients. The decision about whether to start treatment with
k warfarin or an NOAC should be made after an informed discussion k
between the patient and the clinician about the relative risks and
benefits of each agent.
All patients starting anticoagulants should receive an anticoagulant
therapy card and be counselled fully on the use of the drug
Warfarin1 When warfarin is used for stroke prevention in atrial fibrillation (SPAF),
the desirable INR range is 2–3. Most strokes occur when the INR is less
than 2.0. After the initial 3 months of treatment, consider changing to an
NOAC (if indicated) in patients with poor anticoagulant control
(following a review of the cause), defined as:
● Two INR values higher than 5.0 or one INR value higher than 8.0
within the last 6 months
● Two INR values less than 1.5 within the past 6 months
● Time in therapeutic range: less than 65%
Apixaban3 Usual dose for SPAF is 5 mg twice daily, reduced to 2.5 mg twice daily if
two or more of the following are present: age >80 years, body weight
<60 kg or serum creatinine >133 micromol/L. Patients with creatinine
clearance between 15 and 29 mL/min should also have the dose reduced
to 2.5 mg twice daily
Contraindicated in patients taking ketoconazole, itraconazole,
voriconazole, posaconazole and HIV protease inhibitors
k
k
Dabigatran3 Usual dose for SPAF is 150 mg twice daily, reduced to 110 mg twice A
daily in patients aged >80 years and in those taking verapamil. Dose
reduction should also be considered when the thromboembolic risk is
low and the bleeding risk is high, if the patient weighs <50 kg or in
patients with gastritis, oesophagitis or gastroesophageal reflux.
Contraindicated in patients taking ketoconazole, itraconazole,
dronedarone, tacrolimus and ciclosporin
Rivaroxaban3 Usual dose for SPAF is 20 mg once daily, reduced to 15 mg daily in
patients with a creatinine clearance between 15 and 49 mL/min.
Contraindicated with ketoconazole, itraconazole, voriconazole,
posaconazole, dronedarone and HIV protease inhibitors
Anticoagulant ● Avoid the combination of antiplatelet and anticoagulant in most
plus patients due to increased bleeding risk
antiplatelet ● Consider combining warfarin and aspirin in patients who have
combination4 had an MI and have had it managed medically, have undergone
balloon angioplasty or have undergone coronary artery bypass graft
surgery
● Consider combining warfarin with clopidogrel in patients who have
had an MI and have undergone percutaneous coronary
intervention with bare metal or drug-eluting stents
● After 12 months, review the continued need for antiplatelet therapy
Rate ● Offer rate control as the first-line strategy for most patients
control1,2 presenting with AF (see rhythm control section below for
exceptions)
Initial monotherapy should be with a standard beta-blocker (not
k k
●
sotalol) or a rate-limiting calcium-channel blocker (verapamil or

diltiazem)
● Only consider digoxin monotherapy in sedentary patients or those
presenting with significant pulmonary oedema/acute heart failure
symptoms
If monotherapy does not control symptoms, and if continuing
symptoms are thought to be due to poor ventricular rate control,
combine any two of the following:
● beta-blocker
● rate-limiting calcium-channel blocker (but not verapamil and
beta-blocker due to the risk of heart block)
● digoxin
Avoid routine use of amiodarone for long-term rate control due to the
risk of side effects
k
k
A Rhythm Consider rhythm control for patients: with a reversible cause for their
control1 AF (e.g. acute infection), heart failure thought to be primarily due to
their AF, new-onset AF (less than 48 hours’ duration), with atrial flutter
suitable for ablation therapy or if a rhythm control strategy is the
preferred clinical option.
Cardioversion may be pharmacological (if AF is present for less than
48 hours) with intravenous flecainide (if no IHD, structural heart
disease or CHF) or intravenous amiodarone, or electrical.
In patients with AF greater than 48 hours’ (or uncertain) duration,
therapeutic anticoagulation (with warfarin or an NOAC) should be
given for at least 3 weeks before cardioversion or TOE-guided
cardioversion (to rule out the presence of thrombus). Continuation of
anticoagulation postcardioversion depends on overall stroke risk but
should be for at least 4 weeks.
Amiodarone may be used for 4 weeks before elective cardioversion
and continued for up to 1 year to increase the success rate.1
Standard beta-blockers are the first-line choice for long-term rhythm
control. If beta-blockers are contraindicated or unsuccessful, consider:
● flecainide or propafenone if no IHD, structural heart disease or CHF
● dronedarone if no left ventricular systolic dysfunction (LVSD) or
CHF present
● amiodarone if LVSD or CHF is present
Pill in the May be suitable for some patients with a history of paroxysmal AF. The
pocket1,5 patient does not take regular antiarrhythmic therapy but is given a
single dose to use if the AF recurs. Standard agents are flecainide
k (300 mg for patients over 70 kg, 200 mg if below 70 kg) and k
propafenone (600 mg for patients above 70 kg, 450 mg if below
70 kg). Consider for patients who have no history of LVSD, valvular
disease or IHD and have a history of infrequent paroxysms of AF and
are not haemodynamically compromised during an episode of AF.
Advise the patient to take the drug if AF persists beyond 5 minutes and
go to hospital if the AF does not revert within 6–8 hours or if they
develop new symptoms such as dyspnoea or presyncope. They should
be advised to take no more than one dose in 24 hours. Following an
episode they should see their general practitioner for a cardiology
referral
Continued ● In those with a CHA2 DS2 VASc score of 0, reassess the need for
monitoring anticoagulation periodically
● For those on warfarin, assess level of anticoagulant control
● For those on NOACs, check renal function annually
● If using amiodarone, warn the patient about photosensitivity and
possible effect on night vision. Advise patients to use
high-ultraviolet sun blocks. Thyroid function tests should be made
before commencing treatment, then every 6 months until off
amiodarone for a year
● Avoid hypokalaemia if antiarrhythmic drugs are used
REFERENCES
1 NICE (2014) NICE Clinical Guideline 180. Atrial Fibrillation: The management of
Atrial Fibrillation. http://www.nice.org.uk/guidance/cg180 (accessed 11 November
2014).
k
k
2 Camm AJ et al. (2012). 2012 focussed update of the ESC Guidelines for the man-
agement of atrial fibrillation. Eur Heart J 33: 2719–2747.
A
3 eMC (2014). http://www.medicines.org.uk/emc/ (accessed 11 November 2014).
4 NICE (2013) NICE Clinical Guideline 172. MI-secondary prevention: Secondary pre-
vention in primary and secondary care for patients following a myocardial infarction.
http://www.nice.org.uk/guidance/cg172 (accessed 11 November 2014).
5 Alboni P et al. (2004). Outpatient treatment of recent-onset atrial fibrillation with
the ‘pill-in-the-pocket’ approach. N Engl J Med 351: 2384–2391.
k k
k
k
54 Bariatric surgery
B
B
Bariatric surgery
Patients undergoing bariatric surgery are highly complex and require
pharmacist input to ensure safety of medicines administration.
Pharmacy has an important role to play in the care and management
of bariatric patients both pre- and postoperatively in view of
anatomical changes that occur as a result of this type of surgery,
which can affect the absorption and metabolism of medication.
Examples of bariatric surgery include:1
● gastric balloon: the placement of a balloon inside the stomach via

endoscopy, reducing the overall stomach capacity
● gastric banding: an adjustable band is fitted around the top of the
stomach, creating a small pouch, thus reducing the amount of food
that may be consumed
● sleeve gastrectomy: the reduction of stomach size by
k approximately 75% k
● Roux-en-Y bypass: a large section of the stomach and duodenum is
bypassed. The remaining stomach is attached to the small intestine,
creating a small pouch, reducing possible food consumption and fat
absorption.
A member of the pharmacy team should complete medicines
reconciliation at preoperative assessment; regular medication should
be reviewed, taking into consideration any modified anatomy that
may result in altered absorption and bioavailability of medication.
To aid the healing process and encourage drug absorption, the
formulation of medication will require amendment to sugar-free
liquid preparations where possible, or crushing tablets/opening
capsules for 6 –8 weeks postsurgery.
Postsurgery, the patient’s stomach pouch capacity is reduced to
approximately 50 –70 mL, which can cause problems when
administering medication in a liquid form, as the patient will feel full.
The altered anatomy also results in a change in pharmacokinetic and
pharmacodynamic profiles of some medications; the patient will need
close monitoring for symptoms of under- and overdosing. The patient
should be clinically reviewed postoperatively and counselled prior to
discharge, ensuring that the GP is aware of all pharmaceutical issues,
both long- and short-term.
k
k
Bariatric surgery 55
Cost implications
Bariatric surgery is a costly intervention; however, weight loss may
improve comorbidities such as diabetes or hypertension, resulting in B
reduced polypharmacy and medication costs. Liquid preparations
may need to be sourced from ‘specials’ manufacturers; this can be
expensive, but these are not required long-term, and should be
reviewed at the 6 –8-week follow-up.
Medicines Complete at preassessment clinic to enable appropriate, timely
reconciliation advice and recommendations pre- and postoperatively. Counsel
the patient regarding potential changes to regular medications,
including information on what additional medications will be
prescribed on discharge
Smoking status If the patient is currently smoking the operation may be
cancelled due to increased risks of complications
Medicines Additional counselling may be required if adherence is an issue,
adherence as postoperative supplements must be taken lifelong. Patients
using a compliance aid will require extra support as they may
struggle with crushing tablets and measuring liquid
preparations. Involve families and carers in discussions where
possible. A medication reminder chart will be required;
consider pictures if necessary
Medication review Review regular medications for risk and withhold if appropriate
k preassessment clinic as per local guidelines for surgical procedures. Review for
necessity postoperatively and stop where appropriate, e.g.
k
regular laxatives should be stopped as they are contraindicated
immediately postoperatively in this group of patients
Liquid preparations Where possible, liquids should be sugar-free to avoid dumping
syndrome (a group of symptoms that occur when food is
emptied too quickly from the stomach). Liquids containing
fructose, glucose and sucrose are not classed as sugar-free;
those containing mannitol, sorbitol and hydrogenated glucose
syrup are sugar-free.2
Consider total volume of any liquids required due to pouch
capacity restrictions; administration times may need to be
distributed throughout the day to reduce volume. On converting
to liquid preparations, consider bioavailability differences
between formulations that may require dosage adjustment.
‘Specials’ may need to be sourced if tablets/capsules cannot be
crushed/opened; consider how future supplies may need to be
obtained by the patient and whether the community
pharmacist needs informing of supplier/formulation details
Crushed Prescribers should be aware that this is an unlicensed use. Use
tablets/opened appropriate reference sources or contact manufacturer for
capsules advice. Consider any issues associated with medication once in
powder form, such as stability of the drug and third-party
contact
k
k
56 Bariatric surgery
Modified-release Unsuitable postoperatively, due to altered gastrointestinal (GI)

preparations tract anatomy. Convert to immediate-release preparations or
B consider alternatives. Consultant may need to be involved in
this process due to disease instability; for example, respiratory,
psychiatry and gastroenterology
Chronic pain relief Patients should see their GP for alternatives to modified-release
preparations before the surgery date to ensure adequate pain
control; options include converting morphine sulfate
modified-release to an immediate-release preparation or
fentanyl patches.
Non-steroidal anti-inflammatory drugs are contraindicated in
this group of patients due to site of absorption and increased
risk of bleeding and ulceration.
Consider involvement of specialist pain team for postoperative
acute pain management
Soluble/effervescent Avoid due to the high salt content of soluble tablets and risk of
medicines stomach bloating with effervescent tablets
Management of Specialist diabetes team must be involved postoperatively as
diabetes dosing requirements will alter dramatically with changes to
diet and the frequency of food intake. Blood glucose
concentrations must be regularly monitored.
● Type I: require close monitoring and adjustment of insulin
once sliding scale has discontinued
● Type II: diabetes medication should be stopped
postoperatively; this may be represcribed at appropriately
k reviewed doses dependent on blood glucose concentration. k
Dipeptidyl peptidase-4 inhibitors and glucagon-like
peptide-1 agonists should be used with caution due to
satiety
Venous As per local policy for venous thromboembolism prophylaxis.
thromboembolism Consider duration of 7–10 days postoperatively due to
prophylaxis increased risk factors
Gastroprotection Prescribe an oro-dispersible proton pump inhibitor for
3 months (6 months for balloon patients, i.e. for the duration of
the balloon’s placement)
Supplements Due to malabsorption, these patients will inevitably develop
deficiencies in vitamins and minerals, such as calcium, vitamin
D, vitamin B12 and iron. Lifelong supplementation is therefore
recommended and should be given to all patients
Antiemetics Gastric balloon patients require antiemetics – possibly a
combination of two for the first few days postinsertion
REFERENCES
1 Dent M et al. (2010). Bariatric Surgery for Obesity. Oxford: National Obesity
Observatory.
2 NICE (2013). NICE Guideline PH47. Managing overweight and obesity among
children and young people: lifestyle and weight management services. http://
www.nice.org.uk/guidance/ph47 (accessed 20 August 2014).
k
k
Benzodiazepines and ‘z’ hypnotics 57
Benzodiazepines and ‘z’ hypnotics

Benzodiazepines are generally divided by half-life: short-half-life B
agents are anxiolytics, e.g. lorazepam, and longer half-life agents are
hypnotics, e.g. temazepam. They and ‘z’ hypnotics (zaleplon,
zolpidem and zopiclone) are usually effective, safe and well tolerated;
however, long-term use can lead to dependence and withdrawal,
especially with shorter-half-life agents.
Considerations
Classification under the Misuse of Drugs Act 1971 will dictate storage
and documentation.1 Legislation pertaining to driving whilst using
these agents needs to be considered.2
They should only be used on a short-term (and ideally
intermittent) basis, where function is significantly compromised
despite identification and mitigation of any physical or psychological
contributing factors.3 Non-pharmacological measures (e.g. sleep
hygiene4 or cognitive behavioural therapy-type psychological
education) should always be used concomitantly.3,5
There is little to differentiate between short-acting
benzodiazepines and the ‘z’ hypnotics, so the lowest acquisition cost
should drive choice.6 Shorter-acting agents may be better for people
who have difficulty initiating sleep and longer-acting agents for
people who have difficulty staying asleep.5 Switching between
k hypnotics should not occur due to lack of efficacy, but may occur if an k
agent-specific adverse effect occurs.
Withdrawal
Benzodiazepine withdrawal symptoms are unpleasant and potentially
dangerous. They can start within a few hours, or be delayed for a few
weeks, after benzodiazepine cessation. They may manifest as
stiffness, weakness, gastrointestinal disturbances, insomnia, anxiety,
depression, appetite loss, tremor, perspiration, tinnitus, confusion,
psychosis, convulsions or a condition resembling delirium tremens.1,5
A withdrawal regimen from benzodiazepines usually consists of
switching to an equivalent dose of diazepam, and then decreasing the
total daily dose by roughly one-eighth every fortnight.1
Diazepam is the drug of choice due to its relatively long half-life
(it can be given once daily if tolerated) and range of available forms
and strengths.5,6 The withdrawal regimen is normally negotiated and
agreed in advance; the rate of withdrawal and dose decrease
increments are determined by clinical presentation and the person’s
ability to cope with the withdrawal symptoms, or anticipation of
those symptoms.
Concomitant psychological interventions (e.g. relaxation or
cognitive behavioural therapy) increase the likelihood of successful
withdrawal.5,6 Withdrawal is less likely to succeed if previous
attempts have failed, there is a lack of social support, there is a history
of substance use, in the older adult, if there has been previous severe
k
k
58 Benzodiazepines and ‘z’ hypnotics
TABLE B1
Oral benzodiazepine dose equivalents
B Approximate equivalent oral dose to 5 mg oral diazepam1,5,7,8
Benzodiazepine Equivalent oral dose
Alprazolam 0.5 mg (range 0.25–0.5 mg)
Chlordiazepoxide 15 mg (range 10–25 mg)
Clobazam 10 mg
Clonazepam 0.5–1 mg (range 0.25–4 mg)
Loprazolam 0.5–1 mg
Lorazepam 0.5–1 mg
Lormetazepam 0.5–1 mg
Nitrazepam 5 mg (range 2.5–20 mg)
Oxazepam 15 mg (range 10–40 mg)
Temazepam 10 mg
Zaleplon 10 mg
Zolpidem 10 mg
Zopiclone 7.5 mg
withdrawal (including seizures), a concomitant severe physical or

mental illness or previous higher-dose/longer-term use.5,6
Equivalent doses
Equivalent doses are approximate. Calculations may be complicated
k by the half-lives of the different agents and their sedative potential.
k
Calculated doses should always be checked against the SPC so
unlicensed doses are not inadvertently used.
REFERENCES
2 Guidance for Health Professionals on Drug Driving. https://www.gov.uk/government/
uploads/system/uploads/attachment data/file/325275/healthcare-profs-drug
-driving.pdf (accessed on 17 August 2014).
3 NICE (2011). Clinical Guidance 113. Generalised anxiety disorder and panic disorder
(with or without agoraphobia) in adults. http://www.nice.org.uk/guidance/cg113
(accessed 17 August 2014).
4 NHS Choices (2013). Treating Insomnia. http://www.nhs.uk/Conditions/Insomnia/
Pages/Treatment.aspx (accessed 17 August 2014).
5 Taylor D et al. (2012). The Maudsley Prescribing Guidelines in Psychiatry, 11th edn.
6 NICE (2004). Technology Appraisal 77. Guidance on the use of zaleplon,
zolpidem and zopiclone for the short-term management of insomnia.
http://www.nice.org.uk/guidance/ta77 (accessed 17 August 2014).
7 Bazire S (2014). Psychotropic Drug Directory 2014: The professionals’ pocket hand-
book and aide memoire. Dorsington: Lloyd-Reinhold.
8 Ashton C (2002). Benzodiazepines: How they work and how to withdraw (aka The
Ashton Manual). http://www.benzo.org.uk/manual/index.htm (accessed 17 August
2014).
k
k
Bicarbonate 59
Bicarbonate
Normal range for serum bicarbonate: 20 –30 mmol/L B
Local range . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Sodium bicarbonate is a buffer which breaks down to water and
carbon dioxide after combining with hydrogen ions. It is reabsorbed
in the kidneys following glomerular filtration and this action is
balanced by the excretion of hydrogen ions to maintain the
systemic pH. A blood pH <7.35 is classified as acidosis and a blood
pH >7.45 is classified as alkalosis. In acidosis there is an increase in
hydrogen ions or a reduction in bicarbonate ions in circulation, and in
alkalosis there is an increase in bicarbonate ions or a decrease in
hydrogen ions in circulation.1
In metabolic disorders the primary abnormality is a change in the
serum bicarbonate concentration.2
Causes of metabolic acidosis include:
● increased acid production, which occurs in lactic acidosis or
diabetic ketoacidosis (DKA), and also in salicylic intoxication,
methanol and ethylene glycol ingestion
● decreased acid excretion, which occurs in renal failure and distal
renal tubular acidosis (type 1)
● loss of bicarbonate from the GI tract through severe diarrhoea or
fistula or by renal loss (proximal renal tubular acidosis type 2).
k k
Causes of metabolic alkalosis include:
● loss of hydrogen ions – either from the GI tract or by renal losses
● excessive alkali administration – occurs during ingestion of large
amounts of alkali, e.g. milk alkali syndrome, or when large
amounts of bicarbonate are given.2
In most cases of metabolic alkalosis or acidosis, the lungs compensate
for the change in serum bicarbonate by increasing or decreasing
respiratory drive to change the blood carbon dioxide concentration.
Potassium is moved out of cells in an attempt to buffer the acidosis
and so hyperkalaemia may occur.1
Treatment depends on the severity, underlying cause and speed of
response to interventions.
Oral sodium bicarbonate3
Sodium bicarbonate is used orally in patients with chronic acidotic
states such as uraemic acidosis or renal tubular acidosis. For the
correction of metabolic acidosis, a starting dose of 500 mg to 1 g three
times daily may be given, but doses of 4.8 g daily or more may be
required based on the patient’s response. Patients on long-term
prescribed therapy are usually under the care of a specialist.
Oral sodium bicarbonate may be used to alkalinise the urine for
the relief of discomfort in mild urinary-tract infections. The initial
dose is 3 g in water every 2 hours until urinary pH exceeds 7; for the
maintenance of alkaline urine, 5 –10 g daily is sufficient.
k
k
60 Bicarbonate
Sodium bicarbonate alone is not routinely recommended for the

treatment of dyspepsia but is still found in many antacid preparations.
B As such, many patients may self-medicate with considerable
quantities and this should be borne in mind when taking a medication
history. Common side effects include belching and there is a risk of
alkalosis with prolonged use.3
Intravenous sodium bicarbonate
In mild metabolic acidosis associated with volume depletion the
patient should be managed with appropriate fluid replacement. This
normally allows the acidosis to resolve as tissue and renal perfusion is
restored.
In severe metabolic acidosis (pH <7.1) or when the acidosis
remains unresponsive to correction of anoxia or hypovolaemia,
sodium bicarbonate 1.26% or 1.4% can be infused over 3 –4 hours
with plasma pH and electrolyte monitoring.4 Because they are
markedly hypertonic, concentrations exceeding 1.4% should always
be given via a central line except in emergency situations.
Sodium bicarbonate 1.26% may be used as a hydration fluid when
it is undesirable to give chloride, for example, in hyperchloraemic
acidosis, but be aware that it is incompatible with calcium- or
magnesium-containing solutions, e.g. Hartmann’s or Ringer’s.4
Sodium bicarbonate may also be used to induce forced alkaline
diuresis.
k Excess bicarbonate may result in metabolic alkalosis, k
hypokalaemia and hypocalcaemia.
Sodium bicarbonate and DKA
Sodium bicarbonate is not routinely recommended to treat acidosis in
DKA as adequate fluid and insulin therapy will resolve the acidosis.
Administration of excessive bicarbonate may lead to a paradoxical
increase in CSF acidosis and delay the fall in blood lactate. There is
also some evidence that bicarbonate treatment may be implicated in
the development of cerebral oedema in children and young adults.5
Sodium bicarbonate in cardiac arrest
For acidosis in cardiac arrest, the best treatment is a combination of
effective chest compression and ventilation. The routine use of
sodium bicarbonate in cardiac arrest, cardiopulmonary resuscitation
or after return of spontaneous circulation is not recommended.
50 mmol of sodium bicarbonate (50 mL of 8.4% solution) may be
given if the cardiac arrest is associated with hyperkalaemia or tricyclic
antidepressant overdose. The dose may be repeated according to the
clinical condition of the patient and the results of repeated blood
gas analysis.6
k
k
TABLE B2
Bicarbonate content of various preparations1
Product Strength Strength Millimoles B
(%) (mmol/L) contained in
this presentation
Sodium bicarbonate capsules 500 mg ≈6 mmol/capsule
Sodium bicarbonate tablets 600 mg ≈7 mmol/tablet
Sodium bicarbonate infusion bag (500 mL) 1.26% 150 mmol/L 75 mmol
Sodium bicarbonate infusion bag (1000 mL) 1.26% 150 mmol/L 150 mmol
Sodium bicarbonate 4.2% 500 mmol/L 5 mmol
Minijet 4.2% 10 mL
Minijet 8.4% 10 mL
Minijet 8.4% 50 mL
Sodium bicarbonate Polyfusor 1.26% 500 mL 1.26% 150 mmol/L 75 mmol
Urine alkalinisation and methotrexate therapy

See separate entry on Methotrexate: calcium folinate rescue regimen.
REFERENCES
1 Doughtery J, Lamb J (eds) (2009). Intravenous Therapy in Nursing Practice,
k 2nd edn. Oxford: Wiley-Blackwell. k
2 Swaminathan R (2011). Handbook of Clinical Biochemistry. New Jersey: World
Scientific.
3 Joint Formulary Committee (2014). British National Formulary (68th edn).
London: BMJ Group and Pharmaceutical Press.
4 Gray A, Wright J, Goodey V, Bruce L (eds) (2011). Injectable Drugs Guide. London:
5 Joint British Diabetic Society Inpatient Care Group (2013). The Management of
Diabetic Ketoacidosis in Adults, 2nd edn. http://www.diabetes.org.uk/Documents/
About%20Us/What%20we%20say/Management-of-DKA-241013.pdf (accessed 14
November 2014).
6 Resuscitation Council UK (2010) Resuscitation Guidelines. http://www.resus.
org.uk/pages/gl2010.pdf (accessed 14 November 2014).
Body surface area calculation

Body surface area (BSA) is employed in some circumstances as a basis
for calculation of drug doses on the premise that drug handling
(renal/liver function) can be related to BSA.1 The evidence for this
relationship is based on old research methods2 and more recent work
throws doubt on this.3
k
k
B
TABLE B3
Body surface area based on the Mosteller formula
Height (cm) Body surface area
200 0.53 0.75 0.91 1.05 1.18 1.29 1.39 1.49 1.58 1.67 1.75 1.83 1.90 1.97 2.04 2.11 2.17 2.24 2.30 2.36 2.42
195 0.52 0.74 0.90 1.04 1.16 1.27 1.38 1.47 1.56 1.65 1.73 1.80 1.88 1.95 2.02 2.08 2.15 2.21 2.27 2.33 2.38
190 0.51 0.73 0.89 1.03 1.15 1.26 1.36 1.45 1.54 1.62 1.70 1.78 1.85 1.92 1.99 2.05 2.12 2.18 2.24 2.30 2.35
185 0.51 0.72 0.88 1.01 1.13 1.24 1.34 1.43 1.52 1.60 1.68 1.76 1.83 1.90 1.96 2.03 2.09 2.15 2.21 2.27 2.32
k
k
180 0.50 0.71 0.87 1.00 1.12 1.22 1.32 1.41 1.50 1.58 1.66 1.73 1.80 1.87 1.94 2.00 2.06 2.12 2.18 2.24 2.29
62 Body surface area calculation
175 0.49 0.70 0.85 0.99 1.10 1.21 1.30 1.39 1.48 1.56 1.64 1.71 1.78 1.84 1.91 1.97 2.03 2.09 2.15 2.20 2.26
170 0.49 0.69 0.84 0.97 1.09 1.19 1.29 1.37 1.46 1.54 1.61 1.68 1.75 1.82 1.88 1.94 2.00 2.06 2.12 2.17 2.23
CPPC c02.tex
165 0.48 0.68 0.83 0.96 1.07 1.17 1.27 1.35 1.44 1.51 1.59 1.66 1.73 1.79 1.85 1.91 1.97 2.03 2.09 2.14 2.19
160 0.47 0.67 0.82 0.94 1.05 1.15 1.25 1.33 1.41 1.49 1.56 1.63 1.70 1.76 1.83 1.89 1.94 2.00 2.05 2.11 2.16
155 0.46 0.66 0.80 0.93 1.04 1.14 1.23 1.31 1.39 1.47 1.54 1.61 1.67 1.74 1.80 1.86 1.91 1.97 2.02 2.07 2.13
150 0.46 0.65 0.79 0.91 1.02 1.12 1.21 1.29 1.37 1.44 1.51 1.58 1.65 1.71 1.77 1.83 1.88 1.94 1.99 2.04 2.09
145 0.45 0.63 0.78 0.90 1.00 1.10 1.19 1.27 1.35 1.42 1.49 1.55 1.62 1.68 1.74 1.80 1.85 1.90 1.96 2.01 2.06
140 0.44 0.62 0.76 0.88 0.99 1.08 1.17 1.25 1.32 1.39 1.46 1.53 1.59 1.65 1.71 1.76 1.82 1.87 1.92 1.97 2.02
135 0.43 0.61 0.75 0.87 0.97 1.06 1.15 1.22 1.30 1.37 1.44 1.50 1.56 1.62 1.68 1.73 1.79 1.84 1.89 1.94 1.98
130 0.42 0.60 0.74 0.85 0.95 1.04 1.12 1.20 1.27 1.34 1.41 1.47 1.53 1.59 1.65 1.70 1.75 1.80 1.85 1.90 1.95
V2 - 11/18/2015 1:45 P.M.
Page 62
k
k
125 0.42 0.59 0.72 0.83 0.93 1.02 1.10 1.18 1.25 1.32 1.38 1.44 1.50 1.56 1.61 1.67 1.72 1.77 1.82 1.86 1.91
120 0.41 0.58 0.71 0.82 0.91 1.00 1.08 1.15 1.22 1.29 1.35 1.41 1.47 1.53 1.58 1.63 1.68 1.73 1.78 1.83 1.87
115 0.40 0.57 0.69 0.80 0.89 0.98 1.06 1.13 1.20 1.26 1.33 1.38 1.44 1.50 1.55 1.60 1.65 1.70 1.74 1.79 1.83
110 0.39 0.55 0.68 0.78 0.87 0.96 1.03 1.11 1.17 1.24 1.30 1.35 1.41 1.46 1.51 1.56 1.61 1.66 1.70 1.75 1.79
105 0.38 0.54 0.66 0.76 0.85 0.94 1.01 1.08 1.15 1.21 1.27 1.32 1.38 1.43 1.48 1.53 1.57 1.62 1.66 1.71 1.75
100 0.37 0.53 0.65 0.75 0.83 0.91 0.99 1.05 1.12 1.18 1.24 1.29 1.34 1.39 1.44 1.49 1.54 1.58 1.62 1.67 1.71
95 0.36 0.51 0.63 0.73 0.81 0.89 0.96 1.03 1.09 1.15 1.20 1.26 1.31 1.36 1.41 1.45 1.50 1.54 1.58 1.62 1.66
90 0.35 0.50 0.61 0.71 0.79 0.87 0.94 1.00 1.06 1.12 1.17 1.22 1.27 1.32 1.37 1.41 1.46 1.50 1.54 1.58 1.62
85 0.34 0.49 0.60 0.69 0.77 0.84 0.91 0.97 1.03 1.09 1.14 1.19 1.24 1.29 1.33 1.37 1.42 1.46 1.50 1.54 1.57
80 0.33 0.47 0.58 0.67 0.75 0.82 0.88 0.94 1.00 1.05 1.11 1.15 1.20 1.25 1.29 1.33 1.37 1.41 1.45 1.49 1.53
75 0.32 0.46 0.56 0.65 0.72 0.79 0.85 0.91 0.97 1.02 1.07 1.12 1.16 1.21 1.25 1.29 1.33 1.37 1.41 1.44 1.48
70 0.31 0.44 0.54 0.62 0.70 0.76 0.82 0.88 0.94 0.99 1.03 1.08 1.12 1.17 1.21 1.25 1.29 1.32 1.36 1.39 1.43
k
k
65 0.30 0.42 0.52 0.60 0.67 0.74 0.79 0.85 0.90 0.95 1.00 1.04 1.08 1.12 1.16 1.20 1.24 1.27 1.31 1.34 1.38
60 0.29 0.41 0.50 0.58 0.65 0.71 0.76 0.82 0.87 0.91 0.96 1.00 1.04 1.08 1.12 1.15 1.19 1.22 1.26 1.29 1.32
55 0.28 0.39 0.48 0.55 0.62 0.68 0.73 0.78 0.83 0.87 0.92 0.96 1.00 1.03 1.07 1.11 1.14 1.17 1.20 1.24 1.27
CPPC c02.tex
50 0.26 0.37 0.46 0.53 0.59 0.65 0.70 0.75 0.79 0.83 0.87 0.91 0.95 0.99 1.02 1.05 1.09 1.12 1.15 1.18 1.21
Weight (kg) 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105
V2 - 11/18/2015 1:45 P.M.
B
Page 63
k
k
64 Body surface area calculation
However, many drugs still require dosing based on BSA and several
formulae exist. Always use the formula approved in your
B organisation. Probably the most frequently used is the Dubois
formula, although the most accurate is the Mosteller formula, which
is based on the Dubois formula (Table B3 provides a range of BSAs for
reference, using the Mosteller formula). Below are alternative
methods of calculating BSA supported by the identified websites.
The online British National Formulary uses a modified Dubois
formula:4
BSA (m2 ) = 0.007184 × height (cm)0.725 × weight (kg)0.425
The Mosteller formula is:5
BSA (m2 ) = ([height (cm) × weight (kg)]/3600) /2
1
Other formulae include:

The Haycock formula:6
The Gehan and George formula:7
The Boyd formula:8
BSA(m2 ) = 0.0003207 × height (cm)0.3
k × weight (grams)(0.7285−(0.0188 × log (grams)) k
REFERENCES
1 Vu TT (2002). Standardisation of body surface area calculations. J Oncol Pharm
Practice 8: 49–54.
2 Macintosh JF et al. (1928). Studies of urea excretion: the influence of body size on
urea output. J Clin Invest 6: 467.
3 Dooley MJ, Poole SJ (2000). Correlation between body surface area and glomerular
filtration rate. Cancer Chemo Pharmacol 46: 523–526.
4 Wang Y et al. (1992). Predictors of body surface area. J Clin Anesth 4: 4–10.
5 Mosteller RD (1987). Simplified calculation of body surface area. N Engl J Med 317:
1098 (letter).
6 Haycock GB et al. (1978). Geometric method for measuring body surface area:
A height weight formula validated in infants, children and adults. J Pediatr 93:
62–66.
7 Gehan EA, George SL (1970). Estimation of human body surface area from height
and weight. Cancer Chemother Rep 54: 225–235.
8 Boyd E (1935). The Growth of the Surface Area of the Human Body. Minneapolis:
University of Minnesota Press.
k
k
Bronchiectasis (non-cystic fibrosis)

B
Overview
Definition Bronchiectasis is the irreversible and abnormal dilation of one or more
bronchi and/or bronchioles.1 – 3 The abnormal pathology impairs normal
mucociliary clearance, which sets up a vicious cycle of infection,
inflammation and further airway damage. The affected airways can
become ulcerated and haemoptysis, occasionally massive, may occur.
Bronchiectasis occurs in cystic fibrosis (CF) but is often seen in other
conditions. Where CF has been excluded, this is referred to as non-CF
bronchiectasis.
The presentation is typically one of chronic production of purulent
sputum associated with cough and recurrent chest infections.
As for CF, the usual order of infections is:
● Staphylococcus aureus (including methicillin-resistant Staphylococcus
aureus)
● Haemophilus influenzae
● Moraxella catarrhalis
● Pseudomonas species
Colonisation with Pseudomonas spp. is associated with accelerated
decline in lung function and a worsening prognosis
Risk factors ● Recurrent respiratory infection
● Childhood
Diagnostic The diagnosis is made on clinical grounds with a high-resolution
k tests computed tomography (HRCT) of the lungs for confirmation (and to rule k
out malignancy in patients with haemoptysis).
A number of disease processes may result in bronchiectasis and
identifying the underlying aetiology may significantly alter the approach
to management.
● Bronchiectasis is hard to identify on a chest X-ray unless it is severe
and an HRCT is generally required to confirm the diagnosis
● CF should be ruled out. The BTS recommends screening sweat
chloride and for genetic mutations in the CF transmembrane regular
(CFTR) gene in all patients ≤40 years and in those older than this
without an identifiable cause1
● Congenital abnormalities of ciliary function (such as primary ciliary
dyskinesia/Kartagener’s syndrome) may be the underlying cause. This
is often associated with recurrent upper respiratory tract infections
and otitis media. Ciliary function can be assessed using the saccharin
test (time taken for a sample of saccharin placed in the nose to be
tasted) or exhaled nitric oxide test
● Sputum samples should be sent to identify infectious organisms,
including atypical organisms, Mycobacteria spp. (including
non-tuberculous mycobacteria – NTM) and Aspergillus spp.
● Aspergillus – specific IgE and IgG immunology screen for allergic
bronchopulmonary aspergillosis (ABPA) as an underlying cause
k
k
66 Bronchiectasis (non-cystic fibrosis)
● Antibody deficiency should be considered, and IgG, IgA and IgM

● Immunodeficiency secondary to HIV, haematological malignancy or
B nephrotic syndrome should be considered
● Pharmacological immunosuppression is a recognised cause of
bronchiectasis, with mycophenolate and other agents increasingly
recognised as a cause of bronchiectasis
● Airway damage due to gastro-oesophageal reflux and aspiration may
have a role and should be considered in those with a history of reflux
symptoms
Treatment ● Identify and manage underlying cause
goals ● Prevent and manage infections
Treatment ● Patient should be taught airway clearance techniques (by respiratory
options physiotherapist) to mobilise and clear secretions
● Regular vaccination against: influenza, pneumococcus and
H. influenzae
Assess ● Are immunosuppressive treatments contributing to the development
of the condition and if so, can an alternative regimen be considered?
Mucolytics ● The role of mucolytics to facilitate expectoration of secretions is
unclear. Nebulised hypertonic NaCl (6% or 7%) and carbocisteine are
commonly used in conjunction with regular airway clearance. Regular
nebulised dornase alpha has been shown to be harmful in non-CF
bronchiectasis (in contrast to that associated with CF) and should not
routinely be used4
k ABPA ● All patients with bronchiectasis should be assessed for evidence of k
ABPA using an appropriate immunological test, such as
Aspergillus-specific IgE and IgG assay
● ABPA is associated with an excessive immune response and can by
managed with corticosteroids ± antifungals (itraconazole,
voriconazole or posaconazole under specialist advice)
Primary ● Primary immunodeficiency should be managed in conjunction with an
immune immunologist and patients may benefit from regular infusions of
deficiency immunoglobulins
● Patients with immunodeficiencies who receive vaccination against
influenza, pneumococcus and H. influenzae should have their
antibody response checked 21 days after vaccination
NTM ● Treatment as per BTS guidelines, generally involving a combination of
active antibiotics1
Exacerbations ● Prompt identification and management of infections, typically with a
minimum of 14 days’ treatment, are recommended. Choice of
antibiotic should be based on known or suspected organism, local
resistance patterns and patient-specific factors, such as: allergy
status, potential for interactions with current medications and
renal/hepatic function
● Patients having ≥3 exacerbations per year may benefit from
antimicrobial prophylaxis. Azithromycin 250 mg daily or 500 mg three
times weekly and twice-daily erythromycin have been evaluated in
clinical trials (BAT5 , BLESS6 and EMBRACE7 )
k
k
● If considering long-term antibacterial prophylaxis, it is important to

exclude NTM infection as use of a single-agent macrolide may result
in resistance in the organism and further complicate subsequent B
treatment
● Consider periodically checking QTc interval, audiometry and hepatic
function in patients on long-term azithromycin
Pseudomonal ● In patients who have Pseudomonas aeruginosa isolated for the first
infection time, an attempt at eradication should be considered. The BTS
recommends an initial 2-week course of ciprofloxacin 750 mg twice
daily and, if unsuccessful either:
(i) 2 weeks of intravenous antipseudomonal antibiotics or
(ii) 4 weeks of ciprofloxacin 750 mg twice daily + 3 months’
nebulised colistimethate 2 mega units twice daily or
(iii) 3 months’ nebulised colistimethate 2 mega units twice daily
● Where eradication of P. aeruginosa cannot be achieved, nebulised
antipseudomonal antibiotics may be considered as prophylaxis –
typically colistimethate, tobramycin or gentamicin
● For patients experiencing an exacerbation due to P. aeruginosa, a
14-day course of intravenous antipseudomonal antibiotic is generally
required. This often requires hospital admission, although Outpatient
Parenteral Antibiotic Therapy (OPAT) services, if available and
appropriate, may allow treatment outside of the hospital setting
Nebulised ● A range of antibiotics may be administered for the treatment of
antibiotics infections in non-CF bronchiectasis. Nebulised antibiotics may cause
bronchospasm and patients should have a supervised test dose with
k pre- and postdose spirometry
k
REFERENCES
1 Pasteur MC et al. (2010). British Thoracic Society guideline for non-CF
bronchiectasis. Thorax 65(Suppl 1): i1–58.
2 McShane PJ et al. (2013). Non-cystic fibrosis bronchiectasis. Am J Respir Crit Care
Med 188: 647–656.
3 Barker AF (2002). Bronchiectasis. N Engl J Med 346: 1383–1983.
4 O’Donnell AE et al. (1998). Treatment of idiopathic bronchiectasis with aerosolized
recombinant DNAse I. Chest 113: 1329–1334.
5 Altenburg J et al. (2013). Effect of azithromycin maintenance treatment on infec-
tious exacerbation among patients with non-cystic fibrosis bronchiectasis: the BAT
randomised controlled trial. JAMA 309: 1251–1259.
6 Serisier DJ et al. (2013). Effect of long-term, low-dose erythromycin on pulmonary
exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS
randomised controlled trial. JAMA 309: 1260–1267.
7 Wong C et al. (2012). Azithromycin for prevention of exacerbation in non-cystic
fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled
trial. Lancet 380: 660–667.
k
k
68 Calcium
C C
Calcium
Overview
Normal Normal range (‘corrected’, if appropriate): 2.1–2.6mmol/L1
range
Local range
Background ● Calcium is the most abundant mineral in the body. It is required for
bone and tooth formation, and as an essential electrolyte
Reference 17.5 mmol/day (700 mg)
nutrient
intake1
Corrected Approximately 40–50% of calcium present in serum is bound to plasma
k calcium proteins, particularly albumin. Since only free calcium ions are active, the
total calcium measured in the serum is adjusted to account for the bound
k
ions. This is called the corrected calcium. Commonly used formulae to
calculate corrected calcium, in mmol/L, are:
● If albumin is <40 g/L,
Corrected calcium = serum calcium level
+ ((40 − serum albumin level) × 0.02)
● If albumin concentration is 40–45 g/L, no adjustment is necessary

● If albumin is >45 g/L,
Corrected calcium = serum calcium level
− ((serum albumin level − 45) × 0.02))
Hypercalcaemia
Symptoms ● Symptoms include thirst, polyuria, anorexia, constipation, muscle
weakness, fatigue and confusion. In severe cases there may be
nausea and vomiting and, rarely, cardiac arrhythmias. Extreme
hypercalcaemia may result in coma and death. Chronic hyper-
calcaemia can lead to interstitial nephritis and calcium renal calculi
Causes ● Primary hyperparathyroidism
● Malignant disease
● Less commonly: granulomatous diseases, e.g. sarcoidosis, familial
benign hypercalcaemia and renal failure
● Drug causes include vitamin D intoxication (N.B. the duration of
action of ergocalciferol injection is about 2 months), calcium
supplements (+/− vitamin D) and thiazide diuretics (by reducing
urinary excretion of calcium). Check use of OTC osteoporosis
supplements and antacids as a cause of milk-alkali syndrome
k
k
Calcium 69
Treatment ● Mild hypercalcaemia is best corrected by increasing oral fluid intake,

and then identifying and treating any underlying aetiology
● Remember to stop implicated drugs
● If hypercalcaemia is severe, the first step is to rehydrate the patient C
with NaCl 0.9% (avoid calcium-containing fluids) to maintain
intravascular volume and promote calcium diuresis. N.B. Normal adult
fluid requirements are generally about 40 mL/kg/24 hours
● Furosemide may be used to increase urinary calcium excretion at
doses of 80–100 mg intravenously. Give every 1–2 hours as required,
taking care to maintain fluid balance
● Bisphosphonates are usually an effective treatment for
tumour-induced hypercalcaemia. A significant fall in serum Ca is
generally seen within 24–48 hours of initial IV administration; the full
effect may not be seen for 3–7 days so be guided by the individual
product SPC and avoid dosing again too early2
● As an adjunct to the treatment of hypercalcaemia, calcitonins can
have a rapid effect, particularly in patients with an increased bone
turnover.1 If other measures fail, calcitonin (salmon) is licensed for
the treatment of hypercalcaemia of malignancy given at an initial
dose of 100 units every 6–8 hours by SC or IM injection, but nausea
and vomiting can be problematic. If tolerated, the dose may be
gradually increased after 1–2 days to a maximum dose of 400 units
every 6–8 hours if necessary3
● In the emergency treatment of hypercalcaemia, calcitonin (salmon)
has also been used intravenously at a dose of up to 10 units/kg
diluted in 500 mL of sodium chloride 0.9% and given by slow IV
infusion over at least 6 hours3
k k
Hypocalcaemia
Symptoms ● Increased neuromuscular excitability, e.g. paraesthesias, carpopedal
spasm, muscle cramps, tetany and convulsions; ECG changes; and
mental disturbances, e.g. irritability and depression
Causes ● Impaired or reduced absorption from the gastrointestinal tract, e.g. in
vitamin D-deficiency disorders
● Chronic renal failure
● Deficient parathyroid hormone secretion
● Post thyroid or parathyroid surgery
● Excessive phosphate administration
Assessment ● Measure: urea U, Cr, CrCl (or eGFR), serum Ca, serum Mg
● ECG
● IV calcium should generally be avoided in patients receiving cardiac
glycosides because of the risk of the development of potentially
life-threatening digitalis-induced arrhythmias4
● Do not use IV for hypocalcaemia caused by renal impairment
● Do not use in conditions associated with hypercalcaemia and
hypercalciuria (e.g. some forms of malignant disease) and in severe
renal impairment
● Use with caution in patients with mild-to-moderate renal impairment,
cardiac disease, sarcoidosis, respiratory acidosis or respiratory failure
Treatment ● Any underlying disease should be identified and managed. Oral
calcium supplements are commonly used
● Vitamin D-deficiency disorders and hypoparathyroidism are corrected
with vitamin D supplements, sometimes in combination with calcium
salts
k
k
70 Calcium
Parenteral Calcium salts are irritant and may cause tissue necrosis and sloughing if
treatment1 given via the IM or SC route. Calcium chloride is more irritant than
calcium gluconate when given IV, although both may cause irritation and
C should be given with care to avoid extravasation.
Acute hypocalcaemia: 2.25 mmol (calcium gluconate 10% injection
10 mL) by slow IV injection over a minimum of 3 minutes.
In tetany this should be followed by 9 mmol (calcium gluconate 10%
injection 40 mL) in 500 mL sodium chloride 0.9% or glucose 5% by IV
infusion daily over 8–24 hours with frequent monitoring of serum Ca
and Mg. Smaller volumes may be used in fluid restriction.
An alternative regimen is to give 22.5 mmol Ca (calcium gluconate 10%
injection 100 mL) in 1 litre of sodium chloride 0.9% or glucose 5%
solution by IV infusion at an initial rate of 50 mL/hour. Adjust the rate of
infusion according to 4–6-hourly serum Ca and Mg measurements
Oral Calcium supplements should be taken 3–4 hours after the following
supplements drugs to avoid reduced gastrointestinal absorption:5
● levothyroxine
● bisphosphonates
● iron supplements
● sodium fluoride
● quinolones and tetracyclines (apart from doxycycline)
Calcium supplements should not be given within 1 hour of enteric-coated
preparations.
Calcium supplements are usually only required where dietary calcium
intake is deficient.5 Dietary requirement varies with age and is relatively
k greater in childhood, pregnancy and lactation, due to an increased
k
demand, and in old age, due to impaired absorption. In osteoporosis, a
calcium intake of approximately 1400 mg (which is double the
recommended daily amount) is given in combination with vitamin D,
which reduces the rate of bone loss. Flavour, dose volume and texture
are important factors in patient acceptance and adherence with therapy
TABLE C1
Calcium content of various oral preparations
Product Calcium content5
Calcium gluconate tablets 53.4 mg (1.35 mmol)
Calcium gluconate effervescent tablets 89 mg (2.25 mmol)
Calcium lactate tablets 39 mg (1 mmol)
Adcal tablets 600 mg (15 mmol)
Cacit tablets 500 mg (12.6 mmol)
Calcichew tablets 500 mg (12.6 mmol)
Calcichew Forte tablets 1 g (25 mmol)
Calcium-500 tablets 500 mg (12.6 mmol)
Calcium Sandoz syrup 108.3 mg/5 mL (2.7 mmol/5 mL)
Sandocal-1000 tablets 1 g (25 mmol)
k
k
Carbamazepine 71
TABLE C2
Calcium content of various parenteral preparations
Calcium gluconate 10% injection 8.9 mg/mL (225 micromol/mL) C
Calcium chloride 10% injection 27.3 mg/mL (680 micromol/mL)
Calcium chloride 13.4% injection 36 mg/mL (910 micromol/mL)
TABLE C3
Calcium content of various oral calcium and vitamin D
preparations
Calcium and ergocalciferol tablets 97 mg (2.4 mmol) + 400 IU ergocalciferol
Accrete D3 tablets 600 mg (15 mmol) + 400 IU ergocalciferol
Adcal D3 tablets 600 mg (15 mmol) + 400 IU colecalciferol
Adcal D3 effervescent tablets 600 mg (15 mmol) + 400 IU colecalciferol
Adcal D3 caplets 300 mg (7.5 mmol) + 200 IU colecalciferol
Cacit D3 granules 500 mg (12.5 mmol) + 440 IU colecalciferol
Calceos tablets 500 mg (12.5 mmol) + 400 IU colecalciferol
Calcichew D3 tablets 500 mg (12.5 mmol) + 200 IU colecalciferol
Calcichew D3 Forte tablets 500 mg (12.5 mmol) + 400 IU colecalciferol
Calcichew D3 500/400 caplets 500 mg (12.5 mmol) + 400 IU colecalciferol
Calfovit D3 powder 1.2 g (30 mmol)/sachet + 800 IU colecalciferol
k k
Kalcipos-D tablets 500 mg (12.5 mmol) + 800 IU colecalciferol
Natecal D3 tablets 600 mg (15 mmol) + 400 IU colecalciferol
REFERENCES
3 SPC (2013). Miacalcic 400 IU/2ml Solution for Injection and Infusion.
www.medicines.org.uk (accessed 5 September 2015).
4 Baxter K (ed.) (2014). Stockley’s Drug Interactions. London: Pharmaceutical Press.
http://www.medicinescomplete.com/ (accessed 3 September 2014).
Carbamazepine
Carbamazepine is licensed for use in the treatment of epilepsy (includ-
ing generalised tonic-clonic and partial seizures), trigeminal neuralgia
and the prophylaxis of bipolar disorders unresponsive to lithium.1
Pharmacokinetic overview
Carbamazepine is almost completely absorbed, albeit slowly from
the gut, and metabolised in the liver.2 Carbamazepine induces its own
metabolism and the half-life is markedly reduced in the first few weeks
k
k
72 Carbamazepine
TABLE C4
Drug monitoring information
Half-life2 25–45 hours (single dose)
C 8–24 hours (chronic dosing)
Pretreatment measures FBC, U&Es, LFTs
Individuals of Han Chinese or Thai origin should be screened
for the HLA-B*1502 allele before starting carbamazepine
treatment because this increases their risk of developing
severe Stevens–Johnson syndrome
Therapeutic range 4–12 mg/L (20–50 micromol/L)1
In bipolar disorders, trough levels >7 mg/L (>29 micromol/L)
are associated with a therapeutic response
Sampling time2 Blood samples should be taken pre-dose. Samples should not
be taken until steady state is achieved, which takes 2–4
weeks after commencing therapy. Further samples can be
taken 4 days after any subsequent dose changes.
Blood should be taken in ‘brown-top’ sample tubes
Other monitoring1 FBC, U&Es, LFTs every 2 weeks for 2 months, then annually
of therapy. Towards the end of the first month of therapy, plasma con-
centration falls by about 25% and the dose may need to be increased
to maintain anticonvulsant effect. It should therefore be initiated at
a low dose, and gradually increased over 1 month to the optimal dose.
k Rationale for monitoring k

The serum concentration of carbamazepine should be checked:
● in epilepsy, if seizure control is poor
● when toxicity is suspected
● if non-compliance is suspected
● to monitor the effects of drug interactions
● to help avoid escalating dose to levels above the usual quoted range
associated with more risk of toxicity.
Bioequivalence
Different brands of oral preparation may vary in bioavailability.
The MHRA guidance3 classifies carbamazepine as a category 1
antiepileptic drug: doctors are advised to ensure that their patient is
maintained on a specific manufacturer’s product in order to avoid
reduced effect or excessive side effects. This does not apply to
indications other than epilepsy.
The bioavailability of the different formulations varies. In the
management of epilepsy the modified-release formulation is
generally preferred. However, the dose of the controlled-release
formulation needs to be slightly higher to achieve the same effect.
One suggested rough guide when moving from one to another is that
approximately 100 mg of standard-release carbamazepine is
equivalent to about 120 –125 mg of the controlled-release
preparation. The bioavailability of the rectal formulation is also lower
than the standard-release oral preparations (Table C5).4
k
k
Carbamazepine 73
TABLE C5
Carbamazepine dose form bioequivalence
Tablet Liquid Suppository
100 mg 100 mg 125 mg C
Toxicity
Signs and symptoms of toxicity include ataxia, blurred vision, nausea
and vomiting, respiratory depression, dizziness, hypotension or
hypertension, cardiac rhythm disturbances, convulsions and
hyponatraemia.
Treatment of overdose
There is no specific antidote, and management is guided by the
patient’s individual condition. Specialist advice should be sought
from a poisons information service, e.g. Toxbase.5
Interactions with other antiepileptics6

Carbamazepine is metabolized by cytochrome P450 3A4, and
therefore any drug that inhibits the action of this enzyme can raise
the plasma concentration of carbamazepine, and any drug that
induces the enzyme can decrease the serum concentration of
carbamazepine. Discontinuing any of these drugs may lead to a
rebound change in carbamazepine serum concentration.
k Antiepileptic drugs that can decrease carbamazepine concentration k
are: phenytoin, phenobarbitone and primidone. Some reports
suggest clonazepam and oxcarbazepine may have the same effect.
Valproic acid may either raise or lower carbamazepine serum
concentration.
Phenytoin serum concentration has been reported to have been
raised and lowered by concomitant carbamazepine administration.
Carbamazepine may lower the serum concentration of the
following antiepileptics: clobazam, clonazepam, eslicarbazepine,
ethosuximide, lacosamide, lamotrigine, levetiracetam,
oxcarbazepine, perampanel, pregabalin, primidone, retigabine,
tiagabine, topiramate, valproic acid and zonisamide.
REFERENCES
1 SPC. Tegretol Tablets 100 mg, 200 mg, 400 mg. http://emc.medicines.org.uk/
2 Hallworth M, Capps N (1993). Therapeutic Drug Monitoring and Clinical Biochem-
istry. London: Association of Clinical Biochemists.
3 MHRA (2013). Formulation Switching of Antiepileptic Drugs. http://www.mhra.
gov.uk/ (accessed 1 January 2015).
5 National Poisons Information Service. Toxbase. http://www.toxbase.org (accessed 4
August 2014).
6 Baxter K, Preston C (eds) (2013). Stockley’s Drug Interactions, 10th edn. London:
k
k
74 Chemotherapy-induced nausea and vomiting
Chemotherapy-induced nausea
and vomiting
C Chemotherapy-induced nausea and vomiting (CINV) is common,
with an incidence of up to 70%,1 and the likelihood is partly
dependent on the drugs used in the regimen. These can be classified
as high- (>90%), moderate- (30 –90%), low- (10 –30%) and
minimal- (<10%) emetogenic risk.1
It is important to note that these are single-agent classifications.
When combining drugs in regimens, the overall classification will be
guided by the most emetogenic drug included. For lower levels of
emetogenic drug, if two from the same class are used, the
combination will be assigned the next level of emetogenic potential,
e.g. a two-drug regimen with both drugs in ‘low’ level would be
classified as ‘moderate’.
CINV may be subdivided into three classifications: acute (within
24 hours), delayed (beyond 24 hours), commonly caused by
cisplatin-containing regimens, and anticipatory (days or hours prior
to chemotherapy administration).2
For patients not treated with prophylactic antiemetics, it is
estimated that 60 –80% of patients receiving chemotherapy
experience CINV.3 However, the individual risk of developing CINV is
affected by both patient-related and treatment-related factors. Patient
factors associated with a higher risk of CINV include female gender,
k age <50 years, lower chronic alcohol intake (teetotallers are at k
highest risk), no tobacco use, susceptibility to motion sickness and
prior episodes of CINV.4 – 6
It is important to exclude other causes of nausea and vomiting
when assessing CINV. Other causes include radiotherapy, infection,
metabolic/electrolyte disturbances, constipation, gastrointestinal
obstruction, cachexic syndrome, metastases, and other emetogenic
medication (e.g. opioids, antibiotics).7
Table C6 shows the drug combinations of antiemetics commonly
used for CINV. These are given for both the acute and delayed phases
of CINV.
TABLE C6
Antiemetics used for chemotherapy-induced nausea
and vomiting
High-emetic-risk regimen NK1 receptor antagonist plus 5-HT3 receptor antagonist
containing cisplatin plus corticosteroid plus standard antiemetic
(e.g. metoclopramide, prochlorperazine, cyclizine)
High emetic risk 5-HT3 receptor antagonist plus corticosteroid plus
standard antiemetic (e.g. metoclopramide,
prochlorperazine, cyclizine)
Moderate emetic risk Corticosteroid plus standard antiemetic
Low emetic risk Standard antiemetic/none
Minimal emetic risk No routine prophylaxis
k
k
Child–Pugh score 75
Choice of antiemetic for CINV

Oral, intravenous, subcutaneous and rectal routes should all be
considered. The best route for an individual will depend on the
presence of vomiting and platelet count. Where vomiting or nausea is C
present the oral route should be avoided because of poor absorption
and exacerbation of the feeling of nausea. Where a low platelet count
is present, intravenous, subcutaneous and rectal routes should be
avoided in order to reduce bleeding and bruising caused by trauma.
For the anxiety of anticipatory nausea and vomiting, a 1-mg oral
dose of lorazepam 1 hour before chemotherapy is usually effective. In
more resistant cases lorazepam can be given at a dose of 1 –2 mg up to
four times a day.8
Levomepromazine is commonly used for patients not controlled
with combinations of the above. Doses from 6 to 25 mg daily can be
used either orally or subcutaneously and the dose may be divided,
although a single dose at night is often effective.9
REFERENCES
1 Basch E et al. (2011). Antiemetics: American Society of Clinical Oncology clinical
practice guideline update. J Clin Oncol 29: 4189–4198.
2 Berger AM, Clark-Snow RA. Adverse effects of treatment. In: DeVita Jr VT, Helman
S, Rosenberg S (eds) Principles and Practice of Oncology. Philadelphia: Lippincott
Williams and Wilkins, pp. 2869–2880.
3 Jenns K (1994). Importance of nausea. Cancer Nurs 17: 488–493.
4 Osoba D et al. (1997). Determinants of postchemotherapy nausea and vomiting in
patients with cancer. J Clin Oncol 15: 116–123.
k 5 Perez EA (1999). 5-HT3 antiemetic therapy for patients with breast cancer. Breast k
Cancer Res Treat 57: 207–214.
6 Dodd MJ et al. (1996). Differences in nausea, vomiting and retching between
younger and older out-patients receiving cancer chemotherapy. Cancer Nurs 19:
155–161.
7 Bentley A, Boyd K (2001). Use of clinical pictures in the management of nausea
and vomiting: a prospective audit. Palliat Med 15: 247–253.
8 Malik IA et al. (1995). Clinical efficacy of lorazepam in prophylaxis of anticipatory
acute and delayed onset nausea and vomiting induced by high doses of cisplatin.
A prospective randomised trial. Am J Clin Oncol 18: 170–175.
9 Mannix K (2002). Palliation of nausea and vomiting. Cancer Med 1: 18–22.
Child–Pugh score
Drugs metabolised or excreted by the liver may accumulate in the
body if liver function is impaired. Doses should be adjusted or the
drug avoided altogether if necessary. Determining the degree of
hepatic impairment is much trickier than with renal function. Several
methods exist, but the most commonly used is the Child–Pugh
classification, which has been developed as a prognostic tool in
chronic liver disease.1 Many medicines’ SPCs use this classification to
determine dose adjustments.
For the Child–Pugh classification, five clinical measures of liver
disease are given scores of 1, 2 or 3 points in increasing severity, as
shown in Table C7. The scores for each parameter are added together
k
k
76 Chloramphenicol (systemic)
TABLE C7
Scoring system for Child –Pugh classification of hepatic
impairment
C Measure Scores 1 point Scores 2 points Scores 3 points
Bilirubin, total <34* 34–50* (2–3) >50 (>3)
(micromol/L or mg/dL) (<2)
Serum albumin (g/L) >35 28–35 <28
INR or prothrombin time <1.7 1.7–2.3 >2.3
(seconds) 1–3 4–6 >6
Ascites None Moderate or suppressed Refractory
with medication
Hepatic encephalopathy None Grade I–II Grade III–IV
(or suppressed with (or refractory)
medication)
*In primary sclerosing cholangitis and primary biliary cirrhosis, the bilirubin reference
ranges are increased to <68 micromol/L (<4 mg/dL) for 1 point and 68–170 micromol/L
for 2 points (4–10 mg/dL).
and the degree of hepatic impairment is categorised as Child–Pugh

class A–C as follows:
● 5 –6 points: class A
● 7 –9 points: class B
● 10 –15 points: class C.
k k
REFERENCE
1 Pugh RNH et al. (1973). Transection of the oesophagus for bleeding oesophageal
varices. Br J Surg 60: 646–649.
Chloramphenicol (systemic)
Chloramphenicol is a broad-spectrum antibiotic active against many
Gram-positive and Gram-negative organisms. It acts by interfering
with bacterial protein synthesis. Chloramphenicol is known to cause
bone marrow depression. This can occur as a rare but often fatal aplas-
tic anaemia or as a dose-related reversible bone marrow suppression,
e.g. agranulocytosis, hypoplastic anaemia and thrombocytopenia.
Aplastic anaemia is idiosyncratic, may occur at any dose and onset
can occur after cessation of therapy. Only about 20% of cases occur
during a treatment course. Consequently its use should be reserved
for life-threatening infections, e.g. typhoid, meningitis and other
serious infections caused by bacteria-susceptible chloramphenicol.
Chloramphenicol is widely distributed in body tissues and fluids,
including cerebrospinal fluid.1,2 It is predominantly metabolised in
the liver and only small amounts are recovered in bile. In the liver it
undergoes conjugation with glucuronic acid to inactive metabolites.
Consequently, in patients with liver disease, serum levels should be
monitored and the dose reduced as appropriate. It is principally
k
k
Chloramphenicol (systemic) 77
excreted in the urine but only 5 –10% appears in the unchanged

active form. Active chloramphenicol does not accumulate in
renal failure and dose modification is not required. Inactive
chloramphenicol metabolites accumulate in renal failure, though they C
are not associated with toxicity.1 The manufacturer recommends
levels should be monitored in renal impairment and doses adjusted
accordingly.
Rationale for monitoring
Chloramphenicol has a narrow therapeutic range; therefore, levels
should be checked in the following circumstances:
● neonates
● children under 4 years of age
● elderly
● hepatic and renal impairment
● if there are drugs added known to affect chloramphenicol serum
concentration (see section on drug interactions, below).
Once levels are taken, they can be repeated after 5 –7 days (Table C8).
TABLE C8
Chloramphenicol monitoring information
Half-life 1.5–4 hours
Pretreatment measures FBC, U&Es, LFTs prior to commencement
Therapeutic range3 Peak: 10–25 mg/L
k Trough: <15 mg/L k
(Toxic effects observed with peak concentrations >25 mg/L
and trough concentrations >15 mg/L)
Sampling time Trough: 0–30 minutes predose
Peak: 2 hours post oral or intravenous administration
Other monitoring FBC repeated every 2–3 days. Discontinue treatment if
leucopenia, thrombocytopenia or anaemia occurs. U&Es,
LFTs repeated after 1–3 days, then at least weekly
Dose
The adult dose for oral and intravenous administration is 12.5 mg/kg
every 6 hours. In exceptional cases, such as septicaemia and
meningitis, the dose may be doubled to 25 mg/kg every 6 hours. The
dose should be reduced as soon as clinically indicated.3
To prevent relapses, treatment should be continued after the
patient’s temperature has returned to normal for 4 days in rickettsial
diseases, and for 8 –10 days in typhoid fever.3
Administration
Chloramphenicol may be given orally as capsules, or intravenously.
The intramuscular route is licensed, but not recommended, because
absorption may be slow and unreliable; therefore, intravenous bolus
injection is preferred.2 The injection is presented as a powder
containing 1.377 g chloramphenicol sodium succinate (equivalent to
1 g chloramphenicol base). It is reconstituted with water for
injections, sodium chloride 0.9% injection or glucose 5% injection.
k
k
78 Chloramphenicol (systemic)
It should be given at a concentration of 10% (100 mg/mL) or less.2,4

Add 9.2 mL of diluent to a 1 g vial to make a 100 mg/mL solution. The
required dose is withdrawn from the reconstituted vial and can be
C given as a bolus intravenous injection over at least 1 minute. It can be
further diluted with a convenient volume (e.g. 100 mL) of sodium
chloride 0.9% or glucose 5% and given as an intravenous infusion
over 15 –30 minutes.4
Overdose
Symptoms
Symptoms of overdose include abdominal distension, lethargy,
nausea and vomiting, jaundice, respiratory distress, pale cyanotic
skin, hypotension and metabolic acidosis followed by cardiovascular
collapse.
In infants these symptoms are referred to as ‘grey-baby syndrome’.
The occurrence of the syndrome in this group is due to their
immature metabolism and inability to conjugate the drug.
Antidote
Seek specialist medical advice. There is no specific antidote to
chloramphenicol overdose. Activated charcoal may be considered,
though the benefit is uncertain; optimal effects are within 1 hour.
Asymptomatic patients should be observed for 6 hours after ingestion.
For symptomatic patients, as well as stopping therapy, general
supportive therapy is recommended, e.g. haemodynamic support,
k k
correction of metabolic acidosis. Haematology advice should be
sought for patients where bone marrow toxicity is present.5
Drug interactions
Chloramphenicol inhibits several liver enzymes, including CYP2C9
and CYP3A4. It can increase the effects of coumarin anticoagulants,
tolbutamide, sulphonylureas and phenytoin; dose reductions of these
drugs may be required.2
Phenobarbital and rifampicin may reduce plasma concentrations
of chloramphenicol. Concurrent use of phenytoin and
chloramphenicol may result in toxic chloramphenicol serum
concentrations. Dose adjustment may be necessary.
Chloramphenicol may increase the plasma concentration of
ciclosporin and tacrolimus and may reduce the antiplatelet effect of
clopidogrel. Concomitant use with clozapine should be avoided due
to the increased risk of agranulocytosis.3
REFERENCES
1 Grayson M et al. (eds) (2010). Kucers’ The Use of Antibiotics, 6th edn. London:
Hodder Arnold.
2 eMC (2014). SPC Kemicetine succinate injection. http://www.medicines.org.uk/emc
k
k
5 National Poisons Information Service. Toxbase. http://www.toxbase.org (accessed
4 August 2014).
C
Chronic obstructive pulmonary disease

Overview
Definition Chronic obstructive pulmonary disease (COPD) is characterised by air
flow obstruction that is not fully reversible. The air flow obstruction
does not change markedly over several months and is usually
progressive in the long term and not fully reversible. The following
should be used as a definition of COPD:
● Air flow obstruction is defined as a reduced FEV1 /FVC ratio (where
FEV1 is forced expired volume in 1 second and FVC is forced vital
capacity), such that FEV1 /FVC is less than 0.7
● If FEV1 is ≥80% of predicted normal, a diagnosis of COPD should
only be made in the presence of respiratory symptoms, for example,
breathlessness or cough
COPD is now the preferred term for the condition in patients with air
flow obstruction who were previously diagnosed as having chronic
bronchitis or emphysema
Causes ● COPD is predominantly caused by smoking substances
k ●
(approximately 90% of cases)
Other risk factors include chronic or intense exposure to
k
occupational dusts or chemicals, and exposure to smoke from home
cooking and heating fuels
● Alpha-1 antitrypsin deficiency is a genetic risk factor for COPD, but it
accounts for only about 2% of cases of severe COPD
Classification COPD is classified according to the extent of air flow obstruction:
Post-bronchodilator FEV1 % Severity of air flow

FEV1 /FVC predicted obstruction
<0.7 ≥80% Stage 1 – mild*
<0.7 50–79% Stage 2 – moderate
<0.7 30–49% Stage 3 – severe
<0.7 <30% Stage 4 – very severe†
*Symptoms should be present to diagnose COPD in people with mild
air flow obstruction.
†
Or FEV1 < 50% with respiratory failure.
Although FEV1 is the most common variable used to grade the
severity of COPD, it is a poor guide to a patient’s symptoms, quality
of life and mortality
k
k
80 Chronic obstructive pulmonary disease
Signs and At first, COPD may cause no symptoms or only mild symptoms. As the
symptoms disease progresses, symptoms usually become more severe. Common
signs and symptoms of COPD include:
C ● chronic cough (often called ‘smoker’s cough’)
● regular sputum production
● breathlessness on exertion
● wheeze and chest tightness
● frequent chest infections
Systemic manifestations include: weight loss, impaired systemic muscle
function, osteoporosis, depression, pulmonary hypertension and cor
pulmonale
Diagnostic There is no single diagnostic test for COPD. Making a diagnosis relies
tests on clinical judgement based on a combination of history, physical
examination and confirmation of the presence of air flow obstruction
using post-bronchodilator spirometry. A diagnosis of COPD should be
considered in patients over the age of 35 years who have a risk factor,
are generally current or ex-smokers and who present with one or more
of the classic COPD symptoms
Treatment The goals of COPD treatment are to:
goals ● relieve symptoms with no or minimal side effects of treatment
● slow the progress of the disease
● improve the ability to stay active and exercise
● prevent and treat any complications from the disease
● improve health overall
Currently, no treatments have been shown to improve lung function
k Treatment
options1
●
or decrease mortality significantly

k
● Stopping smoking is the only intervention that slows the
progression of the disease. All COPD patients still smoking,
regardless of age, should be encouraged to stop, and offered help to
do so, at every opportunity
● Pulmonary rehabilitation should be offered to all people disabled by
their disease
● Pneumococcal vaccination and an annual influenza vaccination
should be offered to all patients
● Medicines are used to reduce breathlessness, improve exercise
tolerance, aid sputum clearance, improve health status, reduce
exacerbation frequency and manage acute exacerbations
Medicines optimisation
The medication treatment options here are from NICE guidance:1
Short-acting ● Should always be prescribed ‘when required’ to reduce
beta-2 agonist breathlessness
(SABA) ● The onset of action is slower than in patients with asthma
● When patients are very short of breath, combining the inhaler with
a spacer device may be helpful
● Side effects such as tremor, anxiety, cramps, ↓K (monitor),
palpitations are dose-related. There is little clinical benefit in terms
of efficacy in giving more than 1 mg salbutamol at a time in patients
with COPD. Low but frequent doses are more effective for SABAs
k
k
Muscarinic ● Short-acting muscarinic antagonists (SAMA), e.g. ipratropium, used

antagonists to reduce intermittent breathlessness
● Long-acting muscarinic antagonists (LAMA) should be offered in
preference to four-times-daily SAMA to people with stable COPD C
who remain breathless or have exacerbations despite using
short-acting bronchodilators
● SAMA and LAMA should not be prescribed together due to an
increased risk of adverse effects and no added benefit
● Monitor outcomes, such as improvement in symptoms, activities of
daily living, exercise capacity and rapidity of symptom relief
● If ipratropium is being nebulised, the mask must be fitted carefully
or ideally a mouthpiece used to avoid the aerosol coming into
contact with the eyes, as this could cause glaucoma
Inhaled ● None of the ICS currently available is licensed for use alone in the
corticosteroid treatment of COPD
(ICS) and ● Inflammation present in the airways of stable COPD patients is
long-acting mediated by neutrophils, which are relatively insensitive to the
beta-2 agonist effects of steroids
(LABA) ● Recommend an ICS/LABA combination for patients with ≤FEV1
50% predicted, who are having two or more exacerbations requiring
treatment with antibiotics or oral corticosteroids in a 12-month
period
● Be aware of the potential risk of developing side effects, including
non-fatal pneumonia, osteoporosis or diabetes in people with COPD
treated with ICS
● Issue a steroid warning card to all patients receiving high-dose ICS
k (>800 micrograms beclometasone (non-extra-fine)/day or k
equivalent)
LABA ● Unlike in people with asthma, there is no increased risk of death if
used alone without an ICS
● Monitor outcomes, such as improvement in symptoms, activities of
daily living, exercise capacity and rapidity of symptom relief
Oral ● Short courses (7–14 days) are prescribed to manage a COPD
corticosteroid exacerbation
● For steroid courses longer than 3 weeks, provide a steroid warning
card and taper dose down. There is no standard regimen for a
reducing course of oral corticosteroid and it does vary depending on
the patient, e.g. length of time of corticosteroid exposure, any
previous courses of corticosteroid, previous maintenance treatment
– and consultant preference! It is usually fine to drop down to
physiological dose and then reduce the last phase slowly, previous
caveats notwithstanding. In practice many patients are just reduced
by 5 mg every 3 days to zero or their regular maintenance dose
● Maintenance use of oral corticosteroid therapy in COPD is not
normally recommended and carries considerable risks
(i.e. osteoporosis, muscle wasting)
● Consider osteroporosis prophylaxis for people on ≥7.5 mg
prednisolone and/or >4 courses of oral steroids in a year
k
k
82 Chronic obstructive pulmonary disease
Methylxanthine ● Narrow therapeutic window – appropriate dosing and

(e.g. theophylline, monitoring are essential
aminophylline) ● To reduce the adverse effects, introduce at low dose and
C gradually increase according to symptoms and plasma levels
● Aim for a steady-state serum theophylline concentration of
10–20 micrograms/mL
● Measure drug serum concentration: when treatment starts, if side
effects occur, if expected therapeutic benefit is not achieved
and if potential drug interactions are suspected. Monitor levels
daily if intravenous aminophylline is prescribed (see Theophylline
entry–act on results)
● If intravenous aminophylline is being used to manage acute
severe exacerbations, give a loading dose if not currently
prescribed an oral theophylline preparation
● Side effects occur commonly, such as tachycardia, palpitations,
headache, insomnia, nausea and other gastrointestinal
disturbances
● Consider drug interactions with any prescribed, herbal and OTC
medicines
● Prescribe oral products by brand name, as bioavailability may
vary from one brand to another
Mucolytics ● Monitor effect on sputum clearance and/or cough – stop if no
benefit after 4–6 weeks
Antibiotics ● Patients with exacerbations without purulent sputum do not
need antibiotic therapy unless there is consolidation on a chest
radiograph or clinical signs of pneumonia
k ● Initial empirical treatment should be an aminopenicillin, a k
macrolide or a tetracycline according to your local antimicrobial
formulary
Oxygen ● Patients should receive a formal oxygen assessment before being
prescribed home long-term oxygen therapy
● Inappropriate oxygen therapy in people with COPD may cause
respiratory depression
● Oxygen is classed as a drug and should be prescribed
● Patients should be warned about the risks of fire and explosion if
they continue to smoke when prescribed oxygen
Drug ● Give specific training and assessment in inhaler technique before
administration starting any new inhaler treatment
● Ask patients to show you how they use their inhalers; it is not
sufficient just to ask them if they know how to use them
● Make sure the patient’s spacer device is compatible with the
inhaler device and that patients know how to use the spacer
● The use of nebulisers in the day-to-day management of COPD is
rarely appropriate. Confirm that a nebuliser is required and
available
Essential ● Strongly advise patients not to smoke and consider nicotine
interventions replacement therapy
● Ensure patient is offered an annual vaccination against influenza
and a one-off vaccination against pneumococcal disease
● People should be encouraged to seek help early in an exacer-
bation and not wait until they are experiencing severe difficulty
● Provide patients with a self-management plan
● Refer patients to a pulmonary rehabilitation course if disabled by
breathlessness
k
k
Secondary ● Patients with COPD may suffer from anxiety and depression
intervention ● Refer patients with a body mass index <19 for nutritional advice
● Encourage exercise and healthy lifestyle
● If in hospital, refer eligible patients to their community C
pharmacist for an appropriate postdischarge intervention
Monitoring on ● Assessment of functional capacity, cognitive status and
hospital nutritional status
admission ● Obtain chest X-ray, ECG (to exclude comorbidities)
● Review of medication regimen, including the need for any
changes and possible side effects
● Measure ABG tensions, FBC, theophylline level (in patients on
theophylline at admission); if sputum is purulent, a sample
should be sent for microscopy and culture; blood cultures if the
patient is pyrexial; serum u&Es, creatinine and eGFR
Further reading British Lung Foundation: www.blf.org.uk.
Global Initiative for COPD: www.goldcopd.com.
NICE (2011). Chronic Obstructive Pulmonary Disease Quality
Standards for www.nice.org.uk/Guidance/qs10 (accessed 30
April 2015).
REFERENCE
1 NICE (2010). Chronic Obstructive Pulmonary Disease: Management of chronic
obstructive pulmonary disease in adults in primary and secondary care. CG101.
www.nice.org.uk/guidance/CG101/ (accessed 7 January 2015).
k k
Ciclosporin: management and monitoring
Ciclosporin is a potent immunosuppressant, used for the treatment
and prevention of transplant rejection.1 It is also licensed for use in
severe psoriasis and eczema (oral route only), rheumatoid arthritis
and nephrotic syndrome.2 Its immunosuppressant properties have
also been used in an unlicensed capacity for the treatment of
ulcerative colitis.3 – 5
The route of elimination is by hepatic metabolism and excretion into
the bile. Consequently it should be used with caution in patients with
hepatic impairment and the dose adjusted in response to serum
concentrations.
Ciclosporin is nephrotoxic and has a narrow therapeutic range.
Monitoring of ciclosporin serum concentration is considered:
● when treatment is initiated
● where toxicity or non-adherence is suspected
● when hepatic function deteriorates, or gastrointestinal
disturbances develop
● when an interacting drug is prescribed, e.g. erythromycin
● when a dosage change is made
● following a change in formulation.
k
k
84 Ciclosporin: management and monitoring
Therapeutic drug monitoring

The target therapeutic range for ciclosporin is variable and is
dependent on the indication. The relationship between the ciclosporin
C serum concentration and the clinical and toxic effect is not clear, and
in the case of autoimmune diseases, there is no evidence linking a
particular concentration with the desired effect. Nevertheless,
monitoring trough levels of ciclosporin is useful (Table C9).
TABLE C9
Half-life 6–24 hours6
Pretreatment measures FBC, LFTs, U&Es, serum creatinine, blood pressure, lipid
profile
Therapeutic range For transplantation: seek guidance from transplant centre
For ulcerative colitis: 150–350 ng/mL (124–290 nmol/L)4
Sampling time A trough sample of ciclosporin should be taken before the
dose
Other monitoring See below
Dose
Doses for licensed indications can be found in the BNF. An unlicensed
dose for ulcerative colitis is 2 –4 mg/kg/day, given intravenously.
Administration of intravenous ciclosporin
k Intravenous ciclosporin is available as Sandimmun 50 mg/mL. The k
infusion should be prepared by diluting the required dose
1:20 –1:100 with sodium chloride 0.9% or glucose 5%, and then
administering over 2 –6 hours. Care is required in the selection of
infusion bags and giving sets to avoid incompatibilities with some
polyvinyl chloride products.
Once the infusion is commenced, the patient should be observed
for the first 30 minutes and at regular intervals thereafter until the
infusion is completed. This is necessary because the infusion
concentrate contains polyethoxylated castor oil, which has been
associated with anaphylaxis.
The patient’s blood pressure should also be monitored at regular
intervals, as hypertension may occur.
Administration of oral ciclosporin
Oral ciclosporin is available as branded capsules and Neoral oral
solution. These should be taken in two divided doses. Neoral oral
solution should be diluted with water, orange juice or squash
immediately before being taken.
Patients should be prescribed and stabilised on a particular brand
of ciclosporin because switching formulations may cause clinically
important changes in blood ciclosporin levels.
Grapefruit, or grapefruit juice, should be avoided when taking
ciclosporin as grapefruit can affect the P450 enzyme system and lead
to higher serum concentrations of ciclosporin.
k
k
Monitoring
FBC, LFTs and bilirubin should be monitored every 3 months.
Renal function – U&Es and serum creatinine
C
Ciclosporin may cause hyperkalaemia and impaired renal function.
Monitoring schedules are specific to the product licence, as follows:
● psoriasis – monitor renal function on two occasions prior to
commencing therapy, every 2 weeks for the first 3 months of
treatment, then monthly
● rheumatoid arthritis – see Rheumatoid arthritis – drugs suppressing
the disease process entry
● atopic dermatitis – monitor renal function on two occasions prior
to commencing therapy, then every 2 weeks
● transplant – refer to specialist centre protocol
● nephrotic syndrome – refer to local protocol.
Blood pressure
Ciclosporin can cause hypertension; therefore blood pressure should
be monitored every 2 weeks for the first 3 months after the dose is
stable, and then monthly.
Lipid profile
This should be monitored every 6 months.
Overdose
k Seek specialist advice. The adverse effects of ciclosporin are usually
k
dose-dependent and include nephrotoxicity, hepatic dysfunction,
gastrointestinal reactions, convulsions, headache, paraesthesia,
hypertension and hyperlipidaemia.
These are managed by symptomatic treatment and general
supportive measures.
Interactions
Many drugs interact with ciclosporin. Those with clinical implications
include:
● drugs that decrease ciclosporin serum concentration: barbiturates,
carbamazepine, phenytoin, rifampicin, octreotide, orlistat, St
John’s wort, ticlodipine
● drugs that increase ciclosporin serum concentration: allopurinol,
amiodarone, danazol, diltiazem, fluconazole, itraconazole,
ketoconazole, macrolide antibiotics, methylprednisolone (high
doses), metoclopramide, nicardipine, oral contraceptives, protease
inhibitors, ursodeoxycholic acid and verapamil.
Care should be taken when the following drugs are used
concomitantly with ciclosporin, as they may all increase the risk of
nephrotoxicity: aminoglycoside antibiotics, amphotericin,
ciprofloxacin, melphalan, non-steroidal anti-inflammatory drugs,
trimethoprim (and sulfamethoxazole) and vancomycin.
k
k
86 Cigarette smoking: calculation of pack-years
Vaccines may be less effective because of a blunted immune

response. The use of live attenuated vaccines should be avoided
because of the risk of infection.
C Ciclosporin may also affect the serum concentration of digoxin,
leading to digoxin toxicity. Prednisolone serum concentration may
also be raised by ciclosporin.
Miscellany
Oral Sandimmun preparations are available on a named-patient basis
for those patients unable to tolerate Neoral.
If intravenous ciclosporin is used in combination with high-dose
corticosteroids, then consider the prescribing of oral co-trimoxazole
480 mg twice daily three times a week as prophylaxis against
Pneumocysitis jirovecii pneumonia.7
REFERENCES
1 SPC (2014). Sandimmun Injection. www.medicines.org.uk (accessed 28 January
2015).
2 SPC (2014). Neoral Soft Gelatin Capsules. www.medicines.org.uk (accessed 28
January 2015).
3 Parry S, Wilkinson M (2004). Current management of inflammatory bowel disease.
Prescriber 15: 50–60.
4 Van Assche G et al. (2003). Randomized, double-blind comparison of
4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis.
Gastroenterology 125: 1025–1031.
5 Lichtiger S et al. (1994). Cyclosporine in severe ulcerative colitis refractory to
k steroid therapy. N Engl J Med 330: 1841–1845. k
6 Dollery C (ed.) (1999). Therapeutic Drugs (2nd edn). Edinburgh: Churchill
Livingstone.
7 Quan VA et al. (1997). Ciclosporin treatment for ulcerative colitis complicated by
fatal Pneumocysitis carinii pneumonia. BMJ 314: 363–364.
Cigarette smoking: calculation

of pack-years
A pack-year is a measure used to calculate the amount of cigarettes
smoked over a person’s life. A single pack-year is 20 cigarettes smoked
per day for 1 year (see Nicotine replacement therapy (NRT) entry).
Calculation

number cigarettes smoked per day
× number of years smoked
Total pack-years1 =
20
The use of pack-years

Pack-years can be used to estimate the risk a patient has of developing
smoking-related illnesses such as COPD. The pack-years calculation
uses manufactured cigarettes as a standard cigarette. Smoking cigars,
k
k
Cigarette smoking–drug interactions 87
pipes or roll-ups provides different levels of risk to the patient and the
calculation should be adjusted to allow for this (Table C10).
TABLE C10
A guide to cigarette equivalences2 C
Alternative method of smoking Cigarette equivalence
1 cigar 4 cigarettes
1 pipe 2.5 cigarettes
Roll-ups: 25 g Approximately 50 cigarettes
REFERENCES
1 Antoniou S, Barnes N, Khachi H (2010). COPD clinical features and diagnosis.
Clin Pharmacist 2: 382–389.
2 General Practice Notebook (2014). Cigarette Smoking Equivalence to Rollups.
http://www.gpnotebook.co.uk/simplepage.cfm?ID=x20110420091937244716
(accessed 2 December 2014).
Cigarette smoking–drug interactions

The interactions between cigarette smoking and medication are
complex. The majority of interactions are caused by tobacco rather
than nicotine. Monitoring and adjustments of medication may be
k required when patients stop or start smoking due to the changes in k
metabolism that occur1 (see Nicotine replacement therapy entry).
Interactions with nicotine
● Nicotine possibly enhances the effect of adenosine.2
Interactions with tobacco
● Tobacco smoking induces the hepatic metabolic enzyme CYP1A2,
resulting in altered pharmacokinetics of many drugs.3
● Levels of clozapine can increase by up to 50% within 2 –4 weeks of
smoking cessation. Serum concentration levels should be
monitored to guide dose adjustments.1 Other antipsychotics that
may be affected include olanzapine, chlorpromazine and
haloperidol.2
● Theophylline requirements in heavy tobacco smokers or people
who chew tobacco are much greater than in non-smokers. When a
patient stops smoking a reduction of up to 25 –33% of theophylline
may be required within a week. Levels should be taken to guide
dosing (see Theophylline entry).1
● Other medications affected in this manner by smoking include
cinacalcet and ropinirole.2
● Smoking tobacco may also increase insulin resistance, resulting in
higher insulin doses than in non-smokers.1 Insulin requirements
may alter if the patient stops smoking.
k
k
88 Clozapine
REFERENCES
1 Baxter K, Preston CL (eds) (2014). Stockley’s Drug Interactions. www.medicines
complete.com (accessed 2 December 2014).
C BMJ Group and Pharmaceutical Press.
3 Brayfield A (ed.) (2014). Martindale: The complete drug reference. www.medicines
complete.com (accessed 2 December 2014).
Clozapine
Background
Clozapine is an antipsychotic that should be offered to people with
schizophrenia whose illness has not responded adequately to
treatment despite the sequential use of adequate doses of at least two
different antipsychotic drugs. At least one of the drugs should be a
non-clozapine second-generation antipsychotic.1 It is also used to
treat psychosis associated with Parkinson’s disease.
It must be initiated by a specialist, and the psychiatrist and the
pharmacist must be registered with the company supplying the drug.
There are currently three manufacturers supplying clozapine in
the UK:
1 Novartis Pharmaceuticals: Clozaril
2 Denfleet Pharma: Denzapine2
k 3 Ivax Pharmaceuticals UK: Zaponex.2 k
Baseline and regular blood monitoring must be carried out before
medication is supplied. This is because neutropenia, leading to
agranulocytosis, is a known adverse reaction to clozapine. Routine
monitoring of white blood cell count and a differential count of
neutrophils, eosinophils and platelets will identify patients at risk.2
Blood should be taken in ‘red-cap’ sample bottles.
After the start of clozapine treatment, the following are measured:
white blood cells, absolute neutrophils, eosinophils and platelets. The
manufacturer’s clozapine monitoring service will advise on the
frequency of monitoring, which is at least:
● weekly for the first 18 weeks of treatment
● fortnightly for the next 34 weeks of treatment
● at 4-week intervals thereafter.
Monitoring must continue throughout treatment and for 4 weeks
after complete discontinuation of clozapine or until haematological
recovery has occurred. Patients should be reminded to contact their
doctor immediately if any kind of infection, fever, sore throat or other
flu-like symptoms develop. Differential blood counts must be
performed immediately if any symptoms or signs of an infection occur.
k
k
Clozapine 89
A ‘traffic light’ system is used to clarify results as follows:
● green – continue treatment

amber – caution, continue treatment, but extra blood samples will
C
●
be needed as advised by the manufacturer’s monitoring service

● red – stop treatment immediately and act on advice given by the
monitoring service. A red result also means that the patient must
never be re-exposed to clozapine. In this case the patient should be
prescribed whichever therapy previously produced the best
response.
The patient’s pharmacy will only dispense sufficient clozapine to
maintain therapy until confirmation of the patient’s next blood result.
Admission to hospital
If a patient taking clozapine is admitted to hospital, the following will
need to be determined:
● which brand of clozapine is the patient taking?

● where is the patient registered for clozapine? This information will
enable liaison with the patient’s registered pharmacist
● has the patient brought his or her own supply of clozapine into
hospital? If not, ideally the patient’s carer or relative should be
asked to bring the supply into the ward in order to maintain
synchronicity with blood tests.
k Once this information is obtained, contact the patient’s registered k
pharmacist to confirm when the next blood sample is due, and the
patient’s current clozapine dose.
It is important to note that, if there is a break in treatment of more
than 48 hours, clozapine needs to be retitrated. If this happens,
contact the registered pharmacist for advice, or the relevant
monitoring service.
Contact details
To access the website of your monitoring service you will need a:
● user identity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
● password . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Out of hours, the monitoring services can be contacted by telephone,
even by non-registered pharmacists.
Clozaril
Clozaril Patient Monitoring Service (CPMS) contacts for queries:
● Website: https://www.clozaril.co.uk/scrlogon.asp
● General: 0845 769 8269
● Urgent results: 0845 769 8357
● Forgotten passwords: 01276 698125
k
k
90 Cognitive assessment tools
Denzapine
Denzapine Clozapine Monitoring Service (DCMS) contacts for
queries:
C
● Website: https://www.denzapine.co.uk/
● Queries: Tel: 0333 2004141
Zaponex
Zaponex Treatment Access System (ZTAS) contacts for queries:
● Website: http://www.ztas.co.uk/
● Queries: Tel: 0207 365 5842
REFERENCES
1 NICE (2014). Clinical Guideline 178. Psychosis and Schizophrenia in Adults:
Treatment and management. http://www.nice.org.uk/guidance/CG178 (accessed
14 January 2015).
2 eMC (2014). www.medicines.org.uk (accessed 13 January 2015).
Cognitive assessment tools

There is a wide range of tests available for cognitive assessment
screening; each has its own advantages and disadvantages. The tests
vary in the length of time taken to conduct and the amount of
k equipment needed to perform the test. The shorter tests are preferred k
in primary care and general practitioner settings.
When interpreting the scores of the cognitive assessment test, it is
important to take into account any factors that may affect
performance, e.g. educational level or language.
The Alzheimer’s Society has produced a toolkit that provides
guidance on available cognitive tests and how they may be used in
clinical practice.1 The toolkit also contains copies of many of the tests.
Some of the popular tests currently in use are as follows.
Abbreviated mental test score (AMTS)2
This tool was developed in 1972 for assessing cognition. It was
validated in acute geriatric ward inpatients but is frequently used in
primary care settings. This is a 10-question scale that looks at
orientation, memory and concentration. It is simple to perform and
score – the cut-off point for dementia is 6 –8 out of 10.
6-Item cognitive impairment test (6CIT)3
This tool was developed in 1983 and is used in primary care and acute
care settings. It consists of six questions looking at orientation,
memory and concentration.
It takes less than 5 minutes to complete the test but has a complex
scoring system – it is inversely scored and the cut-off point for
dementia is a score of 8 or more out of 28.
k
k
Cognitive assessment tools 91
Mini mental state examination (MMSE)4

This tool was developed in 1975; it has been widely used and is
included in many dementia guidelines. It is used in the memory clinic
setting to aid diagnosis of dementia and assess its progression. C
It is an 11-item question scale that looks at cognitive
functioning; the test takes less than 10 minutes to complete and the
cut-off point for dementia is 24 out of 30. The cut-off point is not
valid in different cultures and in particularly highly or uneducated
people.
This test is subject to copyright restrictions and incurs a cost at
each use.
Addenbrookes cognitive examination 111 (ACE-111)
This is a more detailed assessment of cognition; the ACE-111 version
replaced earlier versions in November 2012. This test is used in
memory clinics and examines five domains: attention and
orientation, memory, verbal fluency, language and visuospatial.
The test takes 10 –20 minutes to complete and the cut-off point for
dementia is 82 –88 out of 100.
Specific training on conducting the test and scoring the test is
recommended (www.neura.edu.au/frontier/research/
test-downloads).
Montreal cognitive assessment (MoCA)5
k This test was devised in Canada in 1996 and has been prospectively k
validated in a UK memory clinic. This test is used in a memory clinic
setting or care home (if a patient has a diagnosis of cognitive
impairment or dementia).
The test looks at executive functioning and attention tasks,
language, memory and visuospatial.
It takes 10 minutes to complete and the cut-off point for dementia
is 26 out of 30.
Guidance and further information are available at
www.mocatest.org.
REFERENCES
1 Alzhheimer’s Society (2013). Helping You to Assess Cognition. A practical toolkit for
clinicians. www.alzheimers.org.uk (accessed 17 January 2015).
2 Hodgkinson HM (1972). Evaluation of a mental test score for assessment of mental
impairment in the elderly. Age Aging 1: 233–238.
3 Brooke P, Bullock R (1999). Validation of a 6 item cognitive impairment test with a
view to primary care usage. Int J Geriatr Psychiatry 14: 936–940.
4 Folstein MF et al. (1975). Mini-mental state. A practical method for grading the
cognitive state of patients for the clinician. J Psychiatr Res 12: 189–198.
5 Nasreddine ZS et al. (2005). The Montreal Cognitive Assessment (MoCA): a brief
screening tool for mild cognitive impairment. J Am Geriatr Soc 53: 695–699.
k
k
92 Constipation
Constipation
Overview
C
Definition Defecation that is unsatisfactory because of infrequent stools,
difficult stool passage or incomplete defecation1
Subtypes ● Faecal loading/impaction – where the retention of faeces is
unlikely to result in spontaneous evacuation1
● Overflow incontinence – leakage of loose stool around
impacted faeces1
Risk factors Drug causes (aluminium, antimuscarinics, antidepressants,
calcium supplements, diuretics, iron supplements, opioids,
verapamil), low-fibre or high-fat diet, reduced exercise,
dehydration and psychological factors
Diagnosis ● Symptoms such as abdominal pain, urinary retention,
nausea
● Faecal mass palpable on examination
● Rectal examination
● X-ray
Treatment goals1 ● To clear faecal loading/impaction
● To relieve symptoms and achieve a normal stool pattern
● To withdraw use of laxatives in chronic constipation where
possible; laxatives should be continued for patients on
constipating drugs that cannot be discontinued, e.g. an
opioid or patients with a medical cause of constipation
k To adjust any constipating medication
k
Non-pharmaceutical ●
advice ● To increase dietary fibre and increase fluid intake

● To increase mobility/exercise
Pharmaceutical ● If non-pharmaceutical measures do not relieve the
management1 constipation, oral laxatives should be used
● Bulk-forming laxatives are recommended first-line
● If stools remain hard then an osmotic laxative should be
used as an alternative or in addition to the bulk-forming
laxative
● If stools are soft but difficult to pass, then a stimulant
laxative should be used
● If a rapid effect is required or oral laxatives fail to provide
relief then suppositories or microenemas can be used.
Phosphate or arachis oil retention enemas should be
reserved for when all other interventions have failed
● Constipation caused by opioid use should be treated with
osmotic and stimulant laxatives, avoiding the use of
bulk-forming laxatives
Discontinuing Once regular bowel movement is achieved with soft stools,
laxatives laxatives should be withdrawn slowly
k
k
Constipation 93
Treatment options
Bulk-forming ● Include ispaghula husk, methylcellulose, sterculia
laxatives2 ● Act to increase faecal mass by retaining fluid within the
stool, and stimulate peristalsis C
● Effect can be seen in 2–3 days1
● Must ensure that adequate fluid intake is maintained to
avoid intestinal obstruction
● Patients should be advised to take with water and should
not be taken before bed
Osmotic laxatives2 ● Include lactulose, macrogols, magnesium salts, rectal
phosphates, rectal sodium citrate
● Act to increase the amount of water in the large bowel by
either retaining fluid or by drawing fluid from the body. This
allows fluid accumulation, causing distension in the lower
bowel, and stimulates peristalsis1
● Lactulose is often used in hepatic encephalitis due to the
osmotic effect lowering the pH and preventing the
proliferation of ammonia-producing organisms
● Effect can be seen in 2–3 days with oral preparations1 N.B.:
there is no rationale for ‘doubling up’ lactulose with a
macrogol – use one or the other (possibly guided by patient
preference), but not both at the same time
● Effect can be seen in 2–5 minutes with rectal preparations3
● Must ensure that adequate fluid intake is maintained to
avoid intestinal obstruction
● Phosphate enemas contain sodium phosphates, and
k therefore sodium and phosphate levels may be elevated and k
calcium and potassium levels may be reduced3
Stimulant laxatives2 ● Include bisacodyl, danthron, docusate sodium, glycerol
suppositories, senna, sodium picosulphate
● Act to increase intestinal motility
● Glycerol suppositories act as a mild irritant
● Effect can be seen in 8–12 hours with oral preparations1
● Effect can be seen in 15–20 minutes with rectal
preparations1
● Danthron is only indicated for use in the terminally ill due to
its potential carcinogenicity and evidence of genotoxicity
Faecal softeners2 ● Include arachis oil and liquid paraffin (avoid arachis oil in
peanut allergy)
● Act as a lubricant to promote bowel movement
Side effects Common side effects of laxatives include flatulence, bloating,
abdominal cramps, nausea and diarrhoea1,2
k
k
94 Corticosteroid oral/intravenous equivalence
Prucalopride2 ● A selective serotonin 5HT4 -receptor agonist with prokinetic

properties enhancing intestinal motility
● Indicated for chronic constipation in women when other
C laxatives fail to produce an adequate response
● NICE guidance recommends the use of ‘prucalopride in
women for whom treatment with at least two laxatives
from different classes, at the highest tolerated
recommended doses for at least 6 months, has failed and
invasive treatment is being considered’.4 It should only be
initiated by clinicians experienced in the treatment of
chronic constipation
● Review needed after 4 weeks
● Common side effects include headache and gastrointestinal
symptoms, which are usually transient
Linaclotide2 ● A guanylate cyclase-C receptor agonist that increases
intestinal fluid secretion and transit and reduces visceral
pain.
● Indicated for moderate-to-severe irritable bowel syndrome
with constipation
REFERENCES
1 NICE (2013). Clinical Knowledge Summary. Constipation. http://cks.nice.org.uk/
constipation (accessed 5 February 2015).
3 eMC (2014). http://www.medicines.org.uk/emc/ (accessed 5 February 2015).
k 4 NICE (2010). Technology Appraisal 211. Prucalopride for the treatment of chronic k
constipation in women. https://www.nice.org.uk/guidance/TA211/chapter/
1-guidance (accessed 5 February 2015).
Corticosteroid oral/intravenous equivalence

Patients taking a maintenance dose of oral corticosteroids present a
problem if the oral route is unavailable. For example, a patient who
has been taking a maintenance dose of prednisolone requires
temporary conversion to intravenous therapy, usually as
hydrocortisone sodium succinate.
The oral bioavailability of prednisolone and other corticosteroids
has a wide interpatient variability, and it is important to appreciate
that it is not possible to provide absolute conversion figures.
When there is stress due to intercurrent illness or surgery, the
exogenous corticosteroid requirement for an individual may be
increased if there is hypothalamic-pituitary-adrenal (HPA) axis
suppression. Even in instances where the corticosteroid has been
discontinued up to 3 months previously, a latent HPA insufficiency
may become important and such individuals should be considered for
interim parenteral corticosteroid supplementation. The NHS Steroid
Card emphasises this with the warning: ‘For one year after you stop the
treatment you must mention that you have taken steroids’.1
k
k
Corticosteroid oral/intravenous equivalence 95
The following information provides broader assistance in the

management of such patients, whilst the BNF contains guidance for
the management of patients undergoing surgery (see ‘Nil-by-mouth’ –
management of long-term medicines during surgery entry). Table C11 C
contains relative data for the commonly encountered oral
corticosteroids.
TABLE C11
Equivalent anti-inflammatory doses of corticosteroids
Oral corticosteroid Equivalent dose (relative to prednisolone 5 mg)1
Prednisolone 5 mg
Betamethasone 750 micrograms
Deflazacort 6 mg
Dexamethasone (as base) 750 micrograms
Hydrocortisone 20 mg
Methylprednisolone 4 mg
Triamcinolone 4 mg
Factors in determining the parenteral dose

If converting to intravenous or intramuscular (rarely used)
hydrocortisone sodium succinate, consideration should be given to
the potency and pharmacokinetics of the usual oral drug relative
k to oral hydrocortisone. The exact dose of corticosteroid administered k
will vary depending upon the previous corticosteroid dose, duration
of therapy and the function of the HPA axis. Doses of supplementary
intravenous hydrocortisone sodium succinate range from 25 mg to
100 mg up to four times a day. Parenteral hydrocortisone is used until
the patient is able to tolerate oral corticosteroid again.2
Bear in mind that doses chosen have to be measurable in the
clinical setting, so round up as necessary.
Interactions with other drugs should be considered, since
clearance of some corticosteroids is increased by enzyme-inducing
drugs. For instance, bioavailability of dexamethasone is markedly
decreased by phenytoin.
Use of a high dose of parenteral hydrocortisone, given for more
than a few days, carries the risk of appreciable mineralocorticoid
effects such as fluid retention.
Dexamethasone
Dexamethasone sodium phosphate injection is usually widely
available and can be used to substitute for oral dexamethasone.
Traditionally the parenteral dose used is the same as the oral dose,
though this will in effect make more dexamethasone available
systemically. Caution is advised when prescribing parenteral
dexamethasone, taking care to differentiate between the base and the
sodium phosphate descriptions. Intravenous dexamethasone should
be prescribed as the dexamethasone base, i.e. 3.3 mg/mL.
k
k
96 Corticosteroids (topical)
Administration
It is preferable to administer hydrocortisone as an infusion
(as opposed to bolus doses) to avoid large swings in plasma cortisol
C concentration.2 Rapid injection of dexamethasone is also associated
with perineal itching.
Intravenous doses of hydrocortisone sodium succinate and
dexamethasone are commonly administered in 50 mL or 100 mL
minibag infusions of sodium chloride 0.9%, over 20 –30 minutes.
N.B.: 100 mL infusions are usually cheaper and are therefore more
suitable for routine use unless the patient is volume- or
sodium-restricted.
REFERENCES
2 Rahman MH, Beattie J (2004). Medication in the peri-operative period. Pharm J
272: 287–289.
Corticosteroids (topical)
Topical corticosteroids (TCs) are used to suppress or relieve the signs
and symptoms of a wide variety of inflammatory skin conditions.
Common conditions include eczema, psoriasis, contact dermatitis and
insect stings. They are not curative and may cause a rebound
k exacerbation when stopped. They are generally used when other k
measures, such as emollients, are not effective (see Emollients entry).
TCs may worsen several concomitant skin conditions; they are
contraindicated in rosacea and are not recommended for acne. They
should be used with caution in ulcerated or secondarily infected
lesions unless combined with an appropriate anti-infective agent.1
Choice of preparation
There are many different TC preparations available and choice is
according to patient preference, formulation and potency.
Formulation
Ointments produce a deeper, more prolonged emollient effect and are
useful for dry, thick, scaly lesions. They also increase efficacy of the
TC by occlusion so tend to be preferred to creams. However, patients
may prefer to use creams on exposed areas such as the face. Creams
may also be of benefit in producing a cooling effect or if the skin is
moist or wet. Creams should be used in preference to ointments if the
skin is infected, to avoid occluding the area. Lotions and gels are
preferred for hairier areas of the body, especially the scalp.
Potency
TCs are divided into four potencies: mild, moderate, potent and very
potent. The least potent corticosteroid to produce the required effect
should be prescribed. Choice of preparation is based on several
factors, shown in Table C12.
k
k
Corticosteroids (topical) 97
TABLE C12
Factors to consider in choice of topical corticosteroid
preparations
Patient’s age Children are more susceptible to adverse effects and are C
usually prescribed milder preparations
Severity of the disease A moderate or potent preparation may be required to treat
a disease flare or where a flare has not responded to a
milder preparation. This should be stepped down to a
lower-potency preparation once the flare comes under
control
Body site A mild preparation should be used for areas where skin is
thin, e.g. face, genitals, flexures. Potent preparations may
be required for thick areas of the skin, e.g. scalp, palms of
hands, soles of feet
Size of the affected area A less potent preparation may be preferred for widespread
use to reduce the risk of systemic absorption of the
corticosteroid
Concomitant treatments Bandaging therapy will increase the potency of the
steroid, so a lower-potency preparation should be used
Dose and application

TCs should be applied once or twice daily. Recommendations to apply
TCs sparingly often result in underdosing and ineffective treatment.
The amount of steroid to be used to treat a particular area is most
k commonly expressed as the fingertip unit (FTU). The FTU is the k
amount of cream or ointment from a tube squeezed from the tip of an
adult index finger to the first crease. One FTU is approximately 0.5 g
and is enough to treat an area of skin equivalent to two adult hands.
Table C13 shows dosing quantities for TCs using the FTU.
TABLE C13
Dosing quantities of topical corticosteroids2,3
Face and Arm and Leg and Trunk – Trunk – back,
neck hand foot front including buttocks
Age Number of fingertip units
3–6 months 1 1 1 1/2 1 1 1/2
1–2 years 1 1/2 1 1/2 2 2 3
3–5 years 1 1/2 2 3 3 3 1/2
6–10 years 2 2 1/2 4 1/2 3 1/2 5
Adult 2 1/2 4 8 7 7
Course length
A course of 1 –2 weeks should be adequate to bring a disease flare
under control. Longer courses of treatment increase the risk of side
effects and of a rebound flare once the steroid is discontinued. Once a
disease flare has responded adequately, treatment should be tapered
to less potent steroids and then to emollients.
k
k
98 CosmoFer
There are concerns about overuse of TCs in psoriasis. They are of

most value in acutely inflamed plaques, and the British Association of
Dermatology has issued the following guidance:4
C ● Do not use regularly for more than 4 weeks without review.
● Do not use potent steroids regularly for more than 7 days.
● Review every 3 months.
● Do not apply more than 100 g per month of a moderately potent or
higher-potency preparation.
● Attempt to rotate topical steroids with non-steroid preparations.
Pharmaceutical care and counselling points
● Steroid phobia due to perceived risks of the side effects of TCs is a
common cause of patients undertreating their skin disease.
Reassure patients that side effects are uncommon when mild or
moderately potent steroids are used in short bursts.
● Ensure patients understand how much steroid to use, where and
when to apply it and for how long. Some patients may have
different-potency preparations for different areas of the body and
will need to be clear which to use where.
● TCs should not be applied within 30 minutes of emollient. There is
no consensus as to the order in which emollients and steroids
should be applied and patients should be advised to choose a
regimen that fits their lifestyle.
k ● Treatment failure with TCs may indicate infection. k
REFERENCE
2 Anonymous (1999). Using topical corticosteroids in general practice. MeReC Bull
10: 21–24.
3 Bewley A (2008). Expert consensus: Time for a change in the way we advise our
patients to use topical corticosteroids. Br J Dermatol 158: 917–920.
4 British Association of Dermatologists (2015). Psoriasis. http://www.bad.org.uk/
healthcare-professionals/psoriasis (accessed 4 May 2015).
CosmoFer
Overview1
Form Iron (III) (as iron (III)–hydroxide dextran complex)
Dose Total dose required (mg iron) = [body weight (kg) × (target
haemogloblin (Hb) – actual Hb (g/L)) × 0.24] + X
X = 500 mg and is the milligrams of iron required to replace the body’s
iron stores (or depot iron) and is only applicable for patients >35 kg
k
k
CosmoFer 99
Administration Intravenous ‘total Intravenous Intramuscular

routes dose’ infusion instalments (intravenous route is
preferred route)
Yes Yes Yes C
Administration ● A dose of ● Doses of ● A series of undiluted
20 mg/kg is the 100–200 mg iron injections of up to
upper limit for a (2–4 mL) 100 mg iron each
total dose infusion preferably diluted ● Given by deep
● Doses >20 mg/kg in 10–20 mL intramuscular (IM)
should be split sodium chloride injection using the
● Dilute dose in 0.9% or glucose z-track technique
adequate volume 5% solution into the upper outer
of sodium chloride ● 25 mg of iron quadrant of the
0.9% or glucose should be injected buttock
5% (usually over 1–2 minutes ● Initial test dose
500 mL) ● If no reaction (prior to first dose
● The first 25 mg occurs within only): withdraw
iron should be 15 minutes the 25 mg (0.5 mL) and
given over a remainder of the give by IM injection.
period of injection may be Observe the patient
15 minutes (this given by slow carefully for signs of
dose is given from intravenous allergic reaction for
the prepared total injection at least 60 minutes;
dose infusion). (0.2 mL/min) if no adverse effects
● The patient should ● Another option is are seen, give the
be observed to give the dose in remainder of the
k closely for at least 100 mL sodium dose k
60 minutes chloride 0.9% and ● Daily injections into
● If no adverse infuse the 25 mg alternate buttocks
reactions are test dose over 15 may be given if the
seen, the minutes observing patient is
remainder of the for adverse moderately active
infusion dose can effects. If no ● Inactive or
be given, over reaction occurs, bedridden patients:
4–6 hours infuse the the frequency of
remainder or the injections should be
dose over 30 reduced to once or
minutes twice weekly
● Should be continued
until an adequate
haemoglobin level is
attained or the
calculated total dose
has been reached
Specific con- ● Decompensate liver cirrhosis and hepatitis
traindications ● Acute or chronic infection
● Acute renal failure
Monitoring ● A test dose must be given prior to the administration of every IV
dose1,2
● Patients should be monitored for signs and symptoms of
hypersensitivity reactions during and following each administration
by any route for at least 30 minutes2
● If hypersensitivity reactions or signs of intolerance occur during
administration, the treatment must be stopped immediately
k
kc03.tex
CPPC V2 - 11/18/2015 1:46 P.M. Page 100
100 C-reactive protein
REFERENCES
1 eMC (2014). Summary of Product Characteristics Cosmofer. https://www.medicines.
org.uk/emc/medicine/14139 (accessed 27 August 2014).
2 MHRA Drug Safety Update (2013). Intravenous iron and serious hypersensitivity
C reactions: strengthened recommendations. https://www.gov.uk/drug-safety-
update/intravenous-iron-and-serious-hypersensitivity-reactions-strengthened-
recommendations (accessed 29 August 2015).
C-reactive protein
C-reactive protein (CRP) is an acute-phase reactant protein used to
diagnose and monitor inflammatory and infectious disease. It is
named because of its ability to react with the C-polysaccharide of
Streptococcus pneumoniae.1 It is part of the innate immune response
and influences multiple stages of inflammation by activation of the
complement system.2 Synthesis is primarily in the liver and initiated
by antigen-immune complexes, bacteria, fungi and trauma.3
Advantages compared with the erythrocyte sedimentation rate
(ESR) include an earlier, more intense response within a few hours,
with concentration increases of 1000-fold possible. Changes also
occur faster relative to the patient’s condition. Disadvantages include
non-specificity (i.e. cause and location of the inflammation or
infection are not identified) and the use of sophisticated laboratory
equipment.2
k Reference range k
Levels of <10 mg/L can be expected in healthy individuals but this
can vary with age, sex and race.2
CRP can be raised in:1,3
● inflammatory disorders, e.g. Crohn’s disease, inflammatory
arthritis, vasculitis
● tissue injury, necrosis or rejection, e.g. in burns, myocardial
infarction, pulmonary emboli, transplant rejection
● bacterial infections, e.g. postoperative wound infections
● malignancy.
Some studies suggest that CRP may be an indicator of cardiovascular
events3 and the development of type 2 diabetes.1 However,
conditions such as viral infections, osteoarthritis, leukaemia,
anaemia, polycythaemia and pregnancy (although elevation may
occur in later stages) cause little or no rise in CRP.1
REFERENCES
1 Patient.co.uk (2014). Acute-phase Proteins, CRP, ESR and Viscosity. http://
www.patient.co.uk/doctor/acute-phase-proteins-crp-esr-and-viscosity (accessed 17
January 2015).
2 UpToDate (2014). Acute Phase Reactants. http://www.uptodate.com/contents/
acute-phase-reactants?source=search resultandsearch=crpandselectedTitle=2∼150
3 Pagana DK, Pagana TJ (2009). Mosby’s Manual of Diagnostic and Laboratory Tests,
4th edn. St Louis: Mosby.
k
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CURB-65 101
CURB-65
Background
All patients should have a CURB-651,2 score calculated when a diagnosis of community- C
acquired pneumonia is made. The scoring determines whether patients are at low,
intermediate or high risk of death, whether patients should be admitted to hospital and
the choice of empirical antibiotics to be commenced.
SCORING SYSTEM
Confusion (new onset – place, time, person) 1
Urea (>7 mmol/L)* 1
Respiratory rate (>30 breaths/min) 1
Blood pressure (diastolic ≤60 mmHg or systolic <90 mmHg) 1
Age (>65 years) 1
*There is a 5-point scoring system for patients presenting at hospital and a 4-point
scoring system for patients presenting in the community; in these patients the score for
urea is removed.
Interpretation
Score = 0–1
● Low risk (<3% mortality risk)
● Home-based care can be considered for those scoring 0 or 1
k ● Consider a 5-day course of a single antibiotic (e.g. amoxicillin) – choice will depend k
on local formulary
Score = 2
● Intermediate risk (3–15% mortality risk)
● Consider hospital-based care for those scoring 2 or more
● Consider a 7–10-day course of dual antibiotics (e.g. amoxicillin and a macrolide) –
choice will depend on local formulary
Score = 3–5
● High risk (>15% mortality risk)
● Consider intensive care assessment for those scoring 3 or more
● Consider a 7–10-day course of dual antibiotics (e.g. beta-lactamase and macrolide)
– choice will depend on local formulary
REFERENCES
1 Lim WS et al. (2003). Defining community-acquired pneumonia severity on pre-
sentation to hospital: an international derivation and validation study. Thorax 58:
377–382.
2 NICE (2014). Pneumonia: Diagnosis and management of community and hospital
acquired pneumonia in adults (CG 191). https://www.nice.org.uk/guidance/cg191
(accessed 8 February 2015).
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102 Cushing’s syndrome
Cushing’s syndrome
C Overview
Definition Cushing’s syndrome is caused by chronic exposure to excess levels of
corticosteroids from either exogenous or endogenous sources1,2
Risk factors Endogenous Cushing’s (Cushing’s disease) is usually a result of a
pituitary tumour (in 70% of cases)
Differential The symptoms of Cushing’s are slowly progressive and non-specific, so
diagnosis can be easily missed or attributed to other common conditions, including
depression and menopause. It may also mimic common metabolic
conditions, such as obesity, poorly controlled diabetes and hypertension
Diagnostic Diagnosis is based on a review of the patient’s medical history, physical
tests examination and laboratory tests:
● X-ray examinations of the adrenal or pituitary glands to locate
tumours
● 24-hour urinary free cortisol (positive result if the value is at least as
high as the upper limit of normal for the assay used)
● Late-night salivary cortisol
● 1 mg dexamethasone suppression test (09:00 serum cortisol (after
dexamethasone); <50 nmol/L excludes the disease)
● Plasma adrenocorticotrophic hormone (ACTH)
Treatment ● Reduction of glucocorticoid levels
goals
k Treatment Dependent on source of glucocorticoid excess:
k
options ● Stop exogenous glucocorticoid
● Surgery to remove pituitary adenoma
● Radiotherapy to destroy pituitary adenoma
● Medication to reduce effects of excess ACTH (usually in ectopic
tumours)
Assess Treatment of Cushing’s syndrome depends on the cause of excess
cortisol. If the cause is long-term use of glucocorticoid hormones to treat
another disorder, the dosage must be gradually reduced to the lowest
dose adequate for control of that disorder. Once control is established,
the daily dose of glucocorticoid hormones may be doubled and given on
alternate days to lessen side effects
Essential Surgical resection of the pituitary, adrenal or ACTH-producing tumour is
intervention the primary treatment of choice and is often curative
Secondary Medical therapy is used to inhibit synthesis and secretion in the adrenal
intervention gland. Originally the choices were restricted to unlicensed therapies, with
inhibition as a known side effect. The three main drugs used were
ketoconazole, metyrapone and mitotane. These drugs are not usually
effective as the sole long-term treatment of the disorder, and are used
mainly either in preparation for surgery or as adjunctive treatment after
surgery, pituitary radiotherapy or both procedures. Frequently, control of
hypercortisolism is lost with corticotropin oversecretion, known as
escape3
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Cushing’s syndrome 103
Secondary There is now one licensed therapy for the treatment of Cushing’s disease
intervention (endogenous) that is not suitable for surgery or where surgery has failed.
Pasireotide (Signifor) is given as a 0.6 mg subcutaneous injection twice a
day.4 Ketoconazole HRA has just been recommended for a licence for the C
treatment of Cushing’s by the EMA. This is so new to the market that
there is currently very little detail about its cost and dosing regimen;
however, it is likely to match the unlicensed use in practice5
Continued Monitoring for signs of treatment effectiveness is required in Cushing’s
monitoring syndrome. The pituitary–adrenal axis must be evaluated 6–12 months
after surgery. Patients who have achieved remission should also be
screened every 6–12 months for recurrence of disease. One of the tests
used for diagnosis should be performed to detect recurrence (see above).
Standard testing, follow-up and management for associated conditions
of hypertension, diabetes and osteoporosis should be undertaken, as
these conditions may persist after effective treatment of hypercortisolism.
Pasireotide has a number of monitoring requirements due to its possible
side effects:4
● Glycaemic status (FPG/HbA1c ) should be assessed prior to starting
treatment. Self-monitoring of blood glucose and/or FPG assessments
should be done weekly for the first 2–3 months and periodically
thereafter, as clinically appropriate, as well as over the first 2–4
weeks after any dose increase. In addition, monitoring of FPG 4
weeks and HbA1c 3 months after the end of the treatment should be
performed
● Monitoring of liver function prior to treatment and after 1, 2, 4, 8 and
12 weeks during treatment. Thereafter, liver function should be
k monitored as clinically indicated k
● An ECG should be performed prior to the start of therapy, 1 week
after the beginning of treatment and as clinically indicated thereafter.
● Hypokalaemia and/or hypomagnesaemia must be corrected prior to
administration of pasireotide and should be monitored periodically
during therapy
● Hypocortisolism is a risk with treatment. Patients should be warned of
the signs and symptoms associated with hypocortisolism
(e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension,
hyperkalaemia, hyponatraemia and hypoglycaemia)
REFERENCES
1 Prague JK (2013). Cushing’s syndrome. BMJ 346: f945.
2 Pluta RM et al. (2011). Cushing syndrome and Cushing disease. JAMA 306: 2742.
3 Newell-Price J et al. (2006). Cushing’s syndrome. Lancet 367: 1605–1617.
4 SPC (2014). Signifor. www.emc.medicines.org.uk (accessed 16 August 2014).
5 European Medicines Agency (2014). Press Release: Ketoconazole HRA recommended
for approval in Cushing’s syndrome. http://www.ema.europa.eu/ema/index.jsp?
curl=pages/news and events/news/2014/09/news detail 002174.jspandmid=
WC0b01ac058004d5c1 (accessed 9 October 2014).
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104 Cytotoxic chemotherapy waste
Cytotoxic chemotherapy waste

The List of Wastes (England) Regulations 2005 specifies that cytotoxic
C waste should be considered to be hazardous.1
The Waste (England and Wales) Regulations 2011, The Special
Waste Amendment (Scotland) Regulations 2004 and Special Waste
Regulations (Northern Ireland) 1998 cover storage and disposal of
cytotoxic waste.2 – 4 It is important to note that the definition of
cytotoxic and cytostatic used in waste classification is broader than
the term ‘cytotoxic’ used by the BNF and as such the BNF should not
be used to classify waste.5
All materials used in the preparation and administration of
cytotoxic chemotherapy should be classed as cytotoxic waste. This
includes syringes, gloves and needles. All waste should be placed in
clearly marked sharps containers, bags or bins for disposal. They must
be segregated from other types of waste.
Spillage of cytotoxic agents must be dealt with promptly. Staff
should be familiar with local standard operating procedures and
regularly trained to deal with cytotoxic spillages. Cytotoxic spill kits
should be made available in all areas where cytotoxic drugs are used.
These should comprise: ChemoSorb pads or absorbent granules, at
least two pairs of gloves (e.g. Chemoprotect), protective gown, shoe
coverings, head cover, masks, safety glasses, dilute alkali detergent
solution, water, tweezers for broken glass and a sign to identify the
k spill. A respirator may be included, as may an eyebath. k
The following principles should apply when dealing with cytotoxic
waste/spillages:
● Safe handling, good practice and training should be adhered to in
order to minimise the risk of spillages.
● Spillages should be treated using different procedures according to
the size and type (dry or liquid).
● All equipment and materials used to deal with the spill should be
treated as cytotoxic waste.
● COSHH data sheets for cytotoxic drugs should be available at all
times.
● Ensure spillage is recorded in an accident reporting form. Note
details of the day, date, drug, approximate volume, liquid or
powder, and the name of the person/people and location involved.
Check with your local procedure for dealing with cytotoxic waste.
A suggested procedure is given below.
Initial procedure for all small and large spills
1 Assess the spill for size, type (dry or liquid), drug involved and
danger to others.
2 Call for assistance and warn others. Do not leave spill site
unguarded. This is to prevent others from being exposed to
cytotoxic material. If a ‘Warning! Cytotoxic spill’ sign is available,
this should be placed at the site of the spillage.
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Cytotoxic chemotherapy waste 105
3 Individuals should be protected by wearing gloves (double-glove),

facemask, goggles, shoe protection and gowns. A respirator may be
required for powder spills.
4 The spill area should be cordoned off to avoid further spread. C
Procedure for managing small spills (<5 mL or 5 g)
1 Gently cover and absorb liquid spills with dry absorbent towels.
Avoid splashing.
2 Pick up solids (powder) with a moistened towel (use water).
3 Pick up sharp/broken material, preferably with forceps or swab;
otherwise always double-glove and ensure adequate thickness.
4 Place sharps in a sharps bin labelled ‘Cytotoxic waste’ and then in
a heavy-duty yellow bag to await destruction.
5 Ensure that bags or bins are sealed and clearly marked as
‘Cytotoxic waste’.
6 All packaging material contaminated with the drug should be
similarly placed in a plastic bag or sharps container for
incineration as appropriate.
7 Label and treat all waste from the spill as cytotoxic.
8 The spillage area should be cleaned at least three times using mild
detergent followed by large amounts of clean water.
9 Wash hands thoroughly and record spill in a cytotoxic spill book.
10 Exposure to cytotoxic drugs should be recorded and notified to the
occupational health department.
k k
Large spills (>5 mL or 5 g)
1 Work from the outside in.

2 Use the cytotoxic spill kit.
3 Lay the ChemoSorb spill pad from the spill kit over the spill or
sprinkle absorbent granules over the spill area.
4 The pad/granules will absorb the liquid and transform the spill
into a gel, which can be handled more easily.
5 Gather up the gel and place in a plastic bag and seal. Ensure that
this is labelled as ‘Cytotoxic waste’.
6 Repeat these steps several times.
7 After removal of the cytotoxic agent, the area should be cleaned at
least three times using a mild detergent and clean water.
8 Use the remaining spill pads to pick up the rinse water and fully
dry the area using absorbent towels.
9 Discard all contaminated material in disposal bag, including
gloves and shoe coverings, and then seal. Ensure the bag is
labelled as ‘Cytotoxic waste’.
10 Wash hands thoroughly and record spill.
11 Inform the occupational health department.
Additional information can be found on the HSE website

(www.hse.gov.uk), where further information on conducting risk
assessments can be found.6
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106 Cytotoxic chemotherapy waste
Patient waste
Patients receiving cytotoxic chemotherapy will also produce cytotoxic
waste. Their faeces, urine, sweat and expired gases may all contain
C cytotoxic drug, either as unchanged drug or active/inactive
metabolite. As such, patient waste must be handled as cytotoxic waste
for up to 14 days after administration. Urinals, bedpans and vomit
bowls should be handled with gloves and disposed of in an
appropriate manner. Hospital policies may vary and should be
consulted. Contaminated bed linen should also be treated in an
appropriate manner, e.g. in alginate bags marked with cytotoxic
material tape.
REFERENCES
1 The List of Wastes (England) Regulations 2005. http://www.legislation.gov.uk/
uksi/2005/895/made (accessed 15 December 2014).
2 The Waste (England and Wales) Regulations 2011. http://www.legislation.gov.uk/
ukdsi/2011/9780111506462/pdfs/ukdsi 9780111506462 en.pdf (accessed 15
December 2014).
3 The Special Waste Amendment (Scotland) Regulations 2004. http://
www.legislation.gov.uk/ssi/2004/112/pdfs/ssi 20040112 en.pdf (accessed
15 December 2014).
4 The Special Waste Regulations (Northern Ireland) 1998. http://www.legislation
.gov.uk/nisr/1998/289/contents/made (accessed 15 December 2014).
5 Department of Health (2013). Health Technical Memorandum 07-01: Safe
management of healthcare waste. https://www.gov.uk/government/uploads/
system/uploads/attachment data/file/167976/HTM 07-01 Final.pdf (accessed 15
k December 2014). k
6 HSE (2014). Safe Handling of Cytotoxic Drugs in the Workplace. http://hse.gov.uk/
healthservices/safe-use-cytotoxic-drugs.htm (accessed 15 December 2014).
k
k
D-dimer 107
D D
D-dimer
D-dimer levels are tested to help diagnose, exclude or monitor
thrombotic or bleeding conditions, such as deep-vein thrombosis
(DVT), pulmonary embolus and disseminated intravascular
coagulation.1 It is a fibrin degradation product and consists of
adjacent fibrin monomers that have been cross-linked (d-dimerised)
by activated factor XIII and subsequently cleaved by plasmin during
the process of clotting and clot degradation.2,3 It is usually
undetectable in the blood.
Reference range
The reference range for a normal D-dimer will depend on the
laboratory performing the test, but commonly a value of <500 μg/L is
considered normal.4
k Local range . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . k
However, the D-dimer test is non-specific and can be raised in many
conditions that involve fibrin formation and degradation (Table D1).
For this reason its main use in clinical practice is excluding venous
thromboembolism and a normal result can rule
out the possibility of DVT in up to 97% of cases.4
TABLE D1
Conditions and factors increasing D-dimer levels
Conditions increasing D-dimer levels5 Factors increasing D-dimer levels5
Severe infection Pregnancy
Trauma Age
Inflammatory conditions Smoking
Unstable angina Haemolysis of sample
Atrial fibrillation Raised rheumatoid factor levels
Acute myocardial infarction Raised bilirubin levels
Vasculitis Presence of fats (from greasy meal)
Treatment with heparins and oral anticoagulants can lower D-dimer

levels.6
REFERENCES
1 Lab Tests Online UK (2014). D-dimer. http://www.labtestsonline.org.uk/
understanding/analytes/d-dimer/tab/glance/ (accessed 17 January 2015).
k
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108 Delirium
2 UpToDate (2014). Clinical Use of Coagulation Tests. http://www.uptodate.com/

contents/clinical-use-of-coagulation-tests?source=search result&search=d+dimer&
selectedTitle=1∼114#H19 (accessed 17 January 2015).
3 Pagana DK, Pagana TJ (2009). Mosby’s Manual of Diagnostic and Laboratory Tests,
4th edn. St Louis: Mosby.
D 4 perinatology.com (2010). Reference Values During Pregnancy. http://
www.perinatology.com/Reference/Reference%20Ranges/D-Dimer.htm
5 NHS Choices (2014). Deep Vein Thrombosis. http://www.nhs.uk/Conditions/
Deep-vein-thrombosis/Pages/Diagnosis.aspx (accessed 17 January 2015).
6 GP notebook (2010). D-dimer. http://www.gpnotebook.co.uk/simplepage.cfm?ID=
26869806 (accessed 17 January 2015).
Delirium
Overview
Definition An acute-onset mental disorder characterised by:
● Change or fluctuating mentation, i.e. mental activity, state of mind
● Inattention
and either one or both of:
● Disorganised thinking
● Altered level of consciousness
Causes Multiple potential causes include (not an exclusive list):
● Drugs (often antimuscarinics, benzodiazepines) or drug withdrawal
k (alcohol, nicotine, illicit drugs or any prescription-only medicine) k
● Eyes, ears and other sensory deficits
● Low oxygen states (hypoxia, MI, cerebrovascular accident (CVA), PE)
● Infection or inflammatory states
● Retention (urinary or constipation)
● Ictal, postictal
● Underhydration and/or undernutrition
● Metabolic (diabetes, postoperative patients, hypernatraemia)
Classification The Diagnostic and Statistical Manual of Mental Disorders (DSM-V)1
recognises classification by aetiology as a result of:
● A general medical condition
● An intoxicating substance (inattention and cognitive effects
predominate)
● Substance withdrawal (inattention and cognitive effects predominate)
● Medication-induced (temporal relationship predominates)
● More than one cause
Delirium is often further specified by motoric form. This system helps
highlight that a large group of patients are delirious but not agitated
(and therefore not drawing attention to themselves):
● Hyperactive: agitated, restless, combative (1–2%)
● Hypoactive: drowsy, withdrawn, non-communicative (40–45%)
● Mixed: oscillates between hyperactive and hypoactive (45–50%)
DSM-V recognises delirium can be acute (lasting a few days) or persistent
(lasting weeks to months)
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Delirium 109
Signs and Sudden changes (over hours or days) or fluctuations in behaviour, often
symptoms more obvious to regular carers or family. Hypoactive behaviour is more
difficult to pick up.2
● Cognitive function, e.g. worsened concentration, slow responses,
confusion
● Perception, e.g. visual or auditory hallucinations D
● Physical function, e.g. reduced mobility, reduced movement,
restlessness, agitation, changes in appetite, sleep disturbance (rule
out other reasons for agitation, e.g. untreated pain, frustration)
● Social behaviour, e.g. lack of cooperation with reasonable requests,
withdrawal, or alterations in communication, mood and/or attitude
Diagnostic Screening tools are available that look for the main points listed under
tests the definition above.
The most widely used tool is the Confusion Assessment Method (CAM).
Patients are interviewed, often by applying another intervention (e.g.
Mini Mental State Examination (MMSE)) in order to generate interaction.
The screener then reflects on the patient interaction to evaluate
systematically for delirium: evidence for acute mental change/fluctuation,
inattention, disorganised thinking, altered level of consciousness
Goals Prevent delirium; alleviate symptoms; control behavioural aspects if
necessary to maintain safety
Prevention A comprehensive intervention package that targets the main drivers for
delirium reduces the incidence of new delirium:
● Drugs: carry out a medication review, removing unnecessary
treatments and reducing exposure to medications known to cause
k delirium. Anticipate and treat withdrawal syndromes k
● Eyes, ears and other sensory deficits: ensure spectacles and hearing
aids are working and available
● Low-oxygen states (hypoxia, MI, CVA, PE): assess for hypoxia and
optimise O2 saturation; treat underlying/causative conditions
● Infection or inflammatory states: look for and treat infection, avoid
unnecessary catheterisation, employ good infection control
procedures
● Retention (urinary or constipation): prescribe laxatives where
necessary; manage urinary retention
● Ictal, postictal: look for seizures and control precipitants
● Underhydration and/or undernutrition: encourage the person to drink,
have fluid management plans. Offer parenteral fluids where
necessary; maintain fluid charts and monitor. Monitor for appropriate
nutrition; ensure dentures fit if needed. Ensure tube feeding where
required
● Metabolic (diabetes, post-op, hypernatraemic): monitor appropriate
biochemical markers
● Monitor and correct underlying problems, manage comorbidities
In addition, NICE Clinical Guideline 1032 advises other sensible
measures, such as promoting good sleep hygiene, managing pain
appropriately and encouraging the person to mobilise/walk and carry out
active range-of-motion exercises. Orientation is important: use clear
signage, clocks and calendars. Reorientate the person by explaining who
the patient is, where s/he is and who you are. Facilitate visits by family
and friends and encourage interaction. Prophylactic antipsychotics are
not recommended
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110 Delirium
Treatment Prevention measures should be (re)visited and employed. In delirium

options2 superimposed upon dementia, treat the delirium as usual.
Delirium treatment with medication has two aims: treating cognitive
defect and maintaining safety. These should be kept clearly in mind, as
targeting one outcome may make the other less achievable and an
D appropriate balance must be sought
Treat cognitive deficit
Antipsychotics are frequently used in an attempt to clear the mind of the
individual afflicted with delirium. NICE Clinical Guideline 1032 bases
recommendations on one study and, although the treatments are
randomised in that study, they are not blinded (i.e. oral olanzapine versus
intramuscular haloperidol versus no drug therapy).
● Haloperidol: 1–5 mg enterally or parenterally, usually three to four
times a day
● Olanzapine: 5–10 mg enterally or parenterally usually once,
occasionally twice, a day
It is clear that the medication does not work immediately. In the study it
took an average of 3 days for the delirium to clear (7 days in control
group). Any acute resolution of behavioural symptoms (e.g. agitation) is
likely due to sedative side effects.
Since NICE Clinical Guideline 103,2 there have been other studies
looking at quetiapine. The studies are well conducted,
placebo-controlled, blinded, randomised, but small. However, they do
show that the number of days in delirium is reduced.3,4
● Quetiapine: 25–100 mg enterally twice a day (larger doses rarely
k used) k
Maintain safety
The dangerously agitated patient is likely to require sedation to maintain
the safety of the patient, staff and visitors. Unfortunately sedatives
further cloud the patient’s consciousness, so although sedatives do help
calm the patient and manage the danger in the situation, they can render
the patient more delirious. An exception to this includes benzodiazepine
administration in alcohol or benzodiazepine withdrawal delirium
(depending on the quantity administered).
● Use the minimum dose necessary for effect
Choose the best drug for the situation (e.g. intramuscular midazolam for
short-acting effect in Critical Care; diazepam for a longer-acting effect in
a general ward area)
Therapeutic Review the medication chart to reduce the burden from medications
review likely to cause delirium, particularly:
● medications with strong anticholinergic drive (e.g. amitriptyline,
hyoscine, cyclizine)
● gamma-aminobutyric acid (GABA) agonists (e.g. temazepam,
lorazepam)
● other medications known to cause confusion (e.g. steroids,
quinolones)
● potential withdrawal (e.g. nicotine, opiates, antidepressants)
Switch to medications with lower deliriogenic potential, or reduce the
dose if possible. Avoid changing the therapeutic approach every day.
Ensure any plan makes the longer-term goals explicit, with
stepwise/short-term goals to measure and highlight progress
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Delirium 111
Antipsy- Antipsychotics are not likely to work immediately, and with florid
chotics delirium are not likely to work at all until the drivers are removed.
● Monitor QTc interval
● Start at an appropriate dose and route
● Recognise that you may need a rescue option for rapid sedation
● Monitor for extrapyramidal side effects and the rare possibility of D
neuroleptic malignant syndrome
● Do not use in patients with Parkinson’s disease – here consider
reducing regular therapy temporarily
● When stopping, reduce the dose/frequency over a few days, with the
nighttime dose being the last to stop
● Make it clear the antipsychotic is for delirium and is expected to cease
in the short- to mid-term. Most prescriptions should stop within
7–14 days and all within 1 month (with the exception of a tiny
minority of cases). Further underscore the short-term nature of
antipsychotic therapy in patients with dementia
Sedatives Used to make the patient safe; they are not to make the patient tidy/easy
to manage.
● They may make delirium worse
● Use the smallest dose for the shortest possible time
● May need repeating
Night Sleep is often fragmented in delirious patients and there is a temptation
sedation and to use sleep aids. Avoid deliriogenic medicines such as GABA agonists
sleep aid (benzodiazepines, z-drugs) and tricyclic antidepressants.
● Try a slightly larger dose of the regular antipsychotic late evening
(e.g. haloperidol 1 mg three times daily and 2.5 mg at night)
k ● Trazodone 50 mg at night, increasing to 100 mg late evening. May
k
cause hypotension, although not normally at these doses. May very
rarely cause priapism
● Mirtazapine 15–30 mg late evening
● Some centres use melatonin, no more than 5 mg late evening
REFERENCES
1 American Psychiatric Association (2013). Diagnostic and Statistical Manual of
Mental Disorders, DSM-5 (5th edn). Arlington: American Psychiatric Association.
2 NICE (2010). Clinical Guideline 103. Delirium: Diagnosis, prevention and manage-
ment. http://www.nice.org.uk/guidance/CG103 (accessed 10 October 2014).
3 Devlin JW et al. (2010). Efficacy and safety of quetiapine in critically ill patients
with delirium: a prospective, multicenter, randomized, double-blind, placebo-
controlled pilot study. Crit Care Med 38: 419–427.
4 Tahir TA et al. (2010). Randomized controlled trial of quetiapine versus placebo in
the treatment of delirium. J Psychosom Res 69: 485–490.
k
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112 Depression
Depression
Overview
Definition Depression is a common and recurrent disorder characterised by
D persistent low mood and anhedonia (the inability to experience pleasure
from activities usually found enjoyable). Depressive disorder is associated
with significant morbidity and mortality
Classification May be classified using either the International Classification of
Disease-10 (ICD-10)1 (‘depressive episode’, further specified as mild,
moderate or severe) or DSM2 (‘major depression’, further specified as
mild, moderate or severe). The current NICE guideline uses DSM-IV
diagnostic criteria and definitions of severity3
Differential May include neurological conditions, other psychiatric conditions
diagnoses (including bipolar affective disorder, anxiety disorders, personality
disorders and negative symptoms of schizophrenia), organic brain
disorder, hypoglycaemia, anaemia, endocrine disorders (including
hypothyroidism), bereavement, sleep apnoea and iatrogenic causes
(e.g. antihypertensives, steroids, oestrogens and central nervous system
depressants)
Diagnostic There is no specific test for depression. Investigations are of importance
tests in order to exclude possible causes
Treatment Remission of symptoms of depression, prevention of relapse, reduction in
goals morbidity and mortality and restoration of premorbid social and
occupational functioning
k Treatment Subthreshold symptoms and mild depression: sleep hygiene and k
options3 active monitoring. Do not use antidepressants unless there is a history of
moderate or severe depression. Consider low-intensity psychological
intervention.
Persistent subthreshold symptoms and those who have not
benefited from low-intensity psychological intervention:
antidepressants or high-intensity psychological intervention.
Moderate or severe depression: antidepressants, high-intensity
psychological interventions and combined treatments (when two
antidepressants are used together)
Choice Patients should be supported to make informed decisions about their
care and these should be considered during development of the care
plan. In addition to patient choice, the following factors should be taken
into account when making decisions regarding choice of medication:
comorbidities and concurrent medication, other patient-specific factors
(e.g. lifestyle, physical health and predominant symptoms), national and
local guidelines/policies, likely adherence to medication, risk of accidental
or deliberate overdose, previous response and potential adverse effects
The options presented here are from NICE guidance3 and concern the treatment of
people aged 18–60 years only. Note that the recommended treatment varies in the
presence of a chronic physical health problem. Consult relevant guidelines in this case
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Depression 113
Assess ● An accurate medication history will aid in decision making regarding

an appropriate treatment plan
● Explore any concerns the patient has regarding the pharmacological
treatment of depression and provide relevant information3
● Determine likely adherence and suicide risk
D
Selective ● SSRIs are usually the first-line choice due to tolerability and relative
serotonin safety in comparison to TCAs3,4
reuptake ● Increase synaptic serotonin levels by inhibiting the serotonin reuptake
inhibitors transporter
(SSRIs) ● Side effects: GI disturbance, sexual dysfunction, motor symptoms
(particularly akathisia), anxiety, increased risk of GI bleeding,
insomnia, serotonin syndrome (see Serotonin syndrome entry for
further details)
● Risk of GI bleeding is further increased in the presence of NSAIDs and
aspirin. Consider gastroprotection
● Fluoxetine (t 1/2 ≈ 140 hours): lower risk of discontinuation
symptoms, higher propensity for drug interactions, associated with
bruxism (grinding the teeth and clenching the jaw)
● Paroxetine (t 1/2 ≈ 24 hours): higher risk of discontinuation symptoms,
inhibits its own metabolism, possibly greater weight gain with
long-term use5
● Sertraline: Most cost-effective of the SSRIs.6 Antidepressant of choice
post-MI; few interactions but higher rates of diarrhoea than others.
● Citalopram: very few interactions. Associated with dose-related QTc
prolongation
● Escitalopram is the S-enantiomer of racemic citalopram
k ● Start with low doses where there is a significant anxiety component k
to the presentation and increase very slowly
Tricyclic ● Increase synaptic levels of serotonin and noradrenaline by blocking
antidepres- the relevant reuptake transporters. Different TCAs block the two
sants transporters to different degrees, leading to slightly different clinical
(TCAs) and side effect profiles
● Can be considered if switching from SSRIs following lack of response
● Doses less than 100 mg daily are unlikely to be effective7
● Greatest risk in overdose
● Increased risk of discontinuation due to side effects compared to
SSRIs
● Dosulepin should not be prescribed due to cardiotoxicity3
● TCAs are as effective as SSRIs but their use is limited by their side
effects: sedation, central and peripheral antimuscarinic effects,
hypotension, cardiac toxicity and behavioural toxicity (reduction in
psychomotor activity or cognitive ability)
● Contraindicated in heart block, recent MI and mania or hypomania
Venlafaxine ● Inhibits reuptake of both serotonin and noradrenaline but also
dopamine at higher doses (i.e. >225 mg). At lower doses (i.e. 75 mg
daily) the pharmacological effect is predominantly on serotonin
reuptake, meaning it behaves similarly to an SSRI. At doses >150 mg
daily, synaptic noradrenaline levels are also increased.
● Clinical effect may therefore be superior at higher doses, but this is
controversial.
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114 Depression
● Side effects and discontinuation rates are more problematic than with
some SSRIs
● Tachycardia, prolonged QTc and seizures can occur in overdose, but
fatality is rare
● Sustained-release formulations may be associated with fewer side
D effects, particularly nausea
Mirtazapine ● Most cost-effective antidepressant in a 2009 analysis6
● 5-HT2/3 antagonism means less nausea and sexual dysfunction than
with SSRIs
● Can be more sedating at lower doses, where alerting effect of
increased noradrenergic transmission is dominated by the sedating
effects of histamine receptor antagonism
● In addition to sedation, weight gain can be problematic in some
patients
● Sometimes combined with venlafaxine (this combination is known as
‘Californian rocket fuel’) for a synergistic effect
● May be preferred for patients on warfarin or heparin. International
normalised ratio may increase slightly
● Withdraw immediately and perform full blood count if blood
dyscrasias suspected
Duloxetine ● May be useful for those with a significant somatic component to their
depressive illness
Monoamine ● Associated with the ‘cheese reaction’ following dietary tyramine,
oxidase which can result in hypertensive crisis and death
inhibitors ● In addition to restrictions to diet, several significant drug–drug
k (MAOIs) interactions exist k
● A 2-week wash-out period is necessary when switching between
MAOIs and other antidepressants to reduce the risk of serotonin
syndrome
Reboxetine ● Least efficacious and least acceptable antidepressant in a 2009
review6
Trazodone ● Serotonergic reuptake inhibition is not saturated at doses less than
150 mg daily and so antidepressant effect is lost
Agomelatine ● Monitor LFTs
● Not associated with weight gain or sexual dysfunction
Combination ● Antidepressants can be combined with other antidepressants or
and aug- augmented using lithium or atypical antipsychotics
mentation ● Where combinations of serotonergic agents are used, monitor for
serotonin syndrome
● With lithium, all the usual monitoring requirements apply (see
Lithium – management and monitoring entry)
● When augmenting with atypical antipsychotics, consider risk of
weight gain and hyperglycaemia in addition to monitoring LFTs, lipids
and electrocardiogram where indicated
Response ● Clinical response can be expected in the first 1–2 weeks of treatment
● Check compliance if there is no improvement in the first 2–4 weeks
● Absent or minimal effect at 3–4 weeks warrants a change in
treatment
k
k
Depression 115
Patient ● Antidepressants are effective

counselling ● It is important to take antidepressant medication as prescribed and
not to stop suddenly due to risk of discontinuation symptoms
● Treatment will continue beyond symptom remission and the duration
will depend on the risk of recurrence
● Antidepressants are not addictive D
● Side effects are relevant to the specific treatment chosen along with
suitable management/monitoring strategies
Continued ● In addition to monitoring for clinical and side effects relevant to the
monitoring individual, be aware that most antidepressants have been associated
with hyponatraemia. If symptoms occur, monitor serum sodium and
consider fluid restriction and withdrawal of the antidepressant
accordingly. If no other cause of hyponatraemia can be identified,
stop the antidepressant immediately and if the patient has serum
sodium below 125 mmol/L, treat medically for hyponatraemia.
Antidepressant withdrawal symptoms should be anticipated, but are
unlikely to occur if the hyponatraemia occurs soon after initiation of
antidepressant treatment
● Following hyponatraemia, use of an antidepressant from a different
class is recommended.7 Start at a low dose and increase slowly.
Monitor serum sodium weekly initially
● Those not deemed to be at increased risk of suicide should be
reviewed 2 weeks after starting an antidepressant. For those under
30 years or considered to present a higher risk, review at 1 week and
then frequently until risk is no longer clinically important3
Duration of The treatment dose of the effective antidepressant should be continued
k treatment for a minimum of 6 months from the point of remission of symptoms, k
taking into account the number of previous episodes, any concurrent
physical health or psychosocial difficulties and the existence of any
residual symptoms
Withdrawing ● Potentially severe discontinuation symptoms can occur when an
treatment antidepressant is stopped
● Gradually withdraw over a period of at least 4 weeks, and consult a
standard reference (Maudsley7 or Bazire8 ) for more detail
Further Bleakley S (2013). Review of the choice and use of antidepressant drugs.
reading Progr Neurol Psychiatry 17: 18–26.
REFERENCES
1 WHO (2015). International Classification of Diseases (ICD). http://www.who.int/
classifications/icd/en/ (accessed 8 May 2015).
2 American Psychiatric Association (2000). Diagnostic and Statistical Manual of
Mental Disorders (4th text revision edn). Washington, 3. DC: American Psychiatric
Association.
3 NICE (2009). Clinical Guideline 90. Depression in Adults. http://www.nice.org.uk/
guidance/CG090 (accessed 27 April 2015).
4 Anderson IM et al. (2008). Evidence-based guidelines for treating depressive
disorders with antidepressants: A revision of the 2000 British Association for
Psychopharmacology guidelines. J Psychopharm 22: 243–296.
5 Deshmukh R, Franco K (2003). Managing weight gain as a side effect of antidepres-
sant therapy. Clevel Clin J Med 70: 614–623.
k
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116 Diabetes insipidus (cranial)
6 Cipriani A et al. (2009). Comparative efficacy and acceptability of 12 new-

generation antidepressants: a multiple-treatments meta-analysis. Lancet 373:
746–758.
7 Taylor D et al. (eds) (2012). The Maudsley Prescribing Guidelines in Psychiatry,
11th edn. Chichester: Wiley-Blackwell.
D 8 Bazire S (2013). Psychotropic Drug Directory 2013/14: The professionals’ pocket
handbook and aide memoire. Cheltenham: Lloyd-Reinhold Communications.
Diabetes insipidus (cranial)

Overview
Definition Diabetes insipidus (DI) is defined as the passage of large volumes
(>3 L/24 hours) of dilute urine (<300 mOsmol/kg). Cranial DI
(neurogenic, pituitary or neurohypophyseal) is characterised by
decreased secretion of antidiuretic hormone (ADH). Another form
(nephrogenic) is caused by malfunction of the kidneys1 – 3
Differential ● Type 1 diabetes
diagnosis ● Hypercalcaemia
● Head trauma
● Sickle cell anaemia
Diagnostic ● A 24-hour urine collection for determination of urine volume
tests (>3 litres)
● Serum electrolyte concentrations and glucose level
● Urinary specific gravity (<1.005)
k ● Simultaneous plasma (>287 mOsmol/kg) and urinary osmolality k
(<200 mOsmol/kg)
● Plasma ADH level
Tests should be carried out when the patient is maximally dehydrated to
ensure highest possible ADH levels and concentration of urine
Treatment ● Maintain fluid balance
goals ● Maintain sodium levels
Treatment ● Fluid replacement
options ● Desmopressin

Essential ● Fluid replacement. Patients must be encouraged to maintain their
intervention fluid levels and most can drink enough fluid to replace their urine
losses. When oral intake is inadequate and hypernatraemia is present,
losses must be replaced with an intravenous fluid that is
hypo-osmolar with respect to the patient’s serum. To avoid volume
overload and overly rapid correction of hypernatremia, fluid
replacement should be provided at a rate no greater than
500–750 mL/hour
Essential ● Desmopressin is a synthetic ADH analogue that is used to treat
intervention cranial diabetes insipidus. It is available in a variety of formulations,
which can be used depending on patient preference or need
Continued ● Sodium levels – overtreatment can result in fluid retention and
monitoring severe hyponatraemia
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Diabetes mellitus 117
REFERENCES
1 Verbalis JG (2003). Diabetes insipidus. Rev Endocri Metab Disord 4: 177–185.
2 Medline Plus (2011). Diabetes Insipidus. http://www.nlm.nih.gov/medlineplus/
ency/article/000377.htm (accessed 15 October 2014).
3 Khardori R (2014). Diabetes Insipidus. Medscape. http://emedicine.medscape.com/
article/117648-overview (accessed 15 October 2014).
D
Diabetes mellitus
Definition of diabetes mellitus
The term diabetes mellitus (DM) describes a metabolic disorder
resulting from defects in insulin secretion, insulin action, or both. It is
characterised by chronic hyperglycaemia and disturbances of
carbohydrate, fat and protein metabolism.1 This metabolic disruption
can lead to the development of retinopathy, nephropathy and
neuropathy (microvascular complications).2 People with DM are also
at increased risk of cardiac, peripheral arterial and cerebrovascular
disease (macrovascular complications).3
DM may present with characteristic symptoms such as thirst,
polyuria, blurring of vision and weight loss, although it is increasingly
being picked up by improved screening programmes. However,
symptoms may not be severe, or may be absent, and metabolic
changes may be present for a considerable time, resulting in the
development of complications before a diagnosis has been made. If
k timely recognition does not occur, diabetic ketoacidosis (see Diabetic k
ketoacidosis entry) or hyperosmolar hyperglycaemic state (see
Hyperosmolar hyperglycaemic state entry) may develop and lead to
severe metabolic disturbance, altered consciousness and, in the
absence of effective treatment, death.
Classification of DM4
● Type 1: absolute insulin deficiency, usually due to autoimmune
destruction of pancreatic beta cells; dependent on exogenous
insulin; prone to ketoacidosis; accounts for 5 –10% of patients.
● Type 2: a combination of resistance to insulin action and
inadequate compensatory insulin secretion; may be ‘insulin
requiring’.
● Gestational diabetes: first recognised in pregnancy, gestational
diabetes disappears after birth; affects about 4% of all pregnant
women; may precede development of (usually) type 2 DM.
● Maturity-onset diabetes of the young (MODY): impaired insulin
secretion most often inherited in an autosomal-dominant manner
● Secondary diabetes: caused by pancreatic injury, e.g. chronic
pancreatitis, pancreatectomy, pancreatic carcinoma, cystic fibrosis,
haemochromatosis; accounts for only 1 –2% of patients
● Endocrine: seen with Cushing’s syndrome (see separate entry),
acromegaly, thyrotoxicosis, phaeochromocytoma (see separate
entry), glucagonoma (because cortisol, growth hormone,
k
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118 Diabetes mellitus
thyroid hormones, glucagon and adrenaline antagonise insulin

action).
● Drug-induced: often occurs in association with insulin resistance;
implicated drugs include thiazide diuretics, glucocorticoids,
beta-adrenergic agonists, atypical antipsychotics, antiretroviral
D protease inhibitors.
Diagnosis of DM5 – 7
1 In a patient presenting with DM symptoms (e.g. polyuria,
polydipsia, unexplained weight loss (for type 1)), the diagnosis of
DM is confirmed with one of the following:
●random venous plasma glucose concentration ≥11.1 mmol/L
●fasting plasma glucose concentration ≥7.0 mmol/L (whole
blood ≥6.1 mmol/L)
●plasma glucose concentration ≥11.1 mmol/L 2 hours after 75 g
anhydrous glucose in an oral glucose tolerance test.
2 Where a patient has no symptoms of DM, diagnosis should not be
based on a single glucose determination. At least one additional
glucose test result on another day with a value in the diabetic range
is essential, whether fasting, from a random sample or 2 hours post
glucose load.
3 A laboratory venous haemoglobin A1c (HbA1c ) test may be used to
diagnose DM, although only in certain circumstances. An HbA1c of
48 mmol/mol is recommended as the cut-off point for diagnosing
k DM; however, a value of <48 mmol/mol does not exclude DM k
diagnosed using glucose tests. In asymptomatic patients, a
laboratory venous HbA1c should be repeated to confirm diagnosis.
REFERENCES
1 WHO (1999). Definition, Diagnosis and Classification of Diabetes Mellitus
and its Complications Part 1: Diagnosis and classification of diabetes mellitus.
http://apps.who.int/iris/handle/10665/66040 (accessed 3 February 2015).
2 Hanssen KF et al. (1992). Blood glucose control and diabetic microvascular compli-
cations: long-term effects of near-normoglycaemia. Diabet Med 9: 697–705.
3 Fox CS et al. (2007). Increasing cardiovascular disease burden due to diabetes
mellitus: the Framingham Heart Study. Circulation 115: 1544–1550.
4 American Diabetes Association (2004). Diagnosis and classification of diabetes
mellitus. Diabetes Care 27: 5–10.
5 WHO (2006). Definition and Diagnosis of Diabetes Mellitus and Intermediate
Hyperglycemia. http://www.who.int/diabetes/publications/diagnosis
diabetes2006/en/ (accessed 3 February 2015).
6 World Health Organization (2011). Use of Glycated Haemoglobin in the Diagnosis
of Diabetes Mellitus. http://www.who.int/diabetes/publications/diagnosis
diabetes2011/en/ (accessed 3 February 2015).
7 Diabetes UK (2015). Diagnostic Criteria for Diabetes. http://www.diabetes.org.uk/
About us/What-we-say/Diagnosis-prevention/New diagnostic criteria for diabetes/
k
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Diabetes mellitus: management of hypoglycaemia 119
Diabetes mellitus: management

of hypoglycaemia (‘hypo’) in adults
Hypoglycaemia is a lower than normal level of blood glucose. It is
considered ‘mild’ if the episode is self-treated and ‘severe’ if assistance D
is necessary.1 For people with diabetes, a blood glucose of
<4.0 mmol/L should be treated2 ; however, adults who have poor
glycaemic control may experience symptoms at blood glucose levels
above this.
Hypoglycaemia is particularly dangerous when symptom
recognition is poor and in those unable to respond appropriately,
e.g. young children, people with dementia.
Symptoms of hypoglycaemia
Symptoms of hypoglycaemia can provide an individual with a useful
warning that blood glucose levels are falling. Symptoms vary between
individuals but can be broadly divided between autonomic symptoms
caused by the activation of the sympathoadrenal system, the
neuroglycopenic symptoms resulting from cerebral glucose
deprivation and symptoms caused by general malaise (Table D2).3
TABLE D2
Symptoms of hypoglycaemia
Autonomic symptoms Neuroglycopenic symptoms General malaise
k (occur at approx. 3 mmol/L) (occur at approx. 2 mmol/L) k
Sweating Confusion Headache
Palpitations Drowsiness Nausea
Shaking Odd behaviour
Hunger Speech difficulty
Incoordination
Hypoglycaemia must be excluded in any person with diabetes who is

acutely unwell, drowsy, unconscious, unable to cooperate or who
presents with aggressive behaviour or seizures.
Patients who lose their autonomic symptoms (e.g. due to
beta-blocker use) can be taught to recognise neuroglycopenic
symptoms. However, these usually occur at lower blood glucose levels
and thus the window for effective treatment is narrower.
Loss of ‘hypo’ awareness may be caused by maintaining a level of
control that is too tight – if this is the case, a period of looser control
may restore recognition.
Management of hypoglycaemia in adults (16 years
and older)
See treatment algorithm (Figure D1) for brief guidance based on
JBDS guidelines.2 The quantity of carbohydrate given should be
k
k
D
Conscious, able to swallow, Conscious, able to swallow, Unconscious or unable to swallow
able to cooperate NOT cooperative (e.g. NBM, having a fit, very aggressive)
15 to 20 g quick-acting oral carbohydrateA 1.5 to 2 tubes glucose gel Check and secure ABC
squeezed between teeth and gums Stop IV insulin if being given
Repeat capillary BG after 10–15 minutes
or
Glucagon IM 10mg (once if appropriate) Give glucagon 1mg IM (once if appropriate)
After maximum 3 treatments if
or
capillary BG < 4 mmol/L consider either:
Repeat capillary BG after 10–15 minutes Intravenous glucose B
Glucagon IM 10mg (once if appropriate)
After maximum 3 treatments if Repeat capillary BG after 10 minutes
or
capillary BG < 4 mmol/L give:
Intravenous glucoseB If capillary BG < 4 mmol/L
(repeat up to 3 times as necessary) Intravenous glucoseB repeat intravenous glucose up to 3 times
(repeat up to 3 times as necessary)
Blood glucose Blood glucose Blood glucose

CPPC
>4mmol/L >4mmol/L >4mmol/L
k
If not NBM,15 to 20 g longer-acting oral carbohydrateD (40 g if received glucagon), if unable to swallow consider continuing IV glucose
kc04.tex
DO NOT omit subsequent doses of insulin (but review regimen if necessary); continue regular capillary BG monitoring for 24–48 hours.
A. Quick-acting oral carbohydrate e.g. B. Intravenous glucose (treatment) D. Longer-acting oral carbohydrate
of the patient’s choice e.g.
• 5–7 Dextrosol or 4–5 Glucotabs • 150–200 mL glucose 10% over 15 mins (=600–800 mL/hour) or
• 90–120 mL original Lucozade • 75–100 mL glucose 20% over 15 mins (=300–400 mL/hour) • Two biscuits
• 1 bottle (60 mL) Glucojuice • One slice bread/toast
• 150–200 mL pure fruit juice C. Intravenous glucose (continuing) • 200–300 mL milk (not soya)
• 3–4 heaped teaspoons sugar • Normal meal if due (must
• Glucose 10% at 100 mL/hour with close BG monitoring
dissolved in water contain carbohydrate)
120 Diabetes mellitus: management of hypoglycaemia
FIGURE D1 Guideline for the treatment of hypoglycaemia in adults with diabetes in hospital (blood glucose [BG] <4 mmol/L)
(if symptomatic but BG >4 mmol/L, give a small carbohydrate snack to relieve symptoms). NBM, nil-by-mouth, IM, intramuscularly; IV, intravenously
V2 - 11/18/2015 1:46 P.M. Page 120
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Diabetes mellitus: management of hypoglycaemia 121
sufficient to treat the hypoglycaemic episode without substantially

raising blood glucose levels after recovery.
Availability of ‘hypo’ treatments in clinical areas
15 –20% of inpatients in England and Wales have known diabetes4
●
D
and the prevalence of severe hypoglycaemia in hospital inpatients
treated with insulin ranges from 5% to 32%.5
● The JBDS has recommended the availability of ‘hypo’ boxes in
clinical areas.2 These should contain quick-acting oral
carbohydrate and also recommended concentrations of
intravenous glucose.
● Intravenous glucose 10% or 20% should be available in all clinical
areas in small-volume containers to avoid the risk of inadvertent
administration of larger volumes: a glucose 20% 100 mL vial is
available for this purpose.
● The use of glucose 50% intravenously is not recommended because
of the higher risk of thrombophlebitis, extravasation injury and
excessively raised posttreatment blood glucose levels.
Pharmaceutical care issues
● Fingers must be cleaned prior to capillary blood glucose testing.
Contamination with glucose/sugar from self-treatment of a ‘hypo’
can mean essential treatment is withheld.
● Glucose 20% should ideally be given via central access but for
k emergency use peripheral administration via a large vein is k
acceptable. Glucose 10% must be given via central access only if the
infusion continues for more than 24 hours. Give using an infusion
pump if readily available but do not delay the infusion if not.
● All inpatients prescribed insulin or sulfonylureas should ideally
also be prescribed an appropriate volume of intravenous glucose
10% or 20% to be given ‘as required’. However, patients receiving
metformin, pioglitazone, DPP-4 inhibitors, SLGT-2 inhibitors and
GLP-1 analogues without insulin or sulfonylureas are unlikely to
experience hypoglycaemia.
● Fruit juice is not an ideal ‘hypo’ treatment in patients following a
low-potassium diet.
● In patients taking acarbose, hypoglycaemia (due to other agents)
cannot be treated specifically with sugar in water because acarbose
delays its absorption.
● Hypoglycaemia caused by sulfonylureas or long-acting insulin may
recur: close monitoring is mandatory for 24 –36 hours and a
glucose infusion may be necessary.
● Intramuscular glucagon is only licensed for the treatment of insulin
overdose. It works by mobilising liver glycogen and is less effective
if patient is NBM, in malnutrition, in excessive alcohol intake, in
severe liver disease, receiving sulfonylureas or experiencing
repeated ‘hypos’. Patients who have received glucagon require a
k
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122 Diabetes mellitus: management of acute illness
double portion of longer-acting carbohydrate to replenish glycogen

stores, but nausea may be an issue.
● After treating hypoglycaemia, do not omit insulin injection if due;
however, the insulin regimen may require review.
D ‘Pharmaceutical’ risk factors for hypoglycaemia
● The most serious and common causes of inpatient hypoglycaemia
are insulin prescribing errors, for example:
● the use of abbreviations such as ‘U’ or ‘IU’ misread as a ‘0’,
resulting in a 10-fold overdose
● confusing the insulin name with the dose, e.g. Humalog Mix50
becoming Humalog 50 units
● inappropriately timed insulin or oral hypoglycaemic therapy in
relation to meals and inappropriate use of ‘stat’ doses
● inadvertent restarting of previously stopped insulin or oral
hypoglycaemic agents particularly at changes in care setting
● transcription errors or unclear handwriting.
● Some drugs given in combination with insulin or sulfonylureas may
increase the likelihood of hypoglycaemia, e.g. warfarin, quinine,
salicylates, fibrates, sulfonamides (including co-trimoxazole),
MAOIs, NSAIDs, probenecid, somatostatin analogues, SSRIs.
● Hypoglycaemia may be caused by sudden discontinuation of
long-term glucocorticoid therapy.
● Whether acute or chronic, severe renal impairment may require
k reduction in insulin dose due to reduced insulin clearance and k
consequent increased insulin half-life.
REFERENCES
1 Diabetes Control and Complications Trial Research Group (1993). The effect of
intensive treatment of diabetes on the development and progression of long-term
complications in insulin-dependent diabetes mellitus. N Engl J Med 329: 977–986.
2 Joint British Diabetes In Patient Care Group (2010: revised 2013). The Management
of Hypoglycaemia in Adults with Diabetes Mellitus. http://www.diabetes.org.uk/
Documents/About%20Us/Our%20views/Care%20recs/JBDS%20hypoglycaemia%
20position%20(2013).pdf (accessed 10 February 2014).
3 Deary IJ et al. (1993). Partitioning the symptoms of hypoglycaemia using multi-
sample confirmatory factor analysis. Diabetologia 36: 771–777.
4 Sampson MJ et al. (2007). A national survey of in-patient diabetes services in the
United Kingdom. Diabet Med 24: 643–649.
5 Farrokhi F et al. (2012). Hypoglycemia in the hospital setting. Diabet Hypoglycemia
5: 3–8.
Diabetes mellitus: management of acute

illness (‘sick-day rules’)
Illness can adversely affect diabetes control because of the increased
release of the counterregulatory hormones (cortisol, glucagon,
growth hormone and catecholamines) during stress. All patients with
diabetes mellitus should know what to do if they become acutely ill.
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Specific guidance may be given to individuals by their own diabetes

teams but the general principles of what to do if unwell are stated
below:1
● Never stop insulin or tablets – illness usually increases the body’s
need for insulin. D
● Test blood glucose level every 2 hours, day and night.
● Test urine for ketones every time you go to the toilet or test blood
ketones every 2 hours if you have the equipment to do this.
● Try to drink at least 100 mL water or sugar-free fluid every hour –
ideally you need at least 2.5 litres per day during illness
(approximately 5 pints).
● Avoid strenuous exercise as this may increase your blood glucose
level during illness.
● Eat as normally if possible. If you cannot eat or if you have a
smaller appetite than normal during illness, replace solid food with
one of the following: 400 mL milk, 200 mL carton fruit juice,
150 –200 mL non-diet fizzy drink, 1 scoop ice cream.
Call your diabetes specialist nurse or general practitioner in the
following circumstances:
● continuous diarrhoea and vomiting and/or high fever
● unable to keep down food for 4 hours or more
● high blood glucose levels with symptoms of illness (above
k 15 mmol/L). You may need an increased insulin dose* k
● ketones at 2+ or 3+ in your urine or blood ketones 1.5 mmol/L or
more. In this case, contact the person who normally looks after
your diabetes immediately as you may need more insulin.**
REFERENCE
1 JBDS (2011). Management of Adults with Diabetes Undergoing Surgery and Elective
Procedures: Improving standards. http://www.diabetes.org.uk/About us/What
-we-say/Improving-diabetes-healthcare/Management-of-adults-with-diabetes
-undergoing-surgery-and-elective-procedures-improving-standards/ (accessed 13
February 2015).
Diabetes mellitus: monitoring and tests

The need for monitoring and control of diabetes mellitus (DM) is well
established, although it is now recognised that raised blood glucose
levels are merely an easily measurable surrogate for the underlying
metabolic abnormalities occurring in uncontrolled DM.
* People with type 1 diabetes using the dose adjustment for normal eating
(DAFNE) regimen are given detailed guidance on how to adjust their own insulin
doses.
** Outside normal working hours contact the local out-of-hours service or attend
your local hospital Emergency Department.
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124 Diabetes mellitus: monitoring and tests
The Diabetes Control and Complications Trial (DCCT) (1993)1

studied 1441 patients with type 1 DM and demonstrated that
improved glycaemic control (and, by inference, other metabolic
markers) decreased the likelihood of microvascular complications
(retinopathy, neuropathy, nephropathy).
D
Similarly, the UK Prospective Diabetes Study Group (1998)2
reported that improved glycaemic control and improved blood
pressure control decreased complications associated with type 2 DM.
Improved blood glucose control reduced the risk of major diabetic eye
disease by a quarter and early kidney damage by a third. Improved
blood pressure control reduced the risk of deaths from long-term
complications of DM by a third, strokes by more than a third and
serious deterioration of vision by more than a third.
Whilst tight blood glucose control produces the best results from
the point of view of minimising complications, the risk of
hypoglycaemia increases with tighter control, and inevitably has a
negative impact on quality of life. All targets for control should be
discussed and agreed with the patient.
Blood glucose monitoring
Generally the aim is to keep fasting and pre-meal capillary blood
glucose levels at physiological concentrations, i.e. between 4 and
7 mmol/L. Tests performed 2 hours after meals should be no more
than 8.5 mmol/L (type 2),3 9 mmol/L (type 1)4 or 10 mmol/L
k (children).4 These targets should be relaxed if there is a significant k
risk of disabling or unrecognised hypoglycaemia.
Frequency of testing for individual patients is determined by type
of treatment and the ability of the patient or carers to respond to
results. Insulin users and those starting new treatments should
generally test more frequently, and blood glucose results should
always be recorded and assessed so that appropriate action can be
taken. N.B.: hypoglycaemic patients may recently have been handling
glucose or sugar of some sort, which can affect capillary blood glucose
results obtained by fingerprick.
Whilst mmol/L is the most common measurement unit used in the
UK, mg/dL is the unit predominantly used in the USA and continental
Europe (see Table D3 for conversions).
TABLE D3
Blood glucose conversions5
mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL
1 18 7 126 13 234 19 342
2 36 8 144 14 252 20 360
3 54 9 162 15 270 21 378
4 72 10 180 16 288 22 396
5 90 11 198 17 306 23 414
6 108 12 216 18 324 24 432
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Urine glucose monitoring

In some patients urine glucose monitoring may be used. The urine
only becomes positive for glucose once the patient’s renal threshold
for glucose excretion is exceeded. The renal threshold can vary widely
between individuals, which can make urine testing unreliable. D
However, an individual’s renal threshold should remain constant,
thus enabling a judgement to be made about the patient’s ongoing
DM management. In most people the renal threshold for glucose is
approximately 10 mmol/L, so a positive urine test indicates poor
glycaemic control.
Urine tests lag behind blood glucose levels – these tests average
what has happened to the patient’s blood glucose level since s/he last
passed urine. A patient may have a strongly positive urine glucose test
and actually be hypoglycaemic.
Monitoring ketones
Ketones are a byproduct of lipid metabolism in the absence of insulin,
so they are normally produced when patients with type 1 DM are
severely insulin-deficient. They may also occur in severely stressed
type 2 DM.
Previously it was only possible to monitor ketones using urine test
strips, but now meters are increasingly available to check blood
ketones (they measure 3-beta-hydroxybutyrate, the most significant
of the three ketone bodies in blood).
k Routine testing for ketones is not normally necessary but urine or k
blood testing may be used at home to assess severity of illness and to
know when to seek medical help. During illness, ketones should be
checked whenever urine is passed, or every 2 hours for blood ketones.
Help should be sought from the diabetes team or general practitioner
if urine ketones are 2+ or 3+ or blood ketones are ≥1.5 mmol/L (see
Diabetes mellitus – management of acute illness (‘sick-day rules’) entry).
Blood ketone monitoring is a significant part of the management of
DKA and hyperosmolar hyperglycaemic state (see respective entries).
Clinic tests
Glycated haemoglobin (HbA1c )
HbA1c is formed when glucose in the blood binds to haemoglobin in
red blood cells: the higher the glucose, the higher the HbA1c . HbA1c
circulates for the lifespan of the red blood cell and so reflects the
prevailing blood glucose levels over the 2 –3 months prior to the test.
Generally, for an individual with DM, a target HbA1c of
48 –58 mmol/mol should be agreed, taking into consideration the risk
of severe hypoglycaemia, cardiovascular status and comorbidities.3,4
Those at increased risk of arterial disease should ideally aim for
>48 mmol/mol, whilst in children and those at risk from
hypoglycaemia, 58 mmol/mol is acceptable.
HbA1c values were previously reported as a percentage (DCCT
units), but now results are reported in mmol/mol (International
k
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126 Diabetes mellitus: monitoring and tests
Federation of Clinical Chemistry (IFCC) units). See Table D4 for a

comparison of these two types of result.
TABLE D4
HbA1c conversion6
D IFCC (mmol/mol) DCCT (%) IFCC (mmol/mol) DCCT (%)
36.6 5.5 63.9 8.0
42.1 6.0 69.4 8.5
47.5 6.5 74.9 9.0
53 7.0 80.3 9.5
58.5 7.5 85.8 10
IFCC, International Federation of Clinical Chemistry; DCCT, Diabetes Control and
Complications Trial.
C-peptide
When insulin is synthesised by the beta cells of the pancreas it is
produced as proinsulin. This molecule is then cleaved at two sites and
the end segments are joined to form the active insulin molecule. The
centre segment (C-peptide) is released with the insulin and the
presence of C-peptide therefore indicates that an individual’s
pancreas is producing insulin. Injected insulin does not have a
C-peptide component so the test can be used to distinguish between
patients who have some residual pancreatic function and those who
k do not. In insulin resistance, C-peptide levels are raised because the k
patient may be hyperinsulinaemic despite being hyperglycaemic.
C-peptide was not previously thought to have any known function
but recent research suggests that it may have a beneficial role in
preventing microvascular complications.
Oral glucose tolerance test (OGTT)
This test may be used to distinguish between impaired glucose
tolerance, impaired fasting glucose and DM.
The OGTT should not be performed during intercurrent illness or
prolonged bed rest. For 24 hours prior to the test alcohol is avoided,
TABLE D5
Interpretation of oral glucose tolerance test results7
Diagnosis Plasma glucose concentration
Diabetes mellitus Fasting ≥7.0 mmol/L
or
2 hours post glucose load ≥11.1 mmol/L
Impaired glucose Fasting <7.0 mmol/L
tolerance and
2 hours post glucose load ≥7.8 mmol/L and <11.1 mmol/L
Impaired fasting Fasting 6.1–6.9 mmol/L
glucose and (if measured)
2 hours post glucose load <7.8 mmol/L
k
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and for 12 hours prior to the test no food should be taken. Water may
be taken freely as required. Glucose (75 g) is consumed within 5
minutes and venous blood samples are taken immediately preceding
and 2 hours after the glucose load. The interpretation of test results is
shown in Table D5.
D
REFERENCES
1 Diabetes Control and Complications Trial Research Group (1993). The effect of
intensive treatment of diabetes on the development and progression of long-term
complications in insulin-dependent diabetes mellitus. N Engl J Med 329: 977–986.
2 UK Prospective Diabetes Study Group (1998). Intensive blood glucose control with
sulphonylureas or insulin compared with conventional treatment and risk of com-
plications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837–853.
3 NICE (2009). Clinical Guideline 87. The Management of Type 2 Diabetes. https://
www.nice.org.uk/guidance/cg87 (accessed 23 February 2015).
4 NICE (2004). Clinical Guideline 15. Type 1 Diabetes: Diagnosis and management
of type 1 diabetes in children, young people and adults. https://www.nice.org.uk/
guidance/cg15 (accessed 23 February 2015).
5 Diabetes UK (2015). Blood Sugar Converter. http://www.diabetes.co.uk/blood
-sugar-converter.html (accessed 21 February 2015).
6 Diabetes UK (2015). HbA1c Units Converter. http://www.diabetes.co.uk/hba1c
-units-converter.html (accessed 21 February 2015).
7 WHO (2006). Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyper-
glycemia. https://www.idf.org/webdata/docs/WHO IDF definition diagnosis of
diabetes.pdf (accessed 23 February 2015).
k k
Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) is a potentially life-threatening, complex
disordered metabolic state characterised by ketonaemia,
hyperglycaemia (although this may have been partially self-treated
before admission) and acidaemia.
It usually occurs in people known to have type 1 diabetes mellitus
(DM) (however, DKA may be the presenting condition in newly
diagnosed patients), but type 2 DM patients can also develop DKA
if sufficiently stressed (e.g. by surgery, severe infection or myocardial
infarction (MI) and mortality remains high among non-hospitalised
patients. Mortality has fallen in the last 20 years in patients receiving
prompt and effective treatment: in this group cerebral oedema is the
most common cause of death in children and adolescents, whereas the
main causes of mortality in adults include severe hypokalaemia, adult
respiratory distress syndrome and comorbid states, e.g. pneumonia,
MI and sepsis1 (see Hyperosmolar hyperglycaemic state entry).
Diagnosis of DKA2
The diagnosis of DKA is made if:
● blood ketones ≥3 mmol/L or there is significant ketonuria, i.e. 2+
or more on urine dipsticks
● blood glucose is >11 mmol/L or known DM
● serum venous bicarbonate <15 mmol/L and/or venous pH <7.3.
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128 Diabetic ketoacidosis
Management of DKA in adults

In 2010 the JBDS Inpatient Care Group published guidance on treating
DKA in adults,2 so all Trusts should have a policy or care pathway in
place. The main focus of treatment is now correction of the underlying
metabolic abnormality rather than simply the normalisation of blood
D
glucose levels. This has been facilitated by the easy availability of
accurate bedside blood glucose and ketone meters, and rapid access to
blood gas and blood electrolyte measurement. Early escalation to crit-
ical care should be considered in pregnant women, as well as patients
with hypokalaemia at presentation, hypoxia, altered consciousness,
hypotension, tachycardia or severe ketoacidosis (as indicated by blood
ketones >6 mmol/L, venous bicarbonate <5 mmol/L or pH <7.1).
Separate guidelines exist for the treatment of children and
adolescents.3
Fluid
Fluid and electrolyte deficits may be significant because of osmotic
diuresis and vomiting (Table D6) and fluid replacement must be
initiated promptly. For patients in whom judicious fluid replacement
is required, e.g. elderly patients or those with impaired cardiac
function, a central venous pressure (CVP) line may be inserted.
TABLE D6
Typical fluid and electrolyte deficits in diabetic
ketoacidosia2
k Water 100 mL/kg k
Sodium 7–10 mmol/kg
Chloride 3–5 mmol/kg
Potassium 3–5 mmol/kg
Sodium chloride 0.9% is currently recommended as the fluid of

choice because of lack of availability of licensed Hartmann’s solution
with adequate ready-mixed potassium.4
Table D7 gives an example of fluid replacement for a previously
well 70-kg adult.2 Slower infusion rates should be considered in
young adults because of the increased risk of cerebral oedema.
TABLE D7
An example of fluid replacement for a previously well
70-kg adult
Sodium chloride 0.9% 1 L* 1000 mL over first hour
Sodium chloride 0.9% 1 L with potassium chloride 1000 mL over next 2 hours
Reassessment of cardiovascular status at 12 hours is mandatory; further fluid may be
required
*Potassium chloride may be required if >1 L sodium chloride has already been given as
fluid resuscitation.
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If blood glucose falls below 14 mmol/L (usually 6 –12 hours into

treatment for DKA), commence 10% glucose at 125 mL/hour while
continuing the sodium chloride 0.9% infusion, as further hydration is
likely to be necessary. Giving glucose enables insulin administration
to continue so that ketogenesis is suppressed.
After 12 hours, if DKA is resolved but patient is still unable to eat D
and drink, then convert to an intravenous variable-rate insulin
infusion policy, as per local guidelines.
Potassium
Patients with DKA usually present with hyperkalaemia because of
insulin deficiency; however, this represents a shift of potassium from
the intracellular to the extracellular fluid and these patients actually
have a total body potassium deficiency. A high initial potassium serum
concentration should prompt cardiac monitoring until levels have
returned to normal.
Once insulin is given, potassium levels can change rapidly: all
patients require serum potassium measurement on admission and at
least every 2 hours throughout treatment to assess requirements.
Potassium is not usually added to the first litre of sodium chloride
0.9% but should be provided in subsequent bags to maintain normal
serum potassium levels (Table D8).
TABLE D8
Suitable potassium replacement levels in diabetic
k ketoacidosis k
Potassium level in first 24 hours Potassium chloride to be added
<3.5 mmol/L Senior review as additional potassium is essential
(if necessary, via a central line in the High Dependency
Unit)
3.5–5.5 mmol/L 40 mmol/L of fluid
>5.5 mmol/L None
Intravenous insulin
1 A fixed-rate insulin infusion is recommended by the JBDS of
0.1 unit/kg/hour to suppress ketogenesis, reduce blood glucose
and correct electrolyte imbalance. This is based on actual body
weight: estimate if necessary.
2 Insulin may be infused in the same line as the intravenous
replacement fluid, provided that a Y-connector with a one-way,
antisyphon valve is used and a large-bore cannula has been placed.
3 A syringe pump should be set up containing 50 units of soluble
insulin in 50 mL sodium chloride 0.9% and this should be infused
at a starting rate of 0.1 unit/kg/hour.
4 Patients admitted on long-acting basal insulin analogues, e.g.
glargine or Levemir, should continue on their usual dose while they
are receiving the fixed-rate insulin infusion.
k
k
130 Diabetic ketoacidosis
Monitoring
Measure blood ketones and capillary blood glucose every hour,
ideally using quality-assured bedside meters. Measure venous blood
gas for pH, bicarbonate and potassium at 60 minutes, at 2 hours and
2-hourly thereafter. Treatment targets are to:
D
● reduce blood ketone concentration by 0.5 mmol/L per hour
● increase venous bicarbonate by 3 mmol/L per hour
● reduce capillary blood glucose by 3 mmol/L per hour (but avoid
hypoglycaemia)
● maintain serum potassium concentration between 4.0 and
5.0 mmol/L
● monitor fluid balance: aim for minimum urine output of 0.5 mL/kg
per hour.
Further action
● If ketones and glucose are not falling as expected, always check
that the insulin infusion pump is connected and working correctly.
● If blood ketones are not falling by at least 0.5 mmol/L per hour, call
a prescribing clinician to increase insulin infusion rate by
1 unit/hour increments every hour until ketones fall at target rates
(if blood ketone levels are not available, use either bicarbonate or
plasma glucose as a surrogate and adjust insulin infusion rate
accordingly).
● Resolution of DKA is defined as ketones <0.3 mmol/L, venous
k pH >7.3. k
Additional pharmaceutical points
● All patients should receive low-molecular-weight heparin venous
thromboembolism prophylaxis.5
● Intravenous bicarbonate is rarely indicated because adequate fluid
and insulin therapy will resolve acidosis in DKA. If used, it should
only be initiated on the instructions of a senior physician.6,7
● The patient’s usual insulin regimen must be determined on
admission so that any contributing factors can be highlighted and
long-acting basal insulin analogues continued if appropriate.
● Subcutaneous insulin should be introduced or restarted as soon as
the patient is biochemically stable and feels able to eat and drink.
For all regimens the intravenous insulin infusion should be
continued for at least 30 –60 minutes after giving the subcutaneous
dose in association with a meal.
● For patients not previously on insulin, the specialist diabetes team
should be involved.
REFERENCES
1 Hamblin PS et al. (1989). Deaths associated with diabetic ketoacidosis and hyperos-
molar coma, 1973–1988. Med J Aust 151: 439–444.
2 Joint British Diabetes Societies Inpatient Care Group (2010). The Management of
Diabetic Ketoacidosis in Adults. London: Diabetes UK. http://www.diabetes.org.uk/
About us/Our Views/Care recommendations/The-Management-of-Diabetic-
Ketoacidosis-in-Adults/ (accessed 14 September 2014).
k
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Digoxin 131
3 BSPED (2009: minor review 2013). Recommended DKA Guidelines. http://

www.bsped.org.uk/clinical/docs/DKAGuideline.pdf (accessed 3 February 2015).
4 NPSA (2002). Potassium Chloride Concentrate Solutions – Patient safety alert. http://
www.nrls.npsa.nhs.uk/resources/?entryid45=59882 (accessed 17 January 2015).
5 NICE (2010). Clinical Guideline 92. Venous Thromboembolism: Reducing the risk of
venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients D
admitted to hospital. http://www.nice.org.uk/guidance/cg92 (accessed 3 February
2015).
6 Morris LR et al. (1986). Bicarbonate therapy in severe diabetic ketoacidosis. Ann
Intern Med 105: 836–840.
7 Hale PJ et al. (1984). Metabolic effects of bicarbonate in the treatment of diabetic
ketoacidosis. BMJ (Clin Res Ed) 289: 1035–1038.
Digoxin
Digoxin is one of the oldest drugs in cardiovascular medicine, and
traditionally used in patients with atrial fibrillation (AF) and heart
failure (HF). In the last 20 years, the use of this drug has markedly
declined and, in the most recent 2012 European Society of Cardiology
(ESC) HF guidelines,1 it is stated that for patients with HF and a left
ventricular ejection fraction ≤40%, who are in sinus rhythm, ‘digoxin
may be used’. This recommendation is based on the Digitalis
Investigation Group (DIG) trial,2 in which the effect of digoxin on
outcome was examined in 6800 patients with HF. For HF patients
with AF, other drugs (in particular beta-blockers) should be
k preferred,1 since they provide better rate control. Both the 2010 ESC k
AF Guidelines3 and 2014 NICE AF guidance4 state that digoxin is
effective for long-term rate control at rest, but not during exercise.
Prospective, randomised, placebo-controlled outcome studies
examining the effect of digoxin in patients with AF (with or
without HF) are not available.
Digoxin in heart failure
In the past, it was assumed that the beneficial effect of digoxin in HF
was due to its (positive) inotropic properties, which are more
pronounced at higher doses of the drug.5 However, a large number of
studies in patients with HF have shown that positive inotropic drugs
lead to an unfavourable effect on outcome, and these drugs are now
contraindicated in patients with chronic HF. In contrast to this
inotropic effect, digoxin also exerts potentially favourable autonomic-
or neurohormonal-inhibiting properties, which primarily occur at
lower serum digoxin concentrations (SDCs).6 This has been
increasingly recognised in the last 25 years, and a post-hoc analysis of
the DIG trial7 showed that, in patients who received digoxin, low SDC
(0.5 –0.9 ng/mL) was associated with a lower all-cause mortality than
in patients in the placebo group (29.3% vs 32.9%, adjusted hazard
ratio 0.77, P < 0.001), while all-cause mortality in patients with SDC
≥1.0 was 41.7% (P = not significant for adjusted hazard ratio).
However, no well-designed prospective trials have been conducted to
confirm these findings.
k
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132 Digoxin
More recently,8 the effects of the sinus node inhibitor ivabradine in

the Systolic Heart failure treatment with the If inhibitor Ivabradine
Trial (SHIFT) were compared with the effect of digoxin in the DIG
trial, and they showed a remarkable similarity. The composite
morbidity–mortality outcome of cardiovascular death and HF
D
hospitalisation (the most common endpoint in current HF trials) was
reduced by 18% in SHIFT and by 15% in the DIG trial. In both trials,
the main effect was on HF hospitalisations, which was –26% in SHIFT
and –28% in DIG. However, it must be noted that in SHIFT this effect
was against a background of other drugs, in particular beta-blockers,
whereas in DIG no beta-blockers were used. Therefore, digoxin in
patients with HF may still have a place, as a neurohormonal
modulator, when given in low doses. Indeed, low-dose digoxin may
still be useful, but trials examining this question are urgently needed.
Digoxin in atrial fibrillation
In a rate control strategy, the main goal of arrhythmia management
becomes control of the ventricular rate. In patients with persistent
and permanent AF, rate control applies continuously. In patients with
paroxysmal AF, the objective of rate control is to limit ventricular
response during an AF episode.
Poor control of the ventricular rate can be a major factor
contributing to disability and symptom limitation in many patients
with AF. Conduction through the atrioventricular node is under
k autonomic control and increases markedly with activity levels, so the k
goal of rate control is to avoid excessive rate increase with activity.4
The primary effect of digoxin is slowing down atrioventricular
conduction, leading to a reduction in ventricular response at rest, but
much less so during exercise.2 This effect of digoxin is due to
enhancement of vagal tone and is less prominent during increased
sympathetic activity, such as exercise, and it is for this reason that the
NICE AF guidance states that digoxin should only be considered as
monotherapy in sedentary patients.4 Beta-blockers are more effective
than digoxin in slowing heart rate during exercise in patients with AF,
and beta-blockers now have a prominent place in AF patients, both
with and without HF, and seem to have replaced digoxin in many
patients. Digoxin should only be considered as monotherapy in
sedentary patients, as it is less effective for rate control during
exercise or in conditions of high sympathetic drive (e.g. infection or
decompensated heart failure).
Formulations
Digoxin is available in three forms: tablet, liquid and injection. Each
form has a different bioavailability (tablets 63%, liquid 75%, injection
100%) and, if changing between forms, the dose will need to be
changed accordingly. It may be necessary to round a dose up or down
to facilitate administration. Table D9 summarises practical dose
equivalences of the formulations.
k
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Digoxin 133
TABLE D9
Dose equivalence of digoxin formulations
Tablet (micrograms) Liquid (micrograms) Injection (micrograms)
62.5 50 50
125 100 75 D
250 200 150

Digoxin has a narrow therapeutic range, and therefore it may be
necessary to check the serum concentration in the following
circumstances:
● in suspected, or actual, overdose

● if the patient is showing signs of digoxin toxicity
● if the patient’s renal function shows signs of deterioration
● if any drugs are added, or withdrawn, that are known to affect the
serum concentration of digoxin or serum potassium concentration
(see section on Significant drug interactions, below).

During therapeutic drug monitoring, the target blood concentration
will depend upon the indication (Table D10). For HF, a positive
inotropic effect is needed and this is achieved at lower concentrations
k than the negative chronotropic effect needed to control AF. k
TABLE D10
Half-life 20–50 hours (in renal impairment it can be up to 100 hours)10
Pretreatment (U&Es particularly potassium), creatinine, weight and age (and
measures height if obese)11
Thyroid function: digoxin sensitivity is enhanced when thyroid
function is subnormal. In hyperthyroidism there is relative digoxin
resistance and the dose may have to be increased
Therapeutic range For heart failure: 0.9–1.5 microgram/L (1.2–1.9 nmol/L)
For atrial fibrillation: 1.5–2.0 microgram/L (1.9–2.6 nmol/L)
Toxic effects become frequent above 2.5 microgram/L (3.2 nmol/L)
Sampling time At least 6 hours postdose.
If monitoring is anticipated, the dose is best given in the evening
and a sample taken the following morning. In some hospitals the
digoxin dose is routinely given in the evening to facilitate this.
Response to dose adjustment should be checked 7–10 days after
the change (because of its long half-life).
Blood should be taken in ‘brown-top’ sample tubes
Other monitoring U&Es occasionally to monitor renal function. Thyroid function
periodically (where thyrotoxicosis is being treated, digoxin dosage
should be reduced as the thyrotoxicosis comes under control)
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134 Digoxin
Potassium depletion increases the response of tissues to digoxin

and can cause toxicity. A reduction in serum potassium concentration
from 3.5 to 3.0 mmol/L is accompanied by an increase in sensitivity to
digoxin of about 50% and digoxin toxicity may be present despite the
serum digoxin concentration being in the apparent therapeutic range.
D To interpret a serum digoxin concentration, the serum potassium
concentration must also be measured at the same time. In patients
with hypokalaemia, the digoxin dose should be withheld (whatever
the serum digoxin concentration) until the hypokalaemia is
corrected.9
Dose
Loading dose (also known as ‘digitalisation’)
If a patient has not received cardiac glycosides in the preceding
2 weeks, a loading dose may be given. There are three approaches to
loading digoxin: parenterally in an emergency situation, and rapid
and slow oral loading. An assessment should be made of the patient’s
age, lean body weight and renal function to help determine the
loading dose.
Emergency parenteral loading
For emergency parenteral loading (in patients who have not received
cardiac glycosides within the preceding 2 weeks), the dose range is
usually 500 –1000 micrograms.10 Approximately half the total
anticipated dose should be given initially, and further fractions of the
k total dose given every 4 –8 hours. The clinical response should be k
assessed after each additional dose to determine if the remainder of
the loading dose is required.
The dose is given as a small-volume infusion. Digoxin injection
must be diluted to at least four times its volume – in practice this will
mean using a 50 mL or 100 mL mini-bag, containing either sodium
chloride 0.9% or glucose 5%. The infusion should be given over at
least 2 hours.
Digoxin should never be given as a bolus injection, as this can
cause heart block and arrhythmia, possibly resulting in patient death.
Rapid oral loading
A dose of 750 –1500 micrograms is given as a single dose. If there is
less urgency, or the patient is at risk of toxicity (elderly, renal
impairment), the dose should be given in divided doses 6 hours apart,
with assessment of clinical response before giving each additional
dose.
Slow oral loading
A daily dose of 250 –500 micrograms is given daily for 1 week,
followed by an appropriate maintenance dose.
Maintenance dose
In practice, prescribers often pick a dose intuitively; however, an
appropriate digoxin dose for a given patient can be calculated using
the steps described below. As interpatient variability can influence the
k
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Digoxin 135
digoxin concentration and therefore the patient’s clinical response,

the predicted values should only be used as a guide.
1 Calculate ideal body weight (IBW):
For men: IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet
For women: IBW (kg) = 49 kg + 1.7 kg for each inch over 5 feet
D
2 Calculate creatinine clearance (CrCl: mL/min):

1.23 × (140–age (years)) × weight (kg)
Male =
serum creatinine concentration (micromol/L)
1.04 × (140–age (years)) × weight (kg)
Female =
serum creatinine concentration (micromol/L)
If the patient’s actual body weight (ABW) is within 20% of IBW, use
the ABW in the above calculation and subsequent dosing.
3 Calculate digoxin clearance (DigCl: L/hour)
DigCl = (0.06 × CrCl) + (0.05 × IBW weight (kg))
Patients with HF require this modified calculation.
DigCl (with HF) = (0.053 × CrCl) + (0.02 × weight (kg))
4 Calculate predicted steady state level for a specific dose
(Cpss : microgram/L):
k Cpss =
(F × D) k
(DigCl × τ )
F = bioavailability (tablets = 0.63; liquid = 0.75; injection = 1)

D = digoxin dose (micrograms), τ = dosage interval in hours.
The units the calculation produces for the predicted steady state of
digoxin are in microgram/L. If a laboratory interprets results using
nmol/L, the figures must be converted (nmol/L = microgram/L
× 1.28).
The predicted steady-state figure should be increased if certain
interacting drugs are present, or added to therapy (see below for
details).
Significant drug interactions12
Amiodarone can approximately double the serum concentration of
digoxin. The effect is evident after a few days and develops over
1 –4 weeks. If amiodarone is stopped, the interaction can continue for
several months due to its long half-life. If the two drugs are prescribed
together, the dose of digoxin should be halved.13
Verapamil increases serum digoxin concentration by about 40%
with a daily dose of 160 mg verapamil, and by about 70% with a daily
dose of 240 mg verapamil. The digoxin dose should be reduced and
serum digoxin concentration monitored if verapamil is added to
therapy.
k
k
136 Digoxin
Spironolactone can increase serum digoxin concentration by 25%.

Furthermore, many digoxin assays are affected by spironolactone and
its metabolite, which makes monitoring difficult.
Potassium-depleting diuretics are thought to be implicated in
increased digoxin toxicity. It is common practice in some hospitals to
D reduce this complication by co-prescribing potassium supplements or
potassium-sparing diuretics.
Macrolide antibiotics (erythromycin, azithromycin and
clarithromycin) can produce a two- to fourfold increase in digoxin
serum concentration. The interaction is unpredictable, however, and
is further complicated as one of the proposed mechanisms of the
interaction may only affect up to 10% of the population. Patients
should be monitored for signs of digoxin toxicity and the digoxin dose
reduced if necessary (azithromycin has a 60-hour half-life so the
interaction may persist for some time after the antibiotic course
has finished).
Overdose – treatment with DigiFab
DigiFab is an immunoglobulin indicated for the treatment of known
(or strongly suspected) life-threatening digoxin toxicity associated
with ventricular arrhythmias or bradyarrhythmias unresponsive to
atropine, where measures beyond withdrawal of digoxin and
correction of serum electrolyte abnormalities are considered
necessary.
There are several formulae for calculating the required dose of
k DigiFab depending on the clinical situation, and these should be k
consulted.14 Each vial of DigiFab contains 40 mg of digoxin immune
Fab and binds approximately 0.5 mg digoxin.
Administration
Each vial of DigiFab should be reconstituted with 4 mL water for
injection and gently mixed, producing a solution of 10 mg/mL that
should be used immediately. This may be added to a suitable volume
of 0.9% sodium chloride (e.g. 50 –100 mL mini-bag) and
administered over at least 30 minutes. If infusion rate-related
reactions occur, the infusion should be stopped and restarted at a
slower rate. If cardiac arrest is imminent, DigiFab can be given by
bolus injection, although there is an increased incidence of
infusion-related reactions.14
DigiFab has a high affinity for digoxin that is greater than the
affinity of digoxin for its sodium pump receptor, the presumed
receptor for its therapeutic and toxic effects. When administered to
the intoxicated patient, digoxin immune Fab binds to molecules of
digoxin, reducing free digoxin levels; this results in a shift in the
equilibrium away from binding to the receptors, thereby reducing
cardiotoxic effects. Fab– digoxin complexes are then cleared by the
kidney and reticuloendothelial system.15
Standard digoxin serum assays cannot be used to determine free,
pharmacologically active digoxin after administration of DigiFab
because these also detect Fab-bound digoxin. Total serum digoxin
concentration may rise precipitously after DigiFab is given, but this
k
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Dobutamine 137
will be almost entirely bound to Fab fragment and will not exert a
pharmacological effect.16
REFERENCES
1 McMurray JJV et al. (2012). ESC guidelines for the diagnosis and treatment
of acute and chronic heart failure 2012: the Task Force for the Diagnosis and
Treatment of Acute and Chronic Heart Failure 2012 of the European Society of
D
Cardiology. Developed in collaboration with the Heart Failure Association (HFA)
of the ESC. Eur Heart J 33: 1787–1847.
2 The Digitalis Investigation Group (1997). The effect of digoxin on mortality and
morbidity in patients with heart failure. N Engl J Med 336: 525–533.
3 Camm AJ et al. (2010). Guidelines for the management of atrial fibrillation.
Eur Heart J 31: 2369–2429.
4 NICE (2014). Atrial Fibrillation: The management of atrial fibrillation (CG180).
https://www.nice.org.uk/guidance/cg180 (accessed 24 January 2015).
5 Gheorghiade M et al. (2006). Contemporary use of digoxin in the management of
cardiovascular disorders. Circulation 113: 2556–2564.
6 Van Veldheuisen DJ et al. (2013). Digoxin for patients with atrial fibrillation and
heart failure: paradise lost or not? Eur Heart J 34: 1468–1470.
7 Ahmed A et al. (2006). Digoxin and reduction in mortality and hospitalization in
heart failure: a comprehensive post hoc analysis of the DIG trial. Eur Heart J 27:
178–186.
8 Castagno D et al. (2012). Should we SHIFT our thinking about digoxin? Obser-
vations on ivabradine and heart rate reduction in heart failure. Eur Heart J 33:
1137–1141.
9 Aronson JK, Hardman M (1992). ABC of monitoring drug therapy: digoxin. BMJ
305: 1149–1152.
k Livingstone. k
11 eMC (2015). www.medicines.org.uk (accessed 24 January 2015).
12 Stockley’s Drug Interactions (2015). www.medicinescomplete.com (accessed 24
January 2015).
14 Resuscitation Council (UK) (2010). DigiFab. http://www.resus.org.uk/newsletr/
nl12Wdf5.pdf (accessed 24 January 2015).
15 DigiFab, 40 mg/vial Digoxin Immune Fab, Powder for solution for infusion.
http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/
con126289.pdf (accessed 5 December 2014).
16 National Poisons Information Service. Toxbase. http://www.toxbase.org (accessed
30 August 2015).
Dobutamine
Dobutamine is a positive inotrope which acts on β 1 , β 2 and α
receptors. Its predominant action on β 1 receptors causes increased
force of cardiac contraction, therefore increasing cardiac output and
stroke volume. At higher doses it will increase heart rate. It is also a
potent vasodilator and as such will speed up the rewarming process
following prolonged surgery.
The main use of dobutamine is in heart failure and cardiogenic
shock, usually in combination with a low dose of dopamine.
Hypovolaemia should be corrected prior to administration.1
The dose range for dobutamine is 2.5 –10 microgram/kg/min
(although up to 40 microgram/kg/min has occasionally been
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138 Dopamine
required).2 It should be given as a continuous intravenous infusion.3

A simple calculation and method for making a dobutamine infusion is
as follows:
● body weight (kg) × 3 (mg) = dose (mg)

D ● dilute to 50 mL with sodium chloride 0.9% (or glucose 5%)
● each mL/hour is equivalent to 1 microgram/kg/min
● dose of dobutamine is usually 5 –10 microgram/kg/min,
i.e. 5 –10 mL/hour.
Administration
Dobutamine infusions may be given at rates up to
5 microgram/kg/min without cardiac output monitoring. Higher
doses require monitoring4 and treatment should be stopped
gradually.2
Dobutamine is compatible with sodium chloride 0.9% and
glucose 5%.5
It is Y-site-compatible with adrenaline, amiodarone, atropine,
calcium gluconate, dopamine, glyceryl trinitrate, hydralazine,
isoprenaline, lidocaine, magnesium sulfate, noradrenaline, potassium
chloride and sodium nitroprusside (in sodium chloride).
It is not compatible with aminophylline, digoxin, furosemide or
sodium bicarbonate.6
REFERENCES
k 1 AHFS Drug Information (2014). Dobutamine. Medicines Complete: AHFS. k
https://www.medicinescomplete.com/mc/index.htm (accessed 15 July 2014).
https://www.medicinescomplete.com/mc/martindale/current/ (accessed 15 July
2014).
3 SPC (2014). Dobutamine. eMC. https://www.medicines.org.uk/emc/medicine/
21491 (accessed 15 July 2014).
4 SPC (2004). Posiject. http://emc.medicines.org.uk/ (accessed 15 November 2004).
5 Welsh Intensive care website (2005). Guidelines. www.clinicalschool.swan.ac.uk/
wics/itugl/dop.htm (accessed 11 December 2004).
6 Shulman R et al. (eds) (2002). Injectable Drug Administration Guide. London:
Blackwell Science.
Dopamine
Dopamine is a positive inotrope and its action relates to the dose
administered. At low doses, i.e. 2 microgram/kg/min, dopamine
stimulates the dopamine receptors in the kidneys, causing renal
dilatation and increased urine output.1
At slightly higher doses, i.e. 2 –10 microgram/kg/min, dopamine
begins to stimulate the β 1 receptors in the heart, producing an
increase in cardiac output. It is used in acute heart failure due to
k
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Dopamine 139
cardiogenic shock or myocardial infarction, renal failure, cardiac

surgery and septic shock.2 Do not offer low-dose dopamine to treat
acute kidney injury.3
Once the dose is increased to more than 10 microgram/kg/min,
dopamine also acts on α-receptors, causing vasoconstriction, which
leads to impairment of renal perfusion. There is also an increased risk
D
of arrhythmias.
Dose should be reduced gradually before discontinuation as
stopping the infusion suddenly may cause hypotension.
It is given as an intravenous infusion using a pump, not a
gravity-controlled intravenous set.4
Dose
● 2 –5 microgram/kg/min increased gradually by increments of
5 –10 microgram/kg/min until optimum dose for patient is
reached.5
● Dilute with sodium chloride 0.9% (or glucose 5%). The usual
dilution is 1600 micrograms per mL.5
Administration
Dopamine should be administered via a central line because of the
risk of extravasation, which can be exacerbated by local
vasoconstriction. If this is not possible, it may be given via the largest
peripheral vein available, provided that the concentration does not
k exceed 1.6 mg/mL. If extravasation occurs, infiltration with k
phentolamine as soon as possible, and certainly within 12 hours, may
relieve pain and prevent tissue necrosis.6 Phentolamine 5 mg is mixed
with 9 mL sodium chloride 0.9%, and a small amount is injected into
the extravasated area; blanching should reverse immediately. If
blanching should recur, additional injections of phentolamine may
be needed.7
Dopamine is compatible with sodium chloride 0.9% and
glucose 5%.7 – 10
It is Y-site-compatible with adrenaline, aminophylline,
amiodarone, atracurium, dobutamine, doxapram, glyceryl trinitrate,
heparin, insulin, labetalol, lidocaine, mannitol, noradrenaline,
potassium chloride and sodium nitroprusside.
It is not compatible with alkaline agents, e.g. sodium bicarbonate
and furosemide.2
Dopamine has significant interactions with MAOIs, α/β adrenergic
blocking agents and general anaesthetics.4
Miscellany
Some hospitals do not use dopamine routinely because it is not
renoprotective, and it is now known to suppress the output of the
anterior pituitary gland (with the exception of adrenocorticotrophic
hormone).11
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140 DVLA
REFERENCES
1 McCrory C, Cunningham AJ (1997). Low-dose dopamine: will there ever be a
scientific rationale? Br J Anaesth 78: 350–351.
2 Martindale (2014). Dopamine. Medicines Complete: Martindale. https://
www.medicinescomplete.com/mc/martindale/current/ (accessed 14 July 2014).
3 NICE (2013). Acute Kidney Injury: Prevention, detection and management of acute
D kidney injury up to the point of renal replacement therapy. NICE: CG169. http://
www.nice.org.uk/guidance/CG169 (accessed 14 July 2014).
4 AHFS Drug Information (2014). Dopamine. Medicines Complete: AHFS. https://
www.medicinescomplete.com/mc/index.htm (accessed 14 July 2014).
5 SPC (2014). Dopamine 40mg/1mL Concentrate for Solution for Infusion.
www.medicines.org.uk (accessed 14 July 2014).
https://www.medicinescomplete.com/mc/martindale/current/ (accessed 15 July
2014).
7 Evanston Northwestern Healthcare (2005). Dopamine Antidote. http://
www.enh.org/healthandwellness/bioterrorism/hf045600.asp?lid=1092/
(accessed 14 July 2014).
8 SPC (2014). Dopamine Hydrochloride 800 mg in 5% Dextrose Injection.
www.medicines.org.uk (accessed 14 July 2014).
9 SPC (2014). Dopamine 160 mg/mL Sterile Concentrate. www.medicines.org.uk
10 SPC (2014). Sterile Dopamine Concentrate BP Selectajet. www.medicines.org.uk
11 Welsh Intensive care website (2005). Guidelines. www.clinicalschool.swan.ac.uk/
wics/itugl/dop.htm (accessed 14 July 2014).
k k
DVLA: advice concerning medication
and medical conditions
Medical conditions
The UK Driver and Vehicle Licensing Agency (DVLA) specifies a set of
notifiable conditions that may affect the ability to drive safely.1 These
can include:
● epilepsy
● stroke
● neurological and mental health conditions
● physical disability
● visual impairments.
Patients must inform the DVLA if they are diagnosed with any of these
conditions or if their condition worsens since being issued with a
licence. A full list of health conditions and advice is available on the
DVLA website: https://www.gov.uk/health-conditions-and-driving.
Medication and driving
Section 4 of the Road Traffic Act 1988 identifies the offence to drive
whilst impaired through drug use. The decision as to whether a
person is impaired on any occasion is the responsibility of the driver.
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DVLA 141
Prescribers and suppliers of medicines must give sufficient clinical

advice to patients. This might include:
● Alert patients that they may experience symptoms of sleepiness,

poor coordination, impaired or slow thinking, dizziness or visual
problems. D
● Warn that the effects of a drug may be greatest at initiation or with
dose changes.
● Consider drug interactions and disease interactions that may
increase the risk of driving being impaired.
A new offence of driving came into force in March 2015, which refers
to driving with a specified controlled drug in the body in excess of a
specified limit.2 A list of these drugs can be found in the guidance
document. However, this legislation allows a patient to raise statutory
medical defence if the drug was lawfully prescribed, supplied or
bought over the counter and the drug was taken in accordance with
advice given by the prescriber or supplier.2
REFERENCE
1 DVLA (2015). Medical Conditions, Disabilities and Driving. https://www.gov.uk/
driving-medical-conditions (accessed 9 February 2015).
2 Department for Transport (2014). Drug driving and medicine: advice for healthcare
professionals. http://www.gov.uk/government/publications/drug-driving-and-
medicine-advice-for-healthcare-professionals (accessed 9 February 2015).
k k
k
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142 Early warning score
E
E
Early warning score
Early warning score (EWS)

Background ● It has been recognised that early recognition of deterioration in a
patient’s condition and appropriate escalation of care
(a physiological ‘track and trigger’ system) improves treatment
outcomes1
● Hospital nursing and medical staff and also the emergency medical
services use the EWS to assess degree of severity of illness in a
patient. It is used at first presentation and also for ongoing
monitoring while patients remain in hospital
● The EWS is derived from the recording and scoring of various
physiological parameters. These are monitored at least every
12 hours unless a decision has been made at senior level to
increase or decrease frequency for an individual patient
● Many different systems are in use across the NHS and the world
k and it has been recommended that use of a national early warning k
score (NEWS), as outlined below, would deliver a standardised
approach across the UK2
National early warning score (NEWS)
Physiological Score Score Score Score Score Score Score
parameter 3 2 1 0 1 2 3
Respiration ≤8 9–11 12–20 21–24 ≥25
rate
(breaths/min)
Oxygen ≤91 92–93 94–95 ≥96
saturations (%)
Any Yes No
supplemental
oxygen
Temperature ≤35.0 35.1–36.0 36.1–38.0 38.1–39.0 ≥39.1
(◦ C)
Systolic blood ≤90 91–100 101–110 111–219 ≥220
pressure
(mmHg)
Heart rate ≤40 41–50 51–90 91–110 111–130 ≥131
(beats/min)
Level of A V, P or
consciousness* U
*Refers to the AVPU scale = alert, voice, pain, unresponsive.
k
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Emollients 143
Interpretation
NEWS total Clinical risk Frequency of monitoring Response2
0 Low Minimum 12-hourly ● Continue routine NEWS
monitoring
1–4 Low Minimum 4–6-hourly Inform registered nurse who
E
●
must assess patient

● Registered nurse to decide if
increased frequency of
monitoring and/or escalation
of care is required
5–6 Medium Increase frequency to a ● Registered nurse to inform
or minimum of 1-hourly medical team urgently
3 in one ● Urgent assessment by clinician
parameter competent to assess acutely ill
patients
● Clinical care in an environment
with monitoring facilities
7 or more High Continuous monitoring ● Registered nurse to inform
of vital signs medical team immediately
(specialist registrar level or
above)
● Emergency assessment by,
e.g., critical care outreach
team
k ● Consider transfer of care to k
level 2 or 3 care facility
REFERENCES
1 NICE (2007). Clinical Guideline 50. Acutely Ill Patients in Hospital. Recognition of
and response to acute illness in adults in hospital. http://www.nice.org.uk/guidance/
cg50 (accessed 17 February 2015).
2 Royal College of Physicians (2012). National Early Warning Score (NEWS): Standar-
dising the assessment of acute-illness severity in the NHS. Report of a working party.
London: RCP.
Emollients
Emollients are the mainstay of treatment for skin conditions such as
eczema, psoriasis, contact dermatitis and dry skin resulting from a
variety of other causes. They rehydrate the outermost layer of skin
and reduce water loss, mimic the barrier effects of deficient lipids and
restore the integrity of the skin barrier. When used correctly they help
to maintain or restore suppleness and pliability of the skin, improve
the cosmetic appearance, soothe and relieve skin irritation and
reduce requirements for topical corticosteroids by helping to prevent
disease flares.1,2 In psoriasis, emollients also help to soften scaly,
thickened plaques, making them more amenable to treatment.
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144 Emollients
Types of emollient
Emollient products include ointments, creams, lotions, soap
substitutes and bath oils.
Ointments
Ointments are greasy semisolids. They have fatty, emulsifying, water-
E soluble or absorption bases. Ointments with fatty bases are not
absorbed but form an occlusive layer on the skin surface and can be
difficult to spread. Although they are effective emollients, their
greasiness makes them cosmetically unattractive. Ointments with
absorption bases spread more easily but are less occlusive than those
with fatty bases. Water-soluble bases spread well and can be washed
off easily.
Creams and lotions
Creams are semisolid emulsions. They are less occlusive than
ointments and therefore less effective. However they feel less greasy,
spread well and can be washed off easily, so are more cosmetically
acceptable.
Emollient lotions are more dilute than creams and contain
additives to increase their spreadability.
Soap substitutes and bath oils
Emollient wash products (or soap substitutes), e.g. aqueous cream or
emulsifying ointment, cleanse the skin effectively, but do not lather
k like soap. They should be used in place of soaps, which otherwise may k
have a drying effect.
Bath oils are an alternative means of applying emollient by leaving
a film of emollient after bathing. Some ointments can also be used as
a bath additive by melting in hot water and adding to a warm, not
hot, bath.
Choice of product
Inappropriate selection of product can result in emollient therapy
being underused and dismissed as ineffective.3 It is essential to find a
product that matches a patient’s needs and preferences. Emollient
choice for an individual patient should involve consideration of the
factors shown in Table E1.
Dosing and application
Emollients must be used in sufficient quantities to be effective. They
should be applied as liberally and as frequently as possible. Table E2
gives approximate quantities for how much emollient an adult would
expect to use over 1 week.
‘Complete emollient therapy’ is recommended in order to obtain
the best effects from emollients (Table E3).
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Emollients 145
TABLE E1
Emollients – factors to consider
Patient needs or preference / lifestyle factors
● Different emollients may be used for different parts of the body, e.g. rich/more greasy
emollients for limbs but a lighter product for the face
● Greasy products may be cosmetically unsuitable for daytime use but acceptable at
night E
● Richer products are required in winter to combat the drying effects of cold weather
and central heating
● In psoriasis, heavier, greasy products are used to soften scaly, thickened plaques,
making them more amenable to treatment
Consistency required
● Creams or lotions are more appropriate if skin is infected or oozing to avoid occlusion
● Ointments are more effective than lighter products on dry, scaly, thick areas of skin
● Creams may feel cooler and lighter on the skin than ointments, so may be preferred
if itching is troublesome
Other ingredients / additives
● Some emollients contain potential allergens that may exacerbate the underlying skin
condition. A patch test should be considered when starting new treatment
● Lanolin is widely considered to be a sensitiser; however, lanolin-sensitivity is
uncommon. Lanolin-containing products are an appropriate option, with a patch test
if necessary
● Some products, notably aqueous cream, contain sodium lauryl sulfate, which is a
well-documented irritant. Products containing sodium lauryl sulfate are
recommended as wash-off products and should not be used as a leave-on emollient
k k
TABLE E2
How much emollient to use. These amounts are usually
suitable for an adult for twice-daily application for
1 week
Face Scalp Both hands Both arms Trunk–front Groin area
and legs and back
Amount of 15–30 g 50–100 g 25–50 g 100–200 g 400 g 15–25 g
emollient to
apply
TABLE E3
Complete emollient therapy1,4
Frequent application of emollient cream or ointment
Apply liberally with clean hands as frequently as possible – ideally, three to four times a
day, but at least twice a day. Warming the emollient will make it easier to apply. If
itching is a major problem, cool the emollient by storing it in a fridge
Emollient bath oil when bathing/showering
Baths should be warm but not hot to avoid exacerbating itching. Patients should be
advised to use a bath mat to prevent slipping and to pat skin dry rather than rub
Routine use of emollient soap substitute
Use whenever washing hands and before getting into a bath or shower. Apply to dry
skin and then rinse off with water
Avoidance of regular soaps/detergents/bubble baths
These remove lipids from the skin and may exacerbate dry-skin conditions
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146 Emollients
Pharmaceutical care and counselling points

● Ensure patients are aware of the importance of emollients as an
active treatment and the need to apply even when the skin is clear.
● Apply emollient creams/ointments liberally with clean hands,
ideally three to four times a day but at least twice a day.
Apply in the direction of hair growth to prevent folliculitis.
E ●
● A sample pack containing a variety of products can help patients

make choices on products that suit their needs and so aid
compliance.
● Ensure patients are aware that other topical preparations, e.g.
topical corticosteroids and vitamin D analogues, should not be
used as emollients.
● Emollient use should generally outweigh topical corticosteroid use
by 10:1 in terms of quantities used.
● Leave at least half an hour between emollient application and other
topical preparations to avoid dilution or spread to unaffected areas.
● Use a high-temperature wash to remove grease from clothes and
bedding and avoid biological washing powder and fabric softener.
Run an empty cycle at high temperature with washing powder to
clear greasy residue.
● Advise patients regarding the fire hazard with paraffin-based
emollients. Emulsifying ointment or Liquid Paraffin 50%/White
Soft Paraffin Ointment 50% in contact with dressings and clothing
is easily ignited by a naked flame. This risk is greater when these
k preparations are applied to large areas of the body, where clothing
k
or dressings become soaked with the ointment. Patients should be
told to keep away from fire or flames, and not to smoke when using
these preparations. The risk of fire should be considered when
using large quantities of any paraffin-based emollient.5
REFERENCES
1 Clark C (2004). How to choose a suitable emollient. Pharm J 273: 351–353.
2 Anonymous (1998). The use of emollients in dry skin conditions. MeReC Bull 9:
45–48.
3 Tucker R (2011). What evidence is there for moisturisers? Pharm J Online. http://
www.pharmaceutical-journal.com/files/rps-pjonline/pdf/pj20110416 cpd.pdf
4 Clark C (2001). Making the most of emollients. Pharm J 266: 227–229.
5 National Patient Safety Agency (2007). Fire Hazard with Paraffin Based Skin Prod-
ucts on Dressings and Clothing. Rapid response report 4. http://www.npsa.nhs.uk/
corporate/news/fire-hazard-with-paraffin-based-skin-products-on-dressings-and
-clothing/ (accessed 29 January 2015).
k
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Endocarditis 147
Endocarditis
Overview
Definition Infective endocarditis (IE) is an infection of the inner lining of the heart
cavity (endocardium), valves and adjacent structures
Causes/risk It is caused by a range of bacteria and fungi. Bacterial endocarditis is E
factors most common; causative organisms include: staphylococci,
streptococci, enterococci, HACEK group of Gram-negative bacteria,
Coxiella burnetii , Bartonella species and a wide range of other
Gram-negative pathogens, for example, Pseudomonas aeruginosa,
Enterobacteriaceae, Acinetobacter species.
Causative fungi include Candida species, Aspergillus species and a wide
variety of others. Fungal endocarditis occurs most commonly in patients
with prosthetic valves but can occur in those who are
immunocompromised, intravenous drug users and neonates.1
Endocarditis tends to occur following bacteraemia; the following
patients are classed as having predisposing risk factors:2
● valve replacement
● acquired valvular heart disease with stenosis or regurgitation
● structural congenital heart disease, including surgically corrected or
palliated structural conditions, but excluding isolated atrial septal
defect, fully repaired ventricular septal defect or fully repaired
patent ductus arteriosus and closure devices that are judged to be
endothelialised
● previous IE
k ● hypertrophic cardiomyopathy k
● intravenous drug use
Classification3 ● Left-sided native valve endocarditis
● Left-sided prosthetic valve endocarditis – this is usually split into
’early’ and ’late’
● Early: occurring less than 1 year after valve surgery
● Late: occurring more than 1 year after valve surgery
● Right-sided endocarditis
● Device-related endocarditis (pacemaker or cardioverter-defibrillator)
Signs and Some patients may present acutely unwell, displaying signs of sepsis;
symptoms others may present with more indolent signs with a low-grade fever
and non-specific symptoms. Common symptoms are fever, malaise, loss
of appetite, night sweats and weight loss.
Signs include: new murmur or a change in the nature of a pre-existing
murmur, anaemia, splenomegaly, clubbing, presence of embolic
phenomena, presence of petechiae, splinter haemorrhages, Janeway
lesions, Osler’s nodes and Roth spots, evidence of congestive heart
failure and evidence of pulmonary embolism (right-sided IE)
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148 Endocarditis
Diagnostic ● Blood cultures: three sets taken at different times from different
tests sites, prior to commencing antibiotic treatment
● Transthoracic echocardiography (TTE). This is recommended as the
first-line initial method of imaging
● Transoesophageal echocardiography (TOE). This should be
conducted in those patients with a negative TTE with a high clinical
suspicion for IE, those with a positive or poor-quality TTE or those
E with a prosthetic valve or intracardiac device
● ECG
● Chest X-ray
● Urinalysis (to check for microscopic haematuria)
● Blood tests: FBC, U&E, LFTs, CRP
● Serology: for those patients with blood culture-negative IE,
serological testing should be performed for Coxiella and Bartonella
● Modified Duke criteria:4 these criteria are used to assist in the
diagnosis of IE. Criteria for a definite diagnosis of IE require the
presence of two major, or one major and three minor, or five minor
criteria
Major criteria
● Evidence of endocardial involvement, identified as a positive
echocardiogram (vegetation or abscess or new partial dehiscence of
prosthetic valve) or new valvular regurgitation
● Positive blood cultures for typical microorganisms consistent with IE
from two separate blood cultures taken >12 hours apart or all three
or a majority of four separate cultures of blood (with first and last
sample drawn at least 1 hour apart)
k Minor criteria
● Predisposing heart condition or intravenous drug use
k
● Fever (>38◦ C)
● Vascular phenomena (e.g. Janeway lesions, septic pulmonary
emboli)
● Immunological phenomena (e.g. Osler’s nodes, Roth spots)
● Microbiological phenomenon that does not meet major criteria
● Polymerase chain reaction tests
● Echocardiographic findings consistent with IE that do not meet
major criteria
Treatment ● Intravenous antibacterial or antifungal treatment dependent upon
options1 the causative pathogen
● Surgery: this can be helpful to remove infected material and drain
any abscesses. Surgical review should be sought for all patients with
intracardiac prosthetic material. Samples of the infected tissue or
valve should be sent for microbiological and histological testing
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Endocarditis 149
Antibacterial treatment
All cases of suspected endocarditis should be discussed with a microbiologist. The

choice of antibiotics may be empirical or targeted if there are positive blood cultures. If
the patient is stable it is recommended to await blood culture results and then treat
accordingly. Listed below are the empirical treatment options for those patients with
suspected IE who have severe sepsis requiring treatment whilst awaiting blood culture
results. Empirical treatment is directed towards the most common causative pathogens
E
and should be based on the type of valve affected and risk factors for resistant
pathogens. Targeted treatment recommendations for the various bacterial and fungal
causes of endocarditis can be found within the British Society for Antimicrobial
Chemotherapy endocarditis treatment guidelines.1 Treatment duration is dependent
upon the causative pathogen and the type of affected valve; it is usually for 4–6 weeks.
In some cases, for example, IE due to C. burnetti, treatment is for 18 months to 4 years
Empirical Native valve and severe sepsis (no risk factors for
treatment1 Enterobacteriaceae, Pseudomonas)
● Vancomycin intravenous* (dosed in accordance with local guidelines)
plus gentamicin* intravenous 1 mg/kg twice daily
● If the patient is allergic to vancomycin, replace this with daptomycin*
intravenous 6 mg/kg daily
● If there are concerns about using gentamicin due to nephrotoxicity or
acute kidney injury, then use ciprofloxacin (usual British National
Formulary (BNF) doses) in place of gentamicin
Native valve and severe sepsis and risk factors for multiresistant
Enterobacteriaceae, Pseudomonas
Vancomycin intravenous* (dosed in accordance with local guidelines)
k k
●
plus meropenem* 2 g three times a day

Prosthetic valve awaiting blood cultures or with negative blood
cultures
● Vancomycin intravenous* (dosed in accordance with local guidelines)
plus gentamicin* intravenous 1 mg/kg twice daily plus rifampicin
300–600 mg twice daily intravenous or oral
*Dose reduction required in renal impairment.
Therapeutic ● Vancomycin monitoring should be undertaken in accordance with
drug local protocols. Doses should be adjusted to achieve a pre-dose level
monitoring1 of 15–20 mg/L
● Gentamicin monitoring should be undertaken in accordance with
local protocols. Doses should be adjusted to achieve a pre-dose level
<1 mg/L and 1-hour post-dose levels of 3–5 mg/L
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150 Enoxaparin dosing in unstable angina
Essential ● Check for any drug allergies (see Antimicrobial allergy management
interventions entry)
and ● Ensure patient is weighed: this is necessary for drug dosing and
monitoring creatinine clearance calculation
● Calculate creatinine clearance and recommend dosing according to
renal function (see Renal disease–assessment of renal function entry)
Where gentamicin is required, dosing should be based on actual body
E ●
weight unless the patient is obese (see Gentamicin entry).

● Check for drug interactions. Rifampicin is a potent cytochrome P450
inducer and can interact with numerous medications, including
warfarin. If daptomycin is used, withhold statins and fibrates
● If rifampicin is used, counsel patients, as it can cause a reddish
discolouration of sputum, urine, sweat and tears
● Ensure therapeutic drug monitoring is undertaken and monitor urine
output for those patients prescribed gentamicin and vancomycin
● Regularly check U&Es, LFTs, FBC, weekly creatine kinase (if on
daptomycin)
● Monitor temperature and inflammatory markers for response to
treatment
● Ensure the indication and duration of antibiotic treatment are written
on the prescription chart
REFERENCES
1 Gould FK et al. (2012). Guidelines for the diagnosis and antibiotic treatment of
endocarditis in adults: a report of the Working Party of the British Society for
Antimicrobial Chemotherapy. J Antimicrob Chemother 67: 269–289.
k 2 NICE (2014). Clinical Guideline 64. Prophylaxis Against Infective Endocarditis: k
Antimicrobial prophylaxis against infective endocarditis in adults and children under-
going interventional procedures. http://www.nice.org.uk/guidance/CG64 (accessed
11 August 2014).
3 The Task Force on the Prevention, Diagnosis, and Treatment of Infective Endo-
carditis of the European Society of Cardiology (ESC) (2009). Guidelines on the
prevention, diagnosis, and treatment of infective endocarditis. Eur Heart J 30:
2369–2413.
4 Li JS et al. (2000). Proposed modifications to the Duke criteria for the diagnosis of
infective endocarditis. Clin Infect Dis 3: 633–638.
Enoxaparin dosing in unstable angina

Enoxaparin is licensed in the UK for the treatment of unstable angina.
The SPC for enoxaparin states that the dose is 1 mg/kg every 12 hours
by subcutaneous injection, usually for 2 –8 days until the patient is
clinically stable; aspirin should be given concomitantly. Patients with
a creatinine clearance <30 mL/min should have a reduced dose of
1 mg/kg once daily.1
The standard treatment for patients presenting with unstable
angina is antiplatelet and antithrombotic agents. In the early
management of unstable angina and non-ST-segment-elevation
myocardial infarction (NSTEMI), the NICE Clinical Guideline
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94 recommends fondaparinux as the antithrombotic of choice, with

unfractionated heparin for patients with raised creatinine or likely to
undergo urgent stenting where reversibility is required.2
Fondaparinux is highly renally excreted and is not recommended in
patients with a creatinine clearance <30 mL/min. NICE Clinical
Guideline 94 does not discuss use of a low-molecular-weight heparin
(LMWH), such as enoxaparin, as an option for unstable angina E
treatment, although many hospitals do use it either as first-line
instead of fondaparinux or instead of unfractionated heparin for
patients with poor renal function.3
The SIGN guideline 93 suggests enoxaparin as an alternative to
heparin for non-ST elevation and ST-elevation acute coronary
syndromes.4 In both cases trials showed that LMWH plus aspirin
reduced myocardial infarction and coronary revascularisation
compared to unfractionated heparin plus aspirin, with no differences
in mortality or major bleeding. The ExTRACT randomised controlled
trial (enoxaparin versus unfractionated heparin for acute coronary
syndromes) confirmed these findings.5 SIGN therefore recommends
fondaparinux or LMWH. Dalteparin is also licensed for unstable
coronary artery disease at a dose of 120 units/kg, with a maximum
dose of 10 000 units twice a day. The trials evaluating dalteparin were
against placebo, where it showed superiority, and against
unfractionated heparin, where it showed equivalence. Tinzaparin
does not have a product licence for unstable angina.
k The dose of enoxaparin must be checked against creatinine k
clearance, then accurately calculated for body weight, to avoid an
increased risk of bleeding.
REFERENCES
1 SPC (2014). Clexane Pre-filled Syringes. www.medicines.org.uk (accessed
11 November 2014).
2 NICE (2013). Clinical Guidelines CG94. Unstable Angina and NSTEMI: The early
management of unstable angina and non-ST-segment-elevation myocardial infarction.
https://www.nice.org.uk/guidance/cg94 (accessed 11 November 2014).
3 SPC (2014). Arixtra Fondaparinux sodium solution for injection 2.5 mg/ 0.5 mL.
www.medicines.org.uk (accessed 11 November 2014).
4 SIGN (2013). Acute Coronary Syndromes. http://www.sign.ac.uk/guidelines/
fulltext/93/ (accessed 11 November 2014).
5 Gabriel RS, White HD (2007). ExTRACT-TIMI 25 trial: clarifying the role of enoxa-
parin in patients with ST-elevation myocardial infarction receiving fibrinolysis.
Expert Rev Cardiovasc Ther 5: 851–857.
Enteral feeding systems and drug

administration
In the course of providing advice about the administration of
medicines via enteral feeding tubes, knowledge of these feeding
systems is of benefit.
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152 Enteral feeding systems and drug administration
Purpose of enteral feeding tubes

Enteral feeding tubes are used to provide nutritional support and
hydration and to prevent or treat malnutrition. Providing nutrition
enterally is preferable to parenteral feeding because feeding via the
GI route is easier, safer, less expensive and more physiological.1
E Selection of access device

Feeding tubes may be placed into the stomach or the small intestine
either in the distal duodenum or proximal jejunum. The expected
duration of feeding is the major determinant of method, but risk of
aspiration, GI function, overall patient condition and placement
technique are all factors.
Nasoenteric tubes are usually intended for short-term therapy and
more commonly take the form of nasogastric (NG) tubes.
Gastrostomy or jejunostomy tubes are devices intended for
placements of 1 month or longer.
Nasoenteric tubes
These tubes are placed through the nose and are advanced to the
point where the tip of the tube lies in the stomach or the small
intestine. Such tubes can be placed at the bedside and cause a
minimum of complications. For feeding purposes, fine-bore
(e.g. 8 –10 Fr) polyurethane or silicone tubes are used. Smaller tubes
are less likely to lead to aspiration or swallowing difficulties, and are
less irritant to the gut. Larger tubes can be used on critical care. All
k tubes used for NG feeding must be licensed for feeding, be
k
radiopaque throughout their length and have externally visible length
markings.2
The position of most nasoenteric tubes may be confirmed by the
pH of aspirate. X-ray is used as a second-line test when no aspirate can
be obtained or the pH paper has failed to confirm the position of the
tube. NG tubes are more frequently used than nasoduodenal/jejunal
tubes in the UK, though the latter have a role in critically ill patients at
particular risk of pulmonary aspiration or delayed gastric emptying.
Complications of nasoenteric tube use may include nasal irritation,
epistaxis, rupture of oesophageal varices, tracheobronchial injury or
pulmonary compromise.
Gastrostomy and jejunostomy tubes
Where use of the nasal route for tube insertion is contraindicated, or
when longer-term tube feeding is anticipated, an enterostomal device
is preferred. In this scenario a tube is inserted percutaneously through
a stoma created on the abdomen.
Percutaneous endoscopic gastrostomy (PEG) has become the most
widely used approach for gastrostomy placement and the dual-access
gastrostomy-jejunostomy (PEG/J) is a variation on this. These tubes
are placed endoscopically under conscious sedation, pushing the tube
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out from the stomach lumen through the stomach wall to emerge
through the skin of the abdomen.
A PEG tube is a single-lumen tube terminating in the stomach,
delivering feeds directly into the stomach. The PEG/J is a
double-lumen tube, one lumen terminating in the stomach and a
longer tube descending into the jejunum – the double-lumen system
allows feeding directly into the jejunum, and stomach decompression E
via the stomach tube.
Both types of tube are held in place by an internal retainer
(a bumper or balloon) and an external retainer (disc, bumper or
cross-bar). The tubes are composed of silicone or polyurethane, which
are resistant to gastric secretions.
Once the placement of the tube has been confirmed by X-ray, tube
patency and patient tolerance are checked by giving a bolus or
infusion of sterile water. If tolerated, feeds can be started slowly with
full-strength formula according to hospital policy. To prevent
aspiration, the head of the bed should be elevated to at least 30 –45◦
from the horizontal during feeds and for 1 hour after feeds. If patients
are asleep they should recline on their right side.
To avoid clogging feeding tubes, the tube should be flushed every
4 –6 hours during feeds, after completion of a feeding session, and
before and after administration of medicines. Water is considered to
be the best liquid for flushing and maintenance of tube patency. Flush
volumes should be included in fluid balance calculations. In hospital
k this should be sterile water but at home it can be tap water or cooled, k
boiled water dependent on the health professional’s risk assessment.
The stoma site should be cleaned daily using warm water
(or sterile sodium chloride 0.9% in a hospital setting) applied with a
sterile gauze swab. The area around the tube and under the flange
should then be gently dried with a sterile swab. The flange should be
left sitting lightly on the skin, allowing air circulation around it. After
4 weeks the tube should also be turned, clockwise and anticlockwise,
180◦ from its original position to keep the stoma healthy.
Feeding via enteral feeding tubes
The dietician will liaise with the patient, family and multidisciplinary
team to work out a feeding regimen that fits with the requirements of
the patient. This can include pump feeding, bolus feeding or a
mixture of both. Overnight feeding may be appropriate for patients
who are able to eat and drink small amounts.
Meticulous mouth care is of great importance in patients with
tube-feeding systems because of limited oral fluid intake. Ice chips,
mouth swabs, throat lozenges, throat sprays and chewing gum may
all have a role to play in this aspect of care.
Some hospitals recommend routine prescribing of proton pump
inhibitors (PPI) for patients who have PEGs as prophylaxis against the
inevitable gastro-oesophageal reflux that accompanies overnight
feeding and gastric distension.
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154 Enteral feeding systems and drug administration
Testing the pH of aspirate

pH testing using pH paper that is CE-marked and intended by the
manufacturer to test gastric aspirate is the first-line method for
confirming NG tube placement. A measured pH of <5.5 is indicative
of gastric placement. The use of acid-suppressing drugs (e.g. PPIs,
H2 -receptor antagonists) will increase gastric pH, leading to
E potentially misleading measurements. Whoosh tests, litmus paper
(rather than pH paper) or assessing the appearance of aspirate must
never be used to test the position of NG tubes.2
Problems with drug administration
A full medication review may reveal options for discontinuation of
unnecessary drugs. Consider alternative administration routes such
as transdermal, rectal, sublingual or parenteral. In some instances the
patient may be able to continue to take medications by mouth. All
medicines should be administered via a suitable oral / enteral syringe
that is compatible with the enteral feeding system. These syringes are
designed so that they do not fit with an intravenous system.3
In the choice of therapeutic agent for any given indication, an
appropriate preparation for tube administration should be selected.
However, the unavailability of many medications in a suitable liquid
formulation is a barrier to effective administration of drugs via tubes.
Some manufacturers have a range of unlicensed drugs available in
liquid form, although cost may be a factor, since many of these
k products are relatively expensive and therapy may be of a long k
duration.
Many sugar-free oral liquids contain sorbitol, which can cause
abdominal cramping and diarrhoea. Sorbitol doses of 7.5 –30 g may
cause adverse effects, with symptoms being particularly severe above
20 g,4 and it is therefore important to minimise the intake of sorbitol
where possible. The bore (internal diameter) of feeding tubes may be
very small, and for this reason viscous fluids should be mixed with an
equal amount of water immediately before administration. An
injection formulation may be appropriate for the preparation of some
liquid doses.
It is recommended to confirm the appropriateness of a medication
for tube administration with a standard reference text5,6 or with the
manufacturer. General principles are explained below.
Crushing tablets
Solid oral dose forms have been widely crushed and mixed with
water, but administration in this fashion is outside the product licence
as it involves manipulation of the product. If this unlicensed method
is chosen, the dose must be prepared immediately prior to
administration. This will minimise drug degradation and reduces the
risk of a drug administration error.
Crushing may be accomplished between two spoons, with a pestle
and mortar, or a proprietary crushing device, and the resulting
powder is then mixed with a small volume of water and transferred to
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the tube using a syringe. Any equipment used must be thoroughly

cleaned after use and tablet-crushing devices should be reserved for
use with one patient only because of the difficulty in removing all
traces of medication. Many tablets will soften and disperse in water
(a process referred to as ‘mungeing’ in some quarters) without the
need for grinding. Modified-release preparations and many
enteric-coated products are not suitable for crushing. E
Use of capsules
Capsules may be opened (unlicensed use) to reveal a powder that
may be miscible with water, or they may contain beads or pellets,
which can sometimes be flushed down tubes (e.g. Slo-phyllin).
It must be borne in mind that pellets may block the tube due to a
‘bridging’ effect.
Blockage management
Tablets or capsules, when given as above, may cause the feeding tube
to become blocked, and some products should not be given in this
way because of the high risk of such an occurrence. The manufacturer
is a source of information if the properties of the product are not
already known. Inadequate tube flushing is the most common cause
of tube blockage. The consequence to the patient of a blocked tube
that cannot be unblocked is potentially no food, fluid or medicine
until a new tube is sited, which may take several days.
Some products manipulated for tube administration require
k special preparation or administration techniques. For instance, k
omeprazole (pellets from capsules) should be dispersed in a
bicarbonate solution to remove the pellet coating but administration
may still be unsuccessful. Losec MUPS should not be dispersed for
tube administration because of the risk of tube blockage; Zoton
FasTabs are a more suitable choice of PPI preparation.
Flushing
Feeding tubes should always be flushed with at least 30 mL of water
before and after the administration of medications. You may have a
local policy determining the quantity and grade of water to be used
(i.e. tap water or sterile water).
Control of Substances Hazardous to Health (COSHH)
The powders liberated by the manipulation of tablets or capsules may
present a hazard to staff preparing doses. Cytotoxic products and
hormonal preparations should not be manipulated in this manner.
Cyclophosphamide and busulfan may be obtained as ‘specials’ in a
liquid form from some specialist manufacturers.
Interactions with feeds
Where possible, give medication doses during breaks in feeding to
minimise the risk of interaction with feeds. To increase potential
feeding time the number of medication doses per day should be
reduced where possible. Medication should never be added directly to
enteral feeds.
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156 Epidural analgesia in the postoperative period
Some pharmaceuticals are known to be incompatible with feeds,

and the standard advice regarding flushing of tubes is not adequate to
prevent interaction. For example, the bioavailability of phenytoin
suspension is reduced by the presence of enteral feed.7 It is
recommended that the feed should be stopped for 2 hours before
administration of the drug and recommenced 2 hours after.8
E Therapeutic drug monitoring may be required to guide dose
adjustment. This may be a consideration with many other drugs, and
therefore it is essential that a full medication review is undertaken
when a patient commences enteral feeding.
REFERENCES
1 Bowers S (2000). All about tubes. Nursing 30: 41–47.
2 NPSA (2011). Reducing the Harm Caused by Misplaced Nasogastric Feeding Tubes in
Adults, Children and Infants. http://www.nrls.npsa.nhs.uk/resources/type/alerts/
?entryid45=129640 (accessed 8 September 2014).
3 NPSA (2007), Promoting Safer Measurement and Administration of Liquid Medicines
via Oral and Other Enteral Routes. http://www.nrls.npsa.nhs.uk/resources/type/
alerts/?entryid45=59808&q=0%C2%ACsyringe%C2%AC (accessed 8 September
2014).
4 Duncan B et al. (1997). Medication-induced pneumatosis intestinalis. Pediatrics 99:
633–636.
5 Smyth JS (ed.) (2010). The NEWT Guidelines for Administration of Medication to
Patients with Enteral Feeding Tubes or Swallowing Difficulties (2nd edn). Wrexham:
North East Wales NHS Trust, 2010.
6 White R, Bradnam V (2010). Drug Administration via Enteral Feeding Tubes (2nd
edn). London: Pharmaceutical Press.
k 7 BAPEN (2004). Administering Drugs via Enteral Feeding Tubes, A Practical Guide. k
http://www.bapen.org.uk/pdfs/d and e/de pract guide.pdf (accessed 8 September
2014).
8 SPC (2014). Epanutin Suspension. https://
www.medicines.org.uk/emc/medicine/13289 (accessed 8 September 2014).
Epidural analgesia in the postoperative

period
Continuous infusion of an analgesic solution (usually a mixture of
local anaesthetic and opioid) into the epidural space close to the
spinal cord via an indwelling catheter has become an increasingly
popular method for postoperative pain relief. Epidural analgesia
offers unique benefits in postoperative pain relief:1
● improved pain relief compared with other analgesic techniques
● reduction in postoperative and post-trauma morbidity, particularly
in high-risk patients
● reduction in postoperative complications, e.g. preventing retention
of secretions and development of pneumonia
● earlier discharge from hospital.
Epidural infusion solutions should be available in pre-prepared bags
or syringes and they should be stored separately to other infusions.
Preparation within the ward environment is discouraged.2
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Epidural analgesia in the postoperative period 157
Medicines used in epidurals

Local anaesthetics
Almost all local anaesthetics can be given by epidural administration.
Levobupivacaine and bupivacaine (0.1 –0.25% (1 –2.5 mg/mL)) are
used most commonly as they have a longer duration of effect
compared with lidocaine. Ropivacaine is a newer agent and may cause
fewer side effects, most notably motor blockade, than bupivacaine. E
Opioid analgesics
Lipophilic opioids, such as fentanyl and diamorphine, are preferred
for epidural analgesia as they penetrate nerves more readily and
result in less spread within cerebrospinal fluid. Fentanyl binds to the
fat in the epidural space, which limits spread to other areas in the
spinal cord where an effect may be undesirable. The usual strength of
fentanyl in epidural solutions is 2 –4 micrograms/mL.
Administration
Dedicated pumps should be used for epidural infusions and together
with giving sets they should be clearly distinguishable from those
used for other routes of administration.2
The epidural infusion rate is usually between 4 and 10 mL/hour.
The continuous infusion can be supplemented by bolus doses given
either by a healthcare professional, or by the patient using a
patient-controlled epidural analgesia (PCEA) handset, typically
2 –3 mL. As with intravenous patient-controlled analgesia
k (see Patient-controlled analgesia entry), for PCEA after a bolus dose k
there is a lock-out period, which prevents further doses being
administered.
Contraindications
Epidurals should not be used where there is a lack of staff fully trained
in the care of patients with epidurals.
Absolute contraindications to epidural analgesia include:
● lack of consent
● full anticoagulation (not venous thromboembolism prophylaxis)
● local or generalised sepsis.
Relative contraindications include:
● hypovolaemia or shock (increased risk of hypotension)
● coagulopathy
● thrombocytopenia (increases the risk of epidural haematoma)
● raised intracranial pressure.
Adverse effects
Potential adverse effects related to the route of administration
include:3
● nerve injury
● epidural haematoma
● epidural abscess.
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158 Epilepsy: TDM of antiepileptics in adults
Monitoring
Epidural analgesia requires regular monitoring. Most hospitals have
specific epidural prescription charts, which allow the recording of
monitoring parameters, including:
● pain intensity
E ● respiratory rate
● sedation score
● blood pressure
● nausea or vomiting
● sensory and motor function
● observation of the infusion site.
REFERENCES
1 Wu CL et al. (2005). Efficacy of postoperative patient-controlled and continuous
infusion epidural analgesia versus intravenous patient-controlled analgesia with
opioids: a meta-analysis. Anesthesiology 103: 1079–1088.
2 National Patient Safety Agency (2007). Epidural Injections and Infusions. http://
www.nrls.npsa.nhs.uk/resources/?EntryId45=59807 (accessed 22 November
2014).
3 Macintyre PE et al. (2010), Acute Pain Management: Scientific Evidence (3rd edn).
Melbourne: ANZCA and FPM. http://www.anzca.edu.au/resources/college
-publications/pdfs/Acute%20Pain%20Management/books-and-publications/
Acute%20pain%20management%20-%20scientific%20evidence%20-%20third%
20edition.pdf (accessed 27 November 2014).
k k
Epilepsy: therapeutic drug monitoring of

antiepileptics in adults
Routine blood monitoring of antiepileptic drug levels is not usually
required if the dose is stable, seizure control is good and the patient is
free of side effects. However, monitoring of serum concentrations is
available for most antiepileptic drugs and may be useful if considered
alongside the clinical presentation in the following circumstances:
● to check adherence
● in suspected toxicity
● to check the effect of a potential/suspected drug interaction
● in therapeutic failure
● after a dose change.
Drug interactions between antiepileptics can be complex. It is

important to remember that adding or removing a drug to or from a
given regimen can significantly affect levels of the other drugs,
possibly resulting in toxicity or increased seizures. Therapeutic drug
monitoring (TDM) can be a useful tool to add to clinical assessment in
the management of these situations, although routine monitoring of
the newer antiepileptic drugs is rarely necessary.
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Epilepsy: TDM of antiepileptics in adults 159
Suicidal ideation and behaviour have been reported in patients

treated with antiepileptic agents in several indications. Therefore, all
patients receiving antiepileptic drugs should be monitored for signs of
this and appropriate treatment considered. Patients and carers should
be advised to seek medical advice if signs of suicidal ideation or
behaviour emerge.
Tables E4 –E23 are summaries of antiepileptic drugs with details of E
TDM rationale. See Carbamazepine and Phenytoin – management and
monitoring entries for details specific to these.
TABLE E4
Clobazam1
Half-life ● 36 hours for clobazam
● 79 hours for the active metabolite
N -desmethylclobazam
Pretreatment measures Contraindicated in patients with:
● history of drug/alcohol dependence
● myasthenia gravis
● sleep apnoea
● severe hepatic insufficiencies
Therapeutic serum range ● 30–300 micrograms/mL
● N -desmethylclobazam 300–3000 micrograms/mL2
Other monitoring ● For dependence (physical and psychological)
● Tolerance
k Interactions with other ● Interactions can occur but are not frequently k
antiepileptics recognised as a problem
TABLE E5
Clonazepam1
Half-life ● 20–60 hours (mean 30 hours)
Pretreatment measures Contraindicated in:
● severe respiratory deficiency
● sleep apnoea
● severe hepatic insufficiency
Therapeutic serum range ● 20–70 micrograms/mL2
Other monitoring ● Concurrent use of other centrally acting agents
can potentiate drug effects, e.g. sedation
Interactions with other ● Clonazepam serum concentration may be
antiepileptics decreased by carbamazepine, phenobarbital,
phenytoin and valproic acid
● Clonazepam can increase or decrease the serum
concentration of phenytoin and primidone
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TABLE E6
Eslicarbazepine1
Half-life ● 13–20 hours
Pretreatment measures ● U&Es, ECG
● For HLA-B*1502 allele in Han Chinese and
HLA-A*3101 allele in European and Japanese
population
E
Therapeutic serum range ● 3–35 mg/L
Interactions with other ● Eslicarbazepine serum concentration may be
antiepileptics increased or decreased by lamotrigine
● Eslicarbazepine serum concentration may be
decreased by carbamazepine and phenytoin
● Eslicarbazepine can increase the serum
concentration of phenytoin
● Eslicarbazepine can decrease the serum
concentration of topiramate
● Eslicarbazepine can increase or decrease
lamotrigine serum concentration
TABLE E7
Ethosuximide1
Half-life ● 40–60 hours (adults), 30 hours (children)
Pretreatment measures ● FBC, U&Es, LFTs
Therapeutic serum range ● 300–700 micromol/L
40–100 mg/L
k ●
Periodically check FBC, U&Es, LFTs

k
Other monitoring ●
Interactions with other ● Ethosuximide serum concentration may be

antiepileptics increased or decreased by valproic acid and
phenytoin
● Ethosuximide serum concentration may be
decreased by carbamazepine, primidone,
phenobarbital and lamotrigine
● Ethosuximide can increase the serum
● Ethosuximide can decrease the serum
concentration of valproic acid1
TABLE E8
Gabapentin1
Pretreatment measures ● U&Es
Therapeutic serum range ● There is much interpatient variability, and the
serum concentration/therapeutic response is not
well established. A putative range is 12–120
micromol/L (2–20 mg/L)2
Interactions with other ● No clinically significant interactions with other
antiepileptics antiepileptics have been reported3
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TABLE E9
Lacosamide1
Half-life ● 13 hours
Pretreatment measures ● U&Es
● ECG (potential PR prolongation)
● (Contraindicated in known second- or
third-degree heart block) E
Therapeutic serum range ● Not established
antiepileptics antiepileptics have been reported
TABLE E10
Lamotrigine1
Half-life ● Range 14–103 hours (mean 33 hours)
● Reduced to a mean of approximately 14 hours if
enzyme inducers are present (see below)
● Increased to a mean of approximately 70 hours if
sodium valproate is present
Pretreatment measures ● LFTs
Therapeutic serum range ● Dosing is usually based on clinical response rather
than a serum concentration, and
concentration/therapeutic response is not well
established. Aim for 12–64 micromol/L
k (3–15 mg/L)4 k
Interactions with other ● Lamotrigine serum concentration may be
antiepileptics increased by valproic acid
● Lamotrigine serum concentration may be
decreased by carbamazepine, phenobarbital,
phenytoin and primidone
TABLE E11
Levetiracetam1
Half-life ● 6–9 hours (elderly: 10–11 hours)
Pretreatment measures ● U&Es, LFTs
Therapeutic serum range ● The serum concentration/therapeutic response has
not been well established. A putative range is
70–269 micromol/L (12–46 mg/L)2
● N.B.: There is low intra- and intersubject variability
and plasma levels can be predicted from the oral
dose of levetiracetam as mg/kg body weight,
reducing the need for monitoring levels2
antiepileptics antiepileptics have been reported3
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TABLE E12
Oxcarbazepine1
Half-life ● 1.3–2.3 hours for oxcarbazepine
● 9.3 hours for 10-hydroxy-carbazepine (active
metabolite)
Pretreatment measures ● U&Es, LFTs
E Therapeutic serum range ● The serum concentration/therapeutic response has
not been well established. A putative range for
10-hydroxy-carbazepine is 50–110 micromol/L
(12–27 mg/L).4
● Toxicity has been observed at 138–158
micromol/L (35–40 mg/L)
● N.B.: pharmacokinetics of active metabolite are
linear and show dose proportionality across the
dose range of 300–2400 mg/day
Other monitoring ● Patients with renal impairment should have U&Es
checked 2 weeks after commencement, and then
monthly for the first 3 months
● N.B.: In patients with cardiac insufficiency and
secondary heart failure, regular weight
measurements are needed to determine
occurrence of fluid retention. In case of fluid
retention or worsening cardiac condition, serum
sodium should be checked
Interactions with other ● Oxcarbazepine serum concentration may be
antiepileptics decreased by carbamazepine, phenytoin,
k phenobarbital and valproic acid k
● Oxcarbazepine can increase the serum
concentration of phenytoin and phenobarbital
● Oxcarbazepine can decrease the serum
concentration of carbamazepine
TABLE E13
Perampanel1
● Reduced to 25 hours in the presence of potent
enzyme inducers
Therapeutic serum range ● No therapeutic serum concentration established
Interactions with other ● Perampanel serum concentration may be
antiepileptics decreased by carbamazepine, oxcarbazepine,
phenytoin and topiramate
● Perampanel can decrease the serum concentration
of carbamazepine, clobazam, lamotrigine,
oxcarbazepine and valproic acid
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TABLE E14
Phenobarbital1
Half-life ● Range: 75–136 hours (mean 100 hours)4
● Shorter in children and with enzyme-inducing
agents
Pretreatment measures ● FBC, U&Es
Therapeutic serum range ● 60–180 micromol/L (10–50 mg/L) E
● N.B.: Modified by development of tolerance
Sampling time ● Sampling time is not critical; however, it can take
3 weeks to achieve steady state4
Other monitoring ● FBC should be checked periodically as
megaloblastic anaemia and blood dyscrasias
occasionally occur5
Interactions with other ● Phenobarbital serum concentration may be
antiepileptics increased by valproic acid, oxcarbazepine,
phenytoin, felbamate and stiripentol
● Phenobarbital serum concentration may be
increased or decreased by phenytoin
● Phenobarbital serum concentration may be
decreased by vigabatrin
● Phenobarbital can decrease the serum
concentration of carbamazepine, phenytoin and
valproic acid, ethosuximide, lacosamide,
lamotrigine, clobazam and clonazepam,
rufinamide, tiagabine, topiramate and
zonisamide3
k Two other important interactions are with alcohol
k
and coumarin anticoagulants.
● Alcohol potentiates the CNS depression of
barbiturates.
● Phenobarbital stimulates the metabolism of
coumarin anticoagulants, and because
phenobarbital has such a long half-life, it can take
14 to 21 days for the liver enzymes to return to
normal upon its withdrawal. This means close
monitoring of the anticoagulation is necessary
during this period to prevent haemorrhage
TABLE E15
Pregabalin1
Half-life ● 6.3 hours
Pretreatment measures ● ECG, U&Es
Interactions with other antiepileptics ● No clinically significant interactions with
other antiepileptics have been reported
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TABLE E16
Primidone1
Half-life ● Range 4–22 hours2
● Mean 10 hours
● The principal metabolite of primidone is
phenobarbital, so effect can persist much longer
E (see above)
Pretreatment measures ● FBC, U&Es, LFTs
Therapeutic serum range ● 23–55 micromol/L (5–12 mg/L)
Other monitoring ● FBC should be checked periodically as
megaloblastic anaemia and blood dyscrasias
occasionally occur
Interactions with other ● See phenobarbital above
antiepileptics ● Additionally carbamazepine and phenytoin can
stimulate the conversion of primidone to
phenobarbital
TABLE E17
Retigabine1
Pretreatment measures ● U&Es, LFTs, ophthalmology review, ECG,
assessment of risk of urinary retention
Therapeutic serum range ● Not established
k Other monitoring ● Six-monthly ophthalmology review k
Interactions with other ● Retigabine serum concentration may be
antiepileptics decreased by carbamazepine and phenytoin
● Caution is advised in the concomitant prescribing
of retigabine and lamotrigine as retigabine levels
may increase and lamotrigine levels may
decrease3
TABLE E18
Rufinamide1
● ECG (can shorten QT interval)
Interactions with other antiepileptics ● Rufinamide serum concentration may be
increased by valproic acid (most
pronounced effects in patients with low
body weight (<30 kg)
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TABLE E19
Tiagabine1
● (2–3 hours if enzyme induction occurs)
not been well established. A putative range is E
200–1100 nmol/L (82–453 mg/L)2
Interactions with other ● Tiagabine serum concentration may be decreased
antiepileptics by carbamazepine, phenobarbital, phenytoin and
primidone
● Tiagabine can decrease the serum concentration
of valproic acid3
TABLE E20
Topiramate1
● Reduced to 12–15 hours with enzyme inducers4
Pretreatment measures ● LFTs, U&Es
6–74 micromol/L (2–19 mg/L)2
Other monitoring ● Bicarbonate level may require monitoring if the
patient shows signs of metabolic acidosis
(although this side effect is rare)
k Interactions with other ● Topiramate serum concentration may be k
antiepileptics decreased by phenytoin and carbamazepine
● Topiramate can sometimes increase the serum
TABLE E21
Valproic acid (sodium valproate)1
Half-life ● Range 8–20 hours
● Mean 12 hours
Pretreatment measures ● LFTs, U&Es
Therapeutic serum range ● 278–694 micromol/L (40–100 mg/L)
● Toxic effects usually observed at >700 micromol/L
(>100 mg/L)
Other monitoring ● LFTs before initiation, monthly for the first 6
months, and then annually
Interactions with other ● Valproic acid serum concentration may be
antiepileptics increased by stiripentol
● Valproic acid serum concentration may be
decreased by carbamazepine, phenobarbital,
phenytoin and tiagabine
● Valproic acid can increase the serum
concentration of ethosuximide, lamotrigine,
phenobarbital, primidone and rufinamide
● Valproic acid can decrease the plasma
concentration of clonazepam and phenytoin (but
increases the amount of free phenytoin, therefore
if monitoring phenytoin measure the free form
rather than the total phenytoin)
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TABLE E22
Vigabatrin1
Half-life ● Range 5–8 hours
Pretreatment measures ● FBC, U&Es
● An ophthalmological examination is required as
vigabatrin can cause visual field defects
E Therapeutic serum range ● The serum concentration/therapeutic response has
6–278 micromol/L (0.8–36 mg/L)2
Other monitoring ● Periodically monitor FBC and U&Es and carry out
an ophthalmological examination
Interactions with other ● Vigabatrin can decrease the serum concentration
antiepileptics of phenytoin, and may reduce phenobarbital and
primidone levels1,4
TABLE E23
Zonisamide1
Half-life ● 60 hours; reducing in the presence of
enzyme-inducing drugs
Pretreatment measures ● Exclude a personal or close family history of renal
stones. Advise adequate hydration
● Exclude hypersensitivity reactions to
sulphonamides
Therapeutic serum range ● 20–30 micrograms/mL
k Other monitoring ● FBC for aplastic anaemia k
Interactions with other ● Zonisamide can gradually decrease the serum
antiepileptics concentration of phenytoin
REFERENCES
1 eMC (2014). www.medicines.org.uk (accessed 11 November 2014).
2 Epilepsy Society (2014). Guidelines for Therapeutic Drug Monitoring of Antiepileptic
Drugs. http://www.epilepsysociety.org.uk/sites/default/files/Therapeutic
-Drug-Monitoring-of-Antiepileptic-Drugs-Table.pdf (accessed 19 November
2014).
3 Baxter K, Preston CL (2013). Stockley’s Drug Interactions: A source book of interac-
tions, their mechanisms, clinical importance and management (10th edn). London:
4 Alarcon G et al. (2009). Epilepsy (Oxford Specialist Handbooks in Neurology).
Oxford: OUP.
Livingstone.
k
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Erythrocyte sedimentation rate 167
Erythrocyte sedimentation rate

Erythrocyte sedimentation rate (ESR) is a widely used test to monitor
inflammatory disease and infections. It is a non-protein acute-phase
reactant where serum levels reflect plasma viscosity and indirectly
measure acute-phase protein concentrations.1
It is defined as the rate (mm/hour) at which erythrocytes E
suspended in plasma in a vertical tube settle.
Advantages include the availability of abundant literature, and
that it is inexpensive and easy to carry out. N.B.: samples require
analysis within 4 hours.2
Disadvantages include non-specificity in that it doesn’t identify the
cause or location of inflammation, and changes occur slowly relative
to the patient’s condition. CRP concentrations generally change more
rapidly.
Temporal arteritis and polymyalgia rheumatica are exceptions
where a high ESR is used to diagnose and monitor disease activity.1
ESR can be raised in any inflammatory disorder and conditions
such as tuberculosis, myocardial infarction, multiple myeloma, renal
disease and anaemia.3 Raised ESR may also be seen in menstruation
and pregnancy.
Low ESR is seen in conditions such as congestive cardiac failure,
sickle cells and some protein abnormalities.3
k Predicted values k
ESR increases with age and is higher in females (see formula below):4
● ESR in men = age in years divided by 2

● ESR in women = (age in years + 10) divided by 2.
Drugs such as methyldopa, oral contraceptives, theophylline and

vitamin A can increase ESR; aspirin, steroids and quinine may
decrease it.1
REFERENCES
1 UpToDate (2014). Acute Phase Reactants. http://www.uptodate.com/contents/
acute-phase-reactants?source=search result&search=crp&selectedTitle=2∼150
2 GP Notebook (2015). Reference Range (ESR). http://www.gpnotebook.co.uk/
simplepage.cfm?ID=389349443 (accessed 21 October 2014).
3 Patient.co.uk (2014). Acute-phase Proteins, CRP, ESR and Viscosity. http://
www.patient.co.uk/doctor/acute-phase-proteins-crp-esr-and-viscosity (accessed 17
January 2015).
4 Miller A et al. (1983). Simple rule for calculating normal erythrocyte sedimentation
rate. Br Med J (Clin Res Ed) 286: 266.
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168 Eye drops: use and care
Eye drops: use and care

Key counselling points for patients administering eye drops are listed
below.
Administration
E 1 With clean hands, unscrew the cap to expose the nozzle, or if the
drops are in a glass bottle, draw up some of the solution into the
glass dropper. Do not breathe on the eye drop nozzle or glass
dropper.
2 Tilt the head back and look up towards the ceiling.
3 The lower eyelid should be gently pulled downwards and, without
touching the eye with the nozzle or dropper, place one drop into
the space between the lower lid and the eye (Figure E1).
4 Release the lid and close the eye for 30 seconds. Try not to blink
more than usual; this removes the drops from the eye by drainage
into the tear ducts.1
5 Replace the dropper or cap on the bottle securely.
Additional counselling points

● Avoid contamination of the eye drops during use.
● Date the bottle when first opened and discard 4 weeks after
opening for multidose preservative eye drops (unless the
manufacturer recommends a longer or shorter period). For ward
k use in some hospitals, this may be reduced to 1 or 2 weeks because k
of the greater risk of contamination. In section 11.2 of the BNF
(control of microbial contamination) it is recommended to discard
1 week after opening, and to obtain a fresh supply on discharge
from hospital.2 Check your local policy.
● Never let any other person use your eye drops.
● It is generally inadvisable to wear contact lenses, particularly soft
lenses, when using eye drops or ointment.
● Store the drops in a cool dry place out of reach of children. Some
eye drops require refrigerated storage (2 –8◦ C),
e.g. chloramphenicol.
FIGURE E1 Instillation of an eye drop
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Eye drops: use and care 169
● If using eye ointment at the same time of day as drops, use the
drops first and wait 5 minutes before using the ointment.
● If using more than one kind of eye drop, wait 5 minutes between
drops.
There are four types of eye drop preparations: multidose preserved
eye drops, preserved eye drop gels, preservative-free single-unit dose
eye drops (which should be used immediately after opening and then
E
discarded immediately after use) and preservative-free multidose
products such as Hylo-Forte. The contents of the Hylo range products
are protected from contamination by the unique design of the delivery
system, which is an airless, preservative-free multi-dose container.3
Once a drop is delivered, the valve immediately closes and backflow is
prevented. These products are sterile for 6 months once opened.4
Professional points
Flooding the eye with a number of drops from the same bottle is a
common administration error. The eye can only accommodate one
drop before overflow occurs. Instillation of more than one drop
should be discouraged, as this may increase systemic side effects.5
The volume of liquid contained in eye drop bottles is variable but for
the calculation of likely number of doses available, each millilitre will
provide about 15 drops.
Some patients demonstrate allergy to their eye drops, which is
often related to the preservative rather than the active ingredient.
k Appropriate eye drops containing a different preservative may be k
prescribed, or alternatively single-use (preservative-free) eye drops
may be used, which are more expensive. In the absence of infection it
is generally acceptable to use one ‘single-use’ eye drop to treat both
eyes if both require treatment. For patients requiring eye drops
long-term, an ophthalmologist should properly diagnose any eye drop
preservative allergy.
A large proportion of a typical eye drop will have drained from the
conjunctival sac within 30 seconds under normal conditions; there
will be no trace of the drop after 20 minutes.1 Systemic side effects
may arise from absorption of drugs into the general circulation from
conjunctival vessels or from the nasal mucosa. Gently pressing on the
inside corner of the closed eye (lacrimal punctum) for at least a
minute reduces drainage into the nasolacrimal channel, therefore
prolonging contact time of the drop in the eye and decreasing
systemic absorption from the nasal mucosa.2
Several devices are also available to help with correct positioning
of eye drop bottles. The Opticare range is available on NHS
prescription, and can accommodate 2.5 mL to 20 mL dropper bottles.
The Auto-Dropper is another example of this kind of device.
Postoperative treatments
When reviewing medications in patients after ophthalmic surgery, the
continuing need for topical corticosteroids and antibacterial agents
can be problematic. The following are examples of ophthalmic
postoperative regimens for eye drops:
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170 Eye ointments: use and care
Glaucoma surgery (trabeculectomy)

● prednisolone acetate 1% eye drops 2-hourly
● atropine 1% eye drops three times a day
● ofloxacin 0.3% eye drops four times a day for 1 week.
Squint surgery
E
● dexamethasone, neomycin and polymyxin B (Maxitrol) eye drops
four times a day for 4 weeks.
Cataract surgery – uncomplicated

● dexamethasone, neomycin and polymyxin B (Maxitrol) four times
a day for 4 weeks.
Cataract surgery – for diabetic patients
● prednisolone acetate 1% eye drops four times a day for 4 weeks
● chloramphenicol 0.5% eye drops four times a day for 1 week.
A fresh supply of eye drops should be provided after any eye surgery
and any used presurgery should be discarded.2
REFERENCES
1 Richards RME (2004). Ophthalmic products. In: Winfield AJ, Richards RME (eds)
Pharmaceutical Practice (3rd edn). London: Churchill Livingstone,pp. 264–279.
k 3 Titcomb L (2010). Are quality standards being reduced as eye drops are classed as
k
devices? Pharm J 284: 633–638.
4 Scope Ophthalmics (2014). Dry Eye Products. http://www.scopeophthalmics.com/
index.php?ECProduct=31&ec=dry-eye-products (accessed 25 October 2014).
Eye ointments: use and care

Eye ointments are available for a limited range of drugs, the most
widely used product being chloramphenicol eye ointment.
The advantages of an ophthalmic ointment (compared with drops)
is that a more sustained drug effect is achieved, which may allow less
frequent administration whilst maintaining effective local drug
concentrations. Use of ointments may also have the advantage of
reducing nursing workload in the ward situation. Systemic side effects
from nasal drainage of drugs applied to the eye are associated with
eye drops much more often than with eye ointments.1
The disadvantages of ophthalmic ointment use are that patients
may find the ointment less easy to apply and vision will be blurred for
a few minutes after application.
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Eye ointments: use and care 171
Advice to patients: how to apply eye ointment

Key counselling points for patients administering eye ointment are
listed below.
1 With clean hands, unscrew the cap from the tube and expel the first
0.5 cm.
2 Gently pull down the lower lid of the eye to be treated and squeeze E
a line of ointment about 0.5 cm ( 1/4 inch) along the inside of the
eyelid (Figure E2).
3 Try to avoid touching the eye or eyelashes with the nozzle.
4 Close the eye for a few minutes. The ointment will melt rapidly;
blinking will help to spread it.
5 Replace the cap on the tube.
k k
FIGURE E2 Application of eye ointment
Additional counselling points

● For a few minutes after application, vision may be blurred. It is
advisable not to drive or operate machinery during this time.
● Avoid contamination of the eye ointment during use.
● Date the tube when first opened and discard 4 weeks after opening.
For ward use in some hospitals this may be reduced to 1 or 2 weeks
because of the greater risk of contamination. Check your local
policy.
● Never let another person use your eye ointment.
● Eye ointments should not be used while wearing contact lenses.
● If using eye drops at the same time of day as an eye ointment, apply
the drops 5 minutes before the ointment.
Dry-eye syndrome
Dry-eye syndrome (keratoconjunctivitis sicca) is a common chronic
eye condition especially in older patients, as tear production decreases
with increased age. It is also common in postmenopausal women and
may be induced by hormone replacement therapy. Dry eyes can also
k
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172 Eye ointments: use and care
be associated with Sjögren’s syndrome and connective tissue

disorders such as rheumatoid arthritis. Artificial tears preparations,
such as simple eye ointment, VitaA-POS or Lacrilube, can be used to
treat dry eyes. The advantage over eye drops is the prolonged
retention time; the disadvantages of eye ointments are they are greasy
and can produce stickiness and blurred vision. Eye ointments tend to
E be used as an adjuvant at night, with eye drops such as hypromellose
used during the day. Patients usually start dry-eye treatment with a
less viscous treatment such as hypromellose 0.3% eye drops or
carbomers, e.g. Viscotears. These are gel-like and cling to the eye
surface, which may reduce frequency of administration to four times a
day. If a patient needs to use dry-eye preparations more than six times
a day, preservative-free treatments should be used to reduce damage
by benzalkonium chloride (preservative) as this disrupts the tear film.
Suitable alternatives are Viscotears, Celluvisc single-dose unit or
Hylo-Forte, Hylo-tear or Hylo-care preservative-free multidose.2
REFERENCES
2 Morrissey EFR, Lloyd F (2013). Pharmaceutical Care of the Eye, Continuing
Professional Development. NI Centre for Pharmacy Learning and Development.
http://www.cppe.ac.uk/learning/Details.asp?TemplateID=EYE-P-01&Format=
P&ID=115&EventID=43178 (accessed 18 August 2014).
k k
k
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F
F
Falls: pharmaceutical care

Defining falls and their importance
A fall is defined as ‘an event which results in a person coming to rest
inadvertently on the ground or floor or other lower level’1 and may be
accidental (such as a slip or trip) or the result of a predictable or
unpredictable physiological factor (e.g. syncope). The chance of
falling and sustaining an injury from a fall increases with age, with
more than half of all reported injuries in older people being due to a
fall.2 A fall and its consequences can be life changing for an older
person, damaging the person’s physical health in the short term and
adversely affecting the individual’s mental health, independence and
life span in the longer term.
k Causes of falls k
It’s important to see falls as a symptom and not a diagnosis – people
can fall for a wide variety of reasons, and any one fall is likely to have
a multifactorial cause. Environmental hazards (e.g. poorly fitting
footwear, thick rugs on the floor) are a significant risk, though an
older person’s physical ability to respond correctively to a slip or trip
increases the chance and severity of a fall. Age-related physiological
changes, such as impaired muscle strength and posture control,
adversely affect gait and balance, whilst changes to visual acuity and
hearing may alter environmental perception. There is increasingly
robust evidence for a causal link between some medicines and the risk
of falling,3 but in practice it is often difficult to be certain one is a
direct cause of a fall. It is also important to remember that reports of a
fall may be a sign of abuse of an adult at risk.
Medicines as a cause of falls
It is known that falls risk increases with each additional medicine a
patient takes beyond a four-drug regimen, regardless of the class of
medicine added.4 There are some classes of medicine that are more
commonly associated with falling, although consideration must be
given to the likelihood of increased side effects, duration of action and
toxicity from inevitable age-related physiological changes for all
medicines.
There is strong evidence linking antipsychotics, benzodiazepines
(including the ‘z-drugs’) and antidepressants to increased falls
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174 Falls: pharmaceutical care
risk, and in some cases fracture rates. It is believed they cause falls
by reducing lower-limb muscle strength, reaction time and balance
control. There is no robust evidence showing SSRIs or atypical antipsy-
chotics carry less risk than more traditional choices, such as tricyclic
antidepressants or typical antipsychotics, respectively. The evidence
of a falls risk from opioids is inconsistent but cannot be discounted.5
The evidence linking falls risk and injury to medicines affecting the
cardiovascular system is generally weak.6 In theory, falls may be
F
caused by postural hypotension, syncope or effects on rhythm, and
the risk will increase with the use of multiple cardiac medicines. Most
patients suffering symptoms related to these medicines often develop
coping strategies, which limit the risk of falls (e.g. rising slowly), but
as patients age the effects of these medicines may become more
pronounced, so their compensatory measures can fail and regular
monitoring becomes more important.
Anticholinergic effects may be contributory to the falls risk of
some medicines (e.g. antipsychotics, antidepressants), although there
is little evidence specifically linking falls risk with these effects as a
defined class of medicines. Anticholinergic effects may include blurred
vision, dry mouth and constipation, all of which may be a contributory
factor of functional falls, including those linked to toileting.
Falls risk assessment and next steps
NICE recommends that older people presenting with falls injury or
reporting recurrent falls should be offered a multifactorial falls risk
k assessment from a healthcare professional with appropriate skills and k
experience, which may include assessment of:7
● home hazards
● gait, balance and mobility, and muscle weakness
● perceived functional ability and fear of falling
● visual impairment
● cognitive impairment and neurological examination
● cardiovascular examination
● urinary incontinence
● osteoporosis risk
● current medication.
There is limited evidence that multifactorial falls prevention
programmes reduce the number of fallers or fall-related injuries8 and,
despite various studies looking at how to reduce medicines-related
falls risks, there is no clear evidence for an effective single
intervention.3 However, the following points are all considered part
of good pharmaceutical care for patients following a fall.
1 Complete a full medicines reconciliation, including
over-the-counter and complementary medicines (see Medicines
reconciliation entry). A discussion should also be had on the
patient’s usual level of alcohol consumption.
2 Stop all potentially inappropriate medication either from adverse
effects or interactions, or because of contraindications. The use of
support tools may be useful, such as the STOPP/START9,10 or
Beers criteria,11 or anticholinergic burden scales.
k
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3 Reduce the dose of medicines linked to the fall where withdrawal

is not desirable or possible: this is particularly important in
psychoactive medication where rapid withdrawal or cessation is
not possible, though challenges exist in maintaining reduction
programmes when care is transferred (e.g. at hospital discharge).
4 Complete osteoporosis screening: confirm that the patient is
receiving optimal bone protection therapy.
5 Further reduce polypharmacy and simplify the medication F
regimen: check all indications are valid, current and essential and
that the medicines have an appropriate evidence base for
effectiveness and acceptable risk profile.
6 Assess patient adherence to therapy and discuss the patient’s
understanding of the medication: falls may be due to inappropriate
self-medication (e.g. taking double doses of an antihypertensive).
7 Explore the patient’s ability to self-medicate effectively: practical
strategies to support self-medication must be considered and
employed wherever possible.
Medication changes made because of a falls risk must be clearly

documented and communicated to the patient’s general practitioner.
Additional steps should also be taken to ensure ongoing support for
patients at home. This may include referral to a local falls service, or
to the patient’s usual community pharmacy for medicines use review
or new medicines service enrolment as necessary, particularly on
k discharge from hospital. k
REFERENCES
1 WHO (2012). Falls. Factsheet No. 344. http://www.who.int/
mediacentre/factsheets/fs344/en/ (accessed 4 June 2014).
2 McMahon CG et al. (2012). Diurnal variation in mortality in older nocturnal
fallers. Age Ageing 41: 29–35.
3 Boyle N et al. (2010). Medication and falls: risk and optimization. Clin Geriatr Med
26: 583–605.
4 Deandrea S et al. (2012). Risk factors for falls in community-dwelling older
people: a systematic review and meta-analysis. Epidemiology 21: 658–668.
5 Huang AR et al. (2012). Medication-related falls in the elderly. Causative factors
and preventative strategies. Drugs Ageing 29: 359–376.
6 Zeimer H (2008). Medication and falls in older people. J Pharm Pract Res 38:
148–151.
7 NICE (2013). Falls: Assessment and prevention of falls in older people. Clinical
guideline 161. http://www.nice.org.uk/
nicemedia/live/14181/64088/64088.pdf (accessed 4 June 2014).
8 Gates S et al. (2008). Multifactorial assessment and targeted intervention for
preventing falls and injuries among older people in community and emergency
care settings: systematic review and meta-analysis. BMJ 336: 130.
9 Gallagher P et al. (2008). STOPP (Screening Tool of Older Persons’ Prescriptions)
and START (Screening Tool to Alert Doctors to Right Treatment): Consensus
Validation. Int J Clin Pharmacol Ther 46: 72–83.
10 ELMMB (2013). STOPP START toolkit. http://www.elmmb.nhs.uk/guidelines/
other-clinical-guidelines/?assetdetesctl522647=53110&p=2 (accessed 21
February 2015).
11 Fick D et al. (2012). American Geriatrics Society updated Beers Criteria for poten-
tially inappropriate medication use in older adults. J Am Geriatr Soc 60: 616–631.
k
k
176 Ferinject
Ferinject
Overview1
Form Ferric carboxymaltose
Dose ● Calculated based on body weight and haemoglobin level (see table
below for cumulative iron dose).
F ● A single dose should not exceed 1000 mg of iron a day.
● Do not administer more than 1000 mg once each week.
● If total dose is greater than 1000 mg of iron, it should be divided and
given over 2 weeks
Body weight
Haemoglobin 35 kg to less than 70 kg ≥70 kg
Less than 100 g/L 1500 mg 2000 mg
≥100 g/L 1000 mg 1500 mg
● A cumulative dose of 500 mg of iron should not be exceeded for patients

with a body weight <35 kg.
● For haemoglobin values ≥140 g/L, an initial dose of 500 mg iron should
be given and iron parameters should be checked prior to repeat dosing
Adminis- Intravenous infusion Intravenous Intra-
tration instalments muscular
routes
k Yes Yes No k
Adminis- ● Up to a maximum single dose ● Intravenous injection using
tration of 1000 mg iron (up to a undiluted injection
maximum of 20 mg/kg body ● Used for doses up to
weight) 1000 mg iron (up to a
● Dilute in sodium chloride 0.9% maximum 15 mg/kg body
to a minimum of 2 mg/mL weight)
● Observe for adverse effects for ● Observe for adverse effects
at least 30 minutes following for at least 30 minutes
each injection following each injection
The diluent volume and rate ofThe administration time varies
depending on the dose.
administration are dependent on
the dose required. ● Doses up to 200 mg: no
prescribed administration
Maximum time
sodium ● ≥200 mg up to 500 mg:
chloride Adminis- iron should be administered
Dose of 0.9% tration
iron volume time at a rate of 100 mg/min
● >500 mg up to 1000 mg
100–200 mg 50 mL -
iron administered over
≥200–500 mg 100 mL 6 minutes
15 minutes
>500–1000 mg 250 mL 15 minutes
Monitoring ● Patients should be monitored for signs and symptoms of

hypersensitivity reactions during and following each administration.
● Observe patient for adverse effects for at least 30 minutes following
each injection.
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Fluid balance 177
REFERENCE
1 eMC (2014). SPC Ferinject. https://www.medicines.org.uk/emc/medicine/24167
Fluid balance
Fluid balance is more than estimating the input and output of fluid in
F
the body. It must also account for redistribution of fluid and
electrolytes outside the plasma volume (Figure F1).
In principle, all fluid into and out of the body should be measured
and recorded on a fluid balance chart. In actual clinical practice it is
more common to express an opinion about fluid status. Fluid inputs
are estimated but fluid output is often unmeasured unless the patient
is in intensive care. Fluid balance charts are notable for their omission
of data and inaccuracy of the mathematics. Thus, medical staff tend to
ignore them and this psychologically feeds back into poor attention to
detail by the nursing staff. One of the first steps in managing a
deteriorating patient is to contact the critical care outreach team
whose actions include catheterising patients and starting an accurate
fluid balance chart.
Fluid management
This includes the assessment of fluid status and the correction of any
k deficit or excess. In 2013 NICE published guidance on intravenous k
fluid therapy for patients on wards, although the data were limited
and drawn from studies from intensive care and peri- and
postoperative patients.1 There is often a lack of understanding about
fluid management with doctors and nurses as well as pharmacists. To
many, fluids are boring, bulky and stored in the hospital dungeons.
However, they are essential to the maintenance and homeostasis of
life. Errors with fluid management are common and significant
education and training are required.
IN OUT
Body
Redistribution
Balancing input and output Accounting for redistribution
Changing osmolality
FIGURE F1 Fluid balance
k
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178 Fluid balance
Fluid physiology
Water comprises almost two-thirds of body weight and two-thirds of
the water is within cells. Fluid manipulation occurs within the plasma
volume that represents only one-twentieth of body weight;
redistribution then occurs.
Assessment of fluid status
Consider:
F
● signs of pulmonary or peripheral oedema
● dry mucosa, sunken eye appearance or patient feeling thirsty
● poor urine output (<0.5 mL/kg/hour)
● slow capillary refill (more/less than 2 seconds)
● blood pressure – central venous or jugular or postural hypotension
● pulse and heart rate
● altered conscious state
● loss of weight over days (not weeks)
● concentration of biochemistry.
These data may be captured from simple clinical parameters (pulse,
temperature and pressure charts) but have now been replaced by
National Early Warning Scores (NEWS) charts, which also include
urine output (see Early Warning Score entry). This comes from NICE
guidance on the acutely deteriorating patient, where signs of
hypovolaemia are a prelude to shock, and particularly that due to
sepsis.1,2
k k
Leg elevation
If a patient is lying horizontal in bed, raising one leg will move the
blood volume into the central compartment and improve venous
return to the heart, and therefore should increase cardiac output and
blood pressure. If the patient’s heart is failing the heart will become
congested, pulmonary oedema will form and the patient will cough
up pink sputum. In this latter case the leg can be lowered again and
normality restored. This manoeuvre can be described as a reversible
fluid challenge: a positive finding suggests the need for intravenous
fluids and a negative finding indicates adequate fluid filling and
possibly the need for diuretics. A similar (but reverse) test is to elevate
the patient’s head above the heart; if the patient feels dizzy or blood
pressure falls, this shows the individual is hypovolaemic.
Fluid challenge
A fluid challenge is the administration of 500 mL of intravenous fluid
over 15 minutes. A blood pressure rise, fall in heart rate or increase in
urine output is a positive sign. If it remains at normal parameters then
the challenge has corrected the condition and decisions about
maintenance fluid can be considered. If the blood pressure does not
change or starts to fall, then further fluid challenges can be given to
resuscitate the patient.3
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Fluid balance 179
Five Rs of NICE fluid guidelines

Arguably, the most important activity is to review the decisions made
as the patient’s condition changes and responds to treatment.
Repetition of the same plan without review is likely to be harmful.
TABLE F1
Five Rs with descriptions and actions F
Component Description Action
Resuscitation with Acutely (1–4 hours), restoring 500 mL of intravenous fluid
fluids normal fluid balance (containing 130–154 mmol/L
sodium)
Routine Preferably delivered 25–30 mL/kg/day water,
maintenance orally/enterally but may require 1 mmol/kg/day sodium
intravenous support. It should be chloride and potassium
sufficient to maintain organ chloride and 50–100 g/day
perfusion and kidney output glucose (to avoid ketosis)
Replacement Abnormal losses such as fistulas, Fluids that match the
surgical drains, diarrhoea, composition of losses
vomiting or nasogastric losses
Redistribution Water and electrolytes that have Possibly hypertonic solution
left the vascular space and moved or colloids (albumin), but
into extracellular spaces (e.g. usually vasoconstrictors and
ascites) or into tissues (oedema) diuretics to increase vascular
osmotic pressure (Figure F2)
k k
Review Regularly reassess the fluid status Communication and
and effects of treatments with a education
plan for the next 24 hours
Plasma 5%
Extracellular
Interstitial fluid 20%
fluid 15%
BV = 5L
PV = 3.5L
ECF = 15L
Intracellular ICF = 27L
fluid 40%
body weight
Total body water
= 60% body weight
= 42L
FIGURE F2 Fluid compartments. BV, blood volume; PV, plasma volume;

ECF, extracellular fluid; ICF, intracellular fluid
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180 Fluid balance
Like any science experiment, outcomes of interventions should be

regularly (sometimes frequently) reviewed. In practice this is one of
the biggest failings and where pharmacists can contribute. Shift
patterns and limits on working hours mean that often the same junior
doctor will not review the same patient each day. This lack of
continuity means that fluid balance is not assessed on a daily basis nor
reviewed over several days or a week. Cumulative fluid overload can
F amount to 20 litres by the time a patient enters the intensive care unit.
However, fluid and electrolyte undertreatment is the far more
common phenomenon.
Patients should be weighed twice a week in hospital so that rapid
weight changes can be detected and attributed to sudden changes in
fluid balance.
In addition, significant education is required to restore
understanding and enthusiasm about the importance of fluid
management.
Vasoconstrictors and vasodilators
Use of vasoconstrictors is not an adequate substitute for poor fluid
management but is used in the critically ill when a patient needs
rescue. Vasoconstrictors effectively shrink the plasma volume so the
fluid that is available can perfuse the vital organs. Similarly,
vasodilators can produce a relative underfilling of the vascular
compartment and produce tachycardia. Where there is insufficient
k blood in the vascular system, the heart tries to compensate by pushing k
it more quickly around the vital organs. Tachycardia is a precursor of
arrhythmias and should be corrected by giving volume (Figure F3).
Postoperative fluids
Surgery and trauma produce a systemic inflammatory response
syndrome (SIRS) that is not limited to a swelling up of injured tissues.
In addition, a number of stress hormones are produced, including
adrenaline and aldosterone. Adrenaline drives metabolic activity and
Vessel capacity Vasoconstriction Vasodilatation

Volume fill fixed volume fixed volume
FIGURE F3 Vasodilation and volume
k
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Fluid balance 181
can produce tachycardia. Aldosterone causes sodium retention and

potassium loss. During an operation, perfusion pathways may be
altered, either because some anaesthetics are vasodilating (e.g.
propofol) or because nitric oxide synthetase (NOS) is stimulated. NOS
causes the release of nitric oxide that produces a profound
vasodilatation. Reduced tissue oxygenation may produce acidosis.
SIRS, anaesthetics and blood loss all produce a postoperative patient
who is actually (or relatively) hypovolaemic, vasodilated, F
tachycardiac/arrhythmogenic and sodium-retentive or in acute renal
failure. Whilst fluid resuscitation is required, consideration must be
given to the sodium load, the potassium content and the temporary
use of vasoconstrictors (such as phenylephrine).4
Anaesthetists often like to use compound sodium lactate
(Hartmann’s) because it contains a relatively low sodium content
(131 mmol/L) and the buffer lactate (converted in the liver to
bicarbonate). However, a combination of products may be needed to
restore normal fluid balance.
Sodium chloride 0.9% is not physiologically normal and should
not be referred to as ‘normal’. It contains 154 mmol/L of sodium,
whereas normal plasma contains 130 –145 mmol/L sodium. It is a
resuscitation fluid and should not be used for routine maintenance.
It can be alternated with glucose 5% for postoperative patients if
sufficient potassium is added – or preferably use a combined product
of glucose 4% and sodium chloride 0.18% with potassium. As a rough
k guide, a patient who has lost a litre of blood may require 2 –3 L of k
sodium chloride 0.9% for resuscitation, but progress must be
regularly reviewed because of the SIRS response described above.
The water and sodium ions will distribute into the extracellular fluid
compartment, so may require repeat dosing to support intravascular
volume.
Glucose 5% will quickly disperse from the vascular space. The
water will be drawn osmotically into the extracellular and then
intracellular compartments. Some glucose is needed to maintain
blood sugar levels and avoid generation of ketones. However, this is
not a substitute for proper nutrition (containing proteins, fats,
vitamins and minerals as well as carbohydrates). In skilled hands it
can be used to manage sodium distribution and balance as well as
deliver potassium to the tissues.
Glucose 4% and sodium chloride 0.18% with 40 mmol potassium
in 1 litre is not a resuscitation fluid because it only contains 30 mmol
of sodium. However, 2 litres/day of this makes a useful maintenance
fluid (60 mmol sodium, 80 mmol potassium, 88 mmol chloride and
80 g carbohydrate) in the postoperative phase. Fluid and electrolyte
levels must be reviewed as, if used longer term, it will produce
hyponatraemia.
There is much debate about the role of colloids containing
macromolecules such as gelatines, starches and proteins (albumin).
More research is clearly needed to clarify their potential role as blood
substitutes or in septic resuscitation.
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182 Food–drug interactions
Mannitol (a non-reabsorbable sugar) may be given for head injuries

or for patients with cerebral oedema. This will increase plasma
oncotic pressure and redistribute water from tissues into vascular
spaces. It also acts as an osmotic diuretic by a similar mechanism.
Glucose should not be used in head-injury patients because it
lowers plasma osmotic pressure and would worsen cerebral oedema.
REFERENCES
F 1 NICE (2013). Intravenous Fluid Therapy in Adults in Hospital (CG174). http://
www.nice.org.uk/guidance/cg174 (accessed 17 July 2014).
2 NICE (2007). Acutely Ill Patients in Hospital: Recognition of and response to acute ill-
ness in adults in hospital (CG50). http://www.nice.org.uk/guidance/cg50 (accessed
17 July 2014).
3 Cecconi M et al. (2011). What is a fluid challenge? Curr Opin Crit Care 17:
290–295.
4 Cochrane JPS (1978). The aldosterone response to surgery and the relationship of
this response to postoperative sodium retention. Br J Surg 65: 744–747.
Food–drug interactions
Many drugs undergo clinically significant food–drug interactions,
where food may cause changes in the pharmacokinetic or
pharmacodynamic properties of the drug. Interactions may be
generic where the presence of any food will affect the drug. Food may
aid the absorption of drugs such as saquinavir and griseofulvin and
patients should be counselled to take the medication with or just
k after food; or food may delay or reduce the absorption of a drug –
k
examples include flucloxacillin and trospium. In these cases, patients
should be counselled to take the medication on an empty stomach, i.e.
an hour before food or at least 2 hours after food. It may also be worth
noting that it may be beneficial to take certain medication at the same
time as food to reduce side effects such as nausea and vomiting, e.g.
co-beneldopa and allopurinol; or to reduce GI disturbance, e.g.
aspirin and NSAIDs.1,2
More specific food–drug interactions are listed in Table F2, and
see also Grapefruit juice–drug interactions entry.
TABLE F2
Interactions with food and oral drugs1,2,3
Food Example of interacting drugs Mechanism
Alcohol Antihypertensives, nicorandil, Increased hypotensive effect
opiates, methyldopa
Opiates, tricyclic Increased sedative effect
antidepressants, antihistamines
Oral antidiabetic drugs Enhanced hypoglycaemic effect
Disulfiram, metronidazole, Disulfiram-like reactions-
procarbazine, levamisole Prevents metabolism of ethanol,
resulting in accumulation of
acetaldehyde, characterised by flushing,
sweating, vomiting and headaches
k
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Food–drug interactions 183
TABLE F2
(Continued)
Food Example of interacting drugs Mechanism
Caffeine Theophylline Drinks containing caffeine may increase
theophylline levels
Cranberry Coumarins Unknown. May cause an increased or
juice unstable international normalised ratio
(INR). Do not consume while taking
coumarins
F
Dairy Quinolones, tetracyclines, The calcium ions present in dairy
products bisphosphonates, estramustine products can form complexes with
certain drugs. These complexes are not
easily absorbed from the GI tract,
resulting in a lower drug concentration
in the systemic circulation
Enteral Phenytoin (withhold feed Some drugs may have a reduced
feeds 2 hours before dose; restart absorption due to binding to some
2 hours after dose), enteral feed ingredients
ciprofloxacin
Tyramine- MAOIs, linezolid (to a lesser Inhibition of the monoamine oxidase
containing extent) enzyme in the gut wall allowing
food and tyramine to enter the systemic
drink circulation and potentiate its pressor
effect, possibly resulting in
life-threatening hypertensive crisis
k Vitamin Coumarins Coumarins are vitamin K antagonists. k
K-rich foods Change in the consumption of vitamin
K-containing foods affects competition
for the receptor site, increasing or
decreasing anticoagulation
REFERENCES
2 eMC (2014). http://www.medicines.org.uk/emc/ (accessed 3 September 2014).
3 Baxter K (ed.) (2014). Stockley’s Drug Interactions. London: Pharmaceutical Press.
http://www.medicinescomplete.com/ (accessed 3 September 2014).
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184 Gastrointestinal bleeding risk management
G
G
Gastrointestinal bleeding risk management
Non-steroidal anti-inflammatory drugs (NSAIDs)
Use of NSAIDS increases the risk of gastrointestinal (GI) bleeding by
approximately fourfold. The following groups are considered
high-risk and should be offered gastroprotection with a proton pump
inhibitor (PPI) if alternative analgesia is not suitable:1
● aged 65 years or older

● history of peptic ulcer disease, GI bleeding, or gastroduodenal
perforation
● concomitant use of medicines known to increase risk of upper GI
adverse events, e.g. anticoagulants, aspirin, corticosteroids,
selective serotonin reuptake inhibitors
● serious comorbidity, such as cardiovascular disease, hepatic or
renal impairment (including dehydration), diabetes or
k hypertension
k
● requirement for prolonged NSAID use, including people with:
● osteoarthritis or rheumatoid arthritis, of any age
● chronic low-back pain, age 45 years or older
● use of the maximum recommended dose of an NSAID.
Antiplatelets
Low-dose aspirin alone increases the risk of bleeding by
approximately twofold, while dual antiplatelet therapy or use with
anticoagulants increases this risk to approximately fourfold.2
American consensus guidelines suggest use of a PPI in the following
groups:3
● history of peptic ulcer disease or GI bleeding

● dual antiplatelet therapy
● concomitant anticoagulant therapy
● more than one of the following risk factors:
● age 60 years or greater
● corticosteroid use
● dyspepsia or reflux symptoms.
In both NSAID and antiplatelet use, where there is a history of ulcer

disease or upper GI bleeding, Helicobacter pylori should have been
tested for and treated if present.
k
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Gentamicin 185
Scoring systems
There are no scoring systems for predicting risk of GI bleeding in the
above groups; however, there are some scoring systems used to
predict risk of bleeding in other scenarios:
● HAS-BLED – recommended by NICE4 to predict the risk of
bleeding on anticoagulation in patients with atrial fibrillation (see
HAS-BLED score, under Stroke and transient ischaemic attack entry)
● Rockall score – prediction of mortality risk after upper GI bleeding
(see Rockall score for gastrointestinal bleed entry) G
● Glasgow-Blatchford score – prediction of the need for blood
transfusion or endoscopic treatment in upper GI bleeding.
Both Rockall and Blatchford scores are recommended by NICE5 in
patients presenting with suspected GI bleeding.
REFERENCES
1 NICE (2013). Clinical Knowledge Summaries. NSAID Prescribing Issues. http://
cks.nice.org.uk/nsaids-prescribing-issues (accessed 11 December 2014).
2 Garcia Rodriguez LA et al. (2011). Risk of upper gastrointestinal bleeding with
low-dose acetylsalicylic acid alone and in combination with clopidogrel and other
medications. Circulation 123: 1108–1115.
3 ACCF/ACG/AHA (2008). Expert consensus document on reducing the gastrointesti-
nal risks of antiplatelet therapy and NSAID use. Circulation 118: 1894–1909.
4 NICE (2014). Clinical Guideline 180. Atrial Fibrillation: The management of atrial
fibrillation. http://www.nice.org.uk/guidance/cg180 (accessed 11 December
k 2014). k
5 NICE (2012). Clinical Guideline 141. Acute upper gastrointestinal bleeding: man-
agement. https://www.nice.org.uk/guidance/cg141 (accessed 11 December 2014).
Gentamicin
Gentamicin is classed as an aminoglycoside antibiotic and is a mixture
of three naturally occurring aminoglycosides produced by
Micromonospora purpurea. It has bactericidal activity against most
strains of the following: Escherichia coli, Klebsiella spp., Proteus spp.,
Pseudomonas aeruginosa, Enterobacter spp., Citrobacter spp.,
Providencia spp. and staphylococci (including some MRSA strains).1,2
It has no activity against anaerobic bacteria and is considered low-risk
for selecting for Clostridium difficile. It inhibits protein synthesis by
binding with the 30S ribosomal subunit of bacterial ribosomes, which
results in bacterial cell death.
It is intrinsically resistant to streptococci and enterococci but it can
be used synergistically with cell wall active agents (e.g. penicillins,
vancomycin) in the treatment of infective endocarditis. It is
contraindicated for use in those patients with myasthenia gravis.
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186 Gentamicin
Gentamicin exhibits concentration-dependent killing and produces a
postantibiotic effect. It is excreted by glomerular filtration, appearing
90% unchanged in urine, and should be used with caution in those
patients on concomitant nephrotoxic agents and those with existing
renal impairment. It is poorly absorbed orally, so is given parenterally.
As it has low protein binding and is water-soluble, it is freely
distributed in the extravascular space and relatively freely in the
interstitial spaces of most tissues.
G Gentamicin has a narrow therapeutic range; it can cause
nephrotoxicity that is dose-related and usually reversible.1 Ototoxicity
caused by gentamicin is independent of drug concentration; it may
present as new tinnitus, hearing loss, poor balance, dizziness and
oscillopsia. Auditory toxicity is usually due to the accumulation of
gentamicin within the inner ear. Vestibular damage is more common
than deafness, caused by damage to sensory hair cells, and effects are
usually permanent.1 Duration of treatment, age (>60 years) and
repeated treatment courses are risk factors; healthcare professionals
should be alert to monitoring for signs of vestibular toxicity and use
the minimum duration possible.3
Gentamicin is not known to be harmful in pregnancy; however, it is
recommended that it be used only in life-threatening situations where
the benefits outweigh the possible risks. It is safe to use during
breast-feeding.2
k k
Adult dose
Gentamicin is given either as a multiple daily dosing regimen every 8
hours, or as a once-daily dosing regimen. Dosing regimens vary
amongst hospitals, so follow your local policy. Low-dose gentamicin
(1 mg/kg twice daily) is used for its synergistic effect in the treatment
of infective endocarditis (see Endocarditis entry).
The calculation of the dose will depend upon the choice of
once-daily (unlicensed) or multiple-daily dosing. Initial dosing is
based on a patient’s weight and renal function. Actual body weight is
used, except in those patients who are obese (i.e. >20% above ideal
body weight (IBW)), where a dose-determining weight (DDW) should
be used. Creatinine clearance (CrCl), calculated using the Cockcroft
and Gault equation, should be used to estimate renal function (see
Renal function – assessment entry). It is important to note that, in
patients who are anuric or have acute kidney injury, this calculation
will not give a true reflection of CrCl.
Ideal body weight calculation
IBW: men (kg) = 50 + 2.3 × (height in inches above 5 feet)
IBW: women (kg) = 49 + 1.7 × (height in inches above 5 feet)
In obese patients, a DDW should be used; this is calculated as follows:
DDW = IBW + 0.4(actual body weight – IBW)
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Gentamicin 187
Creatinine clearance calculation

F × (140 – age) × weight (kg)
CrCl(mL/ min) =
serum Cr (micromol/L)
F = 1.23 for males; 1.04 for females.

Once-daily regimen
Once-daily administration enables effective bactericidal killing
through achieving high peak drug concentrations and is generally
considered to be less nephrotoxic (the effect on ototoxicity remains G
less clear).1,3 The higher the initial concentrations, the more
prolonged the postantibiotic effect. Once-daily dosing is not suitable
for all patients due to lack of published data or due to risks of
accumulation and toxicity. It is inappropriate for use in pregnancy,
patients with major burns or ascites and those on dialysis. Initial
doses usually range from 5 to 7 mg/kg once a day;4 subsequent
changes to dosing or frequency are made based upon the results of
serum concentration monitoring. There are various approaches to
once-daily dosing regimens, therefore ensure you follow your local
policy. Two commonly used dosing options are described below.
Option 1: Hartford regimen
The Hartford once-daily dosing regimen5 was originally developed by
Hartford Hospital in Connecticut, USA. This regimen gives a fixed
dose of 7 mg/kg once daily and the dosing interval is dependent upon
k estimated CrCl. The initial dose given should be as outlined in k
Table G1; doses should be rounded to the nearest 20 mg to aid
administration.
TABLE G1
Hartford recommended dosing regimen5
Creatinine clearance Recommended dose
≥60 mL/min 7 mg/kg every 24 hours
59–40 mL/min 7 mg/kg every 36 hours
39–20 mL/min 7 mg/kg every 48 hours
<20 mL/min 7 mg/kg single dose; only redose when levels <1 mg/L
With this regimen it is important that the time the dose is

administered and the time the serum levels are taken are accurately
recorded. After administration of the first dose a blood sample should
be taken 6 –14 hours after the start of the gentamicin infusion. The
exact time when levels are taken should be recorded on the
prescription chart and on the sample request form. Once the serum
level is known, this should be plotted on the nomogram (Figure G1),
which determines the frequency of future doses. If the result falls on a
line, the longer interval should be chosen. If the level is above the
48-hourly line, therapy should be stopped and no further doses given
until the level is <1 mg/L.
k
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188 Gentamicin
Hartford Gentamicin/Tobramycin
Nomogram
14
12
Gentamicin/Tobramycin
concentration (mg/L)
10
8 48 hours
G 6 36 hours
4 24 hours
0
6 7 8 9 10 11 12 13 14
Hours between start of infusion
and sample draw
FIGURE G1 Hartford nomogram (reproduced with permission from Yorkshire Hartford
prescription chart, based on the original Hartford nomogram)6
Option 2
Some hospitals follow a once-daily dosing regimen where the dosing
k interval is kept the same (every 24 hours) but the dose is reduced k
dependent upon estimated CrCl. The doses recommended in renal
impairment are as listed in Table G2. Serum concentration should be
taken before the second dose (Table G4) and subsequent doses
altered accordingly. For those patients with a CrCl <10 mL/min, a
single dose is given and the dose should only be repeated when serum
concentrations are <1 mg/L.
TABLE G2
Recommended dose reductions in renal impairment7
Creatinine clearance (mL/min) Recommended dose
>30–70 mL/min 3–5 mg/kg daily
10–30 mL/min 2–3 mg/kg daily
<10 mL/min 2 mg/kg single dose; only redose when levels <1 mg/L
Multiple daily dosing regimen

For those patients with normal renal function, a dose of 3 –5 mg/kg in
divided doses every 8 hours is given.4 Doses should be rounded to the
nearest 20 mg to aid administration. Dose reductions in renal
impairment are outlined in Table G3.
Monitoring is essential to ensure that toxicity is avoided and in the
case of multiple daily dosing to ensure that effective levels are
k
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Gentamicin 189
TABLE G3
Recommended dose reductions in renal failure7
Creatinine clearance Recommended dose
>70 mL/min 80 mg* 8-hourly
>30–70 mL/min 80 mg* 12-hourly
10–30 mL/min 80 mg* daily
5–10 mL/min 80 mg* every 48 hours
*60 mg if body weight <60 kg. G
achieved (Table G4). Serum concentrations should be monitored as
follows:
● the first level should be taken before the second dose for once-daily
dosing, or 6 –14 hours after the first dose if using the Hartford
regimen. For multiple daily dosing, levels should be taken before
the third or fourth dose. Levels should be repeated every 2 –3 days
if renal function remains stable
● when there is a dose adjustment or change in renal function
● if drugs are added that are known to affect gentamicin serum
concentration (see section on drug interactions, below).
● if a level comes back high, a decision is required on whether to
withold the dose until a safe trough level is achieved and/or to
reduce the prescribed dose. Gentamicin has first-order
k pharmacokinetics, i.e. reducing the dose by x% should reduce the k
serum concentration by x% also. A new trough level would need to
be checked.
TABLE G4
Gentamicin monitoring information
Therapeutic range ● Once-daily dosing: pre-dose (trough) <1 mg/L
● Multiple daily dosing: peak: 5–10 mg/L4 (3–5 mg/L in
endocarditis)4
● Pre-dose (trough): <2 mg/L2,4 (<1 mg/L in endocarditis)4
Sampling time ● Pre-dose (trough): 0–30 minutes pre-dose, or 6–14 hours
after first dose (if following Hartford once-daily regimen)
● Peak: 1 hour after an intravenous bolus or 1 hour after the
start of an infusion (for multiple-dose regimens only)
● In bacterial endocarditis trough concentrations should be
performed twice weekly (more often in renal impairment)4
Other monitoring ● Urea and electrolytes, urine output; ask patient (if possible)
about vestibular and auditory disturbances
Administration
For once-daily dosing, an intravenous infusion is the preferred
method of administration. The dose should be added to 100 mL of
sodium chloride 0.9%, or glucose 5%, and given over 30 –60
minutes.8 If a multiple daily dosing regimen is being used, then it can
be made up to a convenient volume with the above diluents
(e.g. 10 –20 mL) and be given as a slow intravenous bolus injection
over 3 –5 minutes.8
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190 Glasgow Coma Scale
Overdose
Ototoxicity, nephrotoxicity and neuromuscular blockade can occur.
Neuromuscular blockade presenting as both acute muscle paralysis
and apnoea can occur from rapid intravenous administration.9 There
is no specific antidote to gentamicin overdose. As well as stopping
therapy, U&Es, FBC, LFTs and gentamicin serum concentration
should be taken. Patients should be adequately hydrated and
haemodialysis considered in those patients with acute kidney injury.
Auditory and vestibular function should be checked and a referral
G made to an ear, nose and throat specialist if deemed necessary. The
onset of ototoxicity and nephrotoxicity may be delayed and therefore
follow-up is required at 48 hours and 1 week.9
Drug interactions
The risk of ototoxicity may be increased when given with loop
diuretics, e.g. furosemide. The risk of nephrotoxicity is increased
when gentamicin is coadministered with amphotericin, cisplatin,
ciclosporin, tacrolimus, vancomycin, colistimethate and NSAIDs.4
Neuromuscular blocking agents, e.g. suxamethonium, can enhance
the potential neuromuscular blockade, causing persisting respiratory
paralysis even after the blocking drug is stopped.2
Concurrent use with botulinum toxin is not recommended due to
increased risk of neuromuscular block. Gentamicin will antagonise
the effects of neostigmine and pyridostigmine. There is an increased
risk of hypocalcaemia when given with bisphosphonates.
k k
REFERENCES
1 Grayson M et al. (eds) (2010). Kucers’ The Use of Antibiotics (6th edn). London:
Hodder Arnold.
2 eMC (2014). SPC Cidomycin Adult 80 mg/2 mL Solution for Injection.
http://www.medicines.org.uk/emc (accessed 17 August 2014).
3 Ariano R et al. (2008). Aminoglycoside induced vestibular injury: maintaining a
sense of balance. Ann Pharmacother 42: 1282–1289.
5 Nicolau DP et al. (1995). Experience with a once-daily aminoglycoside program
administered to 2184 adult patients. Antimicrob Agents Chemother 39: 650–655.
6 The Leeds Teaching Hospitals NHS Trust (2009). Gentamicin Prescription Chart
(Yorkshire Hartford). http://www.leedsformulary.nhs.uk/docs/RxGentamicin
Hartford.pdf (accessed 4 May 2015).
7 Ashley C, Dunleavy A (2014). Renal Drug Database. https://www.renaldrug
database.com (accessed 23 August 2014).
8 Gray A, Wright J, Goodey V, Bruce L (eds.) (2011). Injectable Drugs Guide. London:
9 National Poisons Information Service (2014). Toxbase. http://www.toxbase.org
Glasgow Coma Scale

Background
● The Glasgow Coma Scale (GCS) is a commonly used scoring system for determining
impaired consciousness.
● Initially a 14-point scale, the original 1974 version1 has been widely replaced with a
modified 15-point version that distinguishes between abnormal flexion and withdrawal
to pain.
k
k
Glasgow Coma Scale 191
● Three behavioural aspects are independently measured and used alongside a composite
score to rate a person’s overall level of consciousness (see below).
● Although originally designed to assess the impact of head trauma, it is now applied to
all acute medical and trauma patients and can help measure the impact of a variety of
conditions, including acute brain damage from infection, vascular injury or metabolic
disorder.
● It is not suitable for use when assessing children, especially those under 3 years old who
are too young to have reliable language skills.2
● Although some clinical and operational aspects of the GCS have been challenged,
alternatives such as the FOUR score tool have not been universally adopted.
G
SCORING SYSTEM
Clinical feature: eye-opening response (E) Score
Spontaneous (open with blinking) 4
To verbal stimuli, command, speech 3
To pain only (not applied to face) 2
No response 1
Clinical feature: verbal response (V)
Oriented 5
Confused conversation, but able to answer questions 4
Inappropriate words 3
Incomprehensible speech or sounds 2
No response 1
Clinical feature: motor response (M)
k Obeys commands for movement 6
k
Purposeful movement to painful stimulus 5
Withdraws in response to pain 4
Flexion in response to pain (decorticate posturing) 3
Extension response in response to pain (decerebrate posturing) 2
No response 1
Interpretation
A lower GCS score indicates a more severe loss of consciousness; the lowest score of 3
indicates a patient who is totally unresponsive.
● GCS score ≤8: severe brain injury (usually said to be in a coma)
● GCS score 9–12: moderate brain injury
● GCS score 13–15: mild (minor) brain injury
It is clinically important to provide the individual scores in addition to the total score
e.g. ‘GCS of 10 with E3, V3 and M4’.
Consideration should be given to non-traumatic factors that can alter a patient’s level
of consciousness, such as drug use, alcohol intoxication, shock or low blood oxygen.3,4
A GCS score should not be regarded as a static measure; regular repetition is necessary
to monitor patient response to treatment or deterioration.
REFERENCES
1 Teasdale G, Jennett B (1974). Assessment of coma and impaired consciousness.
A practical scale. Lancet 2: 81–84.
2 Simpson DA et al. (1991). Head injuries in infants and young children: the value of
the Paediatric Coma Scale. Childs Nerv Syst 7: 183–190.
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192 Glucosamine
3 Jennett B, Teasdale G (1977). Aspects of coma after severe head injury. Lancet 23:
878–881.
4 Palmer R, Knight J (2006). Assessment of altered conscious level in clinical practice.
Br J Nurs 15: 1255–1259.
Glucosamine
Glucosamine is indicated for symptomatic relief of mild to moderate
G osteoarthritis of the knee. It is a natural substance found in the body
and an important component of cartilage. In the UK, it is available in
two salt forms, glucosamine hydrochloride and glucosamine sulfate,
which are not bioequivalent. Aside from the licensed products, the
strength and quality of the active ingredient may vary between
products of the same salt, so bioequivalence cannot be assumed.
Alateris (hydrochloride), Dolenio (sulfate) and Glusartel (sulfate)
are the three licensed products in the UK for use in adults over
18 years old.
Evidence for effectiveness
The mechanism of action for glucosamine is not understood. Evidence
from clinical trials to support its efficacy is mixed and many of the
studies were of low quality and short duration.1 However, studies
using glucosamine sulfate resulted in a small reduction in pain as well
as improvement in physical function, although the other salts failed to
k do so.
k
NICE2 guidance does not recommend glucosamine for prescribing
on the NHS and the BNF3 classifies it as a drug less suitable for
prescribing. There is insufficient evidence to support the efficacy of
glucosamine hydrochloride as a disease-modifying agent.
Safety profile4
Glucosamine is generally well tolerated and the frequency of side
effects is similar to placebo. Common side effects are mild
gastrointestinal (GI) disturbances (nausea, abdominal pain,
dyspepsia, flatulence, diarrhoea, constipation), drowsiness,
headache, and, less commonly, flushing, rash and itching.
Due to the limited data available, causality has not been clearly
established for many of the glucosamine –disease interactions.
Therefore, the manufactures err on the side of safety with regard to
the cautions and contraindications stated in the Summary of Product
Characteristics.
Glucosamine is contraindicated in people with shellfish allergy;
although it is derived from the shells of shellfish, it is the flesh that
contains the antigens responsible for the allergy. Some studies show
that glucosamine may interfere with blood glucose control; therefore,
diabetic patients and those with impaired glucose tolerance are
advised to monitor blood glucose levels closely at the start of
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Glucosamine 193
treatment and periodically, particularly when they change doses or

products. Isolated cases of asthma exacerbations,
hypercholesterolaemia and renal impairment have been reported in
patients taking glucosamine; therefore, asthma patients starting to
take glucosamine must be advised to look out for signs of worsening
symptoms and those with cardiovascular risk factors must have their
lipid levels monitored. The drug should be used with caution in renal
impairment or those taking nephrotoxic drugs and renal function
monitored accordingly. The manufacturers advise to avoid in
pregnancy and breast-feeding due to limited evidence in these G
circumstances.
Drug interactions
Glucosamine enhances the effects of warfarin and so should be
avoided,3 otherwise patients should be advised to look out for signs of
bleeding and the INR should be monitored closely whenever either
drug is started, discontinued5 – 7 or the dose altered.
Key prescribing advice
It is important to rule out the presence of other joint diseases that may
require other treatment before prescribing glucosamine. It is not
indicated for the relief of acute pain and it may take several weeks for
the benefits to be seen, particularly pain relief. If there is no pain relief
after a 2 –3-month trial, the ongoing need should be assessed and the
drug discontinued. Agree with the patient the criteria and time period
k after which the drug will be discontinued if there are no benefits.
k
The recommended dose for the sulfate is 1500 mg daily or in three
divided doses and the hydrochloride 1250 mg daily or in two divided
doses. Each tablet should be swallowed whole. An oral solution and
effervescent formulation are available for those who cannot, or prefer
not to, swallow tablets.
The sulfate and effervescent formulations have high sodium
content5,6 so should be used with caution in patients on a
reduced-salt diet.
Advice and counselling
Patients should be advised on how to evaluate or measure their pain
before starting glucosamine so that any benefit resulting from its use
can be assessed objectively. Advice on the common side effects, drug
interactions and relevant monitoring required depends on the
patient’s pre-existing conditions and other drug therapy. Advise the
patient to purchase a licensed product for consistency and to avoid
over- or underdosing.
GI symptoms may be reduced if taken with or after food. Patients
should be counselled on the value of weight loss and exercise as core
treatments to be used alongside any pharmacological treatments in
the management of osteoarthritis and to seek professional help if
necessary.
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194 Grapefruit juice –drug interactions
Alternative pharmacological and non-pharmacological

treatments2
All treatments should be offered in addition to core treatments of
weight loss and exercise. Paracetamol is effective for pain relief and
relatively safe, although regular dosing may be required. Topical
NSAIDs or capsaicin can be offered in addition to paracetamol to
provide pain relief to affected knees. The use of local heat or cold
therapy as well as transcutaneous electrical nerve stimulation (TENS)
can also be considered. Those who experience specific problems with
G functioning could be offered expert advice on assistive devices such as
walking sticks.
REFERENCES
1 Towheed T et al. (2005). Glucosamine therapy for treating osteoarthritis. Cochrane
Datab Systemat Rev Issue 2. Assessed as up to date: 12 November 2008.
2 NICE (2014). CG117. Osteoarthritis: Care and management in adults. http://
www.nice.org.uk/Guidance/CG177 (accessed 20 August 2014).
4 UKMI (2012). Medicines Q&As. Glucosamine – What are the adverse effects?
www.medicinesresources.nhs.uk/GetDocument.aspx?pageId=504032 (accessed 20
August 2014).
5 SPC (2011). Dolenio 1500 mg film coated tablets. Blue Bio Pharmaceuticals. Date of
revision of text 20/9/2011. www.medicines.org.uk (accessed 6 May 2015).
6 SPC (2010). Glusartel 1500 mg Powder for Oral Solution. Rottapharm. Date of revi-
sion of text 22/10/10. www.medicines.org.uk (accessed 6 May 2015).
k 7 SPC (2010). Alateris 625 mg Tablets. Laboratories Expanscience. Date of revision of k
text 4/8/2010. www.medicines.org.uk (accessed 6 May 2015).
Grapefruit juice–drug interactions

Many drugs undergo oxidative metabolism by cytochrome P450
enzymes (CYP450) in the intestinal wall and liver. This may produce a
first-pass effect that reduces bioavailability, or may increase
bioavailability from a prodrug precursor. Both these effects can be
significant and may be modified by the ingestion of grapefruit juice.
Mechanism of grapefruit interaction
Constituents of grapefruit juice (particularly flavonoids and
furancoumarins) inhibit a number of CYP450 isoenzymes, primarily
CYP3A4, resulting in reduced metabolism and therefore increased
bioavailability of drugs affected. Enzyme recovery is delayed for up to
24 hours after as little as one glass of grapefruit juice; therefore,
taking medicines at a different time to the juice is not a method for
avoiding the interaction.1 Regular consumption appears to increase
the effect on drug pharmacokinetics.2 Grapefruit also has an effect on
drug pharmacokinetics by a second mechanism that involves
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Grapefruit juice –drug interactions 195
inhibition of an influx transporter protein in the gut wall, leading to a

reduced drug bioavailability and therefore reduced drug efficacy. This
is competitive inhibition and the effect is therefore dependent on the
volume consumed; the inhibition lasts around 4 hours, so ensuring a
4-hour gap is left between consumption and administration of
medication avoids these interactions.
Most information sources refer only to grapefruit juice, although it
seems wise to treat grapefruit flesh with the same caution.
Other problematic fruit G
Sweet oranges, commercially available orange juices and tangerines
do not cause these interactions. However, Seville oranges and
pomelos manifest the interaction.1
Drugs affected by grapefruit
Common drugs known to be affected are listed in Table G5, although
if a drug is not listed it does not mean that an interaction does not
exist. It would be wise to be aware of the potential for interaction of
drugs metabolised by the cytochrome CYP450 isoenzymes. The more
significant and potentially toxic interactions are those with:
amiodarone, carbamazepine, ciclosporin, sirolimus, tacrolimus,
atorvastatin and simvastatin.
TABLE G5
Interactions with grapefruit juice and oral drugs 1,3,4,5
k k
Drug Effect Comments
Aliskiren Reduced bioavailability Avoid grapefruit juice
Amiodarone Reduction of formation of major May be clinically significant –
amiodarone metabolite avoid grapefruit juice
Amlodipine Modest increase in bioavailability Probably subclinical
Atorvastatin Increased bioavailability resulting in May be clinically significant
increased risk of myopathy
Carbamazepine Increased bioavailability May be clinically significant –
avoid grapefruit juice
Ciclosporin Significant increase in bioavailability Serious – avoid grapefruit
juice
Clomipramine Increase in blood levels Monitor for unexpected drug
effects
Colchicine Increased risk of toxicity due to Avoid grapefruit juice
increased absorption
Diazepam Increased bioavailability Avoid grapefruit juice
Dronedarone Significant increase in blood levels Avoid grapefruit juice
Felodipine Increase in bioavailability Avoid grapefruit juice
Fexofenadine Possible decreased effect Avoid grapefruit juice
Indinavir Bioavailability may be reduced by Clinical significance not
about 25% established
(continued )
k
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196 Grapefruit juice –drug interactions
TABLE G5
(Continued)
Drug Effect Comments
Itraconazole May decrease bioavailability with Monitor response to
risk of treatment failure treatment
Ivabradine Increases exposure twofold Restrict grapefruit juice
consumption
Methylprednisolone Increased bioavailability Monitor therapeutic effect
Midazolam Increased bioavailability and risk of Avoid grapefruit juice
G excessive sedation
Nicardipine Increased bioavailability Little change in
haemodynamic effect
Nifedipine Increased bioavailability and risk of Avoid grapefruit juice
adverse effects
Nimodipine Increased bioavailability Avoid grapefruit juice
Omeprazole Small increase in bioavailability Not significant
Quetiapine Possible reduced metabolism, Avoid grapefruit juice
therefore increased exposure
Ranolazine Increased blood levels Avoid grapefruit juice
Saquinavir Increased bioavailability, effect Monitor for adverse
similar to a doubled dose effects/altered response
Sertraline Moderate increase in blood levels Avoid grapefruit juice
Sildenafil Possible increase in blood levels Avoid grapefruit juice
k Simvastatin Large increase in blood Avoid grapefruit juice k
concentration
Sirolimus Increased risk of toxicity from raised Avoid grapefruit juice
blood levels
Tacrolimus Significantly increased risk of toxicity Avoid grapefruit juice
from raised blood levels
Terfenadine Increased blood levels – fatality Avoid grapefruit juice
reported
Tolvaptan Increased blood levels Avoid grapefruit
Warfarin May increase anticoagulant effect Not well documented –
monitor international
normalised ratio (INR)
REFERENCES
1 Drug Data no. 56. (2004). Northern Ireland Regional Medicines and Poisons Infor-
mation Service, The Royal Hospitals.
2 Pirmohamed M (2013). Drug–grapefruit juice interactions. BMJ 346: f1.
3 McNeece J (2002). Grapefruit juice interactions. Aust Prescriber 25: 2.
5 Baxter K (ed.) (2014). Stockley’s Drug Interactions. London: Pharmaceutical Press
http://www.medicinescomplete.com/ (accessed 3 August 2014).
k
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Human immunodeficiency virus treatment 197
H
Human immunodeficiency virus
treatment H
The management of human immunodeficiency virus (HIV) is
continually progressing and over the last decade has seen vast
improvements in the drug options available to patients. These newer
drugs are associated with significantly less toxicity than some of the
older ones and are also associated with reduced tablet burden, which
improves adherence and patient tolerability.
HIV is now managed as a chronic condition, with life expectancy
significantly improved in recent years.1 The main aim of treatment is
to reduce the mortality and morbidity associated with the
condition by:
● suppressing the virus – measured by checking the patients viral

load (copies/mL) with a target of <50 copies/mL or ‘undetectable’
k k
● restoring and maintaining the patient’s immune system –
measured by the patient’s CD4 count (cells/μL). In non-HIV
patients this should be >500 cells/μL.
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198 Human immunodeficiency virus treatment
When treatment should be started

The WHO recommends starting treatment at CD4 counts <500
cells/μL.2 The British HIV Association (BHIVA) recommends that
treatment with antiretroviral therapy (ART) should be initiated in all
HIV-positive patients with CD4 count <350 cells/μL.3 To date there
have been no published randomised trials that directly assess whether
treatment-naı̈ ve people with higher CD4 cell counts should initiate
ART immediately rather than defer to <350 cells/μL. In addition,
BHIVA recommends starting treatment regardless of CD4 count if
there is active hepatitis B virus (HBV) or hepatitis C virus (HCV)
H infection; a high risk for cardiovascular disease, in pregnant women,
symptomatic primary HIV infection, HIV-associated nephropathy
(HIVAN) and in serodiscordant couples.3
Antiretroviral therapy
There are six different classes of antiretroviral drugs that can be used
in combination to treat HIV:
1 nucleoside reverse transcriptase inhibitors (NRTIs)
2 non-nucleoside reverse transcriptase inhibitors (NNRTIs)
3 protease inhibitors (PIs)
4 entry inhibitors
5 fusion inhibitors
6 integrase inhibitors.
Drug summaries, including information on adult doses and side
k effects, can be found in Tables H1 –H5. The relevant product SPC k
should be consulted for further information and for guidance on
dosing in children.
k
k
TABLE H1
Nucleoside reverse transcriptase inhibitors
Generic name Trade name Adult dose/dose adjustment in renal impairment Counselling points/side effects
Abacavir Ziagen4 tablets and solution 300 mg every 12 hours or 600 mg once daily May be taken with or without food
(abacavir) Dose modification in renal impairment: none5 Contraindicated in patients positive for
Combination products the human leukocyte antigen
Trizivir4 tablets (HLA)-B*5701 allelle, which is associated
(abacavir/ lamivudine /zidovudine) with increased risk of hypersensitivity
Kivexa4 tablets reaction
(abacavir/ lamivudine) Lactic acidosis, hepatomegaly, hepatic
Triumeq4 steatosis, lipodystrophy,
(lamivudine/ abacavir/ dolutegravir) dyslipidaemia, hypersensitivity reactions
Emtricitabine Emtriva4 capsules and solution 200 mg daily (as oral solution: 240 mg daily) May be taken with or without food
CPPC
k
(emtricitabine) Dose modification in renal impairment5 Lactic acidosis, hepatomegaly, hepatic
Combination products steatosis, lipodystrophy, dyslipidaemia
eGFR (mL/min) Dose
kc08.tex
Atripla4
(tenofovir/efavirenz/ emtricitabine) 30–50 200 mg every 48 hours
Eviplera4
15–30 200 mg every 72 hours
(tenofovir / emtricitabine/ rilpivirine)
Stribild4 <15 200 mg every 96 hours
(tenofovir/ emtricitabine, elvitegravir, cobicistat)
Truvada4
(tenofovir/emtricitabine)
(continued )
H
V2 - 11/18/2015 1:52 P.M. Page 199
k
k
H
TABLE H1
(Continued)
Generic name Trade name Adult dose/dose adjustment in renal impairment Counselling points/side effects
Lamivudine Epivir4 tablets and solution 300 mg daily or 150 mg 12-hourly May be taken with or without food
(lamivudine) Dose modification in renal impairment in HIV5 Lactic acidosis, hepatomegaly, hepatic
N.B.: generic lamivudine products are now available steatosis, lipodystrophy, dyslipidaemia
Combination products eGFR (mL/min) Dose
Combivir4 30–50 150 mg stat then 150 mg daily
(lamivudine/zidovudine)
15–30 150 mg stat then 100 mg daily
Kivexa4
(abacavir/ lamivudine) 5–15 150 mg stat then 50 mg daily
Triumeq4 <5 50 mg stat then 25 mg daily7 (SPC
(lamivudine/ abacavir/ dolutegravir)
CPPC
licensed dose) or
k
Trizivr4 150 mg stat then 25–50mg daily1,6
(lamivudine, zidovudine, abacavir sulfate)
kc08.tex
Tenofovir Viread4 tablets and granules 245 mg daily To be taken with food
(tenofovir) Dose modification in renal impairment: Proximal renal tubulopathy, renal
Combination products impairment, renal failure, lactic
Atripla4 eGFR (mL/min) Dose acidosis, hepatomegaly, hepatic
steatosis, lipodystrophy, dyslipidaemia

(tenofovir/efavirenz/ emtricitabine) 30–50 245 mg every 48 hours
Eviplera4
10–30 245 mg every 72–96 hours
(tenofovir / emtricitabine/ rilpivirine)
Stribild4 <10 245 mg every 7 days
(tenofovir/ emtricitabine, elvitegravir, cobicistat)
Truvada4
(tenofovir /emtricitabine)
V2 - 11/18/2015 1:52 P.M. Page 200
k
k
TABLE H2
Non-nucleoside reverse transcriptase inhibitors
Generic name Trade name Adult dose/ dose adjustment Counselling points/
in renal impairment side effects
Efavirenz Sustiva4 capsules, tablets and solution 600 mg daily (as oral solution: 720 mg daily) To be taken on an empty stomach, preferably at
(efavirenz) Dose modification in renal impairment: none5 bedtime
Combination products Rash, central nervous system effects – dizziness,
Atripla4 depression. abnormal dreams, sleep disturbances,
psychosis
(tenofovir/efavirenz/ emtricitabine)
Etravirine Intelence4 tablets 200 mg 12-hourly To be taken with food
(etravirine) Dose modification in renal impairment: none4 Rash
CPPC
Nevirapine Viramune4 tablets and suspension 200 mg daily for 14 days, increased to 200 mg 2-week lead in recommended to reduce the
k
(nevirapine) 12-hourly maintenance dose incidence of rash
N.B.: generic nevirapine products now also Dose modification in renal impairment: none5 May be taken with or without food
kc08.tex
available Rash, allergic reactions, hepatitis, abnormal liver

function tests
Rilpivirine Edurant4 25 mg daily Must be taken with food for maximum absorption
(rilpivirine) Dose modification in renal impairment: none4 Should only be used in patients with a viral load
Combination products <100 000 copies/mL
Eviplera4 Dyslipidaemia, insomnia, raised amylase, raised
(tenofovir / emtricitabine/ rilpivirine) transaminase
H
V2 - 11/18/2015 1:52 P.M. Page 201
k
k
H
TABLE H3
Protease inhibitors
Generic name Trade name Adult dose/ dose adjustment in renal impairment Counselling points/side effects
Atazanavir Reyataz4 tablets 300 mg daily taken with ritonavir 100 mg daily To be taken with food
(atazanavir) Dose modification in renal impairment: none5 Jaundice, rash
Darunavir Prezista4 tablets and suspension ART-naive patients – 800 mg daily with ritonavir To be taken with food
(darunavir) 100 mg daily Insomnia, rash, increased alanine aminotransferase,
ART-experienced patients with no evidence of diabetes, dyslipidaemia, peripheral neuropathy
resistance/resistant mutations – 800 mg daily with
ritonavir 100 mg daily
ART-experienced patients – 600 mg 12-hourly with
CPPC
ritonavir 100 mg 12-hourly
k
Dose modification in renal impairment: none5
Lopinavir/ritonavir Kaletra4 tablets and suspension 400/100 mg lopinavir/ritonavir 12-hourly To be taken with food
kc08.tex
(lopinavir/ritonavir) Dose modification in renal impairment: none5 Dyslipidaemia, pancreatitis. diabetes, anxiety,
hypertension, hepatitis, erectile dysfunction, menstrual
disorders
Ritonavir Norvir4 tablets and solution Only to be used as a pharmacokinetic enhancer with To be taken with food
(ritonavir) other PIs – see information on previous PIs for dosing Hypersensitivity, dyslipidaemia, dysgeusia, peripheral
Combination products advice neuropathy, oral and peripheral paraesthesia, rash,
Kaletra4 tablets and suspension pharyngitis, cough (refer also to side effects of the
(lopinavir/ritonavir) co-administered PI)
V2 - 11/18/2015 1:52 P.M. Page 202
k
CPPC
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TABLE H4
Entry inhibitors
Generic Trade name Adult dose/ dose adjustment Counselling points/
name in renal impairment side effects
Maraviroc Celsentri4 300 mg 12-hourly – will Should only be used in
tablets need dose adjustment if patients with CCR5 tropic
(maraviroc) on interacting medication: virus. May be taken with or
consult SPC without food
Dose modification in renal Anaemia, anorexia,
impairment may be depression, rash, increases in
required if patient on alanine transaminase (ALT),
potent CYP3A4 inhibitors: increases in aspartate H
consult SPC4 transaminase (AST)
TABLE H5
Integrase inhibitors
Generic Trade name Adult dose/dose adjustment Counselling points/
name in renal impairment side effects
Dolutegravir Tivicay4 No/not suspected May be taken with or with-
tablets integrase resistance – out food. In the presence of
(dolutegravir) 50 mg daily known integrase resistance,
Combination Known/suspected take with food to enhance
products integrase resistance – exposure
Triumeq4 50 mg 12-hourly Insomnia, abnormal
(lamivudine/ Dose modification in dreams, rash, pruritus,
abacavir/ renal impairment: none5 raised ALT, raised AST,
k dolutegravir) raised creatine k
phosphokinase
Raltegravir Isentress4 400 mg tablet 12-hourly May be taken with or
tablets (N.B. other formulations without food
(raltegravir) are not bioequivalent) Decreased appetite, abnor-
Dose modification in mal dreams, insomnia,
renal impairment: none5 depression, vertigo, rash,
raised AST, raised ALT,
hypertriglyceridaemia
Elvitegravir/ Stribild4 Each tablet contains: To be taken with food
cobicistat (elvitegravir, elvitegravir 150 mg, Rash – but see also side
cobicistat, cobicistat 150 mg, effects of tenofovir and
emtricitabine, emtricitabine 200 mg, emtricitabine for
tenofovir) tenofovir 245 mg combination tablet side
Dose: one tablet daily effects
Dose modification in
renal impairment4
CrCl
(mL/min) Dose
70– 90 Only use if other
treatment options
have been
discussed and
Stribild is still the
preferred option
<70 Do not use
k
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Which antiretrovirals should be used?

In treatment-naı̈ ve patients standard therapy should be initiated with
a backbone of two NRTIs plus a third agent, which can be a
ritonavir-boosted PI, an NNRTI or an integrase inhibitor3 (Figure H1).
The current BHIVA first-line treatment algorithms are also
summarised in Figure H1.
H
1. PI
AND ONE
2 NRTIs 2. NNRTI
of the following
3. Integrase
inhibitor
PREFERRED
NRTI 3rd agent
k Tenofovir and emtricitabine Atazanavir/ritonavir

k
Darunavir/ritonavir
Efavirenz
Raltegravir
Elvitegravir/cobicistat
ALTERNATIVE
NRTI 3rd agent
Abacavir (ABC)* and lamivudine (3TC) Rilpivirine (RPV)**
Lopinavir/ritonavir
Fosamprenavir/ritonavir
Nevirapine (NVP)***
*ABC is contraindicated if HLA-B*5701 positive

**Use recommended only if baseline viral load <100 000 copies/mL: RPV as a third
agent, ABC/3TC as NRTI backbone.
***NVP is contraindicated if baseline CD4 cell count is greater than 250/400 cells/mL in
women/men.
FIGURE H1 Standard antiretroviral therapy. NRTI, nucleoside reverse transcriptase

inhibitor; PI, protease inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor
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Drug choice should be tailored to the individual patient, with

considerations of:
● efficacy
● toxicity/side effect profile
● pill burden – both the number of tablets per day and the frequency
with which they need to be taken
● comorbidities, that could contraindicate/caution some ART
● drug interactions
● patient preference.
Side effects H
Minor side effects common to all antiretroviral drugs include nausea,
vomiting, diarrhoea, headache and fatigue – these are generally
worse in the first few weeks after initiation and usually subside with
continued treatment. Important side effects specific to certain
antiretrovirals are summarised below and in Tables H1 –H5; consult
the relevant SPC for a complete list of all side effects for each drug.
● Tenofovir is associated with renal impairment and osteoporosis.

● Zidovudine can cause macrocytic anaemia and lipodystrophy.
● Abacavir is associated with life-threatening hypersensitivity rash.
● NNRTIs, particularly efavirenz, may cause neuropsychiatric
symptoms like dizziness and insomnia.
● Nevirapine has a risk of hepatotoxicity and Stevens–Johnson
k syndrome/toxic epidermal necrolysis. k
● PIs are associated with a wide range of side effects, including
hyperlipidaemia, hepatitis, diarrhoea and insulin resistance.
● Integrase inhibitors may cause headache and nausea, although this
is rare.
Drug interactions
Antiretrovirals have the potential to interact with each other and with
other medications. Before initiating ART, or introducing other
medicines to patients already stable on ART, drug interactions should
be checked, as some may be clinically significant. Interactions may be
managed with dose modification or increased monitoring, or may
even necessitate a change in therapy. The use of herbal remedies and
‘recreational drugs’ should also be considered as these often interact
with antiretrovirals. The University of Liverpool has a comprehensive
website that can be used to check interactions of HIV medicines
(available at http://www.hiv-druginteractions.org, and also available
to download as an app). Information on interactions is also available
in the SPC for each drug.
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Nucleoside reverse transcriptase inhibitors

(Abacavir, didanosine, emtricitabine, lamivudine (3TC), rilpivirine
(RPV), stavudine, tenofovir, zidovudine)
NRTIs work by inhibiting the reverse transcriptase enzyme,
preventing the formation of proviral DNA from the viral RNA. This is
achieved by acting as nucleoside substrates during the formation of
proviral DNA, resulting in termination of the DNA chain and therefore
preventing replication. The most commonly used NRTIs are detailed
in Table H1.
Non-nucleoside reverse transcriptase inhibitors
H
(Efavirenz, etravirine, nevirapine, rilpivirine)
NNRTIs also work by inhibiting the reverse transcriptase enzyme,
preventing the formation of viral DNA. This is via a different
mechanism – attaching directly to the reverse transcriptase enzyme,
preventing it from working. The most commonly used NNRTIs are
detailed in Table H2.
Protease inhibitors
(Atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, ritonavir,
saquinavir, tipranavir)
PIs work by blocking the protease enzyme that is needed to break
large chains of viral protein into smaller building blocks that are used
in the assembly of new HIV particles. This results in the production of
an immature, less infectious HIV. The most commonly used PIs are
k detailed in Table H3. All PIs are used in combination with ritonavir, k
which acts as a booster to increase levels.
Entry inhibitors
(Maraviroc)
In order to fuse with the host cell the HIV virus must first bind to
the CD4 receptor and a chemokine receptor 4 or 5 (CXCR4 or CCR5).
The CCR5 inhibitor maraviroc is the only licensed drug in its class and
works by binding to the CCR5 receptor. This prevents the virus from
binding and fusing with the host cell. This will only work in patients
who have CCR5 tropic virus, so tropism testing should be carried out
before initiating maraviroc – dual tropic or CXCR4 tropic virus will
not be successfully suppressed with maraviroc. More detail can be
found in Table H4.
Fusion inhibitor
(Enfuvirtide)
This works by binding to a surface protein on the HIV particle,
preventing fusion with and entry of the virus into the host cell. This
drug is only available as an injection and has had limited use – it will
not be discussed further in this chapter.
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Integrase inhibitors
(Raltegravir, dolutegravir, elvitegravir/cobicistat)
Integrase inhibitors work by blocking the viral integrase enzyme,
which is responsible for inserting and integrating viral DNA into the
host DNA, preventing replication. Elvitegravir is the newest of the
integrase inhibitors and must be co-administered with a
pharmacokinetic enhancer (usually cobicistat), and is used as part of
a single fixed-dose tablet regimen with tenofovir and emtricitabine –
this is called Stribild or ‘quad’ because of its four drug components.
The most commonly used integrase inhibitors are detailed in
Table H5. H
REFERENCES
1 May M et al. (2011). Impact of late diagnosis and treatment on life expectancy
in people with HIV-1: UK Collaborative HIV Cohort (UK CHIC) Study. BMJ 343:
d61016.
2 WHO (2014). Consolidated Guidelines on HIV Prevention, Diagnosis, Treatment
and Care for Key Populations. http://apps.who.int/iris/bitstream/10665/
128048/1/9789241507431 eng.pdf?ua=1&ua=1 (accessed 13 December
2014).
3 Williams I et al. (2014). British HIV Association guidelines for the treatment of
HIV-1-positive adults with antiretroviral therapy 2012 (2013 update). HIV Med
15(Suppl 1): 1–85.
4 eMC (2014). www.medicines.org.uk (accessed 20 October 2014).
5 Ashley C, Currie, A (eds) (2009). The Renal Drug Handbook (3rd edn). Oxford:
k Radcliffe Publishing. k
k
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208 Hyperosmolar hyperglycaemic state
Hyperosmolar hyperglycaemic state

Hyperosmolar hyperglycaemia state (HHS) is a medical emergency
characterised by hypovolaemia, marked hyperglycaemia and raised
serum osmolality.
HHS was formerly known as hyperosmolar non-ketotic syndrome
(HONS or HONK).
HHS typically occurs in the elderly but, as the diabetes pandemic
widens, HHS may now also be the initial presentation of type 2
diabetes mellitus in younger adults and teenagers.
H A precise definition of HHS does not exist; it has different features
to diabetic ketoacidosis (DKA) and it is therefore treated differently
(see Diabetic ketoacidosis entry). Whilst DKA presents within hours of
onset, HHS may develop over many days and consequently
dehydration and metabolic disturbances are more extreme. HHS has a
higher mortality than DKA and may be more complex, with vascular
complications such as myocardial infarction, stroke or peripheral
arterial thrombosis. Other uncommon complications of HHS include
seizures, cerebral oedema and central pontine myelinolysis, the latter
possibly being precipitated by rapid changes in osmolality during
treatment. Some patients present a mixed picture of both DKA and
HHS.
Diagnosis of HHS
k The following are characteristic features of HHS: k
● hypovolaemia
● marked hyperglycaemia (30 mmol/L or more) without significant
blood ketones (<3 mmol/L) or acidosis (pH > 7.3; bicarbonate
>15 mmol/L)
● serum osmolality – usually ≥320 mosmol/kg.
Management of HHS in adults

In 2012, the JBDS Inpatient Care Group published guidance on
treating HHS in adults1 so all trusts should aim to have a policy or
care pathway in place. The main focus of treatment is to treat the
underlying cause and gradually and safely to normalise osmolality,
replace fluid and electrolyte losses and normalise blood glucose
levels. Additionally clinicians should aim to prevent arterial or venous
thrombosis, avoid complications such as cerebral oedema and prevent
foot ulceration.
Early escalation to High Dependency Unit (HDU) should be
considered if one or more of the following is present:
● osmolality >350 mosmol/kg

● sodium >160 mmol/L
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Hyperosmolar hyperglycaemic state 209
● venous/arterial pH <7.1
● hypokalaemia <3.5 mmol/L or hyperkalaemia >6 mmol/L on
admission
● hypoxia, (oxygen saturation <92%, assuming normal baseline)
● altered consciousness (GCS <12 or abnormal AVPU)
● systolic BP <90 mmHg or
● pulse outside 60 –100 bpm.
For management in young people (<16 years), refer to published
paediatric guidance.2
Fluid H
These patients are severely dehydrated because of prolonged osmotic
diuresis (Table H6) and fluid replacement is the first priority. Sodium
chloride 0.9% with ready-mixed potassium as required is currently
recommended as the fluid of choice because the majority of
electrolyte losses are sodium, chloride and potassium.
TABLE H6
Typical fluid and electrolyte deficits in
hyperosmolar hyperglycaemic state3
Water 100–220 mL/kg
Sodium 5–13 mmol/kg
Chloride 5–15 mmol/kg
k Potassium 4–6 mmol/kg

k
Serum osmolality is a useful indicator of severity of illness, and also

for monitoring rate of change with treatment. Because frequent
measurement is not usually available in UK hospitals, calculated
osmolality1 is used to guide treatment, where:
Osmolality = 2Na+ + glucose + urea
(normal range = 280 –300 mosmol/kg)
● The rate of rehydration is determined by assessing initial severity
plus any pre-existing comorbidities. Caution is needed, particularly
in the elderly, where too rapid rehydration may precipitate heart
failure but insufficient rehydration may fail to reverse acute kidney
injury.
● Intravenous fluid replacement aims to achieve a positive balance,
with 3 –6 litres of fluid to be given over the first 12 hours and the
remaining replacement of estimated fluid losses within the next
12 hours, although it may take up to 72 hours for complete
normalisation of biochemistry.
● Calculate (or measure) osmolality every hour initially and adjust
the rate of fluid replacement to ensure a positive fluid balance
sufficient to promote a gradual decline in osmolality.
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210 Hyperosmolar hyperglycaemic state
● Use intravenous sodium chloride 0.9% to reverse severe

dehydration. The rate of fall of plasma sodium should not exceed
10 mmol/L in 24 hours. N.B.: fluid replacement (without insulin)
will lower blood glucose and reduce osmolality, shifting water into
the intracellular space. This inevitably results in a rise in serum
sodium, which is not necessarily a reason to give hypotonic fluids.
A fall in blood glucose of 5.5 mmol/L causes a 2.4 mmol/L rise in
sodium; a greater rise than this indicates insufficient fluid
replacement.
● Maintain an accurate fluid balance chart and aim for a minimum
H urine output of 0.5 mL/kg/hour.
● Only switch to sodium chloride 0.45% if the osmolality is not
declining despite adequate positive fluid balance and an adequate
rate of fall in blood glucose level.
● Patients should be allowed to take oral fluids as soon as they are
able.
Intravenous insulin
A safe rate of fall in blood glucose should be between 4 and 6 mmol/L
per hour to a target of 10 –15 mmol/L in the first 24 hours.
● An intravenous insulin infusion should only be commenced once
the blood glucose is no longer falling with fluid replacement alone
or at the start of treatment for HHS if there is significant
ketonaemia (blood ketones >1 mmol/L).
k ● Insulin may be infused in the same line as the intravenous k
replacement fluid, provided that a Y-connector with a one-way,
antisyphon valve is used, and a large-bore cannula has been placed.
● A syringe pump should be set up containing 50 units of soluble
insulin in 50 mL sodium chloride 0.9% (i.e. 1 unit/mL) and this
should be infused at the lower starting rate of 0.05 unit/kg/hour
because most patients with HHS are insulin-sensitive.
● Avoid hypoglycaemia: if blood glucose falls below 14 mmol/L,
commence glucose 5% or 10% at 125 mL/hour while continuing
the sodium chloride 0.9% infusion.
● Subcutaneous insulin is usually given to provide stability for a short
time (weeks or months) following an episode of HHS. In the longer
term most patients will be able to control their diabetes with either
diet and oral therapy or diet alone.
Potassium
Patients with HHS are potassium-depleted but less acidotic than those
with DKA, so potassium shifts are less pronounced. Patients with
acute kidney injury may present with hyperkalaemia but patients on
diuretics may be profoundly hypokalaemic. Potassium should be
replaced or omitted as required (Table H7).
Anticoagulation
A major cause of death in HHS is thromboembolic disease.
Prophylactic anticoagulation with low-molecular-weight heparin is
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Hypodermoclysis 211
TABLE H7
Suitable potassium replacement levels in hyperosmolar
hyperglycaemic state
Potassium level in first 24 hours Potassium chloride to be added
<3.5 mmol/L Senior review as additional potassium is essential
(if necessary, via a central line in HDU)
3.5–5.5 mmol/L 40 mmol/L of fluid
>5.5 mmol/L None
indicated for the full duration of admission, unless specifically H

contraindicated.4
Antibiotics
Infection is often difficult to exclude in patients with HHS. Antibiotics
should be prescribed according to local guidelines when there are
clinical or other signs to suggest infection.
Aftercare
● The underlying cause of HHS should be determined to minimise
recurrence.
● The patient should have appropriate diabetes education and
follow-up by the diabetes team.
● Prior to discharge there must be a plan in place for ongoing
k management and follow-up of diabetes depending on the patient’s k
lifestyle and home circumstances.
REFERENCES
1 Joint British Diabetes Societies Inpatient Care Group (2012). The Management of
the Hyperosmolar Hyperglycaemic State (HHS) in Adults with Diabetes. London:
Diabetes UK. http://www.diabetologists-abcd.org.uk/JBDS/JBDS IP HHS Adults.pdf
2 Zeitler P et al. (2011). Hyperglycaemic hyperosmolar syndrome in children: patho-
physiological considerations and guidelines for treatment. J Pediatr 158: 9–14.
3 Kitabachi AE et al. (2009). Hyperglycaemic crises in adult patients with diabetes.
Diabetes Care 32: 1335–1343.
4 NICE (2015). Venous Thromboembolism: Reducing the risk of venous thromboem-
bolism (deep vein thrombosis and pulmonary embolism) in patients admitted to
hospital (CG 92). http://www.nice.org.uk/guidance/cg92 (accessed 3 February
2015).
Hypodermoclysis
This is a technique used to administer fluids and electrolytes
subcutaneously to achieve fluid maintenance or replacement in
mildly dehydrated patients or in patients at risk of dehydration, when
the oral or intravenous routes are not available. This might include
patients in the first few days after a stroke, patients with poor venous
access, palliative care patients or those who are agitated or confused
and continually remove venous access devices.
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212 Hypodermoclysis
It is not suitable for patients with severe dehydration, patients in

shock, where more than 3 litres of fluid are required in a 24-hour
period, or where precise control of the volume and rate of infusion is
required.
Normally 500 mL of fluid is given over 8 hours, up to a maximum
of 2 litres over a 24-hour period.
Solutions for hypodermoclysis
Solutions suitable for hypodermoclysis should ideally be isotonic
(or close to isotonicity) with extracellular fluid. The suitability of a
H solution for subcutaneous administration must be established before
use. Examples of solutions that have been used are:
● sodium chloride 0.9% or 0.45% solution
● glucose 5% solution (not more than 2 litres should be given in
24 hours, and the rate of administration should not exceed
2 mL/min. Higher rates or higher strengths have led to shock. The
site should be inspected regularly for signs of irritation and
inflammation due to the low pH of glucose solutions)
● sodium chloride 0.18% with glucose 4% solution
● potassium solutions up to 40 mmol/L (20 mmol/500mL) in
isotonic glucose or saline (ulceration can sometimes occur due to
low pH and high osmolarity, so regular observation of the infusion
site is required).1
k Solutions unsuitable for hypodermoclysis k
The following solutions are not suitable for hypodermoclysis:
● colloids
● total parenteral nutrition
● potassium solutions greater than 40 mmol/L
● glucose solutions greater than 5%
● solutions containing ions other than sodium, potassium or
chloride, unless the solution’s physiological characteristics are
completely understood, e.g. pH and tonicity.2
Administration
Solutions are administered using a standard giving set through a
subcutaneous needle and should always be gravity-fed. The choice of
site should be healthy, clean, non-oedematous and convenient for the
patient’s comfort. Commonly used sites are the abdomen, thigh,
scapula, axillary and subclavicular chest wall.3
Care should be taken in young children and the elderly to control
the speed and total volume of fluid administered and to avoid
overhydration, especially in renal impairment.
Hyaluronidase may be used to increase the rate of absorption of
subcutaneous fluids. In clinical practice, there are three strategies for
k
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Hypopituitarism 213
its use in hypodermoclysis:
1 routinely every 24 hours

2 when required only, e.g. if an infusion is running very slowly, or
there is swelling at the infusion site
3 at the start of the infusion only, and then only on resiting or as
required.
The licensed dose of hyaluronidase is 1500 units per site every
24 hours.4 This dose is dissolved in 1 mL of water for injections, or
sodium chloride 0.9%, and is injected subcutaneously into the site
before the infusion is set up. Alternatively, it can be injected into the H
tubing of the infusion set, about 2 cm back from the needle, at the
start of the infusion. 1500 units is sufficient for administration of
500 –1000 mL of most fluids.
Monitoring the infusion site
The infusion site should be checked when the bag is changed. More
regular monitoring is required for solutions other than sodium
chloride 0.9%. The site should be changed if pain is experienced at
the infusion site, the site becomes inflamed, white or hard, or if blood
is observed in the giving set.
REFERENCES
1 Can potassium be given by subcutaneous infusion? UKMI Q&A 45.6 (accessed via
www.evidence.nhs.uk 19 August 2014).
k 2 Can magnesium sulphate be given subcutaneously? UKMI Q&A 14.5 (accessed via k
www.evidence.nhs.uk 19 August 2014).
3 Hypodermoclysis Working Group (1998). Hypodermoclysis – Guidelines on the tech-
nique. Wrexham: CP Pharmaceuticals.
4 SPC (2011). Hyalase November 2011 revision. http://emc.medicines.org.uk/
Hypopituitarism
Overview
Definition Hypopituitarism is the complete or partial deficiency of one or more of
the pituitary hormones and can occur in adults or children.
Causes of pituitary insufficiency include:
● pituitary tumours
● radiotherapy or surgery
● pituitary infarction
● infection
● head injury.
The symptoms of hypopituitarism depend on the hormones involved and
the degree of insufficiency1,2
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214 Hypopituitarism
Risk factors Initially, a patient with any hormone deficiency may be asymptomatic.
Individuals with the following deficiencies present with the indicated
condition.
● Adrenocorticotrophic hormone (ACTH) deficiency: adrenal (cortisol)
insufficiency
● Thyroid-stimulating hormone (TSH) deficiency: hypothyroidism
● Gonadotrophin deficiency: hypogonadism
● Growth hormone deficiency: failure to thrive and short stature in
children; most adults are asymptomatic, but some may experience
fatigue and weakness and decreased quality of life
H ● Antidiuretic hormone deficiency (ADH) – polyuria and polydipsia
Differential Differential diagnosis depends on the hormones affected

diagnosis
Diagnostic Hormonal studies should be performed in pairs of target gland and their
2
tests respective stimulatory pituitary hormone for proper interpretation.
● Thyroid: TSH, thyroxine (T4), triiodothyronine (T3)
● Adrenal function: ACTH stimulation test (or morning cortisol and
ACTH)
● Fertility: follicle-stimulating hormone (FSH), luteinising hormone (LH)
and either oestradiol (if amenorrhoeic) or morning testosterone (as
appropriate for sex)
● Prolactin
● Growth hormone-provocative testing
k Treatment ● Replacement of affected hormones to physiological levels k

goals
Treatment ● Pituitary hormone deficiencies are treated by replacing either the
options pituitary hormone itself, e.g. growth hormone, or the target hormone,
e.g. levothyroxine, corticosteroids

Essential ● Glucocorticoids are required if the ACTH–adrenal axis is impaired
intervention ● Hypothyroidism is treated with levothyroxine
● Gonadotrophin deficiency is treated with sex-appropriate hormones.
Testosterone replacement is used in men and oestrogen replacement
is used in women, with progesterone in women with an intact uterus
● Growth hormone is replaced in children. It is not routinely replaced in
adults unless the patient is symptomatic of growth hormone
deficiency after all other pituitary hormones have been replaced. The
use of growth hormone is advised by the National Institute of Health
and Care Excellence via two technology appraisals for adults and
children3,4
● Diabetes insipidus is treated using desmopressin. See Diabetes
insipidus (cranial) entry
Continued Hormone levels should be monitored to determine complications of

monitoring under- or overreplacement. Hormone treatment may need to be adjusted
to physiological maintenance levels, using the lowest dose
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Hypopituitarism 215
REFERENCES
1 Jorn Schneider H (2007). Hypopituitarism. Lancet 369: 1461–1470.
2 Corenblum B (2013). Hypopituitarism (panhypopituitarism). Medscape.
http://emedicine.medscape.com/article/122287-overview (accessed 28 August
2014).
3 NICE (2010). Human Growth Hormone (Somatropin) for the Treatment of Growth
Failure in Children (TA188). London: National Institute for Health and Care Excel-
lence.
4 NICE (2003). Human Growth Hormone (Somatropin) in Adults with Growth Hor-
mone Deficiency (TA64). London: National Institute for Health and Care Excellence.
k k
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216 Immunoglobulin for intravenous administration
I
Ideal body weight
I
Ideal body weight (IBW) may be useful for calculating creatinine
clearance to assess renal function. It is also useful for dose
calculations of drugs that are not highly lipid-bound and have narrow
therapeutic ranges, e.g. digoxin, gentamicin.
Many formulae exist to calculate IBW and all have limitations, such
as their unsuitability for children, small women and tall men. An
internet resource gives much information on the history of measuring
IBW, and suggests using the Devine formula for men and the
Robinson formula for women, which represents the best compromise
to the limitations of the formulae:1
● for men: IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet
k ● for women: IBW (kg) = 49 kg + 1.7 kg for each inch over 5 feet k
These formulae are used throughout this book wherever an IBW
calculation is required.
REFERENCE
1 Halls MD (2015). Ideal Weight Formulas by Broca and Devine. http://halls.md/ideal-
weight-formulas-broca-devine/ (accessed 27 January 2015).
Immunoglobulin (normal) for intravenous

administration
Normal immunoglobulin for intravenous administration is made from
the pooled plasma of screened human blood donors, currently from
outside the UK. It contains mainly immunoglobulin G (IgG), with a
small amount of IgA, and has a broad spectrum of antibodies effective
against various infective agents. Extensive guidance is available on
the suitability of intravenous immunoglobulin therapy for various
conditions.1
There are several brands available, with similar dosing regimens
for the various indications, although there may be some variation
from brand to brand. The main difference between brands is in their
excipients, and this may be useful if a patient is sensitive to a
particular ingredient.
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Immunoglobulin for intravenous administration 217
All patients should be adequately hydrated prior to initiation of

therapy in order to protect against potential renal dysfunction
(the normal daily fluid intake for an adult is 1.5 litre). Urine output
and creatinine clearance should be monitored, and loop diuretics
should not be used concomitantly.
Immunoglobulins can precipitate acute renal failure. The products
containing sucrose as a stabiliser have accounted for a
disproportionate number of patients who have experienced renal
dysfunction or acute renal failure, i.e. Vigam.2 Patients with the
following factors carry a higher risk of this occurring: pre-existing
renal impairment, diabetes mellitus, hypovolaemia, overweight,
concomitant nephrotoxic drugs and patients aged over 65 years.3
Intravenous therapy with immunoglobulins may impair the
I
efficacy of live attenuated vaccines, and therefore, live virus vaccines
should only be given at least 3 weeks before or 3 months after an
injection of immunoglobulin.4
The following information summarising administration and dosing
regimens (Table I1) is for Vigam, which has the widest range of
licensed indications. A separate column has been left for insertion of
local variations if a different brand is used.
Administration
Bring the product to room or body temperature before use. The
liquid is given intravenously through a filter (a 15 micron filter is
k recommended), at an initial rate of 0.01 –0.02 mL/kg/min for k
30 minutes. If tolerated, the rate can gradually be increased to
0.04 mL/kg/min. The maximum rate of Vigam is 3 mL/min, although
some brands allow a higher rate of infusion.
The product is preservative-free so administration should start
immediately after piercing the cap. The patient should be observed
for any adverse effects for at least 20 minutes after commencement of
infusion, e.g. a drop in blood pressure or signs of allergy. If anaphylaxis
occurs the patient should be treated as per local guidelines.
Undesirable effects
The most common side effects are chills, hypothermia, headaches,
fever, flushing, urticaria, nausea and vomiting. In most cases adverse
reactions can be avoided or reversed by using low infusion rates. If
influenza-like symptoms recur and reducing the infusion rate does not
prevent them, premedicating the patient with paracetamol may help,
but the possibility of an underlying infection should be considered
and treated if that is the case.
It should be noted that there are human normal immunoglobulin
products available that are suitable for subcutaneous infusion or
intramuscular injection. These may be useful for patients who are
fluid-restricted or for treatment in the home. The appropriate SPC
should be consulted if these products are to be used.
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218 Immunoglobulin for intravenous administration
TABLE I1
Dosing regimens for Vigam3
Indication Dose Frequency Local variations
Replacement therapy in Starting dose: Every 2–4 weeks to
primary immunodeficiency, 0.4–0.8 g/kg obtain IgG trough level
Thereafter: of at least 4–6 g/L
0.2–0.8 g/kg
Replacement therapy in 0.2–0.4 g/kg Every 2–4 weeks to
secondary obtain IgG trough level
immunodeficiency of at least 4–g/L
Congenital AIDS 0.2–0.4 g/kg Every 3–4 weeks
Hypogammaglobulinaemia 0.2–0.4 g/kg Every 3–4 weeks to
I (<4 g/L) in patients after obtain 1 gG trough
allogeneic haematopoietic level above 5 g/L
stem cell transplantation
Immunomodulation in 0.8–1.0 g/kg On day 1, possibly
idiopathic repeated once within
thrombocytopenic purpura or 3 days
0.4 g/kg/day For 2–5 days
Immunomodulation in 0.4 g/kg/day For 5 days
Guillain–Barré syndrome
Immunomodulation in 2 g/kg In one dose usually
Kawasaki disease within 10 days of onset
of symptoms, and with
concomitant aspirin
k (dose as per BNFC)5 k
Allogeneic bone marrow
transplantation
Treatment of 0.5 g/kg Weekly from 7 days
graft-versus-host disease prior to transplantation
and for up to 3 months
after transplantation
Persistent lack of antibody 0.5 g/kg Monthly until antibody
production levels return to normal
REFERENCES
1 Clinical Guidelines for Immunoglobulin Use (2008) https://www.gov.uk/government/
publications/clinical-guidelines-for-immunoglobulin-use-second-edition-update
(accessed 6 September 2015).
2 eMC (2014). www.medicines.org.uk (accessed 23 December 2014).
3 SPC (2015). Vigam Liquid. http://emc.medicines.org.uk (accessed 7 September
2015).
4 Green Book, Chapter 6 (2013). http://www.dh.gov.uk/ (accessed 23 December
2014).
5 Joint Formulary Committee (2015). BNF for children (online). London: BMJ Group
and Pharmaceutical Press. www.medicinescomplete.com (accessed 6 September
2015).
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Inflammatory bowel disease

Overview
Definition Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory
condition of the gastrointestinal tract. It is a broad term for two diseases:
● Crohn’s disease (CD), which can affect any part of the gastrointestinal
tract
● ulcerative colitis (UC), which affects the rectum and colon
Causes ● Most likely a combination of genetic and environmental factors,
resulting in an inappropriate immune-mediated response to
indigenous flora and other antigens
Classification
Severity of disease is classified according to signs and symptoms. I
The most common tools used are the Truelove and Witts criteria for UC
(Table I2)1 and the Harvey–Bradshaw index for CD (Table I3)2
TABLE I2
Truelove and Witt’s severity index
Mild Moderate Severe
Number of bloody stools per day <4 4–6 >6
Temperature (◦ C) Afebrile Intermediate >37.8
Heart rate (beats/min) Normal Intermediate >90
Haemoglobin (g/dL) >11 10.5–11 <10.5
k ESR (mm/hour) <20 20–30 >30 k

TABLE I3
Harvey–Bradshaw index
General well-being (0 = very well, 1 = slightly below average,
2 = poor, 3 = very poor, 4 = terrible)
Abdominal pain (0 = none, 1 = mild, 2 = moderate, 3 = severe)
Number of liquid stools per day
Abdominal mass (0 = none, 1 = dubious, 2 = definite, 3 = tender)
Complications (score 1 per item): arthralgia, uveitis, erythema
nodosum, aphthous ulcers, pyoderma gangrenosum, anal fissure, new
fistula, abscess
Score <4 = remission, >8 = severe disease

Differential Irritable bowel disease, infection, coeliac disease, diverticular disease,
diagnosis bowel cancer
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220 Inflammatory bowel disease
Signs and Depending on the location of disease, both UC and CD can result in
symptoms symptoms of diarrhoea with blood and mucus, abdominal pain, tenesmus,
weight loss, malaise and fever.
Signs may include: anaemia, raised inflammatory markers (e.g. CRP, ESR),
and extraintestinal manifestations of IBD, which may affect joints
(arthritis), skin (erythema nodosum or pyoderma gangrenosum), eyes
(uveitis) or liver (primary sclerosing cholangitis). Fistulae and Intestinal
strictures may also be present in CD
Diagnostic ● Stool culture – to rule out infection
tests ● Faecal calprotectin – can distinguish between inflammatory conditions
such as IBD, and non-inflammatory conditions, e.g. irritable bowel
syndrome
I ● Flexible sigmoidoscopy and colonoscopy allow direct visualisation of
the distribution and degree of inflammation; biopsies taken during
investigation help differentiate between UC and CD
● Radiological tests (e.g. abdominal X-ray, small-bowel meal, CT and
MRI) also provide information on the location and degree of disease
activity
● FBC and CRP – inflammatory markers may be raised with more severe
disease; thrombocytosis and anaemia may be seen
Treatment ● Minimise symptoms and improve quality of life
goals ● Induce and maintain remission
● Promote mucosal healing
● Reduce the need for surgery
Treatment ● Aminosalicylates, corticosteroids, enteral nutrition and
k options2 immunomodulators are the main options for inducing and maintaining k
remission
● Surgery to remove diseased bowel is normally reserved for when
medical therapy has failed. For UC this is normally a colectomy which
is curative; for CD, surgery is conservative, as disease may recur after
resection and further surgery may be required in the future
NICE has published guidance on the treatment of both CD3 and UC4
Aminosali- ● Main role for oral aminosalicylates (>2.4 g) is first-line for mild to
cylates moderate flares of UC. It may be considered in CD if patients decline
steroids, but the evidence is poor. Lower doses (e.g. 1.2 g/day Asacol,
Octasa) are sufficient for maintaining remission in UC. Although
different brands may release in different parts of the gastrointestinal
tract, there is no evidence to suggest any one brand is more effective
than another
● Once-daily mesalazine is as effective as multiple daily doses and may
help adherence, though side effects may be increased
● Rectal mesalazine (suppositories for proctitis, foams/enemas for more
extensive disease) can be combined with oral therapy in UC and can
improve remission rates, and is more effective than rectal steroids
● Blood dyscrasias are rare, but patients should be advised to report any
unexplained bleeding, bruising, sore throat, fever or malaise
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● Renal toxicity is possible; renal function should be checked – the

British Society of Gastroenterology suggests annual creatinine
serum concentration5
Corticosteroids ● Conventional steroids (oral prednisolone, intravenous
hydrocortisone or intravenous methylprednisolone) are first-line
for treating flares of CD and severe UC, and second-line for mild
to moderate UC where there is insufficient response to
aminosalicylates
● In hospital patients on intravenous steroids, monitor for
hypokalaemia (mineralocorticoid effects) and hyperglycaemia
(glucocorticoid effect)
● Steroid regimens should tapered to prevent relapse and adrenal
insufficiency – a typical regimen is 40 mg prednisolone daily, I
reducing by 5 mg a week to zero
● Budesonide is an option for ileal or right-sided colonic CD – it
causes fewer side effects but is less effective than prednisolone
● Enteric-coated beclometasone is another alternative in UC,
although it has not been compared directly with oral
prednisolone
● British Society of Gastroenterology guidelines5 suggest
co-prescribing with calcium and vitamin D. Recent guidelines
from the National Osteoporosis Guideline Group suggest using
the Fracture Risk Assessment Tool (FRAX) osteoporosis risk
assessment tool to quantify risk of fracture and the need to
measure bone mineral density6
Thiopurines Main role is to maintain remission. Thiopurines can induce
k k
●
remission but onset of action is slow (8–12 weeks).

● Started in UC in those with >2 flares year requiring steroids, in
those that flare when steroids are reduced and after an acute
severe flare.
● For CD consider thiopurines to maintain remission, particularly
for patients with poor prognostic factors (e.g. early onset,
perianal disease, severe presentation or steroid use at
presentation).
● Dose is azathioprine 2–2.5 mg/kg/day or mercaptopurine
1–1.5 mg/kg/day.
● Thiopurine methyltransferase (TAMT) should be measured before
starting; avoid thiopurines if levels are low; consider lower doses
if intermediate levels. Some centres measure azathioprine
metabolite levels to guide dosing.
● Up to 20% of patients do not tolerate thiopurines: early side
effects of nausea, headache and flu-like symptoms may be
reduced by splitting the dose or starting at a lower dose.
● Leucopenia, hepatotoxicity and pancreatitis are rarer (<5%);
patients should be advised to report any signs of infection, and
of liver/pancreatic disease such as abdominal pain, yellow skin
and dark urine.
● There may be an increased risk of lymphoma and skin cancer.
Advise patients to wear sun block and minimise sun exposure.
● FBC/LFTs should be monitored, normally under shared care
arrangements; typically at baseline, weekly for 1–2 months,
followed by 3-monthly
k
k
222 Inflammatory bowel disease
Methotrexate ● Alternative in CD if thiopurines are not tolerated, most

commonly given subcutaneously or orally once weekly.
● Side effects include bone marrow suppression, liver toxicity and
pneumonitis. Patients should be advised to report signs of
infection, liver disease, breathlessness or persistent cough.
● FBC/LFTs/U&Es should be measured at: baseline, 1–2-weekly
until stabilised and then every 2–3 months.
● A National Patient Safety Agency (NPSA) alert gives advice on
safe prescribing, dispensing and administration of oral
methotrexate – patients should carry handheld records of
current dose and test results7
‘Biologics’ ● Infliximab (intravenous) and adalimumab (subcutaneous) ‘are’
I approved by NICE for severe CD
● Use in acute severe UC is approved where ciclosporin is
considered clinically inappropriate; maintenance use is not
currently approved by NICE
● Exclude hepatitis B and tuberculosis prior to commencing
(history, chest X-ray, QuantiFERON ± tuberculin testing)
● Advise patients to report signs of infection
Ciclosporin ● Used in acute severe colitis in those patients not responding to
intravenous steroids, normally 2 mg/kg intravenously over
24 hours adjusted to achieve levels of 100–200 micrograms/L
● Normally converted to oral (6 mg/kg/day) for 3 months in those
that respond to allow bridging to azathioprine
● Check magnesium and cholesterol pretreatment; low levels are
associated with nephrotoxicity and neurotoxicity respectively
k ● Risk of nephrotoxicity, hepatotoxicity and hypertension – k
monitor U&Es, LFTs and blood pressure. Dose reduction may be
required
Other medicine- ● All patients admitted to hospital with active disease should
related issues receive thromboprophylaxis
● Avoid antidiarrhoeals, opiates and antispasmodics in acute
colitis, as they may increase the risk of toxic megacolon
● Non-steroidal anti-inflammatory drugs should be avoided
● Patients on immunosuppressants should receive annual influenza
vaccine and pneumococcal vaccine, and avoid live vaccines –
see Department of Health green book for up-to-date guidance8
● Smoking cessation improves the course of CD – support and
encourage patients to stop smoking
REFERENCES
1 Truelove SC, Witts LJ (1955). Cortisone in ulcerative colitis; final report on a
therapeutic trial. Br Med J 2: 1041–1048.
2 Harvey RF, Bradshaw JM (1980). A simple index of Crohn’s-disease activity. Lancet
1: 514.
3 NICE (2012). Crohn’s Disease. Management in adults, children and young people
(CG152). https://www.nice.org.uk/guidance/cg152 (accessed 15 December 2014).
4 NICE (2013). Ulcerative Colitis. Management in adults, children and young people (CG
166). https://www.nice.org.uk/guidance/CG166 (accessed 15 December 2014).
5 Mowat C et al. (2011). Guidelines for the management of inflammatory bowel
disease in adults. Gut 60: 571–607.
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Inhaler devices in respiratory disease 223
6 National Osteoporosis Guideline Group (2013). Osteoporosis Clinical Guideline

for Prevention and Treatment. http://www.shef.ac.uk/NOGG/NOGG Executive
Summary.pdf (accessed 15 December 2014).
7 NPSA (2006). Improving Compliance with Oral Methotrexate Guidelines.
http://www.nrls.npsa.nhs.uk/resources/?entryid45=59800 (accessed 15 December
2014).
8 Public Health England (2014). Immunisation Against Infectious Disease.
https://www.gov.uk/government/collections/immunisation-against-infectious-
disease-the-green-book (accessed 12 February 2015).
Inhaler devices in respiratory disease

Inhalers are fundamental to the management of asthma and chronic I
obstructive pulmonary disease (COPD), delivering medication to the
lungs whilst minimising side effects. Unfortunately, evidence shows
that many people cannot take their inhalers correctly,1 and many
healthcare professionals are unable to teach inhaler technique.2
Suboptimal technique can lead to treatment failure, inappropriate
escalation of treatments and adverse effects and waste valuable
healthcare resources. Pharmacists have a responsibility to ensure that
patients can use their inhaled medications effectively and safely.
Whatever the device, there are steps that all the devices have in
common (Table I4).
TABLE I4
k Seven steps to success to optimise inhaler technique3 k
1 Prepare the device (e.g. remove mouthpiece cover)
2 Prepare the dose (e.g. shake aerosol)
3 Breathe out gently as far as is comfortable, but not into the inhaler
4 Put the mouthpiece in the mouth and close the lips around it
5 Breathe in:
● Check coordination of breathing and actuation of metered dose inhaler
● Encourage people to breathe in slow and steady for all aerosol devices (including
through a spacer device) and quick and deep for all dry-powder devices
6 Remove inhaler from the mouth and hold the breath for up to 10 seconds
7 Repeat dose if required
Replace mouthpiece cover or close device
Remember: patients should always be instructed to rinse their mouth

and throat with water after inhaling corticosteroids.
Patient assessment
The following points are worth considering:
1 What device was the patient using previously?
2 Was the device being used effectively?
3 What problems with manual dexterity or coordination can be
overcome?
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224 Insulins
REFERENCES
1 Broedersa MEAC et al. (2009). The ADMIT series – issues in inhalation therapy.
2) Improving technique and clinical effectiveness. Primary Care Respir J 18: 76–82.
2 Baverstock M et al. (2010). Do healthcare professionals have sufficient knowledge of
inhaler techniques in order to educate their patients effectively in their use? Thorax
65: A117.
3 Inhaler Device Technique Cards – Seven steps to success. www.simplestepseducation
.co.uk (accessed 2 November 2014).
Insulins
Routes of administration
I Subcutaneous (SC) injection
This is the most common route for insulin used in routine treatment.
Unmodified soluble insulin is fairly quickly absorbed from SC sites:
initial blood glucose-lowering effects are seen within 20 –30 minutes.
Insulin then continues to be released from the injection site over the
following 4 –6 hours. However, the onset and duration of action of
most insulin preparations are considerably longer than this because of
their formulation. The anatomical site chosen for injection also
influences the rate of absorption of insulins (see section on injection
technique, below).
Intramuscular (IM) injection
Soluble insulin given by the IM route is slightly more rapidly absorbed
k than that given SC, but it is not routinely used. k
Intravenous (IV) infusion
The half-life of soluble insulin given by IV infusion is only a few
minutes. If using in type 1 patients, i.e. those who have no
endogenous insulin secretion, the rate of infusion should never be
reduced to zero, as the patient will rapidly become ketotic.
Inhaled insulin
The first inhaled insulin, Exubera, was taken off the UK market in
2007 after only a few months due to cost issues. However, Afrezza
was launched in the USA in February 2015 and application has been
made for licensing in the UK. It is a dry-powder formulation of
ultra-short-acting insulin, which is licensed for preprandial
administration in both type 1 and type 2 diabetes mellitus. Because of
its route of administration, use is not recommended in asthma,
chronic obstructive pulmonary disease or in those who smoke.
Prescribing insulins
Unmodified soluble insulin is fairly rapidly absorbed from SC
injection sites, and insulin has therefore been produced in many
different formulations and types aimed at increasing or decreasing
rate of absorption following SC injection.
Mistakes in insulin prescribing and administration rank amongst
the most frequent of all inpatient drug errors and have been
associated with significant morbidity and mortality.1 The National
Patient Safety Agency identified 13 180 incidents in England and
Wales in 2003 –2009.2 Errors typically involve omitted doses,
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Insulins 225
incorrect doses and inaccurate transcription of the type, dose or

timing of insulin. Key points are listed below.2
● Every effort should be made to continue a patient’s usual type of
insulin while in hospital if no change in regimen is deemed
clinically necessary.
● Insulins should always be prescribed by brand name (specifying
species if relevant) because release characteristics may vary even
between insulins in the same category. Excipients such as preserva-
tives may also differ between the brands and can result in local injec-
tion site reactions. A change in insulin brand requires more intensive
monitoring until the effects of the change are fully appreciated.
● Insulin should be prescribed relative to meals rather than to set I
clock times and NBM orders should prompt urgent review of
insulin therapy.
● Insulin prescriptions should always state the word ‘units’ in full: the
use of abbreviations such as ‘U’ or ‘IU’ misread as a number 0 could
cause a 10-fold overdose.
● Insulin should always be measured using insulin syringes designed
for the purpose. The use of other syringes has resulted in fatal
dosing errors.
● Incorrect prescription of insulin mixtures is a common source of
insulin prescribing errors:
● confusing the insulin name with the dose, e.g. Humalog Mix50
becoming Humalog 50 units
k ● omission of part of the name, e.g. Humalog Mix50 becoming k
Humalog, resulting in the administration of a large dose of
rapid-acting insulin.
● In 1983, all insulins available in the UK were standardised
to a single strength: U100 insulin, i.e. insulin providing
100 units/mL. This massive task was undertaken to improve safety
in dosing and reduce prescribing errors. However, new insulin
products have recently become available containing higher insulin
concentrations, e.g. Tresiba, Humalog and Toujeo. A biosimilar
preparation (Abasaglar) and a new preparation containing insulin
in combination with liraglutide (Xultophy) have also recently been
launched. The MHRA has issued a Drug Safety Update providing
extensive guidance on minimising the risk associated with
availability of these non-standard preparations.3
Types of insulin
Insulin is either directly extracted from animal pancreases (porcine or
bovine) or synthesised (human sequence insulins or human insulin
analogues). These broad groups of insulin differ in terms of exact
amino acid sequence.
● Animal insulins are no longer commonly used in the UK. They are
sometimes used in patients who have experienced troublesome
hypoglycaemia with ‘human’ insulins.
● Human sequence insulins are produced semisynthetically by
enzymatic modification of porcine insulin (emp) or
biosynthetically by recombinant DNA technology using bacteria
(crb, prb) or yeast (pyr).
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226 Insulins
● Analogue insulins are genetically modified insulins produced to

enhance the properties of human insulin, e.g. to speed up
absorption of insulins taken with meals or prolong and improve the
uniformity of the action of the basal insulins. They are generally
more expensive.
The main types of insulin are classified as rapid/short-acting, inter-
mediate/long-acting and biphasic. The onset of action, peak activity
and duration of action of each product differ and they are all subject to
interpatient variability. The key points about these insulins are listed
in Table I5: the Joint British Diabetes Societies have published a useful
wall chart outlining the categories and types of insulin available
I with a more specific guide to their onset and duration of action.4
TABLE I5
Insulin categories with key points
Examples Appearance Licensed Approximate Key points
routes onset and
duration (SC)
Rapid-acting insulin analogues
Humalog Clear IV Onset: ● Licensed for IV use but
Novorapid SC 10–20 minutes relatively expensive and
Apidra Duration: have no advantages by
2–5 hours this route
● May be used as the
k ‘bolus’ component of
basal-bolus regimens
k
● Inject just before (ideally),
with or just after food
● May be particularly
helpful where eating
patterns are
unpredictable
Short-acting insulins
Actrapid Clear IV Onset: ● Sometimes referred to as
Humulin S SC 30–60 minutes ‘soluble’ insulin (or
Insuman Rapid IM (not Duration: ‘regular’ in the USA)
Hypurin Bovine Actrapid, 4–6 hours ● Insulins of choice for IV
or Porcine Insuman) insulin infusions
Neutral ● May be used as the
‘bolus’ component of
basal-bolus regimens
● Inject 15–30 minutes
before food to reduce
raised postprandial blood
glucose levels (must eat
within 30 minutes to
avoid hypoglycaemia).
Usually need further
carbohydrate 2–4 hours
later to cover remaining
insulin activity (‘meal and
snack’ pattern of eating)
(continued )
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Insulins 227
TABLE I5
(Continued)
Examples Appearance Licensed Approximate Key points
routes onset and
duration (SC)
Intermediate- and long-acting insulins
Insulatard Cloudy SC only Vary widely ● Must never be used
Humulin I between intravenously
Insuman Basal insulins ● Resuspend particulate
Hypurin Bovine Onset: matter before use (see
or Porcine 1.5–4 hours section on injection
Isophane Duration: technique, below)
Hypurin Bovine 15–36 hours ● Usually injected once or I
Lente twice daily
Long-acting insulin analogues
Lantus Clear SC only Prolonged ● Not appropriate for IV use
Levemir half-life. Steady ● Given once a day at
Tresiba state is reached about the same time
2–4 days after (Levemir is licensed for
first dose twice-daily use – may be
helpful for large daily
doses)
● Clear in appearance, so
potential for confusion
with rapid- or
k short-acting insulins k
Biphasic insulins (i.e. insulin mixtures)
Humulin M3 Cloudy SC only Combinations ● Must never be used
Novomix 30 of short- or intravenously
Hypurin Porcine rapid-acting ● Resuspend particulate
30/70 mix insulins with matter before use (see
Insuman Comb longer-acting section on injection
15 or 25 or 50 component. technique, below)
Humalog Mix 25 Onset and ● Usually injected twice
or Mix 50 duration vary daily
with ● Administration must be
component associated with a meal
insulins because of the
quick-acting component
● The number in the insulin
name gives an indication
of the percentage of the
short-acting component
● High risk of prescribing
errors – see section on
prescribing insulins,
above
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228 Insulins
Typical insulin regimens

All regimens are adjusted on the basis of capillary blood glucose
results.
Once-daily insulin regimens
● used in type 2 diabetes if blood glucose control is inadequate with
other therapy
● insulins used: intermediate- or long-acting insulins
● other types of therapy may be continued to treat insulin resistance
and enhance the efficacy of injected insulin.
Twice-daily insulin regimens
I ● used in type 2 diabetes, but may be used in type 1 if more intensive
insulin regimens are unsuitable
● insulins used: usually biphasic insulins
● regimens vary, but a commonly used starting dose is to give
two-thirds of the total daily dose before breakfast and one-third
before the evening meal.
Basal-bolus insulin regimens
● used in type 1 diabetes to mimic physiological insulin secretion
more closely: insulin doses can be adjusted to reflect the patient’s
needs
● comprise a longer-acting insulin given once (or occasionally twice)
daily to provide a background or ‘basal’ level of insulin secretion,
k plus quick-acting insulin given before meals k
● regimens vary but a commonly used ratio is to give half the total
daily insulin requirement as longer-acting insulin at bedtime, and
then split the remainder into three doses of quick-acting insulin to
be given before meals.
Although these intensive insulin regimens involve giving four or five
injections per day, they have several advantages for patients:
● increased flexibility of lifestyle – eating can be more spontaneous,
so patients can eat when they are hungry instead of when they
have to
● increased patient involvement – the day-to-day monitoring and
adjustment of doses help patients to understand their diabetes and
how to control it
● the potential for improved glycaemic control – better
understanding enables improved decision making, can improve
control and reduce the likelihood of diabetic complications
● improved ability to deal with ‘crises’ – once patients have learnt
how to adjust doses in response to blood glucose results, they are
better able to deal with intercurrent illness and stress.
Dose adjustment for normal eating (DAFNE)5
DAFNE is considered by NICE as the gold-standard education
programme for patients with type 1 diabetes.
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The DAFNE programme involves a formal 5-day training

programme. Participants learn together in groups with other patients
with type 1 diabetes and specialist nurses and dietitians lead the
sessions. The course covers:
● carbohydrate estimation
● blood glucose and ketone monitoring
● insulin regimens and how to adjust doses
● eating out
● reading food labels
● ‘hypos’
● illness (‘sick-day rules’).
I
Continuous SC insulin infusion (CSII)
CSII should be initiated only by a trained specialist team.6 The basic
principle of CSII use is that the pump is set to deliver a basal level of
insulin throughout the 24-hour period, and this is augmented by
bolus doses delivered to coincide with food intake. Rapid-acting
insulins are usually used in the pumps. Patients using pumps are
highly trained and intervention is only usually necessary if the patient
is unwell and an intravenous insulin infusion is more appropriate.
Refer queries to the diabetes specialist team.
SC insulin injection
Injection technique
k The basic principles of SC injection technique are listed below. k
1 Wash hands and ensure injection site is clean (use of alcohol
injection swabs is not recommended because they can cause skin
hardening).
2 If using a ‘cloudy’ insulin, resuspend by rolling the vial, cartridge or
pen gently between the palms or inverting several times. The
insulin suspension should look uniformly milky.
3 If using an insulin pen, fit a new needle, dial up 2 units and perform
an ‘air shot’ to check that there are no air bubbles and the pen
mechanism is working correctly.
4 Withdraw the required dose using an insulin syringe, or dial up the
correct dose according to the manufacturer’s instructions if using
an insulin pen.
5 Select an area on the abdomen or outer thigh. Ideally, use the same
anatomical area at the same time each day – sites on the abdomen
absorb fastest and are therefore best for insulins intended to be
quick-acting; sites on the outer thigh are best for longer-acting
insulins. The buttock or the upper outer arm may also be used but
there is an increased risk of inadvertent IM injection using the arm,
so additional monitoring may be necessary.7
6 Pinch up a skin fold between the thumb and forefinger and hold
throughout the injection. If you are using a short needle (4 or
6 mm) you may not need to do this.
k
k
230 Insulins
7 Insert the needle into the thick part of the skin fold at a 90◦ angle to
the skin.
8 Inject the insulin and continue to hold the needle in place for
several seconds before withdrawing the needle and discarding it
safely.
9 Do not rub the injection site after administration. Rotate sites
within an anatomical area so that individual sites are not reused
within 1 month.
Injection site reactions
It is common to have injection site reactions when insulin is started
but these usually lessen with time. True insulin allergy is rare.
I Overuse of injection sites: lipoatrophy and lipohypertrophy
Repeated insulin injections in the same site can cause fat and scar
tissue to accumulate, causing unsightly hard, fatty lumps. Poor
rotation of injection sites interferes with insulin absorption and is a
significant cause of unexpected variations in blood glucose levels.
Disposal of used needles and blood lancets
Sharps bins are available on FP10 prescription forms, as are needle
clippers. Diabetes specialist nurses and clinical commissioning group
pharmacists should be able to provide information concerning local
policies and services.
General insulin counselling points
k ● Patients on insulin should always carry glucose or some other k
means of treating hypoglycaemia, e.g. 200 mL carton of fruit juice.
● Patients on insulin should always carry a card identifying them as
having diabetes mellitus and ideally an insulin passport.8
● A patient’s main supply of insulin should be stored in a fridge, but
must not be allowed to freeze, because freezing denatures insulin
and makes it unfit for use.
● Insulin that is in use should be stored at room temperature,
because injections are more comfortable and pen mechanisms are
less likely to jam. Higher temperatures also enhance the activity of
preservatives.
● Insulin can be kept out of the fridge for 4 –6 weeks (dependent on
brand). For patients on small doses, for example children, the
pen/vial should be clearly marked with the date use commenced so
that it can be discarded after an appropriate interval.
REFERENCES
1 Department of Health (2004). Building a Safer NHS for Patients. Improving medi-
cation safety. http://webarchive.nationalarchives.gov.uk/+/www.dh.gov.uk/en/
Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/
DH 4071443 (accessed 12 February 2015).
2 NHS Evidence (2010). Safe and Effective Use of Insulin in Hospitalised Patients.
http://www.diabetes.nhs.uk/document.php?o=1040 (accessed 9 February 2015).
k
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Insulin: variable-rate intravenous insulin infusion 231
3 MHRA Drug Safety Update (2015). High strength, fixed combination and biosimilar
insulin products: minimising the risk of medication error. https://www.gov.uk/drug-
safety-update/high-strength-fixed-combination-and-biosimilar-insulin-products-
minimising-the-risk-of-medication-error (accessed 10 September 2015).
4 The Joint British Diabetes in Patient Care Group (2013). The Management of
Hypoglycaemia in Adults with Diabetes Mellitus – Chart on page 26. http://
www.diabetes.org.uk/Documents/About%20Us/Our%20views/Care%20recs/
JBDS%20hypoglycaemia%20position%20(2013).pdf (accessed 12 February 2015).
5 DAFNE Study Group (2002). Training in flexible, intensive insulin management to
enable dietary freedom in people with type 1 diabetes: dose adjustment for normal
eating (DAFNE) randomised controlled trial. BMJ 325: 746–751.
6 NICE (2008). TA151. Continuous Subcutaneous Insulin Infusion for the Treatment of
Diabetes Mellitus. www.nice.org.uk/guidance/ta151 (accessed 12 February 2015).
7 Diabetes UK (2015). The Arm as an Injection Site. www.diabetes.org.uk (accessed 9 I
February 2015).
8 NHS England (2014). The Adult Patient’s Passport to Safer Use of Insulin. http://
www.nrls.npsa.nhs.uk/resources/?EntryId45=130397 (accessed 12 February
2015).
Insulin: variable-rate intravenous

insulin infusion
This entry does not include the treatment of diabetic ketoacidosis (DKA) or hyperosmolar
hyperglycaemic state (HHS) – refer to these respective entries.
k k
When patients with diabetes are nil-by-mouth (NBM), they will often
require insulin to be administered IV and titrated to the capillary
blood glucose (CBG). ‘Sliding-scale insulin’ is a phrase often used;
however, it should be replaced by the term variable-rate intravenous
insulin infusion (VRIII). Such infusions are used to maintain control
of blood glucose levels in patients undergoing elective or emergency
procedures. Many trusts have written policies, so it is important to
check your own hospital’s policy before commencing treatment.
Glucose –potassium– insulin (GKI) infusions are still used in some
parts of the UK.
VRIII is used in patients with diabetes who are expected to have a
starvation period comprising two or more missed meals. For planned
procedures, starvation times should be kept to a minimum. Patients
who are only expected to miss one meal should be managed by
modification of their usual diabetes medication unless preadmission
blood glucose control is poor.1 VRIII is also used in level 3 critical care
patients if blood glucose is above 7 mmol/L.
The aim of VRIII is to achieve and maintain normoglycaemia:
ideally, CBG levels of 6 –10 mmol/L, although 4 –12 mmol/L is
acceptable.1 Additionally, the correct use of VRIII ensures that the
patient with type 1 diabetes has a constant presence of insulin and so
does not become ketotic. Patients who are NBM also require
maintenance of fluid and electrolyte balance and this governs the
choice of IV fluid given.
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232 Insulin: variable-rate intravenous insulin infusion
Key points
● Patients admitted on long-acting basal insulin analogues,
e.g. glargine or Levemir, should normally continue on their usual
daily maintenance dose while they are receiving the VRIII.1
● Only insulin infusions containing 1 unit/mL should be prepared
and used.2
● Draw up 49.5 mL sodium chloride 0.9% into a syringe suitable
for use in a syringe pump.
● Measure 50 units (0.5 mL) soluble insulin (e.g. Actrapid,
Humulin S) using an insulin syringe and add to the prepared
syringe.
I ● Cap the syringe and mix well to give a solution containing
1 unit/mL.
● A glucose-containing infusion must be administered alongside the
insulin, so that hypoglycaemia is avoided. The fluid is given via a
volumetric infusion pump, and the fluid of choice is considered to
be sodium chloride 0.45% with glucose 5% plus potassium
chloride 0.15%,1 which should be supplied as a ready-prepared
fluid.3 Subsequent fluids are adjusted based on at least daily serum
electrolyte evaluations.
● The delivery of the glucose-containing solution and the VRIII must
both be via a single large-bore cannula with appropriate one-way
or antisyphon valves.
The fluid replacement rate is set to deliver the hourly fluid
k k
●
requirements of the individual patient and this rate should not be

altered without senior advice.
● The rate of administration of the insulin infusion is then initiated
and varied to keep the CBG within the target range (6 –10 mmol/L,
although 4 –12 mmol/L is acceptable). CBG is monitored at least
hourly initially and more frequently if the readings are outside the
target range.
● Hypoglycaemia is a common side effect of an insulin infusion and a
CBG less than 4 mmol/L should be treated (see Diabetes mellitus –
management of hypoglycaemia (‘hypo’) in adults entry).
● Once the patient is able to eat and drink, s/he may be transferred
back to usual diabetes therapy.
Adjustment of insulin dosage
An example of a VRIII prescription is shown in Table I6.
If increased doses of insulin are consistently being required (blood
glucose above 15 mmol/L and not falling), first check patency of IV
access and the pump for malfunction. If no mechanical cause is found,
seek advice from the diabetes team.
Changing back to SC insulin
Once the patient is conscious and able to eat and drink, SC insulin can
be reintroduced. For all regimens, the intravenous insulin infusion
should be continued for at least 30 –60 minutes after giving the SC
dose in association with a meal.
k
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Interstitial lung disease 233
TABLE I6
An example of a variable-rate intravenous insulin
infusion prescription
Bedside capillary blood glucose (mmol/L) Infusion rate of insulin solution (units/hour)
<4 0.5
(0.0 if a long-acting insulin analogue has
been continued)
4.1–7.0 1
7.1–9.0 2
9.1–11.0 3
11.1–14.0 4
14.1–17.0 5 I
17.1–20 6
>20 Seek diabetes team or medical advice
Glucose–potassium–insulin (GKI)
Regimens used vary from hospital to hospital (check your local
policy), but generally a single bag is used containing glucose 10%
500 mL plus potassium chloride 0.15% run at 100 –125 mL/hour.
Soluble insulin is added to the bag (5, 10, 15 or 20 units/500 mL).
New infusions are prepared dependent on the patient’s CBG.
Maintaining an accurate fluid balance chart is challenging because of
frequent fluid bag changes; additionally, sodium chloride 0.9% may
k be run alongside because of the risk of hyponatraemia. This regimen k
is most commonly used as a maintenance regimen for patients
undergoing surgery.
REFERENCES
1 JBDS (2011) Management of Adults with Diabetes Undergoing Surgery and Elective
Procedures: Improving standards. http://www.diabetes.org.uk/About us/What
-we-say/Improving-diabetes-healthcare/Management-of-adults-with-diabetes
-undergoing-surgery-and-elective-procedures-improving-standards/ (accessed 13
February 2015).
2 NHS Evidence (2010). Safe and Effective Use of Insulin in Hospitalised Patients.
http://www.diabetes.nhs.uk/document.php?o=1040 (accessed 9 February 2015).
3 NPSA (2002). Potassium Chloride Concentrate Solutions – Patient safety alert. http://
www.nrls.npsa.nhs.uk/resources/?entryid45=59882 (accessed 17 January 2015).
Interstitial lung disease

Overview
Definition The interstitial lung diseases (ILDs) are a heterogeneous group of
respiratory conditions grouped together because they primarily affect the
lung interstitium/parenchyma. For some, the airways and pulmonary
vasculature may also be involved.
The pathogenesis, prognosis and management options across the ILDs
are distinct and the terminology confusing, having been subject to
inconsistencies and reclassification over recent years.
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234 Interstitial lung disease
As a group the pathology is one of varying degrees of inflammation and

fibrosis, with varying propensity for inflammation to progress to fibrosis.
The main ILDs are:1,2
● Hypersensitivity pneumonitis (HP: previously referred to as extrinsic
allergic alveolitis)
● Those associated with connective tissue disease (CTD-ILD)
● Idiopathic interstitial pneumonias (IIPs), further subdivided into:
● Idiopathic pulmonary fibrosis (IPF) (previously referred to as
cryptogenic fibrosis alveolitis)
● Non-specific interstitial pneumonia (NSIP): further classified as
either cellular or fibrotic
● Smoking-related IIPs; desquamative interstitial pneumonia (DIP)
I and respiratory bronchiolitis-associated (RB-ILD)
● Acute/sub-acute IIPs; acute interstitial pneumonia (AIP) and
Cryptogenic organising pneumonia (COP) (COP previously referred
to as bronchiolitis obliterans organising pneumonia, or BOOP)
● Rare IIPs; lymphoid interstitial pneumonia and pleuroparenchymal
fibroelastosis
● Combined pulmonary fibrosis with emphysema
● Sarcoidosis (see Sarcoidosis entry)
● Rarer conditions, including:
● Idiopathic pulmonary haemosiderosis
● Lymphangioleiomyomatosis
● Pulmonary alveolar proteinosis
● Pulmonary Langerhans’ cell histiocytosis (PLCH)
Numerous adverse drug reactions may involve the lung interstitium and
k progress to pulmonary fibrosis.3 A comprehensive database is k
maintained at http://www.pneumotox.com/.
Pneumonconioses caused by toxic accumulation of dusts in the lung and
progressive fibrosis (such as silicosis, coal worker’s lung, asbestosis,
berylliosis) also affect the lung interstitium and are important in the
differential diagnosis of ILDs, but will not be discussed further in this
entry
Risk factors ● The cause is unknown for the majority of ILDs (accounting for ≈65%
of patients)
● Smoking is the main risk factor for DIP, RB-ILD and PLCH, which
generally only occur in patients with a significant smoking history
● IPF has been associated with exposure to metal and wood dust
● Gastro-oesophageal reflux disease (GORD) has also been associated
with the development of IPF and may be asymptomatic in some
patients
● HP is an immunological reaction due to ongoing inhalation of an
organic antigen or chemicals (such as isocyanates), which act as
haptens (i.e. small molecules that elicit an immune response when
attached to a carrier protein, but which would not be immunogenic
themselves). A huge range of antigens are known, giving rise to a
number of eponymous conditions, such as bird fancier’s lung, farmer’s
lung, mushroom worker’s lung, hot tub lung
k
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Differential There is considerable overlap in the clinical, radiological and

diagnosis histopathological presentations of the ILDs.
Diagnosis should be undertaken by a multidisciplinary team comprising a
clinician, radiologist and histopathologist with experience in the
diagnosis of the ILDs.
Important differential diagnoses include: opportunistic infections
(especially in immunosuppressed patients), pulmonary oedema and
carcinomatosis
Diagnostic ● Cough is common and may be either productive or non-productive.
tests4 Cough lasting >3 weeks is a common referral criterion to investigate
the possibility of lung cancer but ILD should also be considered.
Chronic cough may also be caused by postnasal drip, GORD, ACE
inhibitors (see ACE inhibitor-induced cough entry) or active I
inflammation in the lung. Chronic cough due to fibrosis is often
difficult to manage and is frequently distressing and disabling for the
patient
● Patients typically present with breathlessness that is more severe on
exertion and described using the Medical Research Council (MRC) or
modified MRC dyspnoea scale (Table I7)
● Type I respiratory failure with hypoxia is common in advanced
disease. Oxygen saturation on pulse oximetry may be low and fall on
exertion and there may be clinical signs of hypoxia and cyanosis
● Spirometry will typically show a restrictive pattern (↓ FVC with
normal FEV1 )/FVC ratio as lungs are stiffer and volumes are reduced.
This is an important differential from obstructive airways disease such
as COPD, where the pattern is ↓FEV1 /FVC with normal (or slightly
k reduced) FVC k
● Additional pulmonary function tests such as plethysmography or
helium dilution will show a reduced total lung capacity (TLC) with
preserved residual volume (RV)/TLC ratio. In neuromuscular disorders
or severe obesity there is also a restrictive pattern but with ↑RV/TLC
● Diffusing capacity of the lung for carbon monoxide (DLCO) or transfer
factor of the lung for carbon monoxide (TLCO) provides an estimate
of the lungs’ ability to diffuse gases. It is calculated as a percentage
predicted and provides a better estimate of the functional impairment
than FVC. DLCO can be corrected for the TLC to give the rate of
uptake of CO from alveolar gas (kCO)
● The DLCO may also be reduced when there is a ventilation/perfusion
(V/Q) mismatch, such as in pulmonary hypertension or pulmonary
embolism, impairing lung perfusion
● There is a lack of consensus on the description of disease severity
based on DLCO: generally a DLCO <40% is considered as severe,
40–60% moderate and >60% a mild impairment of gas transfer. The
FVC, DLCO and clinical context should be considered when assessing
disease severity
● Squeaks, squawks and fine crackles on auscultation are suggestive,
but not specific, for ILD
● Finger clubbing with loss on nail bed angle (Schamroth’s sign) is
common in ILD, but non-specific, occurring in a number of
non-pulmonary conditions and may be idiopathic. Given the
association with a number of serious pathologies, finger clubbing
should prompt investigation
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236 Interstitial lung disease
● Chest X-ray may be relatively specific for some forms of ILD, such as
cystic pattern in lymphangioleiomyomatosis or PLCH. In the majority
a chest X-ray is non-specific. High-resolution computed tomography
(HRCT) is required for differentiation of the majority of ILD. Two
common patterns are: usual interstitial pneumonia (UIP), which is a
honeycombed pattern seen in fibrosis and the endpoint in a number
of fibrotic processes, and NSIP, with patchy ground-glass opacities
associated with inflammation.
● NSIP is both a pattern on radiology and a diagnosis. The NSIP
pattern is seen in a number of ILDs, including CTD-ILD. Where an
underlying cause cannot be found the condition is termed NSIP
(increasingly, idiopathic NSIP is being used).
● Similarly, UIP is seen in a number of conditions and may represent
I end-stage fibrotic changes. Where no other cause can be found,
this is termed IPF (i.e. idiopathic UIP = IPF).
● Autoimmune screening – if positive, suggest CTD-ILD or vasculitis.
● Precipitants – IgGs to specific antigens, such as avian or mixed
moulds. If positive suggests HP, but precipitants for a number of HP
causes are not routinely available and may be positive in the absence
of association.
● Bronchioalveolar lavage with collection and analysis of cells within
the airways may help differentiate cause (but is neither very sensitive
nor specific):5
● Very high total white cells with a high percentage of pigmented
macrophages in smoking-related ILD
● High lymphocyte count in sarcoidosis (CD4/CD8 ratio >2) and HP
(CD4/CD8 ratio <1)
k ● High neutrophil count in infection or acute respiratory distress k
syndrome
● High eosinophil count in eosinophilic pneumonia and adverse
drug reactions
● In some patients where a confident diagnosis cannot be made based
on the above, a lung biopsy may be needed
Treatment ● Depending on the ILD treatment may be directed at management of
goals inflammation, slowing progression of fibrosis or managing
symptoms6
Treatment ● Oxygen therapy is often required to manage hypoxia. Vagal nerve
options stimulation (fan to face), opioids or benzodiazepines may reduce the
sensation of breathlessness.
● Consider reversible causes of cough, i.e. GORD, rhinitis causing
postnasal drip. Opioid cough suppressants may be helpful, but
frequently are suboptimal. The British Thoracic Society cough
guidelines recommend dextromethorphan because of the lower
incidence of adverse drug reactions, but it is still blacklisted in the
Drug Tariff , although readily available in many over-the-counter
cough mixtures.7 All the opioids (morphine, codeine, pholcodine)
seem to be equally effective but there is no evidence to support one
over the other. There is limited evidence for prednisolone or
thalidomide in the management of IPF-associated cough
● In HP, avoidance of the antigen (if identifiable) may reverse
inflammation. In others corticosteroids, with or without a
steroid-sparing agent, may be required
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● CTD-ILDs are managed as for connective tissue diseases with

corticosteroids and immunosuppressive agents, such as azathioprine,
mycophenolate mofetil or tacrolimus. There is limited evidence for
cyclophosphamide (either oral or intravenously) and rituximab in
some CTD-ILDs
● Corticosteroids or immunosuppressive agents may manage
inflammation in other ILDs, but the evidence base is limited and there
is no consensus on appropriate options
● Immunosuppression with azathioprine and prednisolone has been
shown to be harmful in IPF; the risks associated with
immunosuppression in other fibrotic ILDs is less clear
● N -acetylcysteine is often used in IPF but has recently been
demonstrated to be of no benefit in preventing disease progression
and may be associated with cardiovascular harm8 I
● Recent availability of therapies specifically targeting fibrotic pathways
include nintedanib and pirfenidone (only licensed in IPF)
Assess ● It is important to recognise that ILDs represent a heterogeneous
group of conditions with distinct management options
● Adverse drug reactions may present as an ILD and should be
considered
● Serial measurements of lung function (FVC and DLCO) are useful and
non-invasive means of assessing disease progression. Other
non-invasive measures include the 6-minute walk test, but this tends
not to be used in trials
k Antifibrotic
agents
● Nintedanib and pirfenidone are only licensed for the IPF type of ILD in
the UK and funding is based on disease severity staged using FVC
k
● Nintedanib is associated with impaired wound healing and increased
bleeding risk and should be avoided in those at high risk (including
treatment dose anticoagulants and high-dose antiplatelets).
Diarrhoea and faecal urgency are common problems and may be
managed with loperamide. Patients may experience disturbances in
liver function and LFTs are recommended monthly for the first
3 months and then quarterly
● Pirfenidone is associated with GI disturbances (nausea and anorexia)
and should be slowly titrated to a target dose 3 × 267 mg capsules
three times a day. Splitting the dose, spacing it out throughout a meal
rather than taking all capsules at the same time, may help reduce
gastrointestinal upset. Dose reduction may be required in some
patients.
Photosensitivity rash may occur and all patients should avoid sun
exposure and use a sun cream with a sun protection factor >25
during treatment. Patients may experience disturbances in liver
function and LFTs are recommended monthly for the first 6 months
then quarterly.
Omeprazole may reduce pirfenidone activity and, if required, an
alternative PPI or gastric acid suppressant should be used.
Due to the increased risk of phototoxicity, concomitant doxycycline
should be avoided.
Pirfenidone levels are increased by ciprofloxacin and the combination
should be avoided. If this is not possible temporary dose reduction of
pirfenidone may be required
k
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238 Iron: guidance on parenteral dosing and administration
TABLE I7
Medical Research Council (MRC) and modified MRC
(mMRC) dyspnoea scale
Description MRC scale mMRC scale
Not troubled by breathlessness except on strenuous 1 0
exercise
Short of breath when hurrying or walking up a slight hill 2 1
Walks slower than contemporaries on the level because of 3 2
breathlessness, or has to stop for breath when walking at
own pace
Stops for breath after about 100 metres or after a few 4 3
I minutes on the level
Too breathless to leave the house, or breathless when 5 4
dressing or undressing
REFERENCES
1 American Thoracic Society/European Respiratory Society (2002). International
Multidisciplinary Consensus Classification of the idiopathic interstitial pneumonias.
Am J Respir Crit Care Med 165: 277–304.
2 American Thoracic Society and European Respiratory Society Committee on
Idiopathic Interstitial Pneumonias (2013). An Official American Thoracic
Society/European Reparatory Society statement: Update of the international
multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir
Crit Care Med 188: 733–748.
k 3 Kubo K et al. (2013). Conensus statement for the diagnosis and treatment of drug-
induced lung injuries. Respir Investig 51: 260–277.
k
4 Baughman RP et al. (2012). Monitoring of non-steroidal immunosuppressive
drugs in patients with lung disease and lung transplant recipients: American
College of Chest Physicians evidence-based clinical practice guidelines. Chest 142:
e1S–e111S.
5 Meyer KC et al. (2012). An official American Thoracic Society clinical practice guide-
line: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung
disease. Am J Respir Crit Care Med 185: 1004–1014.
6 Bajwah S et al. (2013). Interventions to improve symptoms and quality of life of
patients with fibrotic interstitial lung disease: a systematic review of the literature.
Thorax 68: 867–879.
7 Morice AH et al. (2006). BTS guidelines recommendations for the management of
cough in adults. Thorax 61: i1–i24.
8 Idiopathic Pulmonary Fibrosis Clinical Research Network (2014). Randomized
trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 370(22):
2093–2101.
Iron: guidance on parenteral dosing

and administration
Parenteral iron is available in several different forms, including iron
dextran (CosmoFer), iron sucrose (Venofer), ferric carboxymaltose
(Ferinject) and iron isomaltoside 1000 (Monofer). They are licensed
for the treatment of iron-deficiency anaemia.
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Iron: guidance on parenteral dosing and administration 239
The use of parenteral iron is complex, requiring dose calculation

and specified administration techniques. (See individual entries for
each product for specific details). The added hazards posed to the
fetus when these products are used in pregnancy further complicate
the issue.
Therapeutic indications for iron-deficiency anaemia
(for adult use only)1
● Demonstrated intolerance to oral iron preparations.
● Where there is a clinical need to deliver iron rapidly to iron stores.
● Demonstrated lack of effect of oral iron therapy, e.g. active
inflammatory bowel disease.
● Patient non-adherence with oral iron therapy. I
Contraindications1
● Non-iron-deficiency anaemia.
● Iron overload or disturbances in utilisation of iron.
● Hypersensitivity to parenteral iron products, including iron mono-
or disaccharide complexes and dextran.
Adverse reactions1
Severe side effects are uncommon but include serious allergic
reactions, e.g. life-threatening and fatal anaphylactic and
anaphylactoid reactions. These reactions can occur even when a
previous administration has been tolerated (including a negative test
k dose). Caution is therefore needed with every dose of IV iron, even if k
previously well tolerated. IV iron should only be given in an
environment where the patient can be properly monitored and where
resuscitation facilities exist.2 These are characterised by sudden onset
of respiratory difficulty and/or cardiovascular collapse; fatalities have
been reported. Other less severe manifestations of immediate
hypersensitivity are also uncommon and include rashes, itching,
nausea and shivering.
Administration must be stopped immediately if signs of allergy are
observed and appropriate treatment instituted.
Other undesirable effects include nausea, hypotension, dyspepsia,
diarrhoea, flushing, headache and pains in joints and muscles.
Exacerbation of joint pain in rheumatoid arthritis can occur. Soreness
and inflammation at the site of the injection have also been reported.
In patients with known allergies, including drug allergies, a history
of severe asthma, eczema or other atopic allergy and in patients with
immune or inflammatory conditions, e.g. systemic lupus
erythematosus and rheumatoid arthritis, the risk of hypersensitivity
reactions is increased.
Pregnancy and lactation
Parenteral iron products are contraindicated during the first trimester
of pregnancy but may be considered for use from the second trimester
onwards where oral iron is ineffective or cannot be tolerated and
anaemia is serious enough to pose a risk to the mother or fetus. Any
k
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240 Iron: guidance on parenteral dosing and administration
benefits of using IV iron should be carefully weighed against the

risks: anaphylactic or anaphylactoid reactions could have serious
consequences for both mother and foetus.2 The choice of drug is
dependent on local practice. The dose should be calculated on the
pre-pregnancy weight.3
The parenteral iron products are considered to be safe for
administration during breastfeeding.4
REFERENCES
1 eMC (2014). http://www.medicines.org.uk/emc/ (accessed 27 August 2014).
reactions: strengthened recommendations; https://www.gov.uk/drug-safety-
I recommendations (accessed 29 August 2015).
3 British Committee for Standards in Haematology (2011). UK Guidelines on the
Management of Iron Deficiency in Pregnancy. http://www.bcshguidelines.com/
documents/UK Guidelines iron deficiency in pregnancy.pdf (accessed on 27 August
2014).
4 Midlands Medicines NHS (2014). UK Drugs in Lactation Advisory Service. http://
www.midlandsmedicines.nhs.uk/apps/ukdilas/resultsBNFcat.asp?SubSectionRef=
09.01.01.02 (accessed 27 August 2014).
k k
k
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Kidney stones (renal calculi) 241
K
Kidney stones (renal calculi) K
Overview
Definition A solid crystal formation as a result of urine saturation with
proteins, salts and minerals, such as oxalates, carbonates and
phosphates
Epidemiology 5–10% of people are affected by kidney stones, with only 1–2%
being symptomatic. Kidney stones are more prevalent in men and
first presentation of symptoms is usually between the ages of 20
and 50 years.
Kidney stones are responsible for more than 12 000 hospital
k admissions each year in the UK1 k
Risk factors A combination of intrinsic factors (heredity, age, sex) and extrinsic
factors (geography, climate, water intake, diet).
Poor fluid intake combined with high-protein diet containing high
proportion of refined sugars is associated with increased risk of
stone formation
Classification Calcium forming (e.g. calcium oxalate), cystine, strivite, uric acid
Causes Anatomical abnormalities of the kidney, excess stone-forming
substances in the urine, lack of stone inhibitors in the urine,
chronic urinary tract infections (UTIs), idiopathic
Symptoms Only become a medical issue when symptomatic.
● Severe lower-back pain (renal colic) – caused when the stones
become large enough to cause obstruction or move into the
ureter
● Increased urine frequency and pain or burning on micturition
● Haematuria
● Fever, signs of infection
Complications Urine obstruction, renal failure, urinary sepsis

Differential UTI, pyelonephritis, bladder/kidney tumour
diagnosis
Diagnostic tests U&Es to measure renal function, calcium levels, FBC
(haemoglobin, white cell count), urine dipstick for traces of
infection and haematuria, CT scan, intravenous urogram
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242 Kidney stones (renal calculi)
Treatment Options depend on symptoms, location and size of stone:2

● Observation and monitoring
● Medical therapy
● Analgesia – NSAID first-line treatment if tolerated with
paracetamol. Opioids can be used during severe painful
episodes
● Alpha-blocker – (off licence) relaxes urethra to facilitate
stone passage
● Antispasmodic – relieves symptoms of renal colic
● Thiazide diuretics – reduce urinary calcium excretion and
incidence of stone formation
● Non-surgical intervention
● Extracorporeal shockwave lithotripsy (ESWL): fragments
the stone to allow easier passage
K ● Ureteroscopy
● Surgical interventions
● Laparoscopic stone removal
● Percutaneous antegrade ureteroscopy
● Insertion of ureteric stent
● Nephrostomy
● Open surgery
Treatment goal Reduce symptom frequency and severity, reduce likelihood of

stone formation, prevent complications
Medicines ● Treatment
k optimisation ● Optimise analgesia during acute flares, include hyoscine k
butylbromide to help alleviate spasmodic pain
● Prevention
● Allopurinol to reduce uric acid production (gout and
chemotherapy-induced)
● Thiazide diuretic
● Long-term prophylactic antibiotics (for cystine-forming
stones)
Lifestyle advice Increase fluid intake (avoid dehydration), reduce intake of

oxalate-rich foods (beetroot, asparagus, chocolate), do not reduce
calcium intake
REFERENCES
1 British Association of Urological Surgeons (2015). Kidney Stones. www.baus.org.uk
/patients/symptoms/calculi (accessed 10 October 2014).
2 Preminger G et al. (2007). Guideline for the management of ureteral calculi.
Eur Urol 52: 1610–1631.
k
k
Lactose-free medicines 243
L
Lactose-free medicines
Some patients are lactose-intolerant due to a lack or reduced activity
of the enzyme lactase, which is responsible for the hydrolysis of
lactose to glucose and galactose in the small bowel. The undigested L
lactose in the colon draws in fluid and is fermented by enteric
bacteria,1 leading to unwanted GI symptoms of abdominal bloating,
cramping, nausea and diarrhoea.1,2
Lactose is an ingredient widely used by the pharmaceutical
industry in the formulation of tablets and capsules, as a diluent or
filler.1 It can also be used in lyophilised products, as a carrier in
dry-powder inhalers, and can be found in liquid formulations.1 The
amount of lactose used in medicinal products is small in comparison
to dairy products and the dose provided is usually less than
k 2 g/day;1,2 as a result, GI symptoms may not be experienced by all
k
lactose-intolerant patients.
For any medicinal product the list of ingredients (excipients) can
be found in the manufacturer’s SPC. The manufacturer may need to
be contacted for the quantity of lactose in a product.
The eMC website (www.medicines.org.uk/emc/) can also be used
to search for all lactose-free products and to find a lactose-free
medicine for a specific condition.3 This can be done as follows:
1 Click advanced search option and select ‘by SPC section’.
2 Select section to search by: either section 4.1 (therapeutic
indication) or 6.1 (excipients).
3 Select add.
4 When selecting excipients, change ‘contains’ to ‘does not contain’
and type in lactose.
5 Click search.
REFERENCES
1 Pickett K (2013). What Factors Need to be Considered when Prescribing for Lactose
Intolerant Adults? https://www.evidence.nhs.uk/search?q=%22What+factors
+need+to+be+considered+when+prescribing+for+lactose+intolerant
+adults%22 (accessed 3 February 2015).
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244 Learning disability and other vulnerable patients
2 UK Medicines Information (2013). What to consider when prescribing for lactose-

intolerant adults. Clin Pharmacist 5: 273.
3 Wills S (2009). Learning light: reacting to additives in medicine. Clin Pharmacist 1:
449–450.
Learning disability: caring for people

with learning disability and other
vulnerable patients
Accessing health services often presents challenges to people with
cognitive difficulties. Learning disabilities and autism spectrum
conditions (including Asperger syndrome) are used as examples, but
the issues involved can be generalised to assist in understanding and
L supporting other vulnerable people.
Pharmacists and other healthcare professionals must ensure that
their services comply with their legal obligations under the Equality
Act 20101 and Mental Capacity Act 2005.2 Briefly, reasonable
adjustments must be made to service provision to enable a person
with a disability to make use of the service, and to follow the law
concerning consent as described in the Mental Capacity Act 2005
when issuing medication to anyone with cognitive disabilities.
Non-compliance with either carries a risk of litigation.
k Learning disability k
Practical difficulties experienced by a person with learning disabilities
include understanding new or complex information, learning new
skills and coping independently. The disability can be mild, moderate
or severe. In the UK approximately 350 000 people have severe
disabilities.3 The most disabled individuals have more than one
disability and limited or no communication, i.e. profound and
multiple learning disability.
Autism spectrum condition
Autism is a lifelong neurodevelopmental disability, which affects how
individuals make sense of the world around them and how they
understand and communicate with others. People with autism often
experience under- or oversensitivity to sounds, touch, taste, smells,
light or colours. Thus, health facilities, particularly hospitals, are
exceptionally ‘autism-unfriendly’ environments and may present
overwhelmingly challenging and frightening experiences for patients.
This, if not understood and catered for, may adversely affect the care
that they receive.
Asperger syndrome is a form of autism where the person, although
often being of ‘average’ or ‘above-average’ intellectual ability and
having few problems with speech, may still have enormous difficulties
with understanding and processing language.4
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Learning disability and other vulnerable patients 245
Issues relating to the care of patients with a learning

disability
These include:
● ‘diagnostic overshadowing’ – an incorrect assumption that other
health problems are associated with the person’s learning disability
● difficulties in communication, understanding the unique way in
which a person indicates that s/he is in pain, understanding the
person’s behaviours and routines
● institutional practice, e.g. drug rounds always being at set times,
which may not be suitable for the patient’s regimen
● inadequate consent and discharge care planning.
People with additional needs may have a reduced ability to
understand and use healthcare information in order to make
informed decisions and follow treatment instructions. Some may have L
depressed pain responses and/or poor bodily awareness. Limited
communication skills may impair their capacity to convey their
symptoms to others. Carers, relatives and support workers may play
key roles in identifying their health needs. However, if people with
such needs do not communicate verbally, even people who know
them well may struggle to recognise their needs or to understand
their experience of pain.
It is well documented that people with learning disabilities
experience significant health inequalities.5,6 In 2013 the Confidential
k Inquiry into Premature Deaths of People with Learning Disabilities
k
(CIPOLD)7 reviewed the deaths of 247 people with learning
disabilities over the 2-year period 2010 –2012. Forty-two per cent
were considered to be premature deaths, with just under half of these
considered to be avoidable using the Office for National Statistics
definition. Over a quarter were amenable to better-quality healthcare.
Whilst 86% of the illnesses that led to death were promptly
recognised and reported to health professionals, 29% experienced a
significant difficulty or delay in receiving a diagnosis and 30% had
problems with their treatment. The lack of reasonable adjustments to
facilitate their healthcare was a contributory factor in a number of
deaths. General practitioners commonly did not mention learning
disabilities, and hospital ‘flagging’ systems to identify people who
needed reasonable adjustments were limited.
Importantly, both health and social care professionals
demonstrated a lack of understanding of, and adherence to, the
Mental Capacity Act 2005, particularly regarding assessments of
capacity, the processes involved in making ‘best-interest’ decisions
and, crucially, when an Independent Mental Capacity Advocate
(IMCA) should be appointed. A lack of recognition of approaching
end of life commonly led to problems in coordination of end-of-life
care for the person and family.
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246 Learning disability and other vulnerable patients
Issues for pharmacists arising from CIPOLD

Many of the people with learning disabilities who died prematurely
were vulnerable in a variety of ways:
● The BMI was different from that of the general population; a

significant proportion were underweight.
● People with learning disabilities had multiple medical conditions –
the median number of conditions was five. The people who died
had seven or more medical conditions. The most frequently
reported long-term conditions were epilepsy, cardiovascular
disease and hypertension.
● The median number of medications prescribed to each person was
seven, although some had up to 21. The most common prescription
was for epilepsy (39%), with more than half of these people on at
least two types of medicine and 5% of them taking five to seven
L
medicines for this condition alone.
● Although most of the people with learning disabilities had received
an Annual Health Check in the previous year, this did not seem to
ensure that they had a Health Action Plan. Of those who did, there
was little evidence that it was used to link them to appropriate
services or to share information about them effectively.
● Although a fifth of people had a type of Hospital Passport, there
was no evidence to suggest that this had supported medical staff in
coordinating the needs of those with multiple comorbidities.
k ● In almost all cases there was no evidence of use of a pain k
assessment tool, although more than a third had difficulty in
identifying or verbally communicating experience of pain. There
was a significant difference in the prescribing of opioid analgesics
according to the severity of learning disability: people with mild
learning disabilities (37%), moderate (16%), severe (17%),
multiple (21%).
Pain management
The reporting of pain is more sophisticated in some people than
others. Over a third of people with learning disabilities had difficulty
in identifying or verbally communicating any pain that they had,
although many of their parents/carers were able to describe what
they believe to be indicators of pain. It is important to be aware that
some people, but especially those with autism spectrum conditions,
have hypo- or hypersensitivities to pain.
CIPOLD noted that 32% of people who could describe their pain
were on opioid analgesics at time of death, compared with 12% who
could not. This significant difference suggests that people with more
severe learning disabilities may not have been having their pain
optimally managed at the end of their lives. In the CIPOLD cohort,
despite difficulties in the recognition of the manifestation of
distress/pain for almost half the group, only four people (1.6%) had
documented use of a pain assessment tool.
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Learning disability and other vulnerable patients 247
Examples of pain assessment tools for adults and children with

cognitive impairment and other vulnerabilities:
● Disability Distress Assessment Tool (DisDAT)8
● Paediatric Pain Profile.
Health/ Hospital Passport
The sensory issues experienced by many people with an autism
spectrum condition can present barriers to them receiving optimal
treatment. Their impact for some patients must not be
underestimated. For example, the texture, taste and colour of some
medication may be intolerable; smells and noises in the hospital may
be overwhelming; the social ‘rules’ and styles of communication
unique to hospitals may be confusing. Sensory overload can occur for
some people and their resultant distress may present challenges.
A Health Passport provides a picture of the whole person. It may L
include descriptions of what the person likes/dislikes over a range of
areas such as physical contact, food preferences, interests and form of
communication, enabling staff to help the individual feel safe and
comfortable and highlighting issues that may help/hinder treatment.
Increasingly, health services in the UK are creating documentation
to be completed with the patient’s carer or relative to assist staff in
making reasonable adjustments to healthcare as required by law.
Having a Health Passport is an aid to this process. Importantly, staff
and carers sign and date the document on completion. There are
k many examples available to download from the internet. The most k
helpful have involved collaboration with the local Adult Learning
Disability service (for paediatric equivalents, the Learning Disability
Team from the local Child and Adolescent Mental Health Service).
Many health passports utilise a recognisable ‘traffic light’ format
customised to suit local requirements.
For example:
● red: things you must know about me immediately
● amber: things that are really important for me
● green: things that are really important to me.
Reasonable adjustments
The NHS Operating Framework 2012 –139 states that ‘All NHS
organisations must comply with the Equality Act 2010 and its
associated Public Sector Equality Duty 2011’. As the focus is on
outcomes, alternative methods of service delivery and availability
may need to be devised. This could include changing the way things
are done, providing extra aids or staff, provision of more
accessible/understandable information and altering physical features
such as signs, toilets and stairs. Adjustments can be any method that
is adapted to the need of the individual to ensure maximum
understanding, e.g. use of pictures, social stories, visual timetables,
clock faces, Easy Read transcriptions to facilitate understanding about
routines and taking medicines.10
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248 LipidRescue
The most effective way to support people with additional needs is

for continued collaboration between acute hospital staff and local
learning disability professionals so as to develop appropriate
documentation and mutual systems of advice, support and training.
REFERENCES
1 The National Archives 2010. Equality Act. www.legislation.gov.uk (accessed 16
August 2014).
2 The National Archives 2005. Mental Capacity Act. www.legislation.gov.uk
3 NHS Choices (2013). What is a Learning Disability? http://www.nhs.uk/livewell/
childrenwithalearningdisability/pages/whatislearningdisability.aspx (accessed 16
August 2014).
4 National Autistic Society (2014). What is Autism? http://www.autism.org.uk/
about-autism/autism-and-asperger-syndrome-an-introduction/what-is-
autism.aspx (accessed 16 August 2014).
L 5 Mencap (2012). Death by Indifference: 74 deaths and counting. https://www
.mencap.org.uk/news/article/74-deaths-and-counting (accessed 16 August 2014).
6 Department of Health (2012). Transforming Care: A national response to Win-
terbourne View Hospital: Department of Health Review: Final report. www.gov.uk
7 Norah Fry Research Centre, University of Bristol (2013). The Confidential
Inquiry into Premature Deaths of People with Learning Disabilities (CIPOLD).
http://www.bris.ac.uk/cipold/ (accessed 16 August 2014).
8 St Oswald’s Hospice (2008). Disability Distress Assessment Tool (DisDAT).
http://www.stoswaldsuk.org/media/14997/DisDAT-19.pdf (accessed 16 August
2014).
k 9 Department of Health (2011). The Operating Framework for the NHS in Eng- k
land 2012–13. https://www.gov.uk/government/publications/the-operating-
framework-for-the-nhs-in-england-2012-13 (accessed 15 May 2015).
10 NHS Choices (2013). Going into Hospital with a Learning Disability.
http://www.nhs.uk/Livewell/Childrenwithalearningdisability/Pages/Going-into-
hospital-with-learning-disability.aspx (accessed 16 August 2014).
LipidRescue
The term LipidRescue refers to the use of a lipid emulsion infusion to
treat a drug overdose. Because of the nature of the condition being
treated, randomised trials to prove its efficacy are not possible, and
the optimal place in treatment cannot be established other than by
case reports. Nevertheless, guidelines for its use have been produced
by many organisations.1 It was first promoted as a treatment for local
anaesthetic toxicity, but has subsequently found a role in the
treatment of overdoses of other, mainly lipophilic, drugs.
Mode of action
The simple mode of action is thought to be through lipid-soluble
molecules partitioning into the lipid, so reducing the amount of drug
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able to act at receptors. While this may be part of the story, it is

probably not the only mode of action. Fatty acids are involved in many
aspects of cellular function, so increasing the availability would be
likely to change how cells behave, which may in turn mitigate against
the effects of drugs. Research is continuing into these effects.
Administration
The current consensus is that a 20% lipid emulsion should be
administered as a bolus of 1.5 mL/kg, followed by an infusion of
0.5 mL/kg/min for 30 minutes. The bolus may be repeated if asystole
persists, and the infusion rate may be increased if the blood pressure
falls.1
Place in therapy
Wherever large volumes of local anaesthetics are used (e.g. regional
blockade), supplies of lipid infusion (with instructions for use) should L
be available in case of toxicity, and its use should be considered early
after identification of a problem.
In cases of severe intoxication with a lipid-soluble drug, there may
be a place for LipidRescue, generally on the recommendation of the
National Poisons Information Service. There would appear to be little
justification in using it for water-soluble drugs.
Follow-up
As noted above, it is extremely difficult to generate evidence of
k efficacy. It is therefore important that, in all cases where LipidRescue k
is used, the outcomes are reported to help construct a more solid
picture of its efficacy. This can be done through the National Poisons
Information Service (http://www.toxbase.org) or the LipidRescue
website.2
REFERENCES
1 AAGBI Safety Guideline (2010). http://www.aagbi.org/sites/default/files/
la toxicity 2010 0.pdf (accessed 19 August 2014).
2 LipidRescue Resuscitation (2012). http://www.lipidrescue.org (accessed 19 August
2014).
Lithium: management and monitoring

Lithium salts are used in the treatment and prophylaxis of mania,
bipolar disorder and recurrent depression. Lithium should only be
initiated by a specialist, and treatment should be carefully
monitored.1 The mechanism of action of lithium as a mood-stabilising
agent is unknown. Many theories have been suggested, but none have
been proven.
Lithium is completely absorbed from the gut within approximately
8 hours from taking the dose. Peak concentrations will occur
2 –4 hours after ingestion and it is excreted by the kidneys.
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250 Lithium: management and monitoring
Lithium is commonly given as slow-release lithium carbonate

tablets at night to facilitate drug monitoring so that samples can be
taken the next morning. When a lithium level is required for a patient
taking a twice-daily dose, the morning dose should be omitted until a
sample has been taken.
Brands should not be switched because preparations vary widely in
bioavailability; changing the preparation requires the same
precautions as initiation of treatment.2 If a liquid is required,
Li-Liquid and Priadel liquid are available as lithium citrate, containing
5.4 mmol/5 mL (∼ = lithium carbonate 200 mg/5 mL), and these are
given twice daily.
Lithium has a narrow therapeutic range and is very toxic in overdose.
It is therefore important to ensure the serum concentration of lithium
L is kept within the normal range, and therapeutic drug monitoring is
indicated in the following circumstances:
● 7 days after the drug was initiated or the dose changed

● if there is no evidence of a therapeutic response (consider
non-adherence)
● toxic symptoms occur (e.g. tremor, ataxia, dysarthria, nystagmus,
renal impairment or convulsions)
● suspected drug interaction
routine monitoring
k k
●
● consider checking lithium level (at the right time) in any lithium
patient admitted to hospital acutely unwell.
Other monitoring
Thyroid function
A small number of patients on long-term lithium therapy will develop
either hypothyroidism or hyperthyroidism. Thyroid function should
be checked, and the patient should be euthyroid prior to commencing
lithium therapy. Once lithium is established, thyroid function tests
should be carried out every 6 months (more frequently if results are
abnormal – see Thyroid function entry).
Renal function
A pretreatment assessment of renal function should be carried out
and lithium therapy initiated only if renal function is within normal
limits. Lithium may be used cautiously in patients with mild to
moderate renal impairment (see Renal function – assessment entry).
Once therapy is established, the patient’s renal function should be
monitored when the lithium serum concentration is checked to
ensure that renal function is not deteriorating as this could lead to
lithium toxicity.
Cardiac function
Cardiovascular effects of lithium are rare; however, the patient’s
cardiac function should be checked prior to initiating therapy. In
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practice, blood pressure should be checked for all patients, and ECG
performed in patients with cardiovascular disease or cardiovascular
risk factors. Once lithium therapy is initiated, any sign of cardiac
disturbance, e.g. arrhythmias, syncope, should be investigated.
TABLE L1
Lithium half-life 10–35 hours3
Pretreatment ● FBC, U&Es, calcium, eGFR
measures ● Thyroid function tests
● Weight or BMI
● ECG for people with cardiovascular disease or cardiovascular
risk factors
Therapeutic range ● 0.4–1 mmol/L (lower end of range for maintenance therapy
and elderly patients)
● Aim for 0.6–0.8 mmol/L for patients being prescribed lithium L
for the first time
● Consider maintaining plasma level at 0.8–1 mmol/L for
6 months for patients who have relapsed on lithium in the
past or have subsyndromal symptoms
Sampling time ● 12 hours post dose (for twice-daily dosing, omit morning dose
until sample taken).
● Blood should be taken in ‘brown-top’ sample tubes
Lithium level: NICE clinical guidelines4 recommend the following regimen:
routine monitoring ● Every 3 months for the first 12 months
k ● Every 6 months after the first 12 months or continue with k
every 3 months if the patient falls into any of the following
categories:
● Older age
● Is taking any medication that interacts with lithium
● Has a risk of impaired renal function or thyroid function,
raised calcium levels or any other complications
● Has poor symptom control
● Has poor adherence
● Where the last plasma level >0.8 mmol/L
Other monitoring ● Thyroid function should be monitored every 6 months (see
below) or more frequently if results are abnormal.
● U&Es, eGFR and calcium should be monitored every 6 months
or more frequently if results are abnormal.
● Weight or body mass index every 6 months
Dose
Lithium is usually initiated at a low dose and titrated upwards to
achieve a serum lithium concentration of 0.4 –1 mmol/L. See
individual SPCs for starting doses.
Overdose
Seek specialist advice from the National Poisons Information Service
(http://www.toxbase.org). There is no antidote to lithium toxicity.
The lithium should be stopped and the patient must be hydrated
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252 Lithium: management and monitoring
appropriately (dehydration leads to increased lithium serum

concentrations). If the lithium has been taken recently, gastric lavage
may be carried out. In some instances, it may be necessary to use
peritoneal dialysis or haemodialysis to remove the lithium.
Interactions
● Drugs that increase the serum concentration of lithium include
ACE inhibitors, ARBs, NSAIDs, diuretics and methyldopa.
Particular care should be taken to avoid sodium-depleting diuretics,
e.g. thiazides, as sodium depletion can precipitate lithium toxicity.
● SSRI antidepressants increase the risk of central nervous system
side effects.
● Lithium increases the risk of extrapyramidal side effects, and
possibly neurotoxicity, when it is given with clozapine, haloperidol
L or phenothiazines.
● Diltiazem, verapamil, carbamazepine and phenytoin can cause
neurotoxicity in combination with lithium therapy.
● Metronidazole increases the risk of lithium toxicity.
● Theophylline and sodium chloride increase lithium excretion,
which leads to a decrease in the serum concentration of lithium.
Counselling – lithium patient information booklet
All patients should be given a purple lithium patient information
booklet which contains a lithium record booklet and a lithium alert
k card.1 Patients should be requested to carry the card at all times and k
should record the brand of lithium they normally take, and the results
of their lithium blood levels, renal function, thyroid function and
weight in the record booklet.
On commencing lithium patients should be counselled on the
information contained in the purple patient information booklet and
advised on the following:
● poor adherence or stopping lithium suddenly can increase risk of

relapse
● monitoring arrangements
● the need to seek medical attention if any signs of toxicity develop,
i.e. diarrhoea, vomiting, severe tremor, muscle weakness
● the need to maintain their fluid intake to avoid dehydration
● potential side effects
● avoid NSAIDs, e.g. ibuprofen.
● check with doctor/pharmacist before buying any over-the-counter
medication
● if you stop taking lithium suddenly, your original symptoms may
come back. If you and your doctor decide that you are going to stop
taking lithium, it will usually be reduced gradually over at least
4 weeks and preferably over 3 months.
● tell your doctor now if you are pregnant or are planning to become
pregnant.
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REFERENCES
1 NPSA Alert (2009). Safer Lithium Therapy. http://www.nrls.npsa.nhs.uk/alerts/
?entryid45=65426 (accessed 15 January 2015).
3 Dollery C (ed.) (1999). Therapeutic Drugs (2nd edn). Edinburgh: Churchill Living-
stone.
4 NICE (2014). Bipolar Disorder: The assessment and management of bipolar disor-
der in adults, children and young people in primary and secondary care (CG185).
Liver disease (chronic)

Liver disease is the fifth commonest cause of death in the UK, and the L
UK is one of the few developed nations with an upward trend in
mortality from liver disease.1 The most common forms of chronic
liver disease include: non-alcoholic fatty liver disease, alcoholic liver
disease and chronic hepatitis C. There are a number of classical
signs/symptoms of chronic liver disease and these include ascites,
spontaneous bacterial peritonitis (SBP), variceal bleeding and hepatic
encephalopathy (HE). The primary management of these
complications routinely involves pharmacological interventions.
k Ascites k
Ascites (an accumulation of fluid in the peritoneal cavity) is the most
common complication of chronic liver disease and 60% of patients
with compensated cirrhosis (i.e. where the liver retains its core
functional capacity) develop ascites.
Ascites occurs when portal hypertension, which results from
increased intrahepatic vascular resistance and portal –splanchnic
blood flow, has developed. The development of ascites is linked to an
inability to excrete an adequate amount of sodium into urine, leading
to a positive sodium balance.2
Patients with ascites will often present with distended abdomen,
hyponatraemia, low arterial pressure and an elevated serum
creatinine – all of which needs to be taken into account when new
medications are initiated.
Treatments
The primary treatment of ascites is aimed at counteracting renal
sodium retention and achieving a negative sodium balance. The latter
can be achieved by reducing dietary sodium intake to approximately
80 –120 mmol/day and promoting renal sodium excretion by
administration of diuretics.
Fluid restriction may also be advised but is usually restricted to
patients with dilutional hyponatraemia.
Diuretics are commonly prescribed for patients who have not
responded to sodium and fluid restriction. The most commonly
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254 Liver disease (chronic)
Volaemia
Heart rate
Cardiac index
Arterial pressure
Systemic vascular resistance
Systemic Sclerotherapy Band

vasodilation ligation
TIPS
(Transjugular
Intrahepatic
L Portosystemic
Shunt)
Portal pressure
Intrahepatic resistance Splanchnic blood flow

k k
Splanchnic vasodilation
Targets for pharmacological therapy
FIGURE L1 Pathophysiology of portal hypertension in cirrhosis8
prescribed is the aldosterone antagonist spironolactone and the loop

diuretic furosemide.3
Frequent monitoring of serum creatinine, sodium and potassium
concentrations should be performed while taking diuretics.
For patients with treatment-resistant or recurrent ascites, options
include large-volume paracentesis (surgical removal of ascitic fluid),
albumin infusion and insertion of transjugular intrahepatic
portosystemic shunts (TIPS) (Figure L1). These procedures may be
used to support a patient before liver transplantation.4
Spontaneous bacterial peritonitis

SBP is an infection of ascitic fluid without a definitive intra-abdominal
source and is another common complication in patients with chronic
liver disease.5,6 The exact pathogenesis of SBP is somewhat unclear
but it is thought it results from a combination of factors linked to
cirrhosis and ascites, such as prolonged bacteraemia secondary to
compromised host defences, intrahepatic shunting of colonised blood
and defective bactericidal activity within the ascitic fluid.
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The diagnosis of SBP is based primarily on a diagnostic

paracentesis where a sample of ascitic fluid will be tested for
pathogens. In approximately 40% of cases there will be growth of
Gram-negative bacteria, usually Escherichia coli and Gram-positive
cocci (mainly Streptococcus species and enterococci).3 It is possible to
have a culture-negative SBP that is identified when the ascitic fluid
sample has a neutrophil count >250 cells/mm3 but there is an
absence of positive growth of bacteria.
Presenting signs and symptoms are typical of general sepsis and
include fever, confusion and abdominal tenderness.
Treatments
Antibiotic treatment is increasingly recognised as standard practice
postdiagnosis of SBP. There is a trend towards using piperacillin with
tazobactam and co-amoxiclav as first-line antibiotics even though the
evidence is currently unclear – check your local formulary. This L
probably reflects the underlying fear of Clostridium difficile infection
associated with the use of quinolones and cephalosporins.
Long-term prophylaxis options still routinely involve the
prescribing of quinolones, such as ciprofloxacin or norfloxacin.
Co-trimoxazole may also be a suitable alternative if quinolones are
not an option. Resistance may become an issue due to the long-term
nature of the prophylaxis and therefore rotating antibiotics may be
necessary.7
k Variceal bleeding k
Varices occur as a result of splanchic arterial vasodilation, which is
common in chronic liver disease. This vasodilation leads to an
increased portal blood flow and hence elevated portal hypertension.
It is this increase in pressure that results in the formation of venous
collaterals/varices. These can form in the oesophagus and the
gastrointestinal tract.8
Approximately half of patients with cirrhosis have varices, and
one-third of all patients with varices will at some point in their
disease develop variceal haemorrhage, a major cause of morbidity
and mortality in patients with cirrhosis. It is linked with mortality
rates of at least 20%.9
Treatments
The primary aims of variceal treatments are to:
● decrease portal hypertension (with beta-blockers, surgical portal

decompression or TIPS)
● treat the varices directly (with variceal banding or sclerotherapy).
Primary prophylaxis of varices that have not yet bled includes the use
of non-selective beta-blockers, such as propranolol or carvedilol.
Secondary prophylaxis for patients who have experienced bleeding
includes beta-blockers and endoscopic interventions, such as
banding.10
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In acute variceal bleeding vasoactive drugs, such as terlipressin or

octreotide, used alongside broad-spectrum antibiotics and a
high-dose proton pump inhibitor infusion (e.g. omeprazole) are
recommended to be started as soon as possible.11,12
Hepatic encephalopathy
HE is a neuropsychiatric complication of chronic liver disease.
Symptoms can range from mild confusion and delirium to coma. HE
develops in up to 50% of patients with cirrhosis.13
Ammonia is thought to play a key role in the development of HE.
Hyperammonaemia leads to the development of brain swelling,
suggesting a link between ammonia and inflammation.14 Other
additional causes of HE include hyponatraemia and the presence of
medications, such as benzodiazepines and sedatives.
L Treatments
The primary management strategy of HE involves the identification of
any precipitating factors and initiating a pharmacological approach
targeted at reducing levels of ammonia and other gut-derived
toxins.15
The osmotic laxative lactulose is routinely prescribed in HE. It is
not absorbed from the digestive tract and helps to decrease the
generation of ammonia by gut bacteria and renders any remaining
ammonia to ammonium, which is not absorbable. Doses of 15 –30 mL
three times daily are usually sufficient, with the aim of achieving
k three to five soft stool motions per day. If oral administration is not k
possible then phosphate enemas are used, as they will relieve any
constipation precipitating HE and increase bowel transit.
Rifaximin is a non-absorbable antibiotic from the rifamycin class.
The rationale for its use is the fact that ammonia and other waste
products are generated and converted by intestinal bacteria, and
killing these bacteria would reduce the generation of these waste
products. The landmark study examining the benefits of rifaximin in
HE was published in 2010 and identified that, over a 6-month period,
treatment with rifaximin maintained remission from HE more
effectively than did placebo. However, it is worth noting that 91%
of the study cohort was also on concomitant lactulose!16,17 NICE
guidance recommends rifaximin, used within its marketing
authorisation, as an option for reducing the recurrence of episodes
of overt hepatic encephalopathy in people aged 18 years or
older.18
L-Ornithine and L-aspartate (LOLA) are a combination of amino
acids that play a role in the biochemical pathways that detoxify
ammonia; they are unlicensed in the UK but are used in the EU. LOLA
may be combined with lactulose and/or rifaximin if these alone are
ineffective at controlling symptoms.
k
k
Pruritus
Pruritus is a common symptom in patients with chronic liver disease,
particularly when cholestasis (impaired secretion of bile) is a
prominent feature, such as in conditions like primary biliary cirrhosis.
Pruritus associated with chronic liver disease is usually generalised
and causes significant quality-of-life disruption for patients. It is often
intractable and so can lead to sleep deprivation and suicidal ideation.
It also leads to violent scratching, which can result in broken skin and
infections.19 Intractable pruritus from liver disease is an indication for
liver transplantation even in the absence of liver failure.20
Treatments
The exact pathogenesis of pruritus in liver disease is not fully
understood, making it challenging to identify efficacious treatments.
L
The anion exchange resin colestyramine can bind to bile acids in the
gastrointestinal tract to increase faecal excretion of bile acids.
Colestyramine can interfere with the absorption of other prescribed
drugs and so it is important to counsel patients to take the
colestyramine an hour before, or 4 hours after, other medications.21
There is evidence to suggest that increased opioidergic
neurotransmission in the brain appears to contribute to the pruritus.
Opioid antagonists, such as naltrexone, have been shown to decrease
scratching activity in patients with severe pruritus, with doses
k reported to show efficacy at 50 mg daily.22 Caution should be used, k
however, as dependence can occur and a dose exceeding 50 mg twice
daily should rarely be used.
It is also believed, although the evidence is not robust, that there is
an interrelationship between the opioid and serotonin
neurotransmitter systems. The serotonin antagonist ondansetron has
been reported to alleviate pruritus induced by opioids and it may have
a role to play in pruritus refractory to other therapeutic
interventions.23
Pruritus in chronic liver disease has also been linked to a high
concentration of serum bile acids. The antibiotic rifampicin is thought
to inhibit the uptake of bile acids by hepatocytes and so has been used
to treat pruritus.24 It is important to note that rifampicin is a potent
enzyme inducer and interacts with a multitude of medications and a
drug –drug interaction screen should be completed before rifampicin
is prescribed. This antibiotic is also hepatotoxic and so caution should
be observed when prescribing it in cirrhotic patients. Starting dose for
pruritus should be 150 mg twice daily, with maximum dose
considered to be 300 mg twice daily.
REFERENCES
1 Moore KP, Aithal GP (2006). Guidelines on the management of ascites in cirrhosis.
Gut 55: 1–12.
2 Fullwood D, Purushothaman A (2013). Managing ascites in patients with chronic
liver disease. Nurs Standard 28: 51–58.
k
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3 Runyon B (2012). Management of Adult Patients with Ascites Due to Cirrhosis:

Update 2012. American Association of the Study of Liver Disease (AASLD).
http://www.aasld.org/practiceguidelines (accessed 6 August 2014).
4 NICE (2014). Subcutaneous Implantation of a Battery-powered Catheter Drainage
System for Managing Refractory and Recurrent Ascites. NICE interventional
procedures guidance (IPG479). https://www.nice.org.uk/guidance/ipg479
(accessed 14 May 2015)
5 EASL (2010). Management of Ascites, Spontaneous Bacterial Peritonitis, and
Hepatorenal Syndrome in Cirrhosis, Issue 4. http://www.easl.eu/ clinical-
practice-guideline/issue-4-august-2010-management-of-ascites-spontaneous-
bacterial-peritonitis-and-hepatorenal-syndrome-in-cirrhosis (accessed 6 August
2014).
6 Alaniz C, Regal R (2009). Spontaneous bacterial peritonitis – a review of treat-
ment options. Pharm Ther 34: 201–210.
7 Goel A et al. (2014). Diagnosis and management of spontaneous bacterial
peritonitis: is there a need for an urgent update of national guidelines? Gut 63
L (Suppl 1): A215.
8 Dib N et al. (2006). Current management of the complications of portal hyperten-
sion: variceal bleeding and ascites. CMAJ 174: 1433–1443.
9 NICE (2012). Acute Upper Gastrointestinal Bleeding: Management. NICE guidelines
(CG141) http://www.nice.org.uk/guidance/CG141 (accessed 6 August 2014).
10 Triantos C, Kalafateli M (2014). Primary prevention of bleeding from esophageal
varices in patients with liver cirrhosis. World J Hepatol 6: 363–369.
11 Seo YS et al. (2014). Lack of difference among terlipressin, somatostatin,
and octreotide in the control of acute gastroesophageal variceal hemorrhage.
Hepatology http://www.ncbi.nlm.nih.gov/pubmed/24415445 (accessed 8 August
2014).
k 12 Kim SY et al. (2012). Management of non-variceal upper gastrointestinal bleeding. k
Clin Endoscopy 45: 220–223.
13 Leise M et al. (2014). Management of hepatic encephalopathy in the hospital.
Mayo Clin Proc 89: 241–253.
14 Montagnese S et al. (2012). Encephalopathy or hepatic encephalopathy? J Hepatol
57: 928–929.
15 Waghray A et al. (2014). Optimal treatment of hepatic encephalopathy. Minerva
Dietol Gastroenterol 60: 55–70.
16 Bass NM et al. (2010). Rifaximin treatment in hepatic encephalopathy. N Engl J
Med 362: 1071–1081.
17 Patel V et al. (2014). Rifaximin is efficacious in the treatment of chronic overt
hepatic encephalopathy: a UK liver multi-centre experience. Gut 63: A14–A15.
18 NICE (2015). Rifaximin for preventing episodes of overt hepatic encephalopathy
(TA337). https://www.nice.org/guidance/ta337 (accessed 11 September 2015).
19 Bergasa NV et al. (2014). Frontiers in Neuroscience: Pruritus of Cholestasis.
http://www.ncbi.nlm.nih.gov/books/NBK200923 (accessed 8 August 2014).
20 Mela M et al. (2003). Review article: pruritus in cholestatic and other liver
diseases. Aliment Pharmacol Ther 17: 857–870.
21 Scaldaferri F et al.(2013). Use and indications of cholestyramine and bile acid
sequestrants. Intern Emerg Med 3: 205–210.
22 Jones EA et al. (2002). Opiate antagonist therapy for the pruritus of cholestasis:
the avoidance of opioid withdrawal-like reactions. Oxf J Med 95: 547–552.
23 Jones EA et al. (2007). Ondansetron and pruritus in chronic liver disease: a
controlled study. Hepatogastroenterology 54: 1196–1199.
24 Chen J, Raymond K (2006). Treatment effect of rifampicin on cholestasis. Ann Clin
Microbiol Antimicrob 5: 3.
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Liver function tests

Overview
Background Liver function tests (LFTs) are a panel of laboratory results that
can be helpful in diagnosing and assessing the extent of hepatic
dysfunction. Since the liver performs a variety of functions, no
single test is sufficient to provide a complete estimate of liver
function.
Effective interpretation of the hepatic function panel requires
knowledge of underlying pathophysiology and the characteristics
of panel tests. It is important to note that abnormal LFTs do not
always indicate liver disease and equally they can be normal in
patients with cirrhosis.
The commonly used LFTs primarily assess liver injury rather than
hepatic function. Indeed, these blood tests may reflect problems
arising outside the liver, such as haemolysis (elevated bilirubin
L
level) or bone disease (elevated alkaline phosphatase level).
You should routinely consider the patient’s clinical picture
combined with abnormal LFT pattern when interpreting the level
of dysfunction
LFTs – reference
Measure Range Local
ranges1 (but check
your local labora- Alanine 5–35 units/L
tory reference aminotransferase
ranges) (ALT)
k k
Alkaline phosphatase Adults: 30–150 units/L
(ALP) (will vary (adolescents have
according to gender higher levels,
and age) particularly during
growth spurts)
Aspartate 5–35 units/L
transaminase (AST)
Bilirubin 3–17 micromol/L
Gamma- Men: 11–51 units/L
glutamyltranspeptidase Women: 7–33 units/L
(GGT)
Albumin 35–50 g/L
INR 0.9–1.2
Child–Pugh system When assessing the severity/scale of hepatic dysfunction using

LFTs then clinicians use a classification system called the
Child–Pugh score.2 This originated in the 1960s and was
modified in the early 1970s. It is a useful predictor of outcomes
and is also used by pharmaceutical companies in their SPCs to
indicate at what level of hepatic impairment their product will
require a dose adjustment (see Child–Pugh Score entry)
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260 Liver function tests
Amino transferases
These include alanine aminotransferase transaminase (ALT) and aspartate transaminase
(AST).
Hepatocellular injury is the main trigger for release of these enzymes into the circulation
ALT ● ALT is an enzyme found in high concentrations in the liver and
is therefore a sensitive marker for hepatocyte injury
AST ● AST is present in mitochondrial enzymes and is found in the
liver, cardiac and skeletal muscle, kidneys, brain, pancreas and
lungs. It is less sensitive and specific for the liver than ALT
Further information ● AST and ALT levels tend to be higher in cirrhotic patients with
continuing inflammation or necrosis than in those without
continuing liver injury.
● As markers of hepatocellular injury, AST and ALT lack some
L specificity because they are found in skeletal muscle. Levels of
these aminotransferases can rise to several times normal after
severe muscular exertion, other muscle injury, or in the
presence of hypothyroidism, which can cause mild muscle
injury and the release of aminotransferases.3
● Other common causes of elevated aminotransferases include:
non-alcoholic fatty liver disease, alcohol, chronic hepatitis B
and C and autoimmune liver disease
Drugs causing ● Amiodarone, steroids, carbamazepine, phenytoin, isoniazid,
elevation antifungals, e.g. voriconazole, posaconazole, fluconazole
When completing a drug history it is essential to enquire about
k prescribed medicines and also herbal or other ‘alternative k
medicines’, which have the potential to cause elevations in ALT
and AST
Alkaline phosphatase (ALP)

ALP ● ALP originates mainly from two sources: liver and bone. The
enzyme may also be found in a variety of other tissues,
including the intestine, kidney and placenta.
● Elevations can be seen in adolescents undergoing growth
spurts and in the third trimester of pregnancy
Further information ● The most common causes of elevated ALP are linked to
extrahepatic biliary obstructions (e.g. gallstones) and
metastases, primary biliary cirrhosis (PBC), primary sclerosing
cholangitis (PSC) (i.e. chronic inflammatory disorder of the
small bile ducts).
● Cholestasis (lack of bile flow) results from the blockage of bile
ducts or from a disease that impairs bile formation in the liver
itself. ALP levels typically rise to several times the normal level
after several days of bile duct obstruction or intrahepatic
cholestasis
Drugs causing ● Anabolic steroids
elevation
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Gamma-glutamyl transferase (GGT)

GGT ● GGT is found in hepatocytes and biliary epithelial cells. It is a
sensitive test of hepatobiliary disease, but its clinical
usefulness is limited as it lacks specificity.4 Raised levels may
be seen in pancreatic disease, diabetes, myocardial infarction,
renal failure, chronic obstructive pulmonary disease and
alcoholism
Further information ● The elevation of GGT alone, with no other LFT abnormalities,
often results from enzyme induction by alcohol or medicines in
the absence of liver disease. GGT level is often elevated in
persons who take three or more alcoholic drinks (45 g of
ethanol or more) per day; hence GGT is a useful marker for
immoderate alcohol intake
Drugs causing GGT ● Elevated GGT levels: alcohol, phenytoin, phenobarbital
Lowered GGT levels: clofibrate, oral contraceptives
level changes ●
L
Bilirubin
Bilirubin ● Bilirubin is formed from the lysis of the haem component of
red blood cells. Serum bilirubin is usually classified as
conjugated or unconjugated. Unconjugated is transported to
liver and is loosely bound to albumin. It is water-insoluble and
cannot therefore be excreted in the urine. Conjugated is
water-soluble and can be excreted in the urine4
Further information ● Serum bilirubin is normally predominantly in the unconjugated
form, reflecting a balance between production and excretion.
k ● Conjugated bilirubin increases in haemolysis, muscle injury, k
PBC, PSC, extra- and intrahepatic obstruction.
● Unconjugated bilirubin increases when there is increased
production in bilirubin as a result of haemolysis, blood
transfusion or in defects in hepatic uptake or conjugation such
as in Gilbert’s syndrome. The latter is a common disorder
characterised by unconjugated bilirubinaemia, which is
exacerbated by fasting3
Drugs causing ● Allopurinol, carbamazepine, co-amoxiclav, diltiazem, total
elevation parenteral nutrition
Albumin
Albumin Albumin production is an essential role of the liver. Albumin
synthesis is immediately and severely depressed in inflammatory
states, such as burns, trauma and sepsis, and is commonly
depressed in patients with active rheumatic disorders or severe
end-stage malnutrition. These factors should be taken into
account when interpreting levels.
In practice, patients with low serum albumin concentrations and
no other LFT abnormalities are likely to have a non-hepatic cause
for low albumin, such as proteinuria or an acute or chronic
inflammatory state.
Albumin has a plasma half-life of 3 weeks, and therefore serum
albumin concentrations change slowly in response to alterations
in synthesis
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262 Low-molecular-weight heparin
Prothrombin time (PT)

Prothrombin time The liver synthesises blood-clotting factors II, V, VII, IX and X. PT
measures the rate of conversion of prothrombin to thrombin, thus
reflecting a vital function of the liver.
PT does not become abnormal until more than 80% of liver
synthetic capacity is lost. This makes PT a relatively insensitive
marker of liver dysfunction; however, abnormal PT prolongation
may be a sign of serious liver dysfunction. Because factor VII has
a short half-life of only about 6 hours, it is sensitive to rapid
changes in liver synthetic function, thus PT is very useful for
following liver function in patients with acute liver failure.3
Vitamin K is required for the carboxylation of the clotting factors
outlined above and so an elevated PT can result from a vitamin K
deficiency or indeed warfarin therapy. This deficiency usually
L occurs in patients with chronic cholestasis or fat malabsorption
from diseases of the pancreas or small intestine. A trial of
vitamin K injections (e.g. 5 mg daily administered subcutaneously
for 3 days) is the most practical way to exclude vitamin K
deficiency in such patients
REFERENCES
1 Longmore M et al. (2004). Oxford Handbook of Clinical Medicine (6th edn).
Oxford: University Press.
2 Johnston D (1999). Special considerations in interpreting liver function tests. Am
Fam Phys 59: 2223–2230.
k 3 Limdi JK, Hyde GM (2003). Evaluation of abnormal liver function tests. Postgrad k
Med J 79: 307–312.
4 Lewis-North P (2008). Drugs and the Liver. London: Pharmaceutical Press.
Low-molecular-weight heparin
Low-molecular-weight heparins (LMWH) are indirect factor Xa
inhibitors. They activate antithrombin-like unfractionated heparin;
the majority of their activity comes from inactivation of factor Xa. The
three LMWHs with UK product licences – tinzaparin, enoxaparin and
dalteparin – all have slightly different factor IIa (thrombin) to factor
Xa activities and different molecular weights due to their method of
preparation.1
In the preparations available, 25 –50% of the molecules inhibit
thrombin and factor Xa, with the remaining 50 –75% only inhibiting
factor Xa. Like any type of heparin, they are of porcine origin. This
may not be acceptable to certain religious groups and it is important
that patients are made aware of this.
All three agents are licensed for the treatment of venous
thromboembolism (VTE) and for prophylaxis of VTE in certain
patient groups. Their licences have slight differences and this should
be borne in mind when selecting a suitable agent, although it is likely
they will all have similar effects. They are less likely to cause
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Low-molecular-weight heparin 263
heparin-induced thrombocytopenia (HIT) than unfractionated

heparin and less osteoporosis. This is due to their shorter chain
lengths. However, patients with a past history of HIT should not
receive LMWH, and alternative agents such as fondaparinux,
danaparoid or argatroban should be used.
All LMWHs are renally excreted to a certain extent, though
enoxaparin is more renally excreted than the others. Dose
adjustments must be made for patients with creatinine clearance
<30 mL/min according to the enoxaparin product licence. Tinzaparin
can be used at its normal recommended dose down to a creatinine
clearance of 20 mL/min, but below this there is no evidence and a risk
of accumulation. The dalteparin SPC does not discuss renal function
or whether any dose reductions are required. Some hospitals advocate
lower doses of dalteparin for patients with poor renal function.
Antifactor Xa monitoring can be done and may be recommended in L
patients with poor renal function, very obese patients, in pregnancy
and in children. A level of 0.5 –1.0 units/mL 4 hours after a dose is a
suitable treatment dose level; 0.2 –0.5 unit/mL 4 hours after a dose is
a suitable prophylactic dose level.
All agents can be used in pregnancy as LMWHs do not cross the
placenta. These are therefore the most suitable agents for
anticoagulated women wishing to become pregnant and for those
who develop a VTE during pregnancy. The exception to this is the
tinzaparin multidose vial; this contains benzyl alcohol, which should
k be avoided in pregnancy. The Royal College of Obstetricians and k
Gynaecologists’ guideline on venous thromboembolism states that
LMWH can be used safely in breastfeeding women, although this is
unlicensed.2
REFERENCES
1 Hirsh J (1998). Low-molecular-weight heparin: a review of the results of recent
studies of the treatment of venous thromboembolism and unstable angina. Circula-
tion 98: 1575–1582.
2 Royal College of Obstetricians and Gynaecologists (2007) Thrombosis and
Embolism during Pregnancy and the Puerperium, the Acute Management of
(Green-top Guideline No. 37b) https://www.rcog.org.uk/en/guidelines-research-
services/guidelines/gtg37b/ (accessed 17 November 2014).
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264 Magnesium
M
Magnesium
Normal range: 0.7 –1.0 mmol/L
Local range . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Magnesium is the second most abundant cation in the intracellular
fluid. It is an essential electrolyte and is a cofactor in many enzyme
systems. Only about 1% of total body magnesium is present in the
M extracellular space, the majority being in bone (85%), muscle and
soft tissue. Hypomagnesaemia in the general population is relatively
common, with an estimated prevalence of 2.5 –15% (prevalence may
be as high as 65% in critical care settings) but this correlates poorly
with total-body magnesium depletion.1 The body is very effective at
maintaining extracellular magnesium concentration through control
of intestinal absorption and renal excretion and reabsorption, which
makes it difficult to establish a daily requirement. However, there is a
k recommended nutrient intake for adults (Table M1).2 k
TABLE M1
Recommended nutrient intake of magnesium
Adult male 12.3 mmol/day (300 mg)
Adult female 10.9 mmol/day (270 mg)
Additional 2.1 mmol (50 mg) required if breast-feeding
Magnesium deficiency
Hypomagnesaemia can be classified as follows:1
Mild hypomagnesaemia 0.5–0.7 mmol/L

Moderate to severe hypomagnesaemia <0.5 mmol/L
Patients may be symptomatic or asymptomatic at either of these

levels.
Causes of hypomagnesaemia1
Causes of hypomagnesaemia include:
● dietary deficiency
● excessive loss via the gastrointestinal tract, e.g. chronic diarrhoea,
malabsorption syndromes, bypass surgery, vomiting or nasogastric
suction, laxative abuse
● inadequate reabsorption via the kidneys, e.g. inherited renal
tubular defects, effects of drugs
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Magnesium 265
● drug causes include laxatives, proton pump inhibitors, diuretics

(loop and thiazide), alcohol, antimicrobials (aminoglycosides,
amphotericin, foscarnet, pentamidine), chemotherapy (cisplatin),
immunosuppressants (ciclosporin, tacrolimus).3
Symptoms
Most patients with hypomagnesaemia are asymptomatic: symptoms
are not usually seen until serum magnesium is <0.5 mmol/L.
Symptomatic magnesium depletion is often associated with other
biochemical abnormalities, such as hypokalaemia, hypocalcaemia
and metabolic acidosis, so symptoms are not specific to
hypomagnesaemia.
Symptoms may include muscle weakness, tremor, muscle
fasciculations (small, local contractions), paraesthesiae, tetany and
seizures. Atrial or ventricular arrhythmias may be seen and cardiac
glycoside toxicity may be exacerbated.4
Treatment of magnesium depletion M
Treatment route is determined by serum magnesium level and
presenting symptoms, as shown in Table M2.
TABLE M2
Mode of treatment of hypomagnesaemia
Serum magnesium Symptoms Mode of treatment
0.5–7 mmol/L Asymptomatic No acute management is required. May consider
oral supplementation with monitoring
k 0.5–0.7 mmol/L Symptomatic Oral magnesium replacement
k
<0.5 mmol/L Asymptomatic Oral magnesium replacement
<0.5 mmol/L Symptomatic Intravenous magnesium replacement
Oral magnesium replacement

In asymptomatic patients, oral replenishment may be sufficient;
however, the oral route is of limited benefit because high doses will
cause diarrhoea leading to further losses, and there may be poor
gastrointestinal absorption.
Whilst several studies have looked at the bioavailability of various
magnesium preparations, none has looked at clinical outcomes.5 The
usual starting dose in adults is about 24 mmol/day of magnesium6
given using a preparation the patient finds acceptable. A number of
different magnesium salts and products are available, including:
● magnesium aspartate – Magnaspartate (KoRa Healthcare) is
classified as a food for special medical purposes and contains
10 mmol magnesium/sachet
● magnesium glycerophosphate – available as an unlicensed product
from various suppliers, usually containing 4 mmol magnesium per
tablet/capsule or 1 mmol/mL in liquid form
● magnesium hydroxide mixture – Phillips’ Milk of Magnesia is
licensed as an antacid and a laxative and contains magnesium
1.4 mmol/mL
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266 Magnesium
● co-magaldrox – Maalox and Mucogel are licensed as antacids and

contain aluminium hydroxide as well as magnesium hydroxide.
Both contain magnesium 6.7 mmol/10 mL and a number of
hospitals recommend their use unlicensed in hypomagnesaemia.7,8
The main side effect of all these products is diarrhoea, although the
aluminium hydroxide component of co-magaldrox is constipating,
and therefore diarrhoea may be reduced.
During oral replacement serum magnesium levels should be
checked once or twice weekly; reversal of hypomagnesaemia may
take 6 –8 weeks. In some cases, long-term maintenance therapy may
be necessary.
Intravenous magnesium treatment
For severe symptoms or if the oral route is unavailable, magnesium
sulfate is given intravenously (by infusion unless symptoms are
severe) (Table M3). Intramuscular injection can be very painful.
M TABLE M3
Magnesium content of different strengths of magnesium
sulfate injection
10% (100 mg/mL) Approx. 0.4 mmol/mL
20% (200 mg/mL) Approx. 0.8 mmol/mL
50% (500 mg/mL) Approx. 2 mmol/mL
k Patients with severe symptoms9 k

Note: rapid administration of magnesium sulfate can cause
vasodilatation and hypotension.
● Haemodynamically unstable patients (e.g. arrhythmias consistent
with torsade de pointes or hypomagnesaemic hypokalaemia) may
require 4 –8 mmol magnesium (1 –2 g magnesium sulfate) over
2 –15 minutes initially. Magnesium sulfate 10% and 20% injections
may be given undiluted in these circumstances.
● Haemodynamically stable patients with severe symptoms (tetany,
seizures) should be given 4 –8 mmol magnesium (1 –2 g
magnesium sulfate) in 100 mL sodium chloride 0.9% or glucose
5% over 5 –60 minutes followed by an infusion (see below).
Intravenous magnesium replacement
The magnesium deficit in symptomatic hypomagnesaemia may be
0.5 –1 mmol/kg. Up to one-half of the intravenous magnesium dose
will be excreted in the urine during replacement, so 1 –2 mmol/kg will
be required to replenish body stores. Body stores are replaced slowly
and the process may take several days. Even if serum magnesium
levels return to normal in 24 hours, it is important to recognise that
body stores will probably not have been replenished in this time.
● In renal impairment (CrCl <30 mmol/L) the dose should be
reduced by 50% to avoid the risk of severe hypermagnesaemia.9
Magnesium levels should be monitored more frequently; consider
k
k
Magnesium 267
giving lower doses or longer intervals between infusions.

● To give as an infusion, add the required dose to 250 –1000 mL of
sodium chloride 0.9% or glucose 5% (maximum concentration
of 0.4 mmol/mL). Infuse at a rate of 4 –8 mmol/hour.
Many regimens are in use and include:
● Giving 16 –32 mmol magnesium over 12 –24 hours, and repeating

daily as necessary. Serum magnesium level should be checked at
least daily.
● Giving 0.5 mmol/kg by infusion on day 1, then 0.25 mmol/kg by
infusion on days 2 –5, rounding the doses to conveniently
measurable volumes. Serum magnesium level should be checked at
least daily.
Hypermagnesaemia
Symptoms
M
Symptoms include nausea, flushing, headache, lethargy, diminished
or absent deep tendon reflexes, hypotension, bradycardia, ECG
changes, muscle paralysis, respiratory failure and cardiac arrest.
Causes of hypermagnesaemia
Causes include:
● excessive parenteral administration of magnesium salts

patients with impaired renal function who have been taking large
k ●
doses orally, for example as laxatives or antacids.

k
Treatment
In mild cases, restricting magnesium intake is sufficient to return the
serum concentration to normal. In renal impairment administration
of isotonic intravenous fluids plus a loop diuretic may be effective.
Haemodialysis (using magnesium-free solutions) may be required.
In severe cases consult a poisons information service, e.g. Toxbase
at www.toxbase.org (password and registration required) for full
details of the management of magnesium toxicity. Ventilatory and
circulatory support may be required and calcium gluconate 10% may
be used to reverse the effect magnesium on the circulatory and
respiratory systems.
REFERENCES
1 Ayuk J et al. (2011). How should hypomagnesaemia be investigated and treated?
Clin Endocrinol 75: 743–746.
2 Nutrient Intakes (2014). www.gov.uk (accessed 13 February 2015).
3 al-Ghamdi SM et al. (1994). Magnesium deficiency: pathophysiologic and clinical
overview. Am J Kidney Dis 24: 737–752.
4 Longmore M et al. (eds) (2004). Oxford Handbook of Clinical Medicine (6th edn).
Oxford: Oxford University Press.
5 UKMI Q&A 111.1 (2013). What Oral Magnesium Preparations are Available in the
UK and Which Preparation is Preferred for the Treatment and Prevention of Hypomag-
nesaemia? www.evidence.nhs.uk (accessed 17 February 2015).
k
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268 Medicines reconciliation
7 Southern Derbyshire (2012). Shared Care Pathology Guidelines Hypomagnesaemia in
Adults. https://www.derbyhospitals.nhs.uk (accessed 17 February 2015).
8 NHS Grampian (2012). Staff Policy for the Management of Hypomagnesaemia in
Adults. http://www.nhsgrampian.com (accessed 17 February 2015).
9 UpToDate (2013). Evaluation and Treatment of Hypomagnesemia. www.uptodate
.com (accessed 17 February 2015).
Medicines reconciliation
There are more than 13 million hospital admissions in England alone
each year. This number is growing and, with the average cost of a
non-elective admission estimated to be £1739,1 the pressure on
health economies is great. It has been widely reported historically
M that 30 –70% of patients have either an error or unintentional change
to their medicines when their care is transferred.2 More recent studies
corroborate these findings and have demonstrated there are 1.3
unintended discrepancies for each medicines reconciliation
completed by a non-pharmacy member of staff,3 and two-thirds of
discharge summary letters are inaccurate or incomplete prior to
pharmacy screening.4
Medicines reconciliation (taking an accurate drug history and
ensuring anomalies are investigated and appropriate action is taken
k to resolve these) is underpinned by NICE guidance.2 It is important
k
that information leaving the hospital is of high quality. Consistently
ensuring that accurate information regarding medicines is included
on the discharge letter starts with taking an accurate drug history on
admission. This necessitates having mechanisms in place to ensure
that any changes to medicines are easily identifiable, i.e. what has
started, stopped, changed, and why, should be documented on charts,
notes or the e-record. This makes completion of discharge
documentation and also medicines reconciliation in the community
postdischarge accurate, safer and easier for all parties.
The Royal Pharmaceutical Society transfer of care guidance5
provides several examples of good practice that are potentially
adoptable or adaptable to different hospital settings.6 Below is an
example of a medicines reconciliation checklist that can be adopted or
adapted for local use. It contains core questions to ask the patient to
elicit a drug history of consistent quality so nothing important is
missed, and is intended as a prompt to underpin a standard operating
procedure. Completed checklists can be inserted into the patient
notes or form the basis of an e-form for hospitals using an electronic
patient record. It should be noted that one of the questions asked at
this first pharmacy encounter is ‘which community pharmacy do you
usually use?’; this information could prove useful for a later referral.
k
k
Medicines reconciliation 269
To find out more about checklists and how they can ensure quality
is built into processes, read the excellent book by Atul Gawande: The
Checklist Manifesto.7
Medicines reconciliation checklist (hospital admission)
Check each box (or leave blank if not appropriate or not possible
to complete)
❑ Insert this checklist into drug history section of notes
❑ Check notes for drug history and likely diagnosis
❑ Introduce yourself: smile, make eye contact, state your name
and role, and ask: ‘Is it OK to talk about your medicines?’
Can you communicate with patient? Yes No
❑ Ask: ‘Who looks after your medicines at home?’
❑ Record if and which regular community pharmacy
❑ Ask: ‘Do you have any difficulties taking your medicines?’ M
❑ Ask: ‘Are they in separate boxes or one big pack?’
❑ Obtain consent for GP summary/summary care record or GP fax
❑ Document drug intolerance/allergy, including reaction in notes,
on chart etc.
❑ Check/document patient’s own drugs (PODs): suitable? +
document quantity
❑ Check medicine administration record (and note whether
administered) or contact care home
k ❑ Ask about PODs at home; document ‘H’ on chart if PODs at home k
❑ Ask: ‘Any recent medication changes or hospital admission?’
❑ Ask: ‘Do you get medicines from anywhere other than your GP?’
e.g. home delivery, hospital, chemo (refer), clinical trial,
community drug team
❑ Ask (where appropriate) if using any of the following:
❑ If warfarin, where is yellow book? Refer to anticoagulant
service
❑ If diabetes mellitus – refer to diabetes specialist nurses
❑ Other monitoring booklets, e.g. disease-modifying
antirheumatic drugs, chemo
❑ Once-weekly medication (state day of week)
❑ Home oxygen
❑ Over-the-counter, herbal, internet, ‘recreational’
❑ Check if smoker: Cigarettes/day? Nicotine replacement therapy?
Smoking cessation referral?
❑ Complete drug history on chart and notes (sign and date)
Take appropriate action to rectify discrepancies
REFERENCES
1 Kings Fund (2012). Data briefing. Emergency Hospital Admissions for Ambu-
latory Care-sensitive Conditions: Identifying the potential for reductions http://
www.kingsfund.org.uk/sites/files/kf/field/field publication file/data-briefing
-emergency-hospital-admissions-for-ambulatory-care-sensitive-conditions-apr-
2012.pdf (accessed 30 August 2014).
k
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270 Methotrexate: calcium folinate rescue regimen
2 NICE (2015). Medicines optimisation: the safe and effective use of medicines to
enable the best possible outcomes. www.nice.org.uk/guidance/NG5 (accessed
20 August 2015).
3 Dodds LJ (2014). Optimising pharmacy input to medicines reconciliation at
admission to hospital: lessons from a collaborative service evaluation of pharmacy-
led medicines reconciliation services in 30 acute hospitals in England. Eur J Hosp
Pharm 21: 95–101.
4 Dodds LJ (2013). Pharmacist contributions to ensuring safe and accurate transfer
of written medicines-related discharge information: lessons from a collaborative
audit and service evaluation involving 45 hospitals in England. Eur J Hosp Pharm
doi:10.1136/ejhpharm-2013-000418.
5 Royal Pharmaceutical Society (2012). Keeping Patients Safe when they Transfer
Between Care Providers: Getting the medicines right. http://www.rpharms.com/
getting-the-medicines-right/keeping-patients-safe-report.asp (accessed 30 August
2014).
6 Gray A et al. (2013). Innovations in transfer of care. Hosp Pharm Eur 2013: 74.
7 Gawande A (2011). The Checklist Manifesto: How to get things right. London: Profile
Books.
M
Methotrexate: calcium folinate

rescue regimen
Calcium folinate (folinic acid, calcium leucovorin, tetrahydrofolate)
can be used in the management of methotrexate overdose and to
reduce the toxicity of high-dose methotrexate chemotherapy. Calcium
k folinate is a reduced form of folic acid, which bypasses the inhibition
k
of dihydrofolate reductase by methotrexate. Calcium folinate also has
a role in combination with fluorouracil in the treatment of bowel
cancer, where its use enhances the effect of fluorouracil by inhibition
of thymidilate synthase.1
Methotrexate serum concentration should be checked every
24 hours from 20 to 24 hours after administration in overdose, or
from 24 hours after completion of therapeutic dosing.2
Calcium folinate should continue until the serum methotrexate
concentration falls to below 0.1 micromol/L.3 Administration of
calcium folinate can be via the oral or intravenous route. This is given
orally as calcium folinate 15 mg tablets every 3 –6 hours depending
on the methotrexate level and chemotherapy protocol. Intravenous
administration is via an intravenous bolus given over 3 –5 minutes or
alternatively as a short infusion in sodium chloride 0.9% or
glucose 5%.
There are a number of dosing schedules of calcium folinate rescue
used for specific methotrexate regimens, with Table M4 being one
example.4
It is sometimes necessary to convert methotrexate into different
units and Table M5 shows equivalent values in moles, micrograms/L
and micromol/L.
Urine must be alkalinised (pH >7), usually with bicarbonate orally
or intravenously. If using the intravenous route a commonly used
k
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Methotrexate: calcium folinate rescue regimen 271
TABLE M4
Example of a folinate rescue remedy
Time after
starting Methotrexate plasma concentration (micromol/L)
methotrexate <0.1 0.1– <2 2– <20 20–100 >100
48 hours None 15 mg/m2 15 mg/m2 10 mg/m2 100 mg/m2
every 6 hours every 6 hours every 3 hours every 3 hours
TABLE M5
Conversion of serum methotrexate units M
Molar (M) micrograms/mL micromol/L
1 × 10 –3 460 1013 (or 1.013 × 103 )
1 × 10 –4 46 101 (or 1.01 × 102 )
1 × 10 –5 4.6 10.1 (or 1.01 × 101 )
1 × 10 –6 0.46 1.01
1 × 10 –7 0.046 0.1 (or 1 × 10 –1 )
1 × 10 –8 0.0046 0.01 (or 1 × 10 –2 )
k To convert micrograms/mL to micromol/L, divide by 0.454.
k
schedule is 50 mmol bicarbonate in 1000 mL sodium chloride 0.9%

given at a rate of 125 mL/m2 /hour initially (this can be doubled to
100 mmol bicarbonate if urine pH is not maintained above 7). Oral
dosing using tablets should be adjusted in response to urine pH to
account for interpatient difference in absorption rates. Two 600-mg
tablets every 4 –6 hours would be a reasonable starting dose. The
urine output should be maintained above 100 mL/m2 /hour (average)
until methotrexate level falls below 0.1 micromol/L.
Methotrexate and other medicines
Drugs that impair renal function should be avoided, e.g.
aminoglycosides, non-steroidal anti-inflammatory drugs, salicylates,
sulphonamides and high doses of penicillins.
Co-trimoxazole (and trimethoprim) should not be given
concomitantly with methotrexate as both the sulfamethoxazole and
trimethoprim components increase toxicity: sulfamethoxazole by
displacement from protein-binding sites and trimethoprim by
additive inhibition of dihydrofolate reductase. Pentamadine or
dapsone may be a suitable alternative for prophylaxis of Pneumocystis
jiroveci pneumonia in such patients.5
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272 Monofer
REFERENCES
1 Bleyer WA (1977). Methotrexate: clinical pharmacology, current status and thera-
peutic guidelines. Cancer Treat Rev 4: 87–101.
2 SPC (2014). Methotrexate Tablets, Injection. www.medicines.org.uk (accessed 29
September 2014).
3 SPC (2014). Calcium Folinate Tablets. Injection. www.medicines.org.uk (accessed 29
September 2014).
4 Medical Research Council Working Party on Leukaemia in Adults (2006). UKALL
XIV Trial Protocol. https://www.ctsu.ox.ac.uk/research/mega-trials/leukaemia-
trials/adult-all/ukall-xii-ph-positive-patients/protocol-v5 (accessed 29 September
2014).
5 Dollery C (ed.) (1999). Therapeutic Drugs (2nd edn), vol. 2. Edinburgh: Churchill
Livingstone, pp. M90–M96.
Monofer
M Overview (see also Iron: guidance on parenteral dosing and administration entry)1
Form Iron (III) isomaltoside
Dose Total dose required (mg iron)
= [bodyweight (kg) × (target Hb – actual Hb (g/L)) × 0.24] + X
iron stores (or depot iron) and is only applicable for patients >35 kg
Administration Intravenous infusion Intravenous instalments Intramuscular
routes Yes Yes No
k Administration ● Can be administered as a ● Doses up to 500 mg
k
single infusion for iron may be given by
cumulative doses up to intravenous bolus
20 mg/kg/body weight injection up to three
or times a week
● As weekly infusions until ● Can be given as
the cumulative dose has undiluted injection
been administered or diluted in a
● Doses exceeding maximum 20 mL of
20 mg/kg body weight sodium chloride
should be split into two 0.9%
administrations with an ● The injection should
interval of at least a week be administered at a
● Dilute in maximum rate of up to 50 mg
volume of 500 mL sodium iron/minute
chloride 0.9% ● Observe for adverse
● Administer over effects for at least
30 minutes for doses up 30 minutes
to 1000 mg iron following each
● Administer over injection
60 minutes for doses
exceeding 1000 mg
● Observe for adverse
effects for at least
30 minutes following
each injection
k
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Mouth ulcers and sore mouth 273
Specific con- ● Decompensated liver cirrhosis and hepatitis

traindications

hypersensitivity reactions during and following each administration2
each injection
REFERENCE
1 eMC (2014). Summary of Product Characteristics Monofer. https://www.medicines.
org.uk/emc/medicine/23669 (accessed 27 August 2014).
reactions: strengthened recommendations. http://www.gov.uk/drug-safety-
M
Mouth ulcers and sore mouth

Mouth ulcers are sores that form in the oral cavity, commonly seen on
the inside of the cheeks or lips. They typically present as painful,
round (or oval) inflamed sores with circumscribed margins and
erythematous haloes.1 They are usually white, red, yellow or grey in
colour2 and are usually self-limiting, healing within 2 weeks. Those
k that are very painful, have lasted more than 3 weeks or are recurrent k
should be referred to a general practitioner.
Causes
Common causes include mechanical trauma (e.g. tongue or cheek
biting) and thermal injury (i.e. contact with hot foods or liquid).
Certain triggers such as stress, hormonal changes and smoking
cessation as well as some foods, medications (e.g. aspirin and
nicorandil) and underlying conditions (e.g. viral infections and
vitamin B12 deficiency) can all increase the risk of mouth ulcers.2
Other common conditions that may also cause a sore mouth
include gum disease such as gingivitis, fungal infections such as oral
candidiasis, herpetic disease such as cold sores and oral mucositis
occurring post-chemotherapy.
Treatment options
Self-management includes treating the cause, using a softer
toothbrush, avoiding spicy or acidic foods and avoiding known
triggers.
Medications should aim to protect the ulcerated area, reduce pain
and inflammation and control secondary infection.3 Options include:
● saline mouth wash – half a teaspoonful of salt in a glass of warm
water used frequently and vigorously
● chlorhexidine gluconate 0.2% – use mouth wash 10 mL twice daily
or apply gel to affected areas once or twice daily
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274 Multiple sclerosis: symptomatic management
● topical corticosteroids, e.g. hydrocortisone oromucosal tablets

allowed to dissolve next to the ulcer; beclometasone dipropionate
inhaler 50 –100 micrograms sprayed twice daily on oral mucosa
(unlicensed indication); betamethasone soluble tablets 500
micrograms dissolved in water and used as a mouth wash but not
swallowed (unlicensed indication)
● local anaesthetics, e.g. lidocaine ointment 5% rubbed sparingly on
the affected areas or lidocaine spray 10% (unlicensed indication).
Proprietary products exist that are additionally mucoadhesive and
form a physical barrier protecting the lesion as it heals4
● local anti-inflammatories, e.g. benzydamine mouth wash or spray
● low-dose doxycycline (20 mg twice daily) is also used for recurrent
aphthous ulceration (unlicensed indication).
REFERENCES
1 Patient.co.uk (2013). Oral Ulceration. http://www.patient.co.uk/doctor/oral
M -ulceration (accessed 17 January 2015).
2 NHS Choices (2014). Mouth Ulcers. http://www.nhs.uk/conditions/Mouth
-ulcer/Pages/Introduction.aspx (accessed 17 January 2015).
3 BNF Online (2015). https://www.medicinescomplete.com/mc/bnf/current/
PHP7340-drugs-for-oral-ulceration-and-inflammation.htm?q=mouth%20ulcers&t=
search&ss=text&p=1# hit (accessed 17 January 2015).
4 SPC (2010). Iglü Gel. http://www.medicines.org.uk/emc/medicine/20777
k k
Multiple sclerosis: symptomatic
management
Multiple sclerosis (MS) is characterised by recurrent or chronically
progressive neurological dysfunction. It is caused by perivenular
inflammatory foci in the white matter of the central nervous system.
Repeated episodes of inflammation result in characteristic widespread,
demyelinated and sclerotic lesions (referred to as plaques) throughout
the brain, optic nerves and spinal cord of affected individuals. An
immune-mediated component is central to disease pathogenesis.1,2
The prevalence is about 100 cases per 100 000 people. The ratio of
women to men with MS is approximately 2:1. The disease shows a
geographic gradient of prevalence, with more cases found at the
northern latitudes of Europe and North America and at the southern
latitudes of New Zealand and Australia.1
To date there is no cure for MS. Disease-modifying therapies aim to
reduce the number of relapses, although it is not clear if they have an
effect on overall disease progression and disability. People with MS
typically develop symptoms in their late 20s, experiencing visual and
sensory disturbances, limb weakness, gait problems, bladder and
bowel symptoms. They may initially have partial recovery, but over
time develop progressive disability.2 Symptomatic relief therefore
forms a huge part of MS treatment, and is targeted around the most
troublesome symptoms for individual patients.
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Fatigue
Fatigue is one of the most common symptoms of MS and can be
incredibly debilitating for patients. It is described as an overwhelming
sense of tiredness with no obvious cause. Non-pharmacological
treatments can be effective and include amending lifestyle to
optimise, e.g. nutrition, relaxation techniques, sleep hygiene, physical
activity and treating depression.1,3
Pharmacological treatments include amantadine, a low-affinity
antagonist at the N-methyl-D-aspartate (NMDA) subtype of glutamate
receptors.2, 4 It is not licensed in the management of MS; however, its
use is recommended where pharmacological management of fatigue
is necessary.
Spasticity
The degree of spasticity can vary from person to person, day to day
and hour to hour. Posture is crucial in managing spasticity and pain;
correct positioning combined with daily stretching and targeted M
exercises can provide effective relief. When managing spasticity it is
also important to assess and offer treatment for factors that may
aggravate spasticity, such as constipation, infections or pressure
ulcers.1 – 3
The goal of treatment is to relieve the spasticity sufficiently to
ensure comfort and prevent complications, without taking away
rigidity needed to function. Baclofen or gabapentin are recommended
k for use first-line in the management of MS spasticity. Baclofen is a k
muscle relaxant, which works by simulating the gamma-aminobutyric
acid-B (GABAB ) receptors; this stimulation in turn inhibits the release
of the excitatory amino acids glutamate and aspartate. Common side
effects include drowsiness, muscle weakness and hypotension that
can limit tolerated doses.5 Gabapentin also exhibits its activity via
GABA receptors and is structurally related to the neurotransmitter
GABA. Common side effects include drowsiness, dizziness and
fatigue.6 Doses should be optimised as tolerated. If dose escalation of
one agent is not tolerated a combination of baclofen and gabapentin
can be used.
Alternative agents include tizanidine and dantrolene (which
requires careful monitoring of liver function). Benzodiazepines, e.g.
clonazepam, are considered as a third-line option, but are limited by
the risk of dependence and sedative effects. They can be useful in the
management of nocturnal spasms.2
If oral preparations are unhelpful, where spasticity is disabling
cannabinoid nasal spray or intrathecal baclofen could be considered.
Botulinum type A is a potential treatment, but limited by quantity and
frequency of administration required.
Bladder dysfunction
The most characteristic bladder complaint is of urgency and
frequency, sometimes with incontinence, but also with hesitancy and
poor stream. The NICE guidance on management of lower urinary
k
k
276 Multiple sclerosis: symptomatic management
tract dysfunction in neurological disease is a useful reference.7

Non-pharmacological management, e.g. reducing caffeine intake and
bladder retraining can be helpful.3 Pharmacological management is
often with antimuscarinic drugs for urge incontinence, including
oxybutynin, propantheline or tolterodine. Use is often limited by
antimuscarinic side effects, e.g. dry mouth. Desmopressin may be
useful in nocturnal frequency and incontinence. Bladder dysfunction
can lead to an increased risk of recurrent urinary tract infections,
which should also be managed.1
Other MS symptoms and potential treatments are shown in
Table M6.
TABLE M6
Overview of other multiple sclerosis symptoms
and potential treatments
Symptom Treatment options
M Bowel dysfunction – constipation Pharmacological: laxatives, loperamide
(most common) and faecal Non-pharmacological: increase dietary fibre,
incontinence (relatively uncommon) exercise and fluid intake
Sexual dysfunction – can be related to Pharmacological for erectile dysfunction:
sensation but also erectile dysfunction phosphodiesterase type 5 inhibitors,
e.g. sildenafil
Ataxia and tremor Pharmacological: propranolol, carbamazepine
Non-pharmacological: thalamotomy, thalamic
pacing, functional electrical stimulation (FES)
k k
Cognitive decline Pharmacological: disease-modifying drugs may
help slow decline
Non-pharmacological: psychological support,
memory aids
Pain – neuropathic, e.g. trigeminal Pharmacological: simple analgesia,
neuralgia and also musculoskeletal neuropathic pain agents
Non-pharmacological: mobility and posture
Depression and anxiety – lifetime Management as for depression in any other
prevalence of major depressive patient
disorder in patients with MS is 50%8
The likelihood of a patient requiring therapy for more than one

symptom is high. Therefore, it is important when managing symptoms
of MS to consider the whole patient, rather than each problem
individually. This helps to prevent polypharmacy and allows
utilisation of one drug for management of multiple symptoms,
e.g. gabapentin for spasticity and pain.
REFERENCES
1 Perkin GD, Wolinsky JS (2005). Fast Facts: Multiple Sclerosis (2nd edn). Oxford:
Health Press.
2 NICE (2014). Multiple Sclerosis: Management of multiple sclerosis in primary and
secondary care (CG 186). https://www.nice.org.uk/guidance/cg186 (accessed 28
January 2015).
k
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3 Rashid W et al. (2013). Guidelines: Symptomatic management of multiple sclerosis

in primary care. http://community.mssociety.org.uk/sites/default/files/resources/
resource files/Symptomatic%20management%20of%20MS%20in%20primary%
20care%20-%20MGP%20guideline.pdf (accessed 28 January 2015).
4 SPC (2014). Symmetrel Capsules. www.medicines.org.uk (accessed 28 January
2015).
5 SPC (2013). Lioresal Tablets 10 mg. www.medicines.org.uk (accessed 28 January
2015).
6 SPC (2015). Neurontin 100 mg. Hard Capsules. www.medicines.org.uk (accessed 28
January 2015).
7 NICE (2012). Urinary Incontinence in Neurological Disease: Management of lower
urinary tract dysfunction in neurological disease (CG 148). https://www.nice.org.uk/
guidance/cg148 (accessed 28 January 2015).
8 Feinstein A (2011). Multiple sclerosis and depression. Mult Scler 17: 1276–1281.
k k
k
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278 Nausea and vomiting
N
Nausea and vomiting
Antiemetics are used to treat nausea and vomiting from many causes,
e.g. in palliative care following chemotherapy (see Chemotherapy-
induced nausea and vomiting (CINV) entry) and postoperatively (see
Postoperative nausea and vomiting (PONV) entry).
To choose an antiemetic the following factors should be
N considered:
● mechanism of action
● ensuring no antagonism will occur if more than one antiemetic is
chosen
● whether an antisecretory effect is sought
● side effects
cost.
k k
●
If more than one antiemetic is required, select ones with different

mechanisms of actions (Table N1).
TABLE N1
Receptor site affinities of antiemetics1
Muscar-
Drug Class D2 H1 inic 5HT2 5HT3 5HT4 NK1
Chlorpromazine ++ ++ +
Cyclizine Histamine and acetyl- ++ ++
choline antagonism
Domperidone Dopamine antagonist ++
Haloperidol Dopamine antagonist +++
Hyoscine +++
hydrobromide
Levome- 5HT2 , dopamine, ++ +++ ++ +++
promazine acetylcholine and
histamine antagonism
Metoclopramide Dopamine antagonism, ++ + ++
5HT4 agonism
Ondansetron 5HT3 antagonism +++
Prochlorperazine ++ +
Aprepitant/ Neurokinin 1 (NK1) ++
fosaprepitant antagonism
Pharmacological activity: + = slight; ++ = moderate; +++ = marked
Reproduced with the permission of the copyright holder.
k
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Neuroleptic malignant syndrome 279
REFERENCE
1 Twycross R et al. (2014). Palliative Care Formulary (5th edn). Oxford: Radcliffe
Medical Press.
Neuroleptic malignant syndrome

Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal
idiosyncratic adverse drug reaction associated predominantly with
the use of antidopaminergic agents, but also the withdrawal of
dopaminergic agents. Other medicines have been implicated.1 The
syndrome can occur hours to months after the drug was initiated and
can vary from a few signs and symptoms to an acute severe attack.
Once the syndrome occurs the symptoms develop quickly over 24 –72
hours. Symptoms last up to 14 days following discontinuation of oral
drug therapy and up to three times as long after discontinuation of a
long-acting medicine.2
Signs and symptoms N
Signs and symptoms include:
● hyperthermia
● muscle rigidity (may include dysphagia and dyspnoea)
● altered consciousness
● autonomic instability, e.g. fluctuating blood pressure (BP),
k tachycardia, diaphoresis k
● raised creatine kinase (CK)
● leukocytosis
● altered liver function.
Risk factors
Risk factors include:
● previous NMS
● organic brain disease
● Parkinson’s disease
● high-potency typical antipsychotics, e.g. haloperidol
● high doses of antipsychotic drugs
● recent or rapid increase in dose
● dehydration/elevated ambient temperature
● agitation or catatonia
● abrupt withdrawal of antimuscarinics.
Management
Action and treatment will depend upon the severity of the syndrome,
and include the following:
● Immediately withdraw antipsychotic medicines or reinitiate
dopamine agonist.
k
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280 Neutropenic sepsis
● Correct dehydration and hyperthermia. Consider:

● intravenous dantrolene
● bromocriptine
● benzodiazepines
● cooling techniques and antipyretics.
● Monitor: temperature, pulse, BP, white cell count, CK (although
this is controversial) and liver function tests.
● Benzodiazepines may be used to sedate patients if necessary
(note that restraint and intramuscular injections can elevate CK).
● Electroconvulsive therapy (ECT) may be considered for treating
psychosis.
Cautious reintroduction of antipsychotics may be considered 2 weeks
after the resolution of NMS. Consider a structurally dissimilar drug,
or one with a low affinity for dopamine, e.g. quetiapine or clozapine.3
Depot injections are contraindicated. Start with a low dose and
increase very slowly. Monitor temperature, pulse and BP.
N REFERENCES
1 Bazire S (2012). Psychotropic Drug Directory 2012. Dorsington: Lloyd-Reinhold
Communications.
2 Cowen C et al. (2012). Shorter Oxford Textbook of Psychiatry (6th edn). Oxford:
Oxford University Press.
3 Taylor D et al. (eds) (2012). The Maudsley Prescribing Guidelines in Psychiatry
(11th edn). Chichester: Wiley-Blackwell.
k k
Neutropenic sepsis
Overview
Definition Systemic anticancer therapy can suppress the ability of the bone marrow
to respond adequately to infection, potentially leading to neutropenic
sepsis.
Neutropenic sepsis is a medical emergency that requires prompt
diagnosis and urgent treatment. Mortality rates of between 2% and 21%
have been reported for this potentially fatal complication of
chemotherapy treatment.1 Delays often occur in recognising neutropenic
sepsis and treating with antibiotics because of a lack of awareness or
because patients may present feeling well
Diagnosis A diagnosis of neutropenic sepsis should be considered in febrile (>38◦ C)
patients who have recently received treatment with chemotherapy or
radiotherapy and are unwell or have confirmed neutropenia.
It is important to note that patients may also be afebrile in certain
situations (e.g. if they have self-medicated with paracetamol)
Susceptibility Increased susceptibility to infection is likely when the neutrophil count
falls below 1 × 109 /L, with increasing risk when the neutrophil count
falls below 0.5 × 109 /L. Duration of neutropenia is also important, with
risk of infection increased especially if neutropenia lasts for more than
10 days2
k
k
Neutropenic sepsis 281
Initial inves- ● FBC

tigations ● CRP
● U&Es
● LFTs
● Blood gases (including lactate)
● Blood cultures (peripheral and also through intravenous catheter
lumens if line is in situ) – these should be repeated if fever persists
despite antibiotics
Assess ● Empirical antibiotic therapy should be given to all patients with

suspected neutropenic sepsis.2
● These should be administered as soon as possible after presentation
and ideally within 60 minutes.
● A typical regimen for a patient with no allergies may be beta-lactam
monotherapy such as piperacillin with tazobactam 4.5 g four times
a day given intravenously. Refer to local policy if penicillin-allergic
Essential ● Multinational Association for Supportive Care in Cancer (MASCC) N

intervention risk-scoring tool should be used to identify patients at low risk of
complications from neutropenic sepsis. Patients should be assessed
by a healthcare professional experienced in the management of
oncological emergencies and patients deemed to be low risk may be
suitable for early discharge with oral antibiotics. Patients who are not
at low risk should receive intravenous antibiotics3
Essential If patients remain febrile after 24–48 hours of antibiotics,
k k
●
intervention consideration should be given to the possibility of invasive fungal

infection and appropriate treatment and investigations commenced –
discussion with microbiology is always advised
Patient ● All patients receiving chemotherapy should be given information

information relating to their cancer treatment and potential side effects, including
what to do and whom to contact if these occur.
● Patients receiving chemotherapy should be advised to monitor their
temperature regularly and to contact their cancer centre or accident
and emergency if their temperature rises above 37.5◦ C. They should
also avoid crowded places and contact with people who are known to
have current infection
Neutropenic ● NICE recommends that prophylaxis with fluoroquinolones (e.g.
prophylaxis ciprofloxacin 500 mg twice daily) should be offered to adult patients
with acute leukaemias, stem cell transplants or solid tumours in
whom significant neutropenia (neutrophil count 0.5 × 109 /L or less)
is an anticipated consequence of chemotherapy.2
● Patients receiving chemotherapy for haematological malignancy may
also require prophylaxis with antiviral and antifungal agents
REFERENCES
1 National Chemotherapy Advisory Group (2009). Chemotherapy Services in England:
Ensuring quality and safety. http://webarchive.nationalarchives.gov.uk/+/www.dh
.gov.uk/en/Consultations/Liveconsultations/DH 090150 (accessed 12 May 2015).
k
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282 Nicotine replacement therapy
2 NICE (2012). Neutropenic Sepsis: Prevention and management of neutropenic sepsis in

cancer patients. NICE Clinical Guideline CG151 http://www.nice.org.uk/guidance/
cg151 (accessed 7 January 2015).
3 Klastersky J et al. (2000). The Multinational Association for Supportive Care in
Cancer Risk Index: a multinational scoring system for identifying low-risk febrile
neutropenic cancer patients. J Clin Oncol 18: 3038–3051.
Nicotine replacement therapy

All smokers should be advised to stop, unless there are exceptional
circumstances. Health professionals should use patient interaction
opportunities to provide brief interventions offering advice and help
with follow-up or provide referrals to specialist smoking cessation
services.1,2
Nicotine replacement therapy (NRT) is the most common form of
support therapy used. There are a wide range of products available,
which aim to reduce withdrawal symptoms associated with stopping
smoking by replacing the nicotine from cigarettes. The use of NRT
N increases the chance of a person succeeding in smoking cessation.3
Options available
Patches that release nicotine transdermally over 16 or 24 hours
provide a controlled prolonged method of preventing cravings from
cigarettes. A 24-hour patch is beneficial in patients who experience
strong nicotine cravings on waking, although higher-dose
k preparations may result in patients experiencing nightmares.1 k
Gums, lozenges, sublingual tablets, inhalators, nasal sprays and
oral sprays are immediate-release nicotine preparations and are used
to treat urges to smoke or prevent cravings.1 Effectiveness of smoking
cessation is more dependent on patient preference and tolerance of
NRT than any differences between the products themselves.3
Combinations of a prolonged-release formulation and an
immediate-release preparation have proved to be most successful,
along with intensive behavioural support from a specialist smoking
cessation service.4
Electronic cigarettes
The Royal Pharmaceutical Society supports the use of licensed
products as an NRT option, but until the MHRA enforces this market
(expected in 20165 ) unlicensed products should not be recommended
due to concerns of safety and efficacy.6
Pharmacokinetics
Nicotine is absorbed well through the skin and mucous membranes.
Orally nicotine has very low bioavailability due to extensive first-pass
metabolism.
Nicotine is well distributed, crossing the blood–brain barrier and
placenta, and is found in breast milk. It is metabolised mainly in the
liver via CYP450 isoenzyme CYP2A6. Nicotine and its metabolites are
excreted in the urine.7
k
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Nicotine replacement therapy 283
Cautions and side effects

Most risks associated with NRT also apply to cigarette smoking, but
starting NRT when patients have acute cardiac changes should be
done under specialist advice. Overall the benefits of smoking
cessation with the use of NRT outweigh the risk of continuing
smoking and should always be encouraged. Consideration should be
given to the potential systemic and local effects of nicotine that vary
in each preparation.1
Systemic side effects can occur with high-strength preparations;
however, patients often confuse nicotine withdrawal symptoms with
side effects from NRT. Common side effects of nicotine withdrawal
include malaise, headache, dizziness, sleep disturbance, coughing,
influenza-like symptoms, depression, irritability, increased appetite,
weight gain, restlessness, anxiety, drowsiness and impaired
concentration.1
Local side effects are common when NRT is commenced due to
nicotine’s irritant effect. Examples include skin irritation from
patches, irritated throat from sprays and increased salivation from N
gum and lozenges. Gastrointestinal disturbances are also common
due to the amount of swallowed nicotine.1
Other information
Nicotine is a highly addictive drug in every form. Patients should be
encouraged to reduce their dosage of NRT over several months to
k prevent transferring dependence from one form of nicotine delivery k
to another.5
Tobacco smoking induces the metabolism of many different
medicines.1 When commencing NRT or advising patients to stop
smoking, consider the need to alter doses of their medication to
prevent toxicity. See entry on Cigarette smoking – drug interactions,
for more detail.
REFERENCES
2 National Institute for Health and Clinical Excellence (2006). N1014. Brief Interven-
tions and Referral for Smoking Cessation in Primary Care and Other Settings, Quick
reference guide. London: NICE.
3 Stead L et al. (2008). Nicotine replacement therapy for smoking cessation. Cochrane
Library 3.
4 National Institute for Health and Clinical Excellence (2013). Public health guid-
ance 48. Smoking Cessation in Secondary Care: Acute, maternity and mental health
services. London: NICE.
5 MHRA (2013). UK Moves Towards Safe and Effective Electronic Cigarettes and Other
Nicotine-Containing Products. http://www.mhra.gov.uk/home/groups/comms-po/
documents/news/con286856.pdf (accessed 7 January 2015).
6 RPS (2013). Guidance on Electronic Cigarettes. http://www.rpharms.com/support-
alerts/support-alert-article.asp?id=880 (accessed 7 January 2015).
7 Brayfield A (ed.) (2014). Martindale: The Complete Drug Reference. www.medicines
complete.com (accessed on 4 December 2014).
k
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284 ’Nil-by-mouth’: management of long-term medicines
‘Nil-by-mouth’: management of long-term

medicines during surgery
‘Doctors and nurses need to understand the difference between
preoperative medication and the full English breakfast.’ This is a
quote taken from the National Clinical Enquiry into Perioperative
Deaths.1 The report stated that many patients had their routine
medication omitted prior to surgery as they were ‘nil-by-mouth’
(NBM). The administration of medicines throughout the
perioperative period should be considered in a timely fashion before
surgery, as some medicines may need to be stopped with sufficient
time to diminish their therapeutic actions or other effects. The
administration and appropriateness of medicines after surgery should
be considered if the NBM status is prolonged and the oral route is
compromised.
Traditionally, patients were kept NBM from midnight the night
before surgery. This led to poor nutritional intake and prolonged
N
recovery, as vital oral medicines were unnecessarily omitted. With the
introduction of enhanced recovery after surgery (ERAS)2 principles,
it is now standard practice to continue regular medication up to the
point of surgery unless contraindicated. Evidence demonstrates that
shortened periods of perioperative fasting do not increase the risk of
harmful events for the patient, such as aspiration pneumonitis.3 Oral
medicines can be taken with clear fluids up to 2 hours prior to surgery
k without any detrimental effects.4
k
The decision whether to stop medication during the perioperative
period or not should be based on the following:5
● consequences of not giving the medication
● indication for the drug
● risk of giving the medication – interactions, contraindications
● potential time scale of NBM and impact
● practicalities of administering the medication
● is replacement therapy indicated?
● administration via feeding tubes
● what are the effects of abrupt withdrawal?
The consequences of withholding certain medicines during the

perioperative period could have detrimental effects on disease
management, cause withdrawal or exacerbate a disease state. This
should be weighed up against the potential risks associated with
giving the drug – haemodynamic instability, bleeding risk, drug
interactions or impaired healing.
There is not a definitive answer for every medicine a patient may
be taking; however, there are numerous literature resources available.
Examples of medicines that are contraindicated during surgery or
that pose a risk if continued are given in Table N2.6
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’Nil-by-mouth’: management of long-term medicines 285
TABLE N2
Examples of groups of medicines and action during
perioperative period
Medicine Action to be taken Additional comments
name/group preoperatively
Antiplatelets Usually stop 7–10 days Indication of antiplatelet must be
prior to surgery considered and risk of stopping versus
depending on half-life risk of surgical bleeding, i.e. use of
of drug and accounts clopidogrel and aspirin post acute
for platelet half-life coronary syndrome within 12 months.
Restart as soon as bleeding risk
reduced
Anticoagulants Stop 5–7 days prior to May require LMWH as bridging
surgery. Require INR to therapy once INR less than therapeutic
be less than 1.5 range. Indication of anticoagulant and
risk of VTE determines whether
treatment dose or prophylactic dose of
LMWH is given
N
Lithium Can discontinue Interacts with many anaesthetic
24–48 hours prior to agents, as can prolong neuromuscular
surgery blockade. Can continue lithium and
use alternative anaesthetic agents to
reduce risk. Avoid use of non-steroidal
anti-inflammatory drugs. Avoid
dehydration and monitor electrolytes
k closely k
MAOIs Stop 2 weeks before Alternatively, continue and avoid
surgery. Newer MAOIs interacting agents during surgery –
are reversible after discuss with anaesthetist
24–48 hours. Take
psychiatric advice
before stopping
Hormone If to be discontinued, If stopped, there is risk of recurrence of
replacement stop 4 weeks prior to menopausal symptoms but there is an
therapy surgery increased risk of VTE if continued. Can
reduce VTE risk through use of LMWH.
This decision must be discussed with
the patient and a plan decided
preoperatively
Oestrogen- Patients can be given If continued, risk of VTE can be
containing the option to reduced through use of LMWH and
contracep- discontinue 4–6 weeks other mechanical precautions
tion prior to surgery but
must ensure adequate
contraceptive cover
Herbal Stop as far in advance Little evidence available about half-life
medicines before surgery as of herbal medicines. Many interactions
possible with perioperative medicines and
effect on patient haemodynamics
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Management of patients with diabetes

As a general principle, when patients who have diabetes require a sur-
gical procedure, steps should be taken to minimise the period of fasting
involved by ensuring the patient undergoes the procedure in the morn-
ing and is placed first on the surgical list. This is not always possible
if the surgery is an emergency but being aware of which patients have
diabetes mellitus is vital. A thorough medical and drug history of such
patients is therefore very important, as this will influence the manage-
ment throughout the perioperative period. Determining factors are:5
● timing of surgery
● usual treatment regimen:
● insulin
● oral hypoglycaemics
● diet control
● how effectively the patient’s diabetes is controlled prior to
admission
N ● duration of starvation.
Type 1 or type 2 diabetes?

Patients who have type 1 diabetes are unable to produce insulin of
their own and care must be taken to ensure that these patients do not
become completely insulin-deficient at any time. The gold standard
when treating these patients is use of the variable-rate intravenous
k insulin infusion (VRIII), previously known as ‘sliding scale’. The use of k
VRIII is determined by the length of time the patient is expected to be
NBM. If more than one meal is missed then an insulin infusion is
indicated. Fewer than this, blood glucose levels can be managed with
the patient’s regular insulin regimen and intravenous fluids.
Patients who have type 2 diabetes can secrete their own insulin
and are therefore much less likely to develop diabetic ketoacidosis.
However, many type 2 patients do effectively become
insulin-dependent during major surgery because of the physiological
stress involved, and should be managed as such. Type 2 patients who
are normally treated with diet alone will require much less aggressive
treatment, particularly during minor surgical procedures, than those
who require oral hypoglycaemic drugs to augment insulin secretion.
The patient’s usual level of diabetes control
Well-controlled diabetic patients will not have to be in hospital for as
long as those whose control is poor. Poorly controlled diabetics are
known to be at increased risk of perioperative complications and
mortality, and are prone to metabolic problems and poor wound
healing. Patients whose HbA1c indicates inadequate diabetic control
will require to be admitted earlier for stabilisation of blood glucose
levels prior to surgery or referred to a diabetes specialist nurse for
drug therapy optimisation preoperatively. This demonstrates the
importance of identification of such patients during the preoperative
assessment or at the point of decision to operate.5
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’Nil-by-mouth’: management of long-term medicines 287
Duration of the surgical procedure and likely postoperative course

For procedures where the patient is expected to eat and drink within
4 hours of the operation, the relatively short duration of the fast
involved for these procedures means that type 2 patients can often
simply omit oral hypoglycaemics on the morning of surgery and
restart therapy as soon as the first meal is eaten. Blood glucose levels
require close monitoring and subcutaneous insulin may be required if
they begin to rise. It is good practice for ‘when required’ short-acting
insulin and glucose rescue therapy to be prescribed on the drug chart
of patients with diabetes during this period.
Intravenous insulin replacement in patients with diabetes
The VRIII is a continuous infusion that is adjusted according to the
patient’s blood glucose concentrations.
● A glucose-containing infusion must be administered alongside the

insulin, so that hypoglycaemia is avoided.
● Potassium-containing fluid must also run alongside to prevent N
insulin-induced hypokalaemia.
● Patients maintained on long-acting subcutaneous insulin should
continue to receive it in order to reduce the risk of the development
of ketonaemia and ketoacidosis.
VRIII should be withdrawn as soon as the patient is able to eat and

k drink. If the patient is usually treated with insulin, the VRIII should be k
continued for at least 30 –60 minutes after giving the SC dose in
association with a meal. For further information see Insulin:
variable-rate intravenous insulin infusion entry.
Management of patients on corticosteroids7

Surgery causes an increase in plasma adrenocorticotrophic hormone
and cortisol concentration. The magnitude of the increase is related to
the amount of physical and psychological stress caused by surgery –
major surgery tends to cause a greater increase compared to minor
surgery. However, in a patient who either usually takes oral corti-
costeroids, or who has taken them recently, the hypothalamic –
pituitary– adrenocortical (HPA) axis may be suppressed and so the
natural stress response is impaired. Without an adequate cortisol
replacement, the patient is at risk of hypoadrenal crisis (i.e.
circulatory collapse and shock). The following factors must be taken
into account when deciding on the level of corticosteroid
replacement, and Table N3 gives further guidance:
● the dose of the steroid and the dosage regimen

● the duration of the steroid therapy
● the original adrenal status
● the type of surgery to be carried out
● if the patient has taken steroids in the past 3 months.
k
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TABLE N3
Perioperative corticosteroid replacement therapy
Patients <10 mg/day Assume Increased corticosteroid cover not
currently prednisolone normal HPA required
taking or equivalent response
corticosteroids
≥10 mg Minor surgery 25 mg hydrocortisone sodium
prednisolone succinate at induction
or equivalent Moderate Usual preoperative corticosteroids,
surgery 25 mg hydrocortisone sodium
succinate at induction and
100 mg/day for 24 hours (this can
be given as divided doses or
continuous infusion)
Major surgery Usual preoperative corticosteroids,
25 mg hydrocortisone sodium
succinate at induction and 100
mg/day for 48–72 hours
N High-dose Give usual immunosuppressive doses during
immuno- perioperative period
suppression
Patients who <3 months Treat as if taking corticosteroids
have stopped ago
taking
corticosteroids >3 months No additional perioperative corticosteroids
ago
k k
Administration of hydrocortisone sodium succinate via infusion,
rather than bolus injection, avoids large swings in plasma cortisol
concentration and is therefore preferred.
Administration of medicines via feeding tubes

The administration of medicines via feeding tubes is one of the most
common causes of tube blockage, and therefore it is extremely
important to ensure the most appropriate formulation is used. To
cover the administration of every medicine down a tube is beyond the
scope of this book; however, there are several useful reference sources
now available both on the internet (which are password-
protected) for advice regarding individual drugs (subscription
required)8 or general advice (password-protected)9 and now as a
handbook10 (see Enteral feeding systems and drug administration
entry). The following basic principles should be remembered.
● Administration of many medicines via tubes is unlicensed.
● Do not crush enteric-coated, modified/slow-release (immediate
release of high doses), cytotoxics and hormone preparations (risk
to operator).
● Interactions may occur with the feed.
● Flushing with water before, after and between medicine
administrations is essential to reduce the risk of blockage.
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REFERENCES
1 National Confidential Enquiry into Perioperative Deaths (2002). Functioning as a
Team? London: CEPOD.
2 Niranjan N et al. (2014). Enhanced Recovery after Surgery – Current trend in
peri-operative care. Update in anaesthesia. www.anaesthesiology.org (accessed
7 October 2014).
3 Royal College of Nursing (2005). Peri-operative Fasting in Adults and Children.
www.rcn.org.uk (accessed 7 October 2014).
4 AAGBI (2001) Pre-operative Assessment. The role of the anaesthetist. Association
of Anaesthetists of Great Britain and Ireland. www.aagbi.org/pdf/pre-operative
ass.pdf (accessed 7 October 2014).
5 ASGBI (2012). Issues in Professional Practice: Peri-operative management of the
adult patient with diabetes. www.asgbi.org.uk (accessed 13 May 2015).
6 Rahman MH, Beattie J (2004). Medication in the peri-operative period. Pharm J
272: 287–289.
7 Nicholson G et al. (1998). Perioperative steroid supplementation. Anaesthesia 53:
1091–1104.
8 White R and Bradnam V (2015). Handbook of Drug Administration via Enteral
Feeding Tubes. www.medicinescomplete.com.
9 BAPEN (2014). http://www.bapen.org.uk/pdfs/drugs%26enteral/practical-guide
-poster.pdf (accessed 7 October 2014). N
10 The Royal Hospitals (2004). Administering Medicines Through Enteral Feeding
Tubes (2 edn). Belfast: Pharmacy Department, Royal Hospitals.
Nutraceuticals for eye health

k Age-related macular degeneration (AMD) affects the central area k
of the eye (macula) and causes central vision to become blurry/
distorted. Over time this progresses to a blank patch in the centre of
vision.1 Although the exact cause is unknown, there are several
factors involved:
● age: more common in those over 65 years of age
● gender: more common in women
● family history of AMD
● smoking: increases the risk
● sunlight and diet.
Several dietary supplements claim to improve eye health; these
supplements are available to buy from pharmacies, online and in
health food shops.
The underlying cause of AMD is thought to be free-radical damage
to the macula. A small percentage of free radicals are produced
naturally by the body as it uses oxygen; however, cigarette smoking
and exposure to ultraviolet radiation and visible blue light, which
occurs naturally in sunlight, greatly increase free-radical generation.
Antioxidants have the potential to combat free radicals, and therefore
their use in protection from AMD has become popular.2
Vitamin C is used for growth and repair of tissues and supports
healthy blood vessels. Vitamin E is a major antioxidant of all retinal
cell membranes. Vitamin A comes in two forms in the human diet –
preformed and provitamin. Preformed vitamin A (retinol) is in food
k
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290 Nutraceuticals for eye health
from animal sources, e.g. fish and meat. Provitamin A carotenoids are
mainly found in fruit and vegetables; beta-carotene is a provitamin A
carotenoid that is converted to vitamin A in the body. Vitamin A is an
essential component of rhodopsin, a protein that absorbs light in the
cells of the eye.
Dietary xanthophylls lutein and zeaxanthin are found in high
concentrations in the macula where they are called the macular
pigment. The macular pigment protects the macula by interacting
with free radicals and filtering out the damaging blue light.3
Evidence
In 2001 the Age-Related Eye Disease Study (AREDS), conducted in
the USA by the National Institutes of Health, established that the
AREDS formula (vitamin A (as beta-carotene) 15 mg, vitamin C 500
mg, vitamin E 400 IU, zinc 80 mg, copper 2 mg) can help slow the
progression of AMD. In the AREDS trial, participants with AMD who
took the AREDS formula were 25% less likely to progress to advanced
N AMD over the 5-year study period compared with placebo.4
Beta-carotene use has been linked to a heightened risk of lung
cancer in smokers and ex-smokers. High zinc doses can cause minor
side effects, such as stomach upset.5
A 5-year follow-up study began in 2006, called AREDS2 and
conducted by the National Eye Institute. The second study aimed to
find out if the original AREDS formulation could be improved by
adding the carotenoid vitamins (lutein and zeaxanthin), omega-3
k k
fatty acids, removing beta-carotene or reducing zinc. No overall
additional benefit was gained from adding omega-3 fatty acid or a
mixture of lutein and zeaxanthin to the AREDS formula. There was no
apparent difference in effect when a lower zinc dose given. There was
an 18% reduction in developing advanced AMD in the subgroup that
received the AREDS formula plus lutein and zeaxanthin with no
beta-carotene. Those with a low dietary intake of lutein and
zeaxanthin who received the AREDS formula plus lutein and
zeaxanthin were 25% less likely to develop advanced AMD compared
to those with a similar dietary intake who did not receive lutein and
zeaxanthin.6 No matter which supplement was taken, after 5 years
30% of patients in AREDS2 progressed to advanced AMD.
Long-term use of the AREDS supplements appears safe and
protective against advanced AMD. Zinc is an important component
but it is unclear how much is necessary. Omega-3 fatty acids and
beta-carotene do not reduce the risk, but adding lutein 10 mg and
zeaxanthin 2 mg in place of beta-carotene may help.7
Products available in the UK
● Recommended daily dose of Viteyes 2 contains the AREDS2
formula (vitamin C 500 mg, vitamin E 400 IU, lutein 10 mg,
zexanthin 2 mg, copper 2 mg, zinc 25 mg).
● Recommended daily dose of PreserVision AREDS2 is the same
except it contains zinc 80 mg.
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Diet
● Lutein is found in kale, red pepper, lettuce, leek, spinach, celery,
broccoli, peas, sprouts and eggs.
● Zeaxanthin is found in corn, eggs, oranges and yellow fruit and
vegetables.
REFERENCES
1 Royal College of Ophthalmologists and Royal National Institute of Blind People
(2013). Age Related Macular Degeneration. http://www.rnib.org.uk/eye-health-eye-
conditions-z-eye-conditions/age-related-macular-degeneration-amd (accessed 21
October 2014).
2 Macular Society (2015). Antioxidant Vitamins. http://www.macularsociety.org/
about-macular-conditions/Nutrition/AntioxidantVitamins-A-C-E (accessed 25
January 2015).
3 Macular Society (2015). Lutein and Zeaxanthin. http://www.macularsociety.org/
about-macular-conditions/Nutrition/Xanthophylls-Lutein-Zeaxanthin-Meso-
zeaxanthin (accessed 28 January 2015).
4 The Royal College of Ophthalmologists (2013). Press release. Diet Study Clarifies
Optimal Nutrient Formula for Protecting Against AMD. http://www.rcophth.ac.uk/ N
news.asp?itemid=1369&itemTitle=Diet+study+clarifies+optimal+nutrient+
formula+for+protecting+against+AMD&section=24&sectionTitle=News (accessed
21 October 2014).
5 National Institute of Health (2013). NIH Study Provides Clarity on Supplements for
Protection Against Blinding Eye Disease. http://www.nih.gov/news/health/may2013/
nei-05.htm (accessed 21 October 2014).
6 Macular Society (2014). AREDS 2 Study Results Show Promise for Some.
k http://www.macularsociety.org/How-we-help/About-us/Newsroom/Press-releases/ k
areds-2-study-results-show-promise-for-some (accessed 21 October 2014).
7 Chew EY et al. (2013). Long-term effects of vitamins C, E, beta-carotene and zinc on
age-related macular degeneration. Ophthalmology 120: 1604–1611.
k
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292 Omeprazole: parenteral administration
O
Omeprazole: parenteral administration
40 mg dry-powder vials
● Omeprazole sodium is a proton pump inhibitor (PPI).

● It is used intravenously (IV) when the oral route is temporarily
unavailable, to treat conditions where inhibition of gastric acid
secretion may be beneficial: treatment and prevention of gastric
O and duodenal ulcers, in gastro-oesophageal reflux disease and
Zollinger–Ellison syndrome.
● It is also used (unlicensed) for acute gastrointestinal bleeding and
to prevent rebleeding following therapeutic endoscopy for acute
bleeding gastric or duodenal ulcers.
There are two preparations available: IV injection and IV infusion.
k k
●
The IV injection preparation is accompanied by 10 mL special

solvent containing macrogol 400, citric acid and water for
injection, and is not suitable for IV infusion.
● Doses are expressed in terms of omeprazole:
Omeprazole 40 mg ≡ 42.6 mg omeprazole sodium.
Pretreatment checks
PPIs may mask symptoms of gastric cancer (and delay diagnosis);
when a gastric ulcer is suspected, the possibility of malignancy should
be excluded before treatment is instituted.
Biochemical and other tests
These include liver function tests (LFTs).
Dose1,2
● Prophylaxis of acid aspiration: 40 mg by IV injection or infusion
completed 1 hour before surgery.
● Benign gastric ulcer, duodenal ulcer and gastro-oesophageal
reflux: 40 mg by IV injection or infusion once daily, until oral
administration is possible (recommended duration of treatment is
up to 5 days).
● Zollinger–Ellison syndrome: 60 mg by IV injection or infusion
twice daily.
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● Gastrointestinal haemorrhage following successful haemostasis of

bleeding peptic ulcers (unlicensed): 80 mg by IV injection followed
by a continuous IV infusion of 8 mg/hour for 72 hours.3
● Dose in hepatic impairment: 20 mg daily by IV injection or infusion
may be sufficient.
Intermittent intravenous infusion (using a preparation
for IV infusion)
Preparation and administration
1 Add approximately 5 mL of compatible infusion fluid from a 100 mL
bag to each omeprazole vial.
2 Mix thoroughly to dissolve and transfer the required dose to the
infusion bag.
3 Repeat steps 1 –2 to ensure the full dose is transferred or use a
double-ended transfer needle device for the whole process.
4 The solution should be clear and colourless. Inspect visually for
particulate matter or discolouration prior to administration and
discard if present.
5 Give by IV infusion over 20 –30 minutes.
O
Intravenous injection
1 Withdraw 10 mL of solvent from the ampoule provided and add
approximately 5 mL to the omeprazole vial.
k 2 Immediately withdraw as much air as possible from the vial back k
into the syringe in order to reduce positive pressure and add the
remaining solvent into the vial.
3 Rotate and shake the vial to ensure all the powder has dissolved.
particulate matter or discoloration prior to administration and
discard if present.
5 Give by IV injection over 5 minutes.
Continuous intravenous infusion (using a preparation

for IV infusion)
Various (unlicensed) regimens are used. The one below produces a
solution containing 200 mg/500 mL.
1 Reconstitute each of five vials (total 200 mg) with 5 mL of
compatible infusion fluid taken from a 500 mL infusion bag and
mix thoroughly to dissolve.
2 Withdraw the required dose (ensuring the entire vial contents
are transferred) and add to the 500 mL bag, e.g. 5 × 40 mg
vials added to 500 mL NaCl 0.9% gives a solution containing
400 micrograms/mL.
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294 Omeprazole: parenteral administration

particulate matter or discolouration prior to administration and
discard if present.
4 Give by IV infusion at a rate of 8 mg/hour, i.e. 20 mL/hour of a 400
micrograms/mL solution. Prepare a fresh infusion bag every 24
hours.
Technical information4
Incompatible with: Lorazepam, midazolam, tigecycline, vancomycin

Compatible with: Flush: NaCl 0.9%
Solutions: NaCl 0.9%, glucose 5%. Some generic brands state
that only glucose 5% may be used as a diluent, but all
preparations are similarly formulated.
Y-site: No information, but likely to be unstable
pH 8.8–10.5
Sodium content Negligible
O
Storage Store below 25◦ C in original packaging
Stability after From a microbiological point of view, should be used
preparation immediately. However:
● Reconstituted vials may be stored at room temperature and
used within 4 hours.
k ● Prepared infusions may be infused (at room temperature) k
within 24 hours
Monitoring
Measure Frequency Rationale

Signs of infection Throughout treatment ● Use of antisecretory drugs may increase
risk of infections, such as
community-acquired pneumonia,
Salmonella, Campylobacter and
Clostridium difficile-associated disease
LFTs Periodically ● Altered LFTs and hepatitis have been

reported
Renal function ● Acute interstitial nephritis has been
reported with PPIs.
● ↓Na has been reported with PPIs
Vitamin B12 ● If on long-term therapy, malabsorption

of vitamin B12 has been reported
k
k
Additional information
Common and Immediate: hypersensitivity reactions, including anaphylaxis and

serious undesirable bronchospasm, have been reported very rarely.
effects Injection/infusion-related
● Local: administration site reactions, particularly with
prolonged infusion.
Other
● Common: nausea, vomiting, abdominal pain, flatulence,
diarrhoea, constipation, headache, dry mouth, peripheral
oedema, dizziness, sleep disturbances, fatigue, paraesthesia,
arthralgia, myalgia, rash and pruritus.
● Rare: taste disturbance, stomatitis, ↑liver enzymes, hepatitis,
jaundice, fever, depression, hallucinations, confusion,
gynaecomastia, interstitial nephritis, ↓Mg, ↓Na, blood
disorders (including leucopenia, leucocytosis, pancytopenia
and thrombocytopenia), visual disturbances, sweating,
photosensitivity, alopecia, Stevens–Johnson syndrome and
toxic epidermal necrolysis
Pharmacokinetics Approximate plasma half-life is 0.5–3 hours. The IV infusion O
produces an immediate decrease in intragastric acidity and a
mean decrease over 24 hours of approximately 90%2
Significant The following may ↓omeprazole levels or effect:
interactions1 Tipranavir.
k Omeprazole may ↑levels or effect of the following drugs (or ↑side k
effects):
Cilostazol (avoid combination), coumarins (monitor INR),
raltegravir (avoid combination).
Omeprazole may ↓levels or effect of the following drugs:
Atazanavir (avoid combination), clopidogrel (avoid combination),
nelfinavir (avoid combination).
Omeprazole may affect the following tests:
Antisecretory drug therapy may cause a false-negative urea
breath test.
May give false-positive tetrahydrocannabinol urine screening test
results
Action in case of Stop administration and give supportive therapy as appropriate
overdose
REFERENCES
1 Joint Formulary Committee (2015). British National Formulary (online). London:
2 Electronic medicines compendium (2014). www.medicines.org.uk (accessed
14 September 2015).
3 Hasselgren G et al. Optimization of acid suppression for patients with peptic ulcer
bleeding: an intragastric pH-metry study with omeprazole Eur J Gastroenterol
Hepatol 1998; 10: 601–606.
4 Trissell LA (2012) Handbook on Injectable Drugs www.medicinescomplete.com
k
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296 Oncological emergencies
Oncological emergencies
Hypercalcaemia
Hypercalcaemia is an oncological emergency associated with
advanced cancer. It can be life-threatening due to the effect of
calcium on the kidneys, heart and brain. Ninety per cent of cases
are caused by primary hyperparathyroidism or cancer.1
Hypercalcaemia may occur with or without bone metastases. It is
caused by the release of parathyroid hormone-related peptide from
cancer cells and most commonly occurs in squamous cell lung cancer,
breast cancer and myeloma. Classification is shown in Table O1.
TABLE O1
Severity classification of hypercalcaemia
Severity Adjusted calcium (mmol/L)
Mild 2.65–3.0
Moderate 3.01–3.4
Severe >3.4
O
Symptoms are often non-specific and depend on the severity of
hypercalcaemia and the rate of onset. Symptoms may include
polyuria/polydipsia, nausea and vomiting, constipation, muscle
weakness, confusion and drowsiness.
k Rehydration is the first-line management of hypercalcaemia k
associated with malignancy. IV bisphosphonates (e.g. pamidronate or
zoledronate) may also be given to reduce calcium resorption from
bone. It is also important to stop any calcium-containing medicines
and thiazide diuretics.
Metastatic spinal cord compression
Metastatic spinal cord compression occurs either through direct
tumour compression of the spinal cord or via vertebral instability due
to bony metastases. Back pain is almost always a feature and this may
occur at any point along the vertebrae. Pain is usually the first sign of
spinal cord compression and may be new or a significant change to
long-standing pain.
Other symptoms caused by pressure on the spinal nerves may
include motor deficits (e.g. muscle weakness, loss of coordination,
paralysis), sensory deficits (e.g. paraesthesia, loss of sensation) or
autonomic dysfunction (loss of control of bladder or bowel).
There are approximately 4000 new cases per year in England and
Wales and 25% of patients may not have an established cancer
diagnosis at the time of presentation.2
Treatment of metastatic spinal cord compression may include
surgery, radiotherapy or corticosteroids (e.g. dexamethasone
16 mg/day with PPI).
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Opioid comparative doses 297
Superior vena cava obstruction

Superior vena cava obstruction (SVCO) may be caused by external
pressure, thrombus or direct tumour invasion. Ninety-five per cent of
cases of SVCO are due to malignancy and 70 –80% are in patients
with lung cancer.3
Symptoms may be gradual or acute in onset and include:
dyspnoea, elevated jugular venous pressure, face/arm swelling, chest
pain, cough and dilated blood vessels over trunk/arms/neck.
Initial treatment of SVCO includes oxygen, corticosteroids (e.g.
dexamethasone 16 mg/day with PPI) and sitting upright.
Chemotherapy may be an effective treatment in chemosensitive
cancers such as lymphoma, germ cell or small-cell lung cancers. If a
clot is the cause for SVCO, anticoagulation should be considered.
Neutropenic sepsis
See Neutropenic sepsis entry.
REFERENCES
1 NICE (2014). Clinical Knowledge Summaries. Hypercalcaemia. http://cks.nice.org.uk/
hypercalcaemia (accessed 7 January 2015).
2 NICE (2008). Metastatic spinal cord compression: Diagnosis and management of
O
adults at risk of and with metastatic spinal cord compression. NICE Clinician Guide-
line CG75. https://www.nice.org.uk/guidance/cg75 (accessed 7 January 2015).
3 NICE (2004). Stent placement for vena cava obstruction. NICE interventional
procedures guidance IPG79. https://www.nice.org.uk/guidance/ipg79 (accessed
7 January 2015).
k k
Opioid comparative doses

Although morphine is still considered the first-choice opioid,1 it is
often necessary to consider converting or switching to an alternative
opioid, perhaps because of lack of analgesic benefit or intolerable
side effects.2 In order to do this safely it is essential to have an under-
standing of the relative analgesic potency of different opioids. Table O2
shows the approximate analgesic potency of other commonly used
oral opioids compared with morphine – this should not be confused
with equivalent doses as some of these opioids have a ceiling effect.3
Conversion for different routes of morphine
administration
If it is necessary to convert to subcutaneous or intramuscular
morphine, the parenteral dose is half that of the oral morphine dose,
e.g. 10 mg oral morphine ≡ 5 mg subcutaneous or intramuscular
morphine.2
Converting between morphine and diamorphine
To convert from oral morphine to diamorphine, the dose is
approximately one-third of the oral morphine dose, i.e. the total dose
of morphine (mg) given during the previous 24 hours divided by 3,
and this gives the dose of diamorphine to be administered over
24 hours by continuous infusion. A dose of approximately one-tenth
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298 Opioid misuse management
TABLE O2
Equianalgesic opioid potency
Opioid Potency ratio with oral morphine
Buprenorphine 75–115
Codeine 1/10
Dihydrocodeine 1/10
Fentanyl 100–150
Hydromorphone 4–7.5
Methadone 5–10
Oxycodone 1.5–2
Pethidine 1/10
Tapentadol 2.5
Tramadol 1/10–1/5
to one-sixth of the total daily dose of diamorphine should be

prescribed by subcutaneous injection for breakthrough pain. The
O patient should be monitored regularly and the dose of diamorphine
given by continuous infusion and breakthrough pain adjusted
according to the total requirement for the previous 24 hours.
It is essential to remember that great caution is always necessary
when switching between different opioids or routes of administration:
careful monitoring of the patient is essential as there is much
k interpatient variability. Subsequent dose adjustments may still be k
necessary. Conversion ratios are never more than an estimate and they
should be used as a guide only, as they are based largely on single-dose
studies in opioid-naive subjects and may not be as relevant when
conversions are made after regular doses of an opioid have been given
(either in the acute or chronic pain setting). Most studies have only
considered opioid switching in one direction and, as the conversions
do not account for incomplete cross-tolerance between opioids,
it may be appropriate to reduce the calculated dose by 25 –50%.
REFERENCES
1 NICE (2012). Clinical Guideline 140. Opioids in palliative care: safe and
effective prescribing of strong opioids for pain in palliative care of adults.
2 Drewes AM et al. (2013). Differences between opioids: pharmacological, experi-
mental, clinical and economical perspectives. Br J Clin Pharmacol 75: 60–78.
3 Twycross R, Wilcock A (2011). Palliative Care Formulary (4th edn). Nottingham:
Palliativedrugs.com.
Opioid misuse management

Oral methadone and oral buprenorphine are recommended for the
management of withdrawal syndrome from opioids.1 If both drugs
are equally suitable for a patient, then NICE recommends methadone
as the drug of choice.
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Opioid misuse management 299
Methadone
Methadone is long-acting (half-life is 15 hours initially; 20 –37 hours
in a regular user), making stability from daily dosing easier to
achieve. It is easy to titrate to achieve the correct dose and is less
likely to be injected than other opioids.
Opioid withdrawal symptoms
Classic opioid withdrawal symptoms are: weakness, insomnia,
yawning/sneezing, irritability/aggression, sweating, muscle spasms
and jerking, diarrhoea, tremors, nausea and vomiting, goose bumps,
loss of appetite, dilated pupils, high temperature but feeling cold,
lacrimation and rhinorrhoea, abdominal cramps, tachycardia,
hypertension and increased bowel sounds.2
If a patient is admitted to hospital who is on a managed opioid
withdrawal regimen, or who is a substance misuser and is likely to
exhibit withdrawal symptoms during admission, it is important to
seek out and follow any local guidelines for your hospital. The
following points should also be borne in mind.
Prior to prescribing methadone
O
The patient’s consent should be obtained to contact the patient’s usual
prescriber or community pharmacist to confirm the dose. If this is not
possible, and the patient has his or her own supply, it should only be
used as a means of identifying the dose if the label has not been
tampered with, and if it has been dispensed within the last 7 days.
k The patient’s community pharmacist and the local drug service k
will need to be informed as soon as possible to avoid potential
diversion of the community supply to another individual.
The telephone number of the local drug service is:
... ... ... ... ... ... ... ... ... ... ... ... ... ... ....
If it is necessary to contact a drug service outside of the locality,
the UK National Drugs Helpline (0800 776600) may be of help. They
provide 24-hour free and confidential advice, including information
on local services.
Prescribing methadone without an established dose3,4
If a patient presents who is receiving methadone, or is in opioid
withdrawal, and it is not possible to establish the patient’s normal
dose, s/he should be prescribed 10 mg or 20 mg of methadone
mixture 1 mg/mL (depending on the severity of the patient’s with-
drawal symptoms) and observed for 2 –4 hours to ensure s/he does
not become intoxicated.
The aim is to provide an effective level of physical and
psychological comfort, while minimising the likelihood of overdose.
Supplementary doses should only be considered where there is
evidence of persistent opioid withdrawal. If a daily dose has been
greater than 40 mg methadone, the patient should be closely
monitored, as deaths have occurred with 40 mg commencement
doses. The prescriber should consider the cumulative effect of
administering methadone because of its long half-life.
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If after 4 hours there are still withdrawal symptoms, another dose

may be given depending on the severity of the symptoms:
● mild withdrawal symptoms: give no further methadone
● moderate withdrawal symptoms (muscle aches, dilated pupils,
nausea, yawning): give 5 –10 mg methadone
● severe withdrawal symptoms (vomiting, piloerection, tachycardia,
elevated blood pressure): give 20 mg methadone.
Remember: methadone overdose can be fatal – withdrawal is not .
Once a whole 24 hours has passed, the total amount of methadone

administered during that period should be prescribed thereafter as a
single daily dose. There is an increased risk of death during
commencement of methadone; toxicity may be delayed, as it takes
five half-lives to reach steady state. Patients must be carefully
monitored for signs of toxicity during this induction period.
Methadone equivalents
If a patient is not on a withdrawal programme, but is a known
O substance misuser and control of withdrawal symptoms is necessary,
then the above advice should be followed. It is not possible to predict
equivalent doses in most cases; purity of street drugs will vary and
half-lives of different opioids are not the same.
If it is necessary to switch between oral and parenteral forms of
methadone, there are a variety of views as to the appropriate
k equivalence. The Department of Health guidelines suggest using the k
same dose.4 In cancer care it has been suggested that the oral dose
should be halved for parenteral use.5 The indications for prescribing
in both cases are different, so dose comparisons may be
inappropriate: a patient switched between forms for any reason
should be monitored for signs of over- or underdosing, and the dose
subsequently adjusted accordingly.
Adjuvant drugs for withdrawal symptoms
As well as methadone, it may be appropriate to control the physical
symptoms of withdrawal with more conventional therapy, e.g.
loperamide for diarrhoea, metoclopramide for nausea and vomiting,
mebeverine for stomach cramps, paracetamol and NSAIDs for
headaches and muscular pains.
Stabilisation and maintenance regimen
Where doses need to be increased during the first week, the increment
should be no more than 5 –10 mg on one day and the total increase
should not exceed 30 mg above the starting dose. For subsequent
weeks the dose of methadone is initially increased by not more than
10 mg weekly, usually over a period of 6 weeks, to between 60 mg and
120 mg daily. During this time the patient and carers should watch for
signs of toxicity. ECG monitoring is recommended before the dose is
increased above 100 mg daily and 1 week after, as cases of QT interval
prolongation and torsade des pointes have been reported.6
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Opioid misuse management 301
The maintenance dose should continue until the patient is suitable

for detoxification.
Missed doses
● If a patient misses 3 days or more of maintenance treatment with
methadone, s/he is at risk of overdose because of loss of tolerance.
In these cases consider reducing the dose of methadone.
● If a patient misses more than 5 days of maintenance treatment, an
assessment of illicit drug use is recommended before
recommencing methadone.
Detoxification
Once a patient is stable and is suitable for detoxification, and provided
there is abstinence from heroin, the dose can be reduced. This will be
by 5 mg every week or fortnight, which typically will result in zero
after 12 weeks. During this period the patient should have approp-
riate psychosocial support and this should continue for at least
6 months after detoxification.
Some patients and prescribers may agree to reduce the dose slowly
over a period of months or years to lead to a formal detoxification. O
The overall goal is to maximise the patient’s health, and this may
actually mean continuing with maintenance treatment.
Buprenorphine
If methadone is not suitable, then buprenorphine is an appropriate
k choice of treatment. Some patients may prefer buprenorphine k
because it is less sedating than methadone.
Buprenorphine is a partial agonist/antagonist of the mu (μ) and
kappa (κ) opioid receptors in the brain. It is used to treat opioid
dependence, but because of the nature of its pharmacology it can
precipitate withdrawal symptoms in opioid-dependent individuals.
This is more likely with patients taking high doses of opioids
(typically >30 mg methadone, or equivalent, daily).
Buprenorphine sublingual tablets are used for the management of
opioid dependence. They have been misused by being crushed and
injected; to prevent this misuse a formulation of buprenorphine plus
naloxone (Suboxone) has been developed.
The SPC for buprenorphine7 recommends an initiation dose from
0.8 to 4 mg is given as a single dose; in clinical practice, initiation
doses may be 4 –8 mg. The dose should be given at least 4 hours after
the last dose of opioid (or 24 –48 hours after the last methadone
dose), or preferably when the first signs of opioid withdrawal occur. If
the patient has been taking methadone, the dose of methadone
should have been less than 30 mg daily (unless withdrawal is to be
conducted by specialist drug services).
The dose is increased on subsequent days, usually by 2 –4 mg
(although 8-mg steps are sometimes used), according to clinical
k
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response, and to a maximum dose of 32 mg daily. It may take

1 –2 weeks for the patient to feel comfortable with the bupre-
norphine, and lofexidine may be needed in the first 2 days to help
with any withdrawal symptoms.
Lofexidine1,8
During sudden withdrawal of an opioid there is an increase in the
amount of noradrenaline released, which results in an increased rate
of neuronal firing, and this is seen in the patient as the symptoms of
the withdrawal syndrome. Lofexidine is a presynaptic adrenergic
alpha-2-receptor agonist. Its pharmacological effect is to decrease
noradrenaline release and neuronal firing rate, thereby dampening
down the withdrawal symptoms. It is used to relieve withdrawal
symptoms in patients undergoing opioid detoxification and not to
treat opioid dependence. It is useful for patients with only a short
history of opioid abuse who have been taking up to a quarter of a
gram of street heroin daily, or to complete methadone withdrawal,
e.g. when the methadone dose falls to 15 mg/day.
Blood pressure should be measured before and during treatment,
O and if there is a clinically significant decrease in blood pressure,
treatment with lofexidine should be discontinued. It is unsuitable for
people with pre-existing low blood pressure or bradycardia.
The starting dose is 800 micrograms daily in divided doses,
increasing in steps of 400 –800 micrograms daily as necessary, to a
maximum of 2.4 mg daily. The maximum single dose should not
k exceed 800 micrograms (4 × 200 microgram tablets). The duration of k
treatment is usually 7 –10 days. It is withdrawn over 2 –4 days, but a
longer period may be needed if withdrawal symptoms manifest.
REFERENCES
1 NICE (2007). Methadone and Buprenorphine for the Management of Opioid Depen-
dence. Technology Appraisal 114. http://nice.org.uk/guidance/TA114 (accessed 29
December 2014).
2 Department of Health (England) and the devolved administrations (2007). Drug
Misuse and Dependence: UK guidelines on clinical management. London: Department
of Health (England), the Scottish Government, Welsh Assembly Government and
Northern Ireland Executive. http://www.nta.nhs.uk/uploads/clinical guidelines
2007.pdf (accessed 22 December 2014).
3 East Lancashire Hospital NHS Trust (2012). Guidelines for Prescribing of Methadone
for Hospital In-patient Opiate Misusers. Blackburn: ELHT.
4 Department of Health (2007). Drug Misuse and Dependence: UK guidelines on clin-
ical management. http://www.nta.nhs.uk/uploads/clinical guidelines 2007.pdf
(accessed 12 May 2015).
5 Säwe J (1986). High-dose morphine and methadone in cancer patients: clinical
pharmacokinetic considerations of oral treatment. Clin Pharmacokinet 11: 87–106.
6 SPC (2014). Methadone 1 mg/mL oral solution. www.medicines.org.uk (accessed 13
January 2015).
7 SPC (2015). Subutex 2 mg sublingual tablets. www.medicines.org.uk (accessed 13
January 2015).
8 SPC (2014). BritLofex Tablets 0.2 mg. www.medicines.org.uk (accessed 18 January
2015).
k
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Osteoporosis 303
Opioid partial agonists

A partial agonist is a drug that binds to and activates a receptor but
has only partial efficacy at the receptor compared with a full agonist.
This means that it may have a ceiling effect and demonstrate both
agonist and antagonist effects. When both a full agonist and partial
agonist are given together, the partial agonist may act as a competitive
antagonist, competing with the full agonist for receptor occupancy
and overall producing less receptor activation than with the full
agonist alone.
There are several opioid partial agonists, including buprenorphine,
pentazocine and nalbuphine, used in clinical practice.
Buprenorphine
Buprenorphine is a partial agonist of the mu-opioid receptor that is
experiencing resurgence in use for persistent pain following
formulation for transdermal administration1 and in the management
of opioid dependence and addiction. In human studies using clinically
relevant analgesic doses, buprenorphine does not have a ceiling effect
to analgesia, hence, contrary to popular conception, it is possible O
to administer another opioid agonist such as morphine for the
management of exacerbations of pain. However, buprenorphine does
have a ceiling effect for respiratory depression2 and it still can readily
be reversed by naloxone, although often larger doses are required
than for other opioids.
k See the Pain management entry for the analgesic equivalence of
k
transdermal buprenorphine compared with other commonly used
opioids.
REFERENCES
1 Budd K, Collett BJ (2003). Old dog – new (ma)trix. Br J Anaesth 90: 722–724.
2 Dahan A et al. (2006). Buprenorphine induces ceiling in respiratory depression but
not in analgesia. Br J Anaesth 96: 627–632.
Osteoporosis
Overview
Definition Osteoporosis is a degenerative disease characterised by low bone mass
and microarchitectural deterioration of bone tissue, leading to increased
bone fragility and susceptibility to fracture.1,2 The World Health
Organization defines osteoporosis as having a bone mineral density
(BMD) of ≤ 2.5 standard deviations below peak BMD, as measured on
dual-energy X-ray absorptiometry (DXA) applied to femoral neck.3
Severe or established osteoporosis is having osteoporosis with one or
more fragility fractures. A fragility fracture is defined as a fracture
following a fall from standing height or less. A major osteoporotic
fracture is one occurring at the spine, hip, forearm or proximal humerus.
The most common fractures are hip, spine or wrist fractures.
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304 Osteoporosis
Osteoporosis is caused by an increased rate of old bone loss or resorption

(osteoclast activity) that is not matched by an increased rate of new bone
formation (osteoblast activity) and results in reduced bone mass and
structural deterioration, which eventually leads to osteoporosis. Ageing
and low oestrogen levels associated with menopause, as well as
secondary causes contribute significantly to this imbalance. Low calcium
and vitamin D levels and hyperparathyroidism also increase
bone loss
Risk factors Increasing age (a 2% risk at 50 years to a 25% risk at 80 years), falls risk
and low BMD are the strongest risk factors for an osteoporotic fracture,
but other clinical risk factors also contribute, e.g. parental history of hip
fracture, alcohol intake of 4 units or more per day, rheumatoid
arthritis,4,5 gender, previous fragility fracture(s), current oral
corticosteroid treatment, current smoking and falls are partly
independent of BMD. In contrast, low BMI and secondary causes of
osteoporosis, such as prolonged immobility, drugs, untreated premature
menopause, ankylosing spondylitis, endocrine and rheumatoid disorders,
chronic obstructive pulmonary disease (COPD), chronic kidney disease
and Crohn’s disease are related to low BMD. SSRIs, PPIs and antiepileptic
drugs also adversely affect bone strength through unknown mechanisms.
O The National Osteoporosis Guidance Group and NICE make different
recommendations on how to assess patients and the tools to be used.
NICE recommendations are used in this section.
High-risk patients should be identified opportunistically and fracture risk
should be assessed in the following groups:
● Women aged ≥65 years; men aged ≥75 years
k ● Women 50–65 years and men 50–75 years who have a risk factor for k
fragility fractures
● Anyone under 50 years if they have a major risk factor for fragility
fractures, e.g. current or frequent use of oral corticosteroids,
untreated premature menopause and previous or multiple
osteoporotic fractures.
The Fracture Risk Assessment Tool (FRAX)6 and QFracture7 are tools
recommended by NICE to calculate fracture risk. They predict the
probability of a hip or major osteoporotic fracture over a 10-year period
(expressed as a percentage). They do not include every risk factor, so may
underestimate risks in certain situations, such as patients who have had
multiple fractures. There are pros and cons to using either tool depending
on the age of the patient and the availability of BMD measurement.
QFracture is based on the UK population, incorporates more clinical risk
factors than the FRAX tool and provides thresholds for which treatment
is recommended. However, it does not utilise BMD measurements
in risk calculation and so the FRAX tool must be used when BMD is
available
Differential ● Osteoarthritis
diagnosis ● Degenerative disc disease
● Osteomalacia
● Skeletal metastases
● Multiple myeloma
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Osteoporosis 305
Diagnostic Generally, osteoporosis is diagnosed by measurement of BMD using

tests central (lumbar spine and proximal femur1 ) DXA scanning, and is
expressed as the T-score. However, a diagnosis of osteoporosis may be
assumed in women aged ≥75 years without the need for DXA
confirmation if the responsible clinician thinks a scan is inappropriate or
unfeasible.
Biochemical markers and radiological X-rays have no role in the
diagnosis of osteoporosis, but the latter may be used to confirm a
suspected spinal fracture.8
Treatment Treatment aims to preserve bone mass and reduce the risks of fractures.
goals This involves modification of risk factors, falls prevention, calcium and
vitamin D supplementation and drugs that reduce bone resorption or
stimulate bone formation. It can also involve managing complications
resulting from fractures, e.g. the use of analgesics and physiotherapy for
acute and chronic pain
Assess Risk modification and falls prevention
All patients should be advised and supported to modify their risk factors
where possible and make appropriate lifestyle changes, particularly
smoking cessation, limiting alcohol intake and taking regular exercise.
O
Useful exercises include low-impact, weight-bearing, strength-training,
balance and gait-training exercises, which should be tailored to the
individual’s needs and abilities.
Calcium and vitamin D status should be assessed and corrected as
needed by increased dietary intake or pharmacological supplementation.
k A dietary calcium intake of 1000 mg daily should be maintained and can k
be estimated using the calcium calculator at
http://www.sign.ac.uk/guidelines/fulltext/71/annex4.html.
All older patients should be routinely asked about falls and associated
risk factors should be identified and modified. Those at high risk should
be referred to specialist falls teams. Multifaceted interventions
recommended by NICE9 to reduce frequency of falls include medication
review, with modification or withdrawal of offending drugs
Calcium and Combination of both is more effective than either drug alone in fractures
vitamin D in patients over 60 years (hip) and those in a care home (hip and
vertebral). Therefore, it should be prescribed routinely for care home
patients with very few exceptions (unless adequate levels or
contraindicated).
The MHRA advises that patients at risk of developing osteopenia or
osteoporosis who are taking long-term carbamazepine, phenytoin,
primidone and sodium valproate should receive vitamin D
supplementation. Therapeutic calcium alone has been associated with
increased risks of myocardial infarction. Calcium levels should be
checked prior to prescribing to avoid hypercalcaemia. Vitamin D
supplementation alone can prevent falls in over-60-year-olds living in
institutionalised settings or the community.
Colecalciferol (vitamin D3 ) oral preparations are available as single
agents or in combination with calcium in various formulations.
Non-adherence is common and the patient’s preference is an important
consideration when choosing the appropriate formulation
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306 Osteoporosis
Anti- Once patients are identified and assessed, the decision to commence
osteoporotic treatment will depend on the level of risk and therapeutic threshold. The
drugs therapeutic threshold is determined by a combination of the patient’s
age, BMD, clinical risk factors, indicators of low BMD and whether there
has been previous fracture(s) or not.
NICE recommends that:
● Those at high risk and exceeding the therapeutic threshold should be
treated without the need for BMD.
● Those at low risk should not be treated or referred for BMD.
● Those at intermediate risk should be referred for DXA to measure
BMD. Then their risk should be recalculated using the FRAX tool.
Those exceeding the therapeutic threshold should be treated and
those below given lifestyle advice and reassessed after 5 years, or
sooner as required. For those just below the treatment threshold,
treatment should be considered if they have risk factors that are
underestimated or unaccounted for in the FRAX tool.
Premenopausal women and those under 50 who have had an
osteoporotic fracture should be referred for specialist management. The
choice of drug will depend on cost-effectiveness, drug safety profile and
patient factors, such as comorbidities, preferences, ability to comply with
O administration instructions and tolerance. All drugs available in the UK
act primarily as antiresorptive agents, except for strontium (dual action)
and teriparatide, which stimulate bone formation.
NICE recommends:
● Alendronate as first-line therapy based on cost-effectiveness and risks
of adverse effects.
k ● Risedronate, if alendronate cannot be tolerated, adhered to or is k
contraindicated.
● Refer to secondary care for raloxifene, teriparatide or denosumab10
according to criteria set by NICE, if alendronate or risedronate cannot
be taken. The use of strontium ranelate is now restricted to severe
osteoporosis when other drugs cannot be used and in those without
cardiovascular contraindications.11 Teriparatide is recommended as
an alternative where there has been an unsatisfactory response to
other drugs. Raloxifene and teriparatide are not recommended for
primary prevention.
Poor adherence and persistence with oral bisphosphonates is a real
problem, particularly within 3 months of initiation, as the risk of fractures
increases when adherence falls below 50%.12 Better education and
intermittent dosing regimen given weekly; alternatively monthly
(ibandronate oral), 3-monthly (ibandronate IV) and annually
(zoledronate IV) preparations have been developed to assist with these
problems
Patient ● Check that the patient (or carer) understands the administration
counselling instructions, particularly for patients with cognitive impairment and
patients whose medicines are dispensed in multicompartment
compliance aids.
● For those on oral bisphosphonates, explain that these must be taken
whole on an empty stomach with a full glass of water and the patient
must remain upright for 30 minutes after taking the medication to
improve absorption and reduce the risks of oesophageal reactions.
● Explain duration of treatment and that the outcome is only to reduce
the risk, not completely eliminate fractures.
k
k
Osteoporosis 307
● Explain common and severe adverse drug effects, including what

signs to look out for and actions to take.
● Explain the need to maintain good oral hygiene, regular dental
check-ups and timing of dental procedures for those taking
bisphosphonates.
● Ask for the presence of common and severe ADRs, e.g. heartburn,
abdominal pain, muscle ache, groin pain with bisphosphonates;
signs of cellulitis with denosumab; allergic rash with strontium.
● Explain complex dosing instructions clearly to reduce the risks of
adverse effects, especially around the time the drug is initiated.
● Signpost patients for more information and support, e.g. the National
Osteoporotic Society, NHS Choices, www.healthtalkonline.org,
patient.co.uk
Continued Review treatment within 3 months and regularly thereafter to check for
monitoring adverse drug effects and adherence. Assess the continuing need for
bisphosphonates after 3–5 years and continue if the patient is at high
risk or refer for DXA. If fracture occurs, exclude secondary causes and
refer to secondary care. Those taking regular corticosteroids should
continue bisphosphonates until they stop, then have the fracture risk
reassessed to determine the need for continuing treatment
O
REFERENCES
1 NICE (2012). CG146. Osteoporosis: Assessing the risk of fragility fracture.
http://www.nice.org.uk/guidance/cg146 (accessed 23 August 2014).
2 NICE (2008). TA 161. Alendronate, etidronate, risedronate, raloxifene, strontium
ranelate and teriparatide for the secondary prevention of osteoporotic fragility frac-
k tures in postmenopausal women (amended). https://www.nice.org.uk/guidance/
k
ta161 (accessed 23 August 2014).
3 Kanis JA, on behalf of the World Health Organization Scientific Group
(2007). Assessment of Osteoporosis at the Primary Health Care Level. WHO
Collaborating Centre for Metabolic Bone Diseases, University of Sheffield.
http://www.who.int/chp/topics/Osteoporosis.pdf (accessed 13 May 2015).
4 NICE (2008). TA 160. Alendronate, etidronate, risedronate, raloxifene and
strontium ranelate for the primary prevention of osteoporotic fragility fractures in
postmenopausal women (amended). Updated 2011. http://www.nice.org.uk/
guidance/ta160 (accessed 23 August 2014).
5 NOGG (2014). Guideline for the Diagnosis and Management of Osteoporosis.
Updated March 2014. http://www.shef.ac.uk/NOGG/NOGG Pocket Guide for
Healthcare Professionals.pdf (accessed 23 August 2014).
6 FRAX (2014). WHO Fracture Risk Assessment Tool. http://www.shef.ac.uk/FRAX/
tool.aspx?country=1 (accessed 23 August 2014).
7 QFracture (2013). Algorithm. http://www.qfracture.org/index.php (accessed 23
August 2014).
8 NICE (2012). CKS. Osteoporosis – Prevention of fragility fractures. Updated
September 2012. http://cks.nice.org.uk/osteoporosis-prevention-of-fragility-
fractures#!topicsummary (accessed 23 August 2014).
9 NICE (2013). CG 161. Falls: Assessment and prevention of falls in older people.
https://www.nice.org.uk/guidance/cg161 (accessed 23 August 2014).
10 NICE (2010). TA 204. Denosumab for the Prevention of Osteoporotic Fractures in
Postmenopausal Women. http://www.nice.org.uk/guidance/ta204 (accessed 23
August 2014).
k
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308 Oxygen
11 MHRA (2014). Strontium ranelate: cardiovascular risk – restricted

indication and new monitoring requirements. Drug Saf Update 7: 8.
http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON392870
12 Compston J, Seeman E (2006). Compliance with osteoporosis therapy is the weak-
est link. Lancet 368: 973–974.
Oxygen
Oxygen is regarded as a drug and must be prescribed. Various devices
are used for the delivery of oxygen to the patient, usually via a
pressure regulator and flow meter, which control the high pressure of
oxygen delivered from the cylinder or other source.
● Nasal cannulae or simple facemasks generally deliver a higher

concentration of oxygen as flow rate is increased. Nasal cannulae
are generally preferred by patients as they are comfortable and
allow patients to eat while in situ.
● Non-rebreathing or reservoir masks are used to deliver higher
O concentrations of oxygen (60 –80% or above) in acute situations.
● Venturi masks deliver a constant oxygen concentration within and
between breaths (increasing flow does not increase oxygen
concentration). They are used in patients who require controlled
oxygen therapy, e.g. COPD patients.
k Oxygen therapy can be used in acute situations where there is hypoxia k
because of reduced ventilation or acute lung injury, when there is
underlying chronic lung disease or when it is important to maintain
oxygen delivery to tissues. A pulse oximeter is used to monitor oxygen
saturation (or ‘sats’, i.e. the fraction of oxygen-saturated haemoglobin
relative to total haemoglobin (unsaturated + saturated) in the blood).
Oxygen should be prescribed to achieve a target saturation of
94 –98% for most acutely ill patients or 88 –92% for those at risk of
hypercapnic (type 2) respiratory failure. Oxygen dosage is titrated up
or down to maintain target oxygen saturation (Figure O1 gives a
summary of available options for stepping dosage up or down).
Generally it is safe to use a high oxygen concentration empirically
in acute situations as long as there is no risk that the patient has
COPD. The main risk in some people with COPD is that CO2 retention
may occur. If COPD is suspected, the oxygen should be given via a
24% or 28% Venturi mask until arterial blood gases can be measured.
Patients at risk of hypercapnic respiratory failure are advised to carry
an oxygen alert card (Figure O2).2
Breathlessness in COPD is likely to increase on exertion, and
simple everyday tasks such as washing, dressing or eating may cause
problems. Some patients feel that a short burst of oxygen improves
their symptoms. However, few patients benefit from this and such
therapy should only be given if assessed formally.3
k
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Oxygen 309
Oxygen therapy flow chart for use on general wards

Is your patient at risk of type 2 respiratory failure*?
No Yes *Type 2 respiratory
failure
Targer sats 94–98% Targer sats 88–92% • pCO2 > 6 kpa
Patients at risk include
Nasal cannulae Venturi 24% • COPD
1 Litres/min 2–4 Litres/min • Morbid obesity
Setting the flow meter
• Chest wall disease
Increase or decrease as encessary to maintain sats
Increase or decrease as encessary to maintain sats

3 3
Nasal cannulae Venturi 28%
2 Litres/min 2 2 4–6 Litres/min
Signs of respiratory
Nasal cannulae 1 1 deterioration
Venturi 35%
4 Litres/min Correct setting of flow 8–10 Litres/min • ↑ respiratory rate
meter to deliver (especially if > 30)
2 Litres/minute • ↓ SpO2
Simple face mask Venturi 40% • ↑ O2 dose needed to
5-6 Litres/min 10–12 Litres/min keep SpO2 in target
range
Oxygen at these • ↑ EWS
Simple face mask Venturi 60%
flow rates may be • CO2 retention
7-10 Litres/min 12–15 Litres/min • Drowsiness
humidified
• Headache
• Flushed face
Reservoir mask Seek medical Reservoir mask
• Tremor
15 Litres/min input immediately 15 Litres/min Seek medical advice
For Venturi masks the higher flow rate should be used if the respiratory rate is > 30
FIGURE O1 Oxygen therapy flow chart for use on general wards

O
Oxygen alert card
k Name: k
I am at risk of type II respiratory failure with a raised CO2
level.
Please use my % Venturi mask to achieve an

oxygen saturation of % to % during
exacerbations.
Use compressed air to drive nebulisers (with nasal oxygen at

2 litres/minute). If compressed air not available, limit oxy-
gen-driven nebulisers to 6 minutes
FIGURE O2 Oxygen alert card
Chronic hypoxia
Chronic hypoxia produces a mixture of permanent and reversible
structural changes in the lung. Reversal of the hypoxia in severe
COPD has been found to reduce mortality if the oxygen is used for a
minimum of 15 hours each day. Correction of hypoxia may have other
benefits, such as reducing polycythaemia, and reducing or preventing
progression of pulmonary hypertension.
Long-term oxygen therapy is indicated in patients with COPD who
have a PaO2 <7.3 kPa when stable or a PaO2 >7.3 and <8 kPa when
k
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310 Oxygen
stable and one of: secondary polycythaemia, nocturnal hypoxaemia

(oxygen saturation of arterial blood (SaO2 ) is less than 90% for more
than 30% of the time), peripheral oedema or pulmonary
hypertension.3
REFERENCES
1 British Thoracic Society (BTS) (2008). Emergency Oxygen Guideline Group.
Guideline for emergency oxygen use in adult patients. Thorax 2008; 63: Suppl
VI. Available at: https://www.brit-thoracic.org.uk/document-library/clinical-
information/oxygen/emergency-oxygen-use-in-adult-patients-guideline/emergency-
oxygen-use-in-adult-patients-guideline/ (accessed 27 November 2014).
2 British Thoracic Society (2010). Oxygen Alert Card. https://www.brit-
thoracic.org.uk/document-library/clinical-information/oxygen/emergency-
oxygen-use-in-adult-patients-guideline/oxygen-alert-card-template/ (accessed 22
February 2015).
3 NICE (2010). CG101. Chronic Obstructive Pulmonary Disease: Management of chronic
obstructive pulmonary disease in adults in primary and secondary care (partial
update). http://www.nice.org.uk/guidance/CG101/ (accessed 27 November 2014).
k k
k
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Pain management 311
P
Pain management
Pain is defined as ‘an unpleasant sensory and emotional experience
associated with actual or potential tissue damage, or described in
terms of such damage’1 and is a universal experience that has
physical, psychological and social effects. The causes of pain vary
considerably and can be acute (e.g. postoperative or acute injury),
or persistent (e.g. lower-back pain or arthritis). Acute pain is usually
associated with tissue damage and healing, whereas chronic
(persistent) pain is continuous, long-term pain of more than
12 weeks, or persisting after the time that healing should have P
occurred.
Pain assessment
k Reliable assessment of pain is essential for both clinical trials and k
effective pain management.2 Unidimensional pain assessment tools
only assess one aspect of pain, such as pain intensity, and are useful for
acute pain. Chronic pain assessment requires assessment of the impact
of pain on physical, emotional and social functions and requires
multidimensional tools and health-related quality-of-life instruments.
Commonly used assessment tools for acute pain include the
following:
● visual analogue score (VAS), where patients mark their pain
intensity on a 10-cm line on a piece of paper, where one end of the
line corresponds to no pain and the opposite end corresponds with
their worst pain imaginable
● numerical rating scale (NRS), where patients rate their pain from
0 to 10, where 0 is no pain and 10 is their worst pain imaginable
● verbal rating scale (VRS), where patients are asked to rate their
pain as words such as: no pain; mild; moderate; severe;
excruciating.
Acute pain must be assessed both at rest (important for comfort) and
during movement (important for function and risk of postoperative
complications).
Many functional scales are used in persistent pain assessment.
Some are disease-specific, such as the Western Ontario and
MacMaster Universities for osteoarthritis, and others have more
general application (e.g. the Brief Pain Inventory).
k
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312 Pain management
Pain rating scales specifically designed for use with children or

patients with cognitive impairment or communication difficulties
also exist.
Principles of pain management
In determining an initial treatment plan it is important to consider the
likely cause of a patient’s pain, the type of pain and its intensity,
together with effectiveness of previous analgesics, which will
determine drug options. Analgesic drugs may be prescribed regularly
if the pain is continuous or when required if the pain is more variable.
Regular reassessment is required to monitor effectiveness as analgesic
requirements may change.
The management of both acute and chronic pain requires a
multidisciplinary approach including anaesthetists, nurses and
pharmacists. Pain management services are usually led by an
experienced clinician, often with access to appropriate physiotherapy
and psychological treatments.3
WHO analgesic ladder
The WHO analgesic ladder was introduced to improve pain control in
P patients with cancer pain.4 It is a simple three-step model to guide
initial selection and titration of analgesics to manage pain effectively;
the pain intensity determines at which step to start.
Step 3
k Paracetamol and/or NSAID,
k
plus a strong opioid, e.g.
Step 2 morphine, diamorphine,
Paracetamol and/or NSAID, fentanyl
Step 1 plus a weak opioid, e.g.
Paracetamol and/or dihydrocodeine, codeine
NSAIDs
Mild pain Moderate pain Severe pain
The principles behind the WHO analgesic ladder are:

● ‘by the ladder’ – according to pain intensity
● ‘by the clock’ – regular analgesia when required
● ‘by the mouth’ – the oral route is preferred
● ‘by the individual’ – doses should be individualised for each
patient.
The principles of the WHO analgesic ladder have been applied to

other types of pain, such as in the World Federation of Societies of
Anaesthesiologists analgesic ladder for acute pain.5
Soluble analgesics may contain high sodium content, and this
should be borne in mind for patients with high blood pressure and/or
on a sodium-restricted diet (see Sodium entry).
k
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Pain management 313
Pharmacological treatment options for pain

Paracetamol
Despite much investigation and being used for over 50 years, the
mechanism of action for paracetamol remains unclear. Paracetamol is
used commonly in acute pain management; however, there is limited
evidence for long-term effectiveness for persistent pain and NICE has
highlighted concerns about potential harms. Paracetamol has a
relatively narrow therapeutic window and it is important that the
maximum dose is not exceeded (oral in adults: 1 g four times a day).
The relatively recent introduction of an intravenous formulation has
revolutionised surgical practice; a dose reduction is required for
patients who weigh <50 kg (15 mg/kg 4 –6-hourly with a maximum
of 60 mg/kg/day) or who have risk factors for hepatotoxicity.
Non-steroidal anti-inflammatory drugs
NSAIDs have analgesic and anti-inflammatory effects by reducing
prostaglandin synthesis by inhibiting the enzyme cyclooxygenase.
However, as prostaglandins have wide-ranging physiological effects,
side effects are relatively common. Well-documented side effects
include GI disturbances, i.e. ulceration and bleeding, reduced kidney
blood flow, prolongation of labour and bleeding. If a patient is P
at risk of GI side effects, e.g. elderly, history of GI ulceration, then a
gastroprotective agent such as a proton pump inhibitor should be
considered. The subsequent discovery of the COX-2 isoform led to
k design of drugs that had fewer GI adverse effects, but an increase in k
cardiovascular thrombotic events has become evident.6
Opioids
As a group, opioids have a broadly similar pharmacology, generally
characterised by moderate to strong analgesia, euphoria (sometimes
dysphoria), miosis, depression of the respiratory centre and cough
reflex, constipation, postural hypotension, and nausea and vomiting.
Technically, an opiate refers to naturally occurring opium
alkaloids, e.g. morphine, codeine and thebaine, while the term
‘opioid’ is properly used to describe semisynthetic or synthetic
compounds acting on opiate receptors, e.g. dihydrocodeine,
fentanyl.
Opioid side effects
All opioids may cause nausea, vomiting, constipation and drowsiness.
It may be necessary to use other pharmacological interventions to
alleviate these symptoms. Tolerance develops to some side effects
(e.g. nausea and drowsiness) but not to others, particularly
constipation.
Treatment with a combination of cyclizine (50 mg three times
daily), metoclopramide (10 mg three times daily) or a 5-HT3 receptor
antagonist (e.g. ondansetron 4 mg three times daily) is usually
effective for nausea and vomiting. Metoclopramide should be used for
no longer than 5 days following guidance from the European
k
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314 Pain management
Medicines Agency to help minimise the risk of potentially serious

neurological adverse effects.7
The combined use of a stimulant laxative (e.g. senna 15 mg at
night) and a stool softener (e.g. docusate 200 mg twice daily) should
be prescribed regularly for constipation.
Sedation may be most prevalent and pronounced during the first
few days of therapy, and can also be related to other centrally acting
drugs prescribed concomitantly, e.g. cyclizine.
Compound (‘co-’) analgesics
Compound preparations containing paracetamol or an NSAID and
weak opioids sit at step 2 of the WHO analgesic ladder. Paracetamol
in combination with low doses of a weak opioid (as in co-codamol
8/500, co-dydramol 10/500) is no more effective at controlling pain
than paracetamol alone (although patient perception may differ).
Only the higher-strength combinations (e.g. co-codamol 30/500)
have an analgesic effect greater than paracetamol alone.8
Tramadol
In addition to an opioid receptor agonist, tramadol produces an
analgesic effect, enhancing serotonin release and inhibiting neuronal
P reuptake of noradrenaline, meaning that it may be less likely to cause
constipation and respiratory depression. However, it can produce
convulsions and can precipitate serotonin syndrome, especially in
combination with other commonly prescribed medicines, e.g. SSRIs
k (see Serotonin syndrome entry). k
Morphine
Morphine is the prototypical opioid. When initiating oral morphine
therapy (step 3), the usual starting dose is 5 –10 mg of an
immediate-release formulation every 2 –4 hours when required. After
dose titration to the minimum effective dose for pain control, the total
amount of morphine given in the previous 24 hours may be
prescribed as a modified-release formulation either once or twice
daily: the first dose is given at the same time as the final dose of the
immediate release form. It takes up to 5 hours to reach steady state
with the modified-release formulations, making them unsuitable for
‘when required’ use.
The dose should be titrated to provide an adequate level of pain
control before changing to once- or twice-daily dosing, and even then
doses of immediate-release morphine should be prescribed for
breakthrough pain.9
Exacerbations of pain (breakthrough pain)
The dose of ‘when required’ morphine for breakthrough pain relief
should be equivalent to one-sixth of the total daily dose of morphine;
or if still in the initial titration period, the dose is the same as the
4-hourly dose. If the patient has predictable movement-related pain, a
dose of breakthrough analgesia may be given 30 minutes before
movement, e.g. when ‘turning’ the patient, or before a dressing
change.
k
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Pain management 315
Once a dose of breakthrough analgesia has been given, the

patient’s response should be observed after 30 minutes. If the pain has
not been controlled, a further dose of breakthrough analgesic should
be given, and the patient reassessed after a further 30 minutes. If
there is still no relief there should be a full reassessment of the
patient’s analgesic requirements.
The dose of morphine for breakthrough pain should be kept
constantly under review and increased in line with maintenance
analgesia.
Diamorphine
Diamorphine is a lipophilic semisynthetic opioid but it has no
advantages over morphine other than it has high water solubility,
making it more suitable for parenteral use. Diamorphine is commonly
given subcutaneously, although it may also be given using the
parenteral or spinal routes.
Oxycodone
Oxycodone is another semisynthetic opioid that is available in oral,
rectal and parenteral formulations. Although oxycodone does have a
different receptor affinity to opioid receptor subtypes compared with
morphine, its analgesic effect and side effects are still largely due to P
interaction with mu-opioid receptors. Oxycodone has fewer active
metabolites than morphine but may still accumulate in severe renal
impairment. It is considerably more expensive than morphine.
k Opioid transdermal patches
k
Fentanyl and buprenorphine are both currently available for
transdermal delivery and they may be useful when a patient cannot
tolerate oral opioid administration.
Patches should be applied to a non-hairy, non-irritated and
non-irradiated area of skin on a flat surface of the torso or upper arm.
Areas with large areas of scar tissue should be avoided. If hair needs
to be removed to create a site, it should be cut off with scissors and not
shaved to avoid irritation and desquamation. If the site requires
cleansing, plain water should be used (soaps, oils, lotions or any other
product that might irritate the skin or affect adhesion of the patch
should be avoided). The skin must be dry before application.
The patch is applied immediately after opening the outer pouch.
It is peeled off from the backing film, pressed firmly to the selected
site with the palm of the hand, and held in position for approximately
30 seconds. Upon removal, a new patch is applied to a different
site and the previous site should not be used again for several
applications.
The patient should be counselled to avoid excessive heat (e.g. heat
lamps, heat pads, hot-water bottles, electric blankets, saunas or hot
baths), as this may cause increases in drug release from the patch and
increased systemic absorption. Similarly, patients who develop fever
should be monitored for opioid side effects as an increase in body
temperature may also potentially increase the release rate.10
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316 Pain management
Patches should never be divided or cut as this can lead to

uncontrolled release of the drug. Any damaged, used or unwanted
patches should be made unusable by folding the patch in half,
adhesive side inwards, and discarding it safely (as clinical waste in
secondary care). The hands should be washed after handling.
Fentanyl
The starting dose for a fentanyl patch is based on an assessment of the
patient’s clinical condition and recent opioid history. If the patient is
opioid-naı̈ ve the maximum starting dose is 25 micrograms/hour. If
the patient has previously received opioids, Table P1 may be used as a
guide for initial selection of a suitable strength of fentanyl patch.11
TABLE P1
Fentanyl patch analgesic equivalence
Fentanyl patch Oral 24-hour morphine (mg/day)
(microgram/hour) (or equivalent)
25 <135
50 135–224
75 225–314
P 100 315–404
125 405–494
150 495–584
175 585–674
k 200 675–764
k
225 765–854
250 855–944
275 945–1034
300 1035–1124
It takes 24 hours to reach maximum analgesic effect, hence the

analgesic effect should not be assessed until 24 hours after application
of the first patch; previous analgesic therapy should be phased out
over this period (e.g. if switching from morphine sulfate
modified-release tablets to fentanyl patches, the first patch is applied
when the final dose of morphine sulfate modified-release tablets is
taken).
Patients may still require additional analgesia for breakthrough
pain. In order to calculate the total morphine (or opioid equivalent)
requirement for this, 25 micrograms/hour fentanyl patch ≈
60 mg/day oral morphine, e.g. a patient with a 100 micrograms/hour
fentanyl patch is receiving approximately 240 mg/day of oral
morphine equivalence, so would require one-sixth of this dose for
breakthrough pain, i.e. 40 mg oral morphine.
Buprenorphine
Buprenorphine is a highly lipophilic semisynthetic opioid with
complex pharmacology (see Opioid partial agonists entry).
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Pain management 317
There are two different formulations that are intended for 7-day
(5, 10 and 20 micrograms/hour) and twice-weekly (35, 52.5 and
70 micrograms/hour) application. Relative potency compared with
other commonly used opioids is shown in Table P2.9
TABLE P2
Buprenorphine patch analgesic equivalence
Strength of buprenorphine patch
5 10 20 35 52.5 70
micrograms/ micrograms/ micrograms/ micrograms/ micrograms/ micrograms/
hour hour hour hour hour hour
Oral 120 mg 240 mg
codeine daily daily
Oral 100 mg 200 mg 400 mg
tramadol daily daily daily
Oral 12 mg 24 mg 48 mg 84 mg 126 mg 168 mg
morphine daily daily daily daily daily daily
It takes at least 24 hours to achieve the full analgesic effect following

the first application, so assessment of therapy should not be made
until after this time. P
Persistent pain
Persistent pain is a complex neurophysiological phenomenon with
k biopsychosocial contributing factors. A wide range of treatments, k
including medicines, stimulation (TENS, acupuncture, ultrasound,
massage and spinal cord stimulation), nerve blocks and ablative
neurosurgical techniques (e.g. sympathectomy or cordotomy)
are used.
Neuropathic pain
Neuropathic pain is pain caused by damage or disease that affects the
somatosensory system and does not respond well to conventional
analgesics. Several antidepressants and antiepileptic drugs have been
used to treat neuropathic pain.12 Some of the drugs are licensed for
this indication (e.g. duloxetine, carbamazepine, gabapentin and
pregabalin); however, other drugs (e.g. amitriptyline and
lamotrigine) are not and it is useful to know typical doses.
● Amitriptyline: usual starting doses are between 10 and 25 mg,
taken in the evening (90 minutes to 2 hours before retiring to bed).
Gradual dose titration to 50 –75 mg daily may be required for
maximum efficacy and tolerability.
● Lamotrigine: suggested dosing regimen starts at 25 mg daily for
1 week, then the dose is doubled at weekly intervals to a maximum
of 400 mg daily in two divided doses. If analgesia is achieved using
lower doses, then no further increase is necessary.
Neuropathic pain responds variably to strong opioids. It may be
necessary to use several other medicines concurrently, necessitating
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318 Palliative and end-of-life care
polypharmacy, with its resulting problems with drug interactions and

side effects.
Topical capsaicin (cream and patch) is licensed for neuropathic
pain. Great care must be taken in its use to avoid inadvertent
application to the eyes and broken or inflamed skin. An intense
burning sensation may occur following initial application.
Adjuvant medicines for muscle spasticity
Skeletal muscle relaxants (e.g. baclofen, tizanidine) may be of use in
spasticity and associated pain but usefulness is usually limited.
Depending on the effects on the relative tone of extensor and flexor
muscles, spasticity may be adversely affected by treatment.
REFERENCES
1 International Association for the Study of Pain (2014). http://www.iasp-pain.org/
Taxonomy?navItemNumber=576#Pain (accessed 23 November 2014).
2 Breivik H et al. (2008). Assessment of pain. Br J Anaesth 101: 17–24.
3 Royal College of Anaesthetists (2014). Guidance on the Provision of Anaesthesia
Services for Chronic Pain Management. Available at https://www.rcoa.ac.uk/system
/files/GPAS-2014-12-CHRONICPAIN.pdf (accessed 22 November 2014).
4 WHO (1986). Cancer Pain Relief . Geneva: WHO.
5 Charlton E (1997). The management of postoperative pain. Update Anaesth 7(2):
P 1–7.
6 Coxib and Traditional NSAID Trialists’ (CNT) Collaboration (2013). Vascular
and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs:
meta-analyses of individual participant data from randomised trials. Lancet 382:
k 769–779.
7 Drug Safety Update 2013; 7: issue 1 S2.
k
8 Moore SA et al.(1997). Paracetamol with or without codeine in acute pain: a
quantitative, systematic review. Pain 70: 193–201.
9 NICE (2012). Clinical Guideline 140. Opioids in Palliative Care: Safe and
effective prescribing of strong opioids for pain in palliative care of adults.
11 Electronic Medicines Companion (2014). http://www.medicines.org.uk/emc/
(accessed 23 November 2014).
12 NICE (2013). Clinical Guideline 173. Neuropathic Pain – Pharmacological
management: The pharmacological management of neuropathic pain in adults in
non-specialist settings. http://www.nice.org.uk/guidance/cg173 (accessed 25
November 2014).
Palliative and end-of-life care

Palliative care is used to describe care that is given to patients with any
advanced progressive disease that impacts on their physical, psychoso-
cial and spiritual well-being. The aim of palliative care is to improve the
quality of life of patients, their families and carers through preventing
and relieving suffering, e.g. physical symptoms such as pain, by means
of early identification, assessment and evidence-based treatments.
Cancer patients remain one of the largest groups who receive palliative
care; however, it is increasingly being provided to patients with
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other advanced progressive diseases, such as COPD, cardiovascular,

renal or hepatic disease, HIV/AIDS and motor neurone disease.
End-of-life care encompasses the principles of palliative care and is
provided to people who are likely to die within the next 12 months.
This includes people whose death is imminent (expected within a few
hours or days), e.g. as a result of disease progression or a
life-threatening acute event such as head trauma.
Medications remain a significant part of the care given to relieve
symptoms and will be the focus of this entry. Other therapies include
radiotherapy, physiotherapy, and complementary therapies. For more
information, see Further reading, below.
Pharmacy and palliative care

Pharmacy professionals in all sectors of healthcare are likely to come
into contact with palliative care patients at some time. They are
ideally placed to provide the following support:
● information about medications and their side effects; effective

management can avoid unnecessary readmission, which is often
not the wish of the dying patient or carers
● offering the patient and carer ways to keep their list of medications P
up to date to facilitate medicines reconciliation, for example when
attending an outpatient appointment to review the dose of a strong
opioid, or following admission to hospital with a syringe pump
k where urgent knowledge of the contents is required k
● understand the importance of timely access to medications for
end-of-life care, and may have processes in place that allow
injectable medications for symptom control to be available in the
place where the patient wishes to be cared for.
Pharmacy members of staff are encouraged to make contact with

their local palliative care team. This will facilitate a multidisciplinary
approach to care as well as shared learning concerning the issues
above. Palliative care teams will often have a specialist pharmacist
who can target support to pharmacy teams working in all healthcare
settings.
Medication treatment of symptoms – overview

Table P3 lists the estimated prevalence of symptoms seen in cancer
patients.1
This section will focus on three of the main symptoms: pain,
constipation, and nausea and vomiting. For information on the
treatment of other symptoms, for example, fatigue, delirium,
shortness of breath, oral problems, confusion and the last hours and
days, see Further reading, below.
Pain
The principles of managing chronic pain follow the recommendations
of the WHO analgesic ladder (see Pain management entry). This
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TABLE P3
Prevalence of symptoms in cancer patients
Symptom Prevalence (%)
Pain 50–70
Weight loss 45–70
Fatigue 40–50
Anorexia 40–75
Insomnia 30–60
Constipation 25–50
Depression 20–30
Nausea and vomiting 15–45
Dyspnoea 20–50
Anxiety 10
stepwise approach to the use of analgesic medications allows optimal

pain control with minimal side effects in up to 80% of cancer patients.
Not all pain is completely opioid-sensitive. Knowing the cause of
the pain may determine a more logical choice and dosage of
medication; for example, prescribing a tricyclic antidepressant can be
P helpful in neuropathic pain. These kinds of medication are known as
‘adjuvant analgesics’ and can be used at any stage of the analgesic
ladder; they may not be primarily analgesic in their mechanism of
action, but have analgesic effects in certain pain conditions.
k This approach can allow the choice and dose of other analgesics k
the patient is taking to be reviewed; for example, a lower dose of
opioid may be sufficient for the pain, avoid unnecessary side effects
and help the patient to adhere to treatment. In some cases, adjuvant
analgesics alone can provide adequate pain relief.
Table P4 lists different adjuvant analgesics and the pain conditions
they may be considered for.
TABLE P4
Adjuvant analgesics in palliative care
Adjuvant analgesic Type of pain Examples of medication(s)
and typical starting doses
Antidepressants and Neuropathic (e.g. tumour ● Amitriptyline 10 mg at
antiepileptics infiltration, spinal cord night
compression, radio- or ● Gabapentin 300 mg at
chemotherapy-induced night (in elderly/frail
damage) consider 100 mg)
● Pregabalin 75 mg twice
daily (in elderly/frail
consider 25–50 mg twice
daily)
Bisphosphonates Metastatic bone pain ● Disodium pamidronate
persisting despite analgesics ● Several regimens exist, for
and radiotherapy example, 90 mg every
3–4 weeks for as long as
benefit is maintained
(Continued)
k
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TABLE P4
(Continued)
Adjuvant analgesic Type of pain Examples of medication(s)
and typical starting doses
Corticosteroids Pain and weakness
associated with:
● Nerve root compression ● Dexamethasone
● Spinal cord compression 4–8 mg/day
● Dexamethasone
12–16 mg/day
N -methyl-D-aspartate Neuropathic pain ● Ketamine and methadone
(NMDA) receptor unresponsive to standard given under specialist
channel blockers analgesics supervision
Skeletal muscle Painful skeletal muscle ● Baclofen 5 mg two to three
relaxants spasm (e.g. tumour times daily
infiltration, cramp, ● Diazepam 2 mg at night
myofascial pain)
Smooth-muscle Visceral distension pain and ● Hyoscine butylbromide
relaxants colic (e.g. tumour infiltration 20 mg subcutaneous
(antispasmodics) of an organ or the bowel injection stat, then
wall, respectively) 20–60 mg/day as a
continuous subcutaneous P
infusion
● Avoid oral route due to
poor oral bioavailability
k k
The concept of ‘total pain’ has physical, psychological (e.g. anxiety
and depression that affect the perception and intensity of pain), social
(e.g. financial concerns or isolation) and spiritual (e.g. religious
struggle as what is happening goes against the person’s beliefs)
components that require management in order to gain control of the
patient’s pain. It is important for the pharmacy team to understand
this multidisciplinary approach to treating pain.
Starting a patient on a strong opioid
The term ‘strong opioid’ refers to medications on step 3 of the
analgesic ladder and includes morphine, oxycodone, alfentanil and
fentanyl in the treatment of severe pain. When starting a patient on a
strong opioid it is important to consider choice of strong opioid, dose
and route of administration.
Initial dose titration
First-line: use regular oral immediate-release morphine:
● 5 mg oral immediate-release morphine 4-hourly, and
● 5 mg oral immediate-release morphine 4-hourly when required for
rescue doses during the titration phase.
Consider reducing the dose in elderly/frail patients, for example a
50% dose reduction.
Seek specialist advice when using strong opioids in patients with
moderate to severe renal impairment (particularly if creatinine
clearance is ≤30 mL/min). The patient should be reviewed regularly
(e.g. daily) with regard to pain control and adverse effects.
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Dose increments are not normally >30% of the previous dose.

When the optimal balance of pain control and side effects has been
reached the patient should be prescribed maintenance treatment.
Specialist advice should be sought if this balance is not reached after a
few dose adjustments.
Maintenance treatment
First-line: use oral modified-release morphine. Once pain is
controlled the total amount of oral immediate-release morphine
given in the last 24-hour period is added up, then divided into two
12-hour release morphine doses, for example:
● 5 mg oral immediate-release morphine 4-hourly = 30 mg oral
morphine in 24 hours. This is converted to 15 mg oral
modified-release morphine twice daily.
Management of breakthrough pain
First-line: use oral immediate-release morphine as rescue medication
for breakthrough pain in patients on maintenance oral morphine.
One-sixth of the total daily dose of morphine should be prescribed as
the ‘when required’ dose (4-hourly as required).
Specialist advice should be sought if the breakthrough dose is not
P effective.
Communication
When patients are started on a strong opioid, aim to discuss any
concerns regarding:
k k
● side effects
● the idea that the introduction of opioids implies the final stages of
life or hastens death (neither of these is correct)
● addiction and tolerance – both of which are rare and do not
significantly affect pain management in the majority of patients.
Offer verbal and written information to patients and carers on strong
opioids, including:
● when and why strong opioids are used to treat pain
● how to take strong opioids for background and breakthrough pain,
and how long pain relief should last
● side effects and signs of toxicity and what to do if they appear
● safe storage and disposal of unwanted medication.
Check the patient and carer have information on out-of-hours
contacts and planned follow-up by their specialist.
Treatment if oral opioids are not suitable
Oral opioids may be unsuitable:
● for people with swallowing difficulties
● when oral absorption is impaired
● when pain is unstable
● for ‘tablet phobia’ or poor adherence with oral medication.
If oral opioids are not suitable, consideration should be given to
alternative routes, including transdermal, transmucosal and
subcutaneous.
k
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Transdermal opioid patches

Caution should be used when calculating the opioid equivalence for
transdermal opioid patches, e.g. a fentanyl 12 micrograms/hour
patch equates to approximately 45 mg oral morphine daily.
It is important to remember that opioid conversion charts are an
approximate guide only.
It can take up to 2 days after starting a transdermal opioid patch,
or changing the dose, for the full effect to be seen. Switching between
opioid preparations should be timed correctly so that pain remains
controlled and side effects are avoided. Patients should always be
reviewed regularly following a change from one opioid to another.
Table P5 details the main safety facts to consider when using
transdermal opioid patches.
TABLE P5
Safety considerations of opioid patches
Fentanyl transdermal patches
● Remove the patch and replace every 3 days
● A range of generic products is available; no clinical difference exists between
products
Buprenorphine transdermal patches P
● Remove and replace patches once a week (7-day patch: BuTrans), or twice a week
(4-day patch: Transtec)
● The 4-day patch can be replaced on fixed days in the week, i.e. after 3 and 4 days
k Patches have a long duration of action k
● Clinically significant levels of opioid can remain in the blood for up to 30 hours after
patch removal
Do not cut patches in half
● Absorption may not be uniform across the surface area of the patch once cut
Factors affecting drug absorption from patches
● Pyrexia or external heat can increase absorption
● Absorption may be reduced in cachectic patients
Old patches still contain medication
● Dispose of carefully; fold in two with the medication side of the plaster facing
inwards
Switching to an alternative strong opioid

Morphine remains the first-line strong opioid of choice. Patients who
are unable to tolerate morphine or where adequate pain relief is not
achieved may be considered for an alternative strong opioid, e.g.
oxycodone. Specialist advice should be sought in these cases and a
clear record of the reason(s) for switching made in the patient’s
clinical notes.
Management of the side effects of strong opioids
Constipation
All patients starting a strong opioid medication should be considered
for a regular laxative. See section below on constipation.
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Nausea
Transient nausea may occur when starting strong opioid treatment or
when the dose is increased. A ‘when required’ antiemetic should be
considered in these situations. Optimise antiemetic treatment before
considering switching opioids.
Drowsiness
Transient and mild drowsiness or impaired concentration may occur
when opioid treatment is started or when the dose is increased.
Patients should be warned that impaired concentration may affect
their ability to drive and undertake manual tasks safely. The Driver
and Vehicle Licensing Agency has produced guidance addressing
medications and fitness to drive.2 Check with your local palliative
care team for a patient information leaflet on driving with strong
opioids (see DVLA: advice concerning medication and medical
conditions entry).
In patients with either persistent or moderate to severe central
nervous system side effects consideration should be given to:
● reducing the dose of the opioid if the pain is controlled.
● switching to an alternative opioid if the pain is not controlled.
P
If adverse effects remain uncontrolled despite optimising treatment,
the patient should be referred to the palliative care team.
Constipation
k Palliative care patients are particularly susceptible to constipation due k
to a variety of causes. Table P6 lists some of these.
TABLE P6
Factors influencing constipation in palliative patients
Organic factors Functional factors
● Pharmacological: antacids, ● Diet: reduced food/ fibre/fluid intake
antimuscarinics, antidepressants, ● Environmental: lack of privacy,
antidiarrhoeals, antiemetics (5HT3 comfort or assistance with going to the
antagonists), opioids, antiepileptics, toilet
antihypertensives, antiparkinsonians, ● Other: reduced physical activity,
antitussives, chemotherapy (vinca dyspnoea preventing effective straining,
alkaloids and platinum-based depression and sedation
chemotherapy), proton pump inhibitors,
diuretics and neuroleptics
● Metabolic: dehydration,
hypercalcaemia, hypokalaemia,
hypothyroidism, uraemia and diabetes
● Neurological: cerebral tumours, spinal
cord involvement, sacral nerve
pathology and autonomic failure
● Structural: pelvic tumour mass,
radiation fibrosis, painful anorectum
(haemorrhoids, anal fissure or perianal
abscess) and uncontrolled pain of any
cause
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The aims of treatment are:
● re-establish comfortable bowel habits the patient is satisfied with

● relieve pain and discomfort
● restore independence in relation to bowel habits
● prevent or reduce related symptoms: nausea and vomiting,
abdominal bloating and pain.
Most cases of constipation in palliative care, including opioid-induced

constipation, are best treated with a combination of a stimulant
laxative and softening laxative, for example:
● stimulant: senna tablets 7.5 –15 mg orally twice daily or senna

syrup (7.5 mg/5 mL) 10 –20 mL twice daily
● softener: docusate 100 –200 mg orally twice daily or macrogol oral
powder 1 –3 sachets daily in divided doses. Macrogol oral powder
given in higher dosage is also used to treat faecal
loading/impaction.
If tablet burden is an issue, consider a combined stimulant and

softener preparation, for example:
P
● co-danthramer: 1 –2 capsules twice daily or suspension 2.5 –5 mL
twice daily
● co-danthramer strong: 1 –2 capsules twice daily or suspension
k 2.5 –5 mL twice daily. k
Patients who do not respond to oral laxatives or where the oral route
is inappropriate should be considered for second-line rectal
treatment. There are specific clinical situations that should also be
considered in the palliative care patient, for example:
● faecal incontinence: danthron (in co-danthramer) should be

avoided due to the risk of local skin burn
● bowel obstruction or colic: stimulant laxatives should be avoided
● opioid-induced constipation unresponsive to oral and rectal
measures: consider methylnaltrexone injection.
When treating constipation in the dying patient, bowel function may

become less of a priority compared to other symptoms as the patient’s
functional status and conscious level deteriorate. The oral route may
become inappropriate.
Nausea and vomiting
Knowledge of the likely cause(s) of nausea and vomiting and the
nerve pathways involved provides a useful starting point when
deciding on the most appropriate antiemetic. A single antiemetic may
be adequate to control symptoms; however, 25% of patients will
require a combination of medications. Reversible causes should be
treated, e.g. infection, cough, hypercalcaemia, tense ascites (causing
excessive pressure on the stomach and bowel), raised intracranial
k
k
pressure, emetogenic medications, the sight and smell of foods and

anxiety can all exacerbate symptoms.
Table P7 lists possible causes of nausea and vomiting and the
antiemetics that may be considered.
TABLE P7
Antiemetics in palliative care
Nerve pathway involved Possible causes Consider treatment with
Chemoreceptor trigger zone Medications (e.g. opioids, Haloperidol
(D2 , 5HT3 , acetylcholine) NSAIDs, antibiotics), Metoclopramide
lies outside of the metabolic (e.g. Domperidone
blood–brain barrier and hypercalcaemia, renal
Granisetron
susceptible to chemical failure) and toxicity (e.g.
Ondansetron
changes in the blood chemotherapy,
radiotherapy)
Gut mucosa (D2 , 5HT3 , Delayed gastric emptying, Metoclopramide,
acetylcholine, NK1) gastrointestinal obstruction, domperidone (prokinetics
colic, tumour mass, gastric are contraindicated if colic
irritation and constipation present or bowel is
obstructed),
P levomepromazine,
granisetron/ondansetron,
aprepitant, a
gastroprotectant and
suitable laxative(s).
k Octreotide may be k
considered for bowel
obstruction associated with
large-volume vomits (under
specialist supervision)
Vestibular apparatus (H1 , Motion sickness Cyclizine, hyoscine
acetylcholine) hydrobromide
Cerebral cortex Emotions, sights, smells and Dexamethasone,
raised intracranial pressure. benzodiazepines
Repetitive stimulation can
lead to ‘anticipatory’
nausea and vomiting (a type
of conditioned behaviour
that can be difficult to treat)
Further reading
Centre for Pharmacy Postgraduate Education (2012). Palliative
Care – An open learning programme for pharmacists and pharmacy
technicians. www.cppe.ac.uk/learning/Details.asp?TemplateID
=PALLIATIVE-P-02&Format=P&ID=115&EventID=42008 (accessed
26 April 2015).
Help the Hospices (2011). Current Learning in Palliative Care –
online tutorials. http://www.hospiceuk.org/what-we-offer/courses-
conferences-and-learning-events/e-learning (accessed 15 May 2015).
k
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Pancreatitis 327
NICE (2014) Clinical Knowledge Summaries. http://cks.nice.org.uk/

SIGN (2008). Control of Pain in Adults with Cancer. Edinburgh: SIGN.
Twycross R, Wilcock A (eds) (2012). Palliative Care Formulary
(4th edn). Nottingham: Palliativedrugs.com.
Watson M et al. (eds) Palliative Care Adult Network Guidelines Plus.
http://book.pallcare.info/ (accessed 22 September 2015).
REFERENCES
1 Grond S et al. (1994). Prevalence and pattern of symptoms in patients with cancer
pain: a prospective evaluation of 1635 cancer patients referred to a pain clinic.
J Pain Symptom Manage 31: 58–69.
2 Department of Transport (2014). Guidance for Healthcare Professionals on Drug
Driving. https://www.gov.uk/government/publications/drug-driving-and-medicine-
advice-for-healthcare-professionals (accessed 21 September 2014).
Pancreatitis
Pancreatitis is an inflammation of the pancreas. This organ plays a
vital digestive role in producing enzymes that help to break down P
food in the small bowel.1 When inflammation and scarring of the
pancreas occur, such as in pancreatitis, the organ is unable to function
optimally, which may result in a patient being unable to digest fat and
k key elements of food. k
Types of pancreatitis
There are two types of pancreatitis:
1 acute: where the inflammation may be sudden, after which the

pancreas returns to normal
2 chronic (ongoing): where there is a long-standing functional deficit
of the pancreas. Chronic pancreatitis is characterised by disabling
pain and progressive endocrine and exocrine insufficiency.
Endocrine pancreatic insufficiency results from damage to the

endocrine tissue of the pancreatic gland (islets of Langerhans), with
failure to produce insulin causing glucose intolerance and diabetes
mellitus.2 Exocrine pancreatic insufficiency results from damage to
the acinar cells (exocrine tissue of the pancreatic gland), with failure
to produce digestive enzymes causing maldigestion and
malabsorption.
Risk factors
Risk factors include the following:
● alcohol: accounts for 70 –90% of all cases of chronic pancreatitis,

although the exact mechanism is unknown. Only 5 –10% of heavy
drinkers develop chronic pancreatitis, suggesting that important
cofactors are involved
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328 Pancreatitis
● gallstones: stones of hardened bile that form in a patient’s biliary

ducts
● idiopathic: chronic pancreatitis is classified as idiopathic after all
other possible causes have been ruled out
● autoimmune disease
● obstructive causes
● radiotherapy
● smoking: raises the risk for pancreatic calcification that results in
pancreatic duct obstruction and pancreatic tissue damage
● medications: several can cause pancreatitis, including:
● sodium valproate
● azathioprine
● furosemide
● corticosteroids
● angiotensin-converting enzyme inhibitors
● statins
● didanosine
● lamivudine
● oral contraceptives
● interferon
P ● exenatide.
Signs and symptoms of pancreatitis

Symptoms of acute and chronic pancreatitis include severe pain in the
k upper abdomen, loss of appetite, nausea and vomiting, fever, and k
swollen tender abdomen.
Additional symptoms for chronic pancreatitis include:
● steatorrhoea, which presents as pale-coloured, oily faeces. This

presentation is as a result of the reduced production and secretion
of pancreatic enzymes, thereby causing nutrient malabsorption.
Malabsorption of all macronutrients occurs; however, fat
malabsorption tends to be the most clinically evident.
● failure to gain weight despite routine eating habits and calorie
intake. Other symptoms of malabsorption that are less obvious are
bloating, flatulence and nausea. Bloating and wind may be due to
the passage of undigested carbohydrate into the colon, where
fermentation by the colonic flora occurs.
Diagnosis
For a formal diagnosis of pancreatitis the following tests are
undertaken:
● pancreatic elastase-1 (faecal elastase) is an enzyme that is not

degraded during intestinal transit, is enriched five- to sixfold in the
faeces, and is therefore a good test of pancreatic exocrine function3
● serum amylase is a digestive enzyme that can be at least three times
the normal level in acute pancreatitis
● serum IgG4 is used for diagnosing autoimmune pancreatitis
k
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Pancreatitis 329
● serum lipase, a protein released by the pancreas into the small

intestine. It assists in the absorption of fat
● serum trypsinogen is produced in the pancreas and released into
the small intestine and converted to trypsin, which then starts the
process of breaking proteins down to amino acids
● imaging is useful if the above are indeterminate as inflammation,
calcium deposits of the pancreas, or changes to the ducts of the
pancreas may be seen on an abdominal CT scan.
Treatment
The treatment goals of pancreatitis are to correct the underlying
cause, relieve pain and treat malabsorption and impaired blood
glucose control. The treatment plan involves a multidisciplinary
approach with surgeons, dieticians, endocrinologists, diabetologists,
substance misuse specialists and pharmacists, amongst others.
Pain
Pain, secondary to pancreatitis, classically presents as generalised
severe abdominal pain at times associated with intense back pain. It is
often persistent and refractory to simple analgesia and so at times
necessitates admission to hospital to optimise control. There are no P
current NICE or SIGN guidelines with associated grading for the
pharmacological management of this symptom in pancreatitis.
Typically the pharmaceutical analgesic plan involves pain control
k titrated according to the WHO ladder principle (see Pain management k
entry), but in some situations and commonly in acute presentations a
top-down approach may be useful to control pain. Adjuvant
analgesics, such as amitriptyline, gabapentin or pregabalin, should be
considered at an early stage and combinations of drugs are often
used. Pancreatic enzyme therapy such as Creon, somatostatin
analogues such as octreotide and various antioxidants (vitamins A, D,
E or selenium) may be considered as supplements to conventional
analgesics in special situations.4
Pancreatic enzyme therapy
This has been the subject of several randomised trials and
meta-analyses. The proposed mechanism of action is the ability to
degrade cholecystokinin (CCK)-releasing factor in the duodenum and
thereby lower levels of CCK.5 An elevated level of CCK has been
reported in pancreatitis patients and may generate pain by increasing
the pressure in the pancreatic duct.
Somatostatin analogues
Somatostatin analogues inhibit pancreatic secretion by blocking CCK
and secretin release and also by a direct inhibitory effect on acinar
cells. Whilst an early pilot series of subcutaneous octreotide at a dose
of 100 micrograms three times a day showed an effect on pain control,
this effect could not be confirmed in a double-blind cross-over study
enrolling pancreatitis patients treated with octreotide or placebo.6
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330 Pancreatitis
Antioxidants
The proposed analgesic mechanism of action underlying this therapy
is an anti-inflammatory and blocking effect of free radicals.7 The
current evidence base in pancreatitis, however, is not sufficient to
recommend antioxidant therapy.
Malabsorption
Exocrine insufficiency develops in up to 40% of people with chronic
pancreatitis, and can cause malabsorption of fat-soluble vitamins,
such as vitamin D.8
The deficiency of fat-soluble vitamins appears to have a variable
prevalence, and therefore, biochemical assessment of serum
fat-soluble vitamin levels is advised and ‘blind’ routine
supplementation should be avoided.
Aggressive nutrition support, such as enteral nutrition, at times is
required if malabsorption is severe. Parenteral nutrition is necessary
in <1% of cases. Indications include gastric outlet obstruction and
when jejunal access is unachievable, complex pancreatic fistulae, and
in the severely malnourished patient pre-surgery, where enteral
feeding is not possible.
P Pancreatic enzyme insufficiency
Pancreatic enzyme replacement therapy (PERT) is recommended by
NICE for people with alcohol-related chronic pancreatitis and who
have steatorrhoea or have a poor nutritional status, and this
k recommendation can be reasonably extrapolated to chronic k
pancreatitis with other causes.9
Patients with pancreatic insufficiency need to receive an
appropriate dose of PERT, usually starting with a dose of
40 000 –50 000 units lipase per meal and 10 000 –25 000 units lipase
per snack; this is increased in a stepwise manner depending on the
patient’s response.
Suppression of stomach acid with, for example, a proton pump
inhibitor is often required as pancreatic enzymes are denatured at a
low pH. Fortunately the majority of pancreatic enzymes on the market
are enteric-coated and so are only released once in the high pH of the
small bowel.
Blood glucose control
The development of diabetes occurs late into the onset of pancreatitis
and occurs as a result of damage to the pancreatic alpha cells (which
produce glucagon) and to the islet cells (which produce insulin).
The diabetes that results secondary to pancreatitis should be
referred to as type 3 but is often misclassified as type 1 or 2, although
it is distinctly different from both of these.10 Typically those with type
3 diabetes are older than those with type 1 diabetes and have a lower
BMI than in type 2 diabetes.
Many patients with type 3 diabetes have difficulty with glucose
control. The combination of glucagon deficiency, malnutrition and
alcohol intake increases the risk of spontaneous hypoglycaemia.
k
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Hyperglycaemia is also frequent due to unsuppressed hepatic glucose

production.
Oral hypoglycaemic drugs are often used for as long as possible
due to the risk of insulin-induced hypoglycaemia.
REFERENCES
1 BUPA (2014). Health Topics: Pancreatitis. http://www.bupa.co.uk/health-
information/directory/p/pancreatitis (accessed 24 July 2014).
2 Kocher HM (2008). Chronic pancreatitis. Am Fam Physician 77: 661–662.
3 NICE (2010). Clinical Knowledge Summaries. Chronic Pancreatitis. http://cks.nice
.org.uk/pancreatitis-chronic (accessed 17 July 2014).
4 Paisley P, Kinsella J (2014). Pharmacological management of pain in chronic
pancreatitis. Scot Med J 59: 71–79.
5 Olesen S et al. (2013). Pharmacological pain management in chronic pancreatitis.
World J Gastroenterol 19: 7292–7301.
6 Bai Y et al.(2008). Prophylactic octreotide administration does not prevent post-
endoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis of
randomized controlled trials. Pancreas 37: 241–246.
7 Bhardwaj P et al.(2009). A randomized controlled trial of antioxidant supplemen-
tation for pain relief in patients with chronic pancreatitis. Gastroenterology 136:
149–159.
8 Duggan SN, Conlon KC (2013). A practical guide to the nutritional management
of chronic pancreatitis. Pract Gastroenterol 24–32.
9 Borman P, Beckingham I (2001). ABC of diseases of liver, pancreas and biliary
P
system. BMJ 322: 660–663.
10 Cui Y, Andersen DK (2011). Pancreatogenic diabetes: special considerations for
management. Pancreatology 11: 279–294.
k k
Parenteral nutrition: a practical

overview
Parenteral nutrition (PN) is used to provide the nutritional needs of
patients where there is a failure of the GI tract to perform its normal
function of processing and absorbing food, e.g. short-bowel
syndrome. It can also be used where enteral nutrition is insufficient to
maintain nutritional status, e.g. malabsorption. NICE guidance states
that PN should be considered for people who are malnourished or are
at risk of being malnourished and meet either of the following
criteria:
● inadequate or unsafe oral and/or enteral nutritional intake
● a non-functional, inaccessible or perforated (leaking) GI tract.1
PN is not an emergency intervention in adults and there is rarely an
indication to start it out of hours or at the weekend.2 PN is not
without risk, e.g. line sepsis, metabolic disorders, compromised
immune function, thrombosis and air embolus. Hospitals should have
written guidance for the initiation and management of PN and it is
important to be aware of these.2
PN mixtures can be administered via a peripheral or a central
venous catheter. Peripheral lines are most often used if PN is
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332 Parenteral nutrition: a practical overview
anticipated to last up to 2 weeks. Peripheral cannulas need resiting

every 1 –2 days.1 Central venous catheters are used if PN is to be
prolonged or in intensive care settings where central lines are used
routinely. Central venous catheters should be inserted under sterile
conditions and the position of the catheter tip must be confirmed
radiologically prior to commencing therapy.3 Following insertion it is
important that the line is cared for correctly to minimise the risk of
infection and a lumen should be dedicated to the PN.2
A baseline assessment of a range of biochemical markers
(Table P8) is needed prior to treatment. The patient’s weight should
be recorded and nutritional requirements documented in the medical
notes. These markers will then need regular reviews, the frequency of
which will depend on the individual marker, whether the patient is
considered metabolically stable or not, and for any other reason
specific to that patient.3
TABLE P8
Monitoring parameters
Parameter Frequency
Sodium, potassium, urea, creatinine Baseline
P Daily until stable, then twice weekly
Weight Baseline
Daily until stable and then weekly
Magnesium, phosphate Baseline
k Daily if risk of refeeding syndrome k
Three times a week until stable, then weekly
LFTs Baseline
Twice weekly until stable, then weekly
Glucose Baseline
Once or twice per day (or more if needed) until
stable, then weekly
Calcium, albumin Baseline
Weekly
CRP Baseline
Two or three times per week
Zinc, copper Baseline
Every 2–4 weeks depending on result
Iron, ferritin Baseline
Every 3–6 months
Folate, vitamin B12 Baseline
Every 2–4 weeks
Refeeding syndrome
The reason for close monitoring, particularly in the first few days, is
the concern of refeeding syndrome. As the name suggests, this
syndrome can occur when feeding is recommenced, either enterally
or parenterally following a period of starvation. During a period of
starvation, various electrolytes are lost and there is compensatory
k
k
movement of the electrolytes, i.e. magnesium, calcium and

phosphate, from the cells into the plasma to maintain near-normal
plasma levels. When feeding recommences there is an increase in
insulin production that causes these electrolytes to move
intracellularly and their serum concentrations consequently fall.
The syndrome is characterised by hypophosphataemia,
hypomagnesaemia, hypocalcaemia and fluid retention, and there may
be a thiamine deficiency, particularly if the patient has a history of
alcohol abuse. This can lead to congestive heart failure and
life-threatening arrhythmias.
PN for people at high risk of developing refeeding problems should
consider:
● starting nutrition support at a maximum of 10 kcal/kg/day,

increasing levels slowly to meet or exceed full needs by 4 –7 days
● using only 5 kcal/kg/day in extreme cases (for example, BMI
<14 kg/m2 or negligible intake for more than 15 days)
● providing immediately before and during the first 10 days of
feeding: oral thiamine 200 –300 mg daily (or full-dose daily
intravenous vitamin B preparation, if necessary), and a balanced
multivitamin/trace element supplement once daily P
● providing oral, enteral or intravenous supplements of potassium,
phosphate and magnesium unless prefeeding plasma levels are
high. Prefeeding correction of low plasma levels is unnecessary.
k k
Monitoring
Baseline measurements should be taken prior to commencement of
PN and should then be measured at the intervals shown in Table P8.1
The frequency of monitoring of these parameters may also depend
on the individual patient. For instance, glucose readings may need to
be performed hourly until glycaemic control is achieved in a patient
who is metabolically unstable and has impaired glucose tolerance.
The patient may need a sliding-scale insulin regimen prescribed to aid
glycaemic control. Electrolyte readings may need to be more frequent
if the patient shows evidence of refeeding syndrome or other
electrolyte disturbances.4
It is important that the overall clinical well-being of the patient is
taken into account as this can be an indication of an improvement in
the patient’s condition, or the first sign of a PN-related complication
developing.
Drug interactions
Drugs should not be added to the PN admixture, either directly to the
bag or via the same catheter. It is imperative that the lumen is
dedicated for the PN infusion administration.
The bag should be protected from direct light, so consideration
should be given to making sure the patient is not beside a window, or
that the PN bag is covered with a bag made of a light-protecting
material.
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334 Patient consultation
REFERENCES
1 NICE (2006). Nutrition Support in Adults: Oral nutrition support, enteral tube feeding
and parenteral nutrition. CG32 http://www.nice.org.uk/guidance/cg32/chapter/
guidance (accessed 30 September 2014).
2 NCEPOD (2010). Parenteral Nutrition: A mixed bag. http://www.ncepod.org.uk/
2010pn.htm (accessed 30 September 2014).
3 British Society of Gastroenterology (1996). Guidelines on Artificial Nutritional Sup-
port. http://www.bsg.org.uk/pdf word docs/art nutrit.pdf (accessed 30 September
2014).
4 Medicines Information Leaflet (2001). Oxford: Oxford Radcliffe Hospitals NHS Trust,
Medicines Advisory Committee, vol. 2 no. 5.
Patient consultation
The term ‘patient consultation’ is used here to describe the interaction
between patients and health professionals around medicines-related
issues. It replaces the term ‘patient counselling’ as this term is poorly
understood outside the pharmacy profession where the word
‘counselling’ describes a therapeutic relationship of a psychological
nature.
P Purpose of a consultation
For many years, consultations were regarded as opportunities to
educate patients about medicines and highlight risks identified by the
pharmacist as important. More recently it has been acknowledged
k that effective consultations require patient understanding, memory k
and satisfaction with a consultation. Patient engagement with the
pharmacist is key to a successful clinical encounter and supports
creation of a shared agenda between the clinician and patient and the
development of an agreed explicit goal. NHS Health Education
England and the Centre for Postgraduate Pharmacy Education have
recently produced a number of resources for pharmacists to support
this as part of the drive to focus on a patient-centred approach to
consultations.1
The NICE Medicines Adherence guidance2 recognises the need for
pharmacists to provide patient support around adherence. Effective
consultations are an integral part of medicines optimisation to
support improved outcomes for patients. In order to improve
medicines adherence, an understanding of patients’ perspective on
their illness, their health goals and their beliefs and concerns about
medicines is required. The pharmacist can use this information to
tailor the consultation around medicines-related issues for each
patient and support patients in addressing their issues of medicines
adherence.
Structure of the consultation
In order to make best use of the time allocated for patient
consultation, it is helpful to think of the interaction in terms of both
content and structure. There are a number of models used for medical
patient consultations. Roger Neighbour’s five-step model3 is a helpful
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guide to developing consultation structure and includes key features

such as development of rapport with the patient and agreeing a way
forward and safety netting (advising the patient what to do if things
go wrong). Neighbour adds that clinicians need time to look after
themselves between consultations in order to serve their patients
optimally. The Calgary Cambridge model4 is used by a large number
of medical schools in the UK and is also focused on relationship
building, gathering information from the patient and explaining,
agreeing and planning next steps with the patient.
In a medicines-related consultation, pharmacists are usually
focused on ensuring that they have told the patient key information
about the medicines prescribed, including how and when to take
them, common side effects and key warnings. The recent
developments in consultations structure suggest that the pharmacy
structure can be improved to engage patients better in their own care.
The medicines-related consultation framework (MRCF)5 is a
validated method of assessing consultations.
The four e’s structure for consultations
The four e’s is a structure for consultations,1 developed from the
GROW model, widely used in coaching generally and specifically in P
health coaching.6 This model acknowledges the requirements for
pharmacists in a medicines-related consultation while ensuring that
patients are engaged and their agenda is fully addressed.
The model looks like this:
k k
Explore
Educate
Empower Enable
The four e’s model is built on a foundation of engagement and

empathy with patients, and thus the consultation needs to begin with
rapport building.
This is most effectively done by introducing yourself by name and
asking what medicines-related conversation the patient would like to
have with you. This allows patients to refuse a consultation at that
time, so you can offer them alternatives for discussion in the future,
whether that is rescheduling, giving a medicines helpline number or a
website. If the patient agrees to a consultation, you then need to ask
the patient what s/he wants to discuss (around medicines) and tell
the patient what you would like to cover in the consultation. This
conversation will lead to creation of an agreed agenda before the
consultation begins.
The first part of the consultation needs to focus on the patient’s
current knowledge, beliefs and concerns about his or her medicines.
If the patient is taking a number of medicines, s/he should be given
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the opportunity to talk about the medicine that s/he is most

interested in first.
Questions that facilitate this part of the consultation are listed
below.
Explore
● What do you already know about your medicines?
● What do you want to know?
● What worries/concerns you about your medicine?
● How do you think your medicine helps you?
While pharmacists are adept at providing patient education, this
model suggests that education should be tailored to the patient
agenda and key safety information given in response to patient lead
where possible.
Educate
● Give information in response to patient questions.
● Include safety information as it relates to patient agenda wherever
possible.
● Ensure the patient has understood by using a teachback technique,
e.g. I’d like to review what we’ve discussed to make sure I have
P explained things clearly. Please let me know what you have
understood from our conversation about your medicine.
In a standard pharmacy consultation, patients are rarely asked
whether they are going to take the medicines. There is a tacit
k k
assumption that having been prescribed the medication they have
already agreed to take it as prescribed. In the UK, up to 50% of
medicines are not taken as intended2 and poor medicines adherence
is known to be a global issue. This model acknowledges patient choice
in adherence and empowers both the pharmacist and the patient to
address the issue within the consultation. In order for this to be
effective and to maintain rapport, the pharmacist must respect the
patient’s decision and support improving health outcomes in a way
that is acceptable to the patient, which may include developing or
signposting to an alternative strategy.
Empower
The final part of the consultation allows the patient to consider the
reality of taking a medicine. Try asking one of the following:
● So, what do you think about taking this medicine now?
● What would you like to do about your medicine now?
● How do you feel about the medicine now?
Regular medicines taking requires development of the ‘habit’ of
medicines taking so that it becomes an automatic part of daily
activities, rather than one that has to be thought about every day,
which is much more difficult to sustain. Consideration of the reality of
how a new medicine fits into an existing medicines regimen or
exploring how a new medicines-taking habit can be integrated into
the patient’s daily activities is important in helping the patient to
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consider the reality of medicine taking. The following questions are

useful in structuring this part of the consultation.
Enable
● How will you fit your medicines into your day? Probe further (to
help make the actions real for the patient).
● When will you take them? How will you remember to take them?
Where will you keep them?
● How will you know if this system works?
● What will you do to find out if the medicine is working for you?
While the model has been described here in a linear way, the diagram
illustrates that the agenda is fluid and education can be included at
any time in the consultation.
Closing the consultation
As in Neighbour’s model, it is important to ensure that safety
information has been received and understood and that the patient
knows where to go for additional information or help. It is valuable
for both you and the patient to summarise your agreed respective
actions following the consultation to reinforce the way forward.
P
Identifying and supporting patients with adherence
issues
Medicines adherence
k The WHO identified key factors affecting adherence, including: k
● social, economic and cultural, e.g. age, race, medicine cost
● health system and healthcare team
● therapy, e.g. length of treatment, desire for treatment, side effects
● condition treated, e.g. chronic versus acute, disability, severity
● patient, e.g. anxiety, forgetfulness, fear of dependency.
However, while it is known that beliefs about medicines influence
adherence, none of the above factors independently predicts poor
adherence.
Identifying non-adherence
Patient may express non-adherence openly to the pharmacist or this
may be identified through other means, such as irregular ordering or
collection of repeat prescription, or widely varying dates of
dispensing on medicines brought in on hospital admission. Neither
age nor socioeconomic status is a reliable predictor of adherence and,
while there is no clear disease-related predictor of adherence,
depression, smoking and unhealthy lifestyle choices have been linked
to poor adherence in some studies. Effective healthcare systems that
support patients appear to improve medication adherence. Patients
with knowledge of their disease and medication and high self-efficacy
are thought to be more adherent.
There are a number of questionnaires in development that help
practitioners and patients to identify issues of non-adherence;
k
k
however, these are not widely available. To date, there is no validated

simple predictor of medicines adherence that is currently in use in
pharmacy consultations. From a pharmacist’s perspective, this leaves
us with exploration of the patient’s beliefs and concerns about
medicines, and the practical implications of taking medicines.
This can also be considered using the COM-B model7 of adherence-
related behaviour. This includes capability (physical and
psychological), opportunity (physical and social) and motivation
(automatic/habit and reflective/requiring active thought).
Managing challenges in consultations

Changing consultation style to a more open conversation is inevitably
challenging. Common concerns include the difficulty of not giving
patients solutions, especially when that is what patients expect of you,
managing the rambling patient and managing time to support
behaviour change in this type of consultation.
Challenge 1: I came here for you to tell me what to do!
While some patients are happy to discuss their options with you,
others may consider this question as abrogation of your responsibility
P as a healthcare practitioner. If patients want you to tell them what to
do, it is useful to say that, while you are happy to give your
recommendation, your question is asked in recognition that they have
choice.
k Challenge 2: How to manage the rambling patient k
Many pharmacists fear that asking patients open questions will lead
to a protracted conversation that may veer off the subject in question.
While patients do need uninterrupted time at the beginning of a
consultation to tell their story, the four e’s method helps to prevent
rambling as the agenda is agreed with the patient at the start of the
consultation. This means that, if the patient diverts from the agreed
agenda, you can politely remind her of what she said she wanted to
speak about to do with medicines, and ask if this is still relevant to
her. The patient may tell you that she now has the information she
needs, which means you can close the consultation, or it will remind
the patient of her question, which she will then reconsider.
Challenge 3: Time
The issue of time is always tricky. Some practitioners find it helpful to
introduce this at the beginning of a consultation so that the patient
knows how much time you have and you can refer to this during the
consultation if you need to and schedule another visit if required.
Further reading
Horne R et al. (2005). Concordance, Adherence and Compliance
in Medicines Taking: Report for the National Coordinating Centre
for NHS Service Delivery and Organisation R&D. http://www.nets.
nihr.ac.uk/ – data/assets/pdf file/0007/81394/ES-08-1412-076.pdf
k
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Patient-controlled analgesia 339
NHS England (2013). Making Medicines-taking a Better Experience.

http://www.england.nhs.uk/wp-content/uploads/2014/04/mo-ws-
report-02-14.pdf (accessed 26 April 2015).
Review: Medication adherence: where are we now? A UK perspective.
Eur J Hosp Pharm ejhpharm-2013-000373. Published online first:
18 December 2013. http://ejhp.bmj.com/content/early/2013/12/18/
ejhpharm-2013-000373.full (accessed 26 April 2015).
World Health Organization (2003). Adherence to Long-Term Ther-
apies: Evidence for action. http://www.who.int/chp/knowledge/
publications/adherence full report.pdf (accessed 26 April 2015).
REFERENCES
1 NHS Health Education England and Centre for Postgraduate Pharmacy Educa-
tion (2014). Consultation Skills for Pharmacy Practice: Taking a patient centred
approach. http://www.consultationskillsforpharmacy.com/docs/docb.pdf (accessed
19 January 2015).
2 NICE (2009). Medicines Adherence. Involving patients in decisions about
prescribed medicines and supporting adherence. NICE guidelines. CG76.
3 Neighbour R (2004). The Inner Consultation (2nd edn). Milton Keynes: Radcliffe
Publishing.
4 Calgary Cambridge (2015). Teaching and Learning Communication Skills in P
Medicine. http://www.gp-training.net/training/communication skills/calgary/
5 Abdel-Tawab R et al. (2011). Development and validation of the medication-related
consultation framework (MRCF). Patient Educ Counsel 83: 451–457.
k 6 Whitmore J (2002). Coaching for Performance: The new edition of the practical guide k
(people skills for professionals). London: Nicholas Brealey.
7 Jackson C et al. (2014). Applying COM-B to medication adherence. Eur
Health Psychologist February: 7–17. http://www.ehps.net/ehp/issues/
2014/v16iss1February2014/16 1 EHP Februay2014%20Jackson%20et%20al.pdf
Patient-controlled analgesia
Patient-controlled analgesia (PCA) refers to methods of pain relief
that allow a patient to self-administer small doses of an analgesic,
usually an opioid, as required. Most often, the term PCA is associated
with programmable infusion pumps that deliver opioids
intravenously.
Intravenous PCA provides better pain relief than conventional
intermittent opioid administration regimens (e.g. intramuscular or
subcutaneous administration): although the difference is small,
opioid consumption is greater; there are similar opioid-related side
effects, but patient satisfaction is higher.1
PCA is a safe and effective method of analgesia that is commonly
used after major surgery and has the following benefits:2
● tailoring of doses to individual requirements
● patient control of delivery of analgesic
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340 Patient-controlled analgesia
● improved patient satisfaction with their pain relief

● less labour-intensive for ward staff
● lower total opioid dose compared with bolus ‘rescue’ analgesia.
Administration
The patient activates an opioid bolus within preset limits by pressing a
hand-held button. The machine is set with a ‘lock-out’ time during
which no further drug can be delivered even if the button is pressed.
The standard dosing schedule is a bolus dose, followed by a lock-out
period of 5 minutes.
Background infusions may be considered for patients who have
previously been taking regular high doses of opioids and occasionally
a larger bolus dose may be required for patients with increased
analgesic requirements. In such cases, the patient may need to be
nursed in a high-dependency environment for greater monitoring.
Some hospitals allow the PCA solutions to remain in situ for over
24 hours in accordance with local infection control policies.
Medicines
The most commonly used opioid in PCA is morphine. The usual
P concentration used is morphine sulfate 1 mg in 1 mL in sodium
chloride 0.9%, with the pump delivering a 1-mg bolus dose with a
5-minute lock-out period. Lower doses may be required in renal
impairment. Many manufacturers supply prefilled syringes or bags, or
vials of morphine sulfate 50 mg in 50 mL.
k k
Alternative regimens
Other medicines used include oxycodone, fentanyl and tramadol:
● oxycodone: 1-mg bolus dose and 5-minute lockout
● fentanyl: 20 –40-microgram bolus dose and a 5-minute lockout
● tramadol: 10 –20-mg bolus dose and 5-minute lockout.
Monitoring
The pump records the volume of drug administered, the number of
times the patient has made requests and the number of doses
administered. If the number of successful requests is greatly
outweighed by the number of overall requests it may indicate that the
patient may not fully understand how to use the pump, or that the
patient’s pain is not adequately managed.
Patients receiving an opioid by intravenous PCA require regular
monitoring and details should be recorded in addition to the standard
conventional postoperative recordings, including:
● pain score
● respiratory rate
● nausea or vomiting
● sedation score
● observation of the infusion site.
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Phaeochromocytoma 341
Additional medicines that should be prescribed

Antiemetics should be prescribed for patients receiving an
intravenous PCA.
Simple analgesics, such as paracetamol and NSAIDs, should be
prescribed and regularly administered to reduce opioid requirements.
Other opioids may be discontinued during the use of the PCA to
minimise side effects.
Naloxone should be available in all areas where PCA is
administered to patients.
Some hospitals may have introduced preprinted stickers to place
over appropriate sections of the prescription chart, or have order sets
of medicines if using e-prescribing, so that these anticipated adjuvant
medicines can be quickly and accurately prescribed for the
convenience of prescribers and the patient.
Discontinuing the PCA

Intravenous PCA is normally continued until the patient is eating and
drinking; most patients require PCA for 2 –3 days following surgery. A
dose of oral opioid is often administered before PCA is disconnected
to ensure adequate pain relief and it is usual to prescribe an oral
opioid ‘when required’ for exacerbations of pain. Other analgesics P
should continue to be administered regularly, or on a ‘when required’
basis as appropriate.
k k
REFERENCES
1 Hudcova J et al. (2006). Patient controlled opioid analgesia versus conventional
opioid analgesia for postoperative pain. Cochrane Datab Systemat Rev4: CD003348.
2 Macintyre PE et al. (2010). Acute Pain Management: Scientific evidence
(3rd edn). Melbourne: ANZCA and FPM. http://www.anzca.edu.au/resources/
college-publications/pdfs/Acute%20Pain%20Management/books-and-
publications/Acute%20pain%20management%20-%20scientific%20evidence
%20-%20third%20edition.pdf (accessed 27 November 2014).
Phaeochromocytoma
Overview
Definition Phaeochromocytoma is a tumour of the adrenal gland that causes excess
release of catecholamines: adrenaline and noradrenaline
Risk factors The prevalence of phaeochromocytoma in hypertensive patients
attending medical outpatient clinics is 0.1–0.6%1
Differential The symptoms vary greatly and are episodic, often non-specific and
diagnosis similar to those of many common conditions such as anxiety. As a result,
diagnosis is often delayed1,2
Differential diagnosis includes:
● hyperthyroidism
● hypoglycaemia
● menopause
● heart failure
● arrhythmias
k
k
342 Phaeochromocytoma
● migraine
● stroke
● porphyria
● panic disorder or anxiety
● drug treatment (monoamine oxidase inhibitors, sympathomimetic
drugs)
● illegal drugs (e.g. cocaine)
Diagnostic The following tests and results may be associated with this syndrome:
tests ● an adrenal biopsy that shows phaeochromocytoma
● an MIBG scintiscan that shows a tumour
● an MRI or abdominal CT scan of abdomen that shows adrenal mass
● measurement of catecholamine metabolites either in a 24-hour urine
collection or in plasma
Treatment ● Removal of tumour
goals ● Prevention of hypertensive crisis
Treatment ● Surgery
options ● Alpha-blocker medication
Assess ● Current blood pressure
P Essential The definitive treatment is removal of the tumour by surgery. Secretion of
intervention adrenaline and noradrenaline usually returns to normal after surgery.
High blood pressure may not be cured in a quarter of patients after
surgery, yet control is usually achieved in these people with standard
treatments for hypertension. Recurrence of tumour may occur in 10% of
k cases k
Essential The major aim of medical pretreatment is to prevent
intervention catecholamine-induced, serious and potentially life-threatening
complications during surgery. These include hypertensive crises, cardiac
arrhythmias, pulmonary oedema and cardiac ischaemia.
Traditional regimens include the blockade of alpha-adrenoceptors with
phenoxybenzamine, prazosin or doxazosin. Phenoxybenzamine is often
preferred because it blocks alpha-adrenoceptors non-competitively. This
type of blockade offers an advantage, as it avoids drug displacement
from alpha-adrenoceptors by excessive increases in catecholamines
during surgery
Secondary Treatment usually lasts for 10–14 days. The initial dose of
intervention phenoxybenzamine is 10 mg twice a day, increased every 2–3 days by
10–20 mg to a total daily dose of 1 mg/kg.
Doxazosin is given in increasing doses from 1 to 16 mg once a day. A
beta-adrenoceptor blocker (e.g. propranolol 40 mg three times daily or
atenolol 25–50 mg once daily) can be included after several days of
alpha-adrenergic blockade. This addition is especially useful in patients
who also have tachycardia.
Blockade of beta-adrenoceptors should never be initiated before
blockade of alpha-adrenoceptors, since the loss of
beta-adrenoceptor-mediated vasodilatation leaves alpha-adrenoceptor
stimulation unopposed, which could result in hypertensive crises
Continued ● Blood pressure
monitoring ● Monitored annually for symptoms of recurrence
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Pharmacocultural issues 343
REFERENCES
1 Jones AG et al.(2012). Phaeochromocytoma. BMJ 344: e1042.
2 Lenders JWM et al. (2005). Phaeochromocytoma. Lancet 366: 665–675.
Pharmacocultural issues
The term pharmacocultural is used here to describe those aspects of
medication choice and use influenced by religious and cultural
factors.
The UK population contains peoples with diverse faiths and
lifestyle philosophies (vegetarian, vegan) and these should be
appreciated and respected by pharmacists in their practice.
● Some patients want and need to understand the nature of their

prescribed medication – it is essential for informed consent and
central to adherence with drug regimens.
● Informing patients about the origins of their medication
demonstrates respect for their beliefs and will assist them in
making informed decisions about treatments.
● Pharmacists should appreciate that within faiths there are many
schools of thought with different interpretations of religious laws. P
● Patients and families may place more emphasis on religious needs
in times of illness.
k Dietary factors k
Judaism and Islam strictly forbid pork and other foods derived from
pigs within the diet. Hinduism forbids consumption of cow-based
products and Jainism requires a strictly vegetarian diet that may also
be vegan and exclude root vegetables. Vegetarianism is considered to
be spiritually pure in the Buddhist, Sikh and Hindu faiths.1
Medicines for Jewish patients
Jewish law permits the oral consumption of porcine and other
non-kosher materials in a ‘non-edible’ manner in the case of any
illness. A key point is the distinction made relating to the ‘edible’ or
‘non-edible’ nature of a pharmaceutical product. For example, Saliva
Orthana is considered an edible product containing the
animal-derived active ingredient glucosamine, which is derived from
shellfish but is acid-treated and therefore not ‘edible’; chondroitin is
shark or bovine cartilage and is considered to be edible.
Non-kosher parenteral products, such as porcine/bovine insulin or
porcine heparin, may be used by Jewish patients as this is not classed
as consumption.
Porcine products present a clear pharmacocultural dilemma;
however, there is no exhaustive list of kosher or halal medicines, nor
is there a list of unacceptable medicines. Patients can be supported
through medicines information centres for up-to-date, specific advice.
Note that there are a number of religious authorities within Judaism
and Islam, so it is important to establish with patients which authority
k
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344 Pharmacocultural issues
they follow. For a further explanation of medicines implications in

Judaism and Islam, see http://www.medicinesresources.nhs.uk/
upload/documents/Evidence/Medicines%20Q%20&%20A/QA381
1KosherandHalal FINAL.doc.
Blood products
Some Jehovah’s Witnesses refuse to accept blood products (red and
white blood cells, platelets and plasma) in any circumstances, even at
the cost of their life. They may accept so-called minor fractions of
blood, such as albumin and globulin, as a personal choice. Anticipated
blood loss may be managed by autologous blood transfusion. Epoetin
injections and plasma expanders are also considered acceptable
for use.2
Gelatin
Gelatin is a component of capsules and may be an excipient in other
formulations. It can be of animal (meat or fish) or vegetable origin;
some manufacturers obtain gelatin from non-animal sources and this
will be stated in the product SPC. Many over-the-counter products are
now labelled as vegetarian but this may not be acceptable to vegans.
P Where no differentiation is made, this is usually because varying
sources are used, and this should be borne in mind when advising
patients.
Muslim patients and Ramadan
k Fasting during Ramadan is prescribed for every healthy, adult k
Muslim, whereas the weak, the sick, children, travellers and
menstruating women are among those exempt. Pregnant women are
also exempted from fasting if they believe that fasting will harm them
or their baby.
Muslims observing the fast are required to abstain from eating and
drinking during daylight hours and also from taking oral medicines
and injecting intravenous nutritional fluids. Some Muslims who are ill
may insist on fasting in any case and this can cause problems if not
supervised by health professionals. Advice from pharmacists about
changing prescriptions to equally effective drugs that have reduced
dosing, such as sustained-release formulations, may be beneficial to
the fasting Muslim, to allow dosing during the period between sunset
and dawn.3
Advice for patients is available at http://www.nhs.uk/Livewell/
Healthyramadan/Pages/faqs.aspx, which includes health and
medicines use during Ramadan as part of the frequently asked
questions. Be aware that, during Ramadan, Muslim patients often
unilaterally change the time and dosage of drugs without taking
medical advice.
Diabetics taking oral hypoglycaemic agents or injecting insulin
should exercise extreme caution if they decide to fast, and dose
adjustments must be considered.
k
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Phenytoin: management and monitoring 345
When does Ramadan begin?

The timing of Ramadan varies from year to year and is associated
with the ninth lunar month of the Islamic calendar. When Ramadan
falls during the summer months the daily period of fasting is
extended because of the increased number of daylight hours.
Cultural issues around medicine taking
Patients have a wide variety of beliefs around medicines that are
influenced by culture as well as religion. Common cultural beliefs can
include receipt of a medicine being the only acceptable conclusion to
a consultation and medicine only being useful if its effect on
symptoms is immediately obvious. If a patient comes from a culture
where antibiotics were always given for minor ailments, it will be
difficult to accept the refusal of such treatment by a clinician. In
addition to this, some patients are used to being able to purchase
medication without consulting any healthcare professional and may
feel that pharmacy involvement is an unnecessary barrier to
treatment. Conversely, some patients may believe that medicines are
generally harmful and will use them only as a last resort, even if the
patient appears to be suffering as a result (e.g. use of pain relief).
From a pharmacy perspective, consultation with a patient around P
medicines taking will be more effective if this is borne in mind.
REFERENCES
1 Mynors G et al. (2004). Drugs Derived from Pigs and Their Clinical Alternatives. Ask
k about Medicines/Medicines Partnership/Muslim Council of Britain. Booklet sup-
ported by educational grant from Sanofi. http://www.scribd.com/doc/80247519
k
/Drugs-Derived-From-Pigs-and-Their-Clinical-Alternatives#scribd (accessed 15 May
2015).
2 Muramoto O (2001). Bioethical aspects of the recent changes in the policy of refusal
of blood by Jehovah’s Witnesses. BMJ 322: 37–39.
3 Ethnicity Online (2014). http://www.ethnicityonline.net (accessed 27 November
2014).
Phenytoin: management and monitoring

Phenytoin is an anticonvulsant drug used in the treatment of epilepsy.
It is licensed for the treatment of tonic-clonic seizures (grand mal
epilepsy), partial seizures (focal, including temporal-lobe) or a
combination of these, and for the prevention and treatment of
seizures occurring during or following neurosurgery and/or severe
head injury.1 – 3
Oral phenytoin is slowly but almost completely absorbed from the GI
tract. The rate of absorption is variable and affected by the presence
of food in the stomach. Once absorbed, phenytoin is highly
protein-bound (approximately 90%), but may be displaced from
plasma proteins by various drugs, e.g. sodium valproate. Protein
binding may also be lower in certain patient groups, e.g. those with
renal or hepatic disease, neonates and in the third trimester of
pregnancy.4
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346 Phenytoin: management and monitoring
The major route of metabolism of phenytoin is oxidation via the

liver to an inactive metabolite. This metabolism is a saturable process
resulting in a non-linear relationship between the dose of phenytoin
and serum concentration. Therefore, small increases in dosage may
result in substantial increases in plasma phenytoin concentration and
toxicity.1–3
The main indications for phenytoin therapeutic drug monitoring
(Table P9) are:
● on initiation of therapy
● during intravenous therapy in status epilepticus
● when there is a loss of seizure control (including an adherence
check)
● to monitor the effects of drug interactions
● where formulation changes are made
● when toxicity is suspected.
TABLE P9
Phenytoin drug monitoring information
P Half-life 7–42 hours4
Pretreatment measures FBC, U&Es, LFTs5
Therapeutic range 40–80 micromol/L (10–20 mg/L)6
Sampling time Middle of dose interval, but this is not critical once steady
k state is achieved due to the long half-life. Usual time to k
steady state is 7–10 days
Other monitoring Megaloblastic anaemia and blood dyscrasias occasionally
occur. FBC should be checked periodically. Phenytoin may
affect glucose metabolism and therefore should be used with
caution in diabetes. LFTs and folic acid should be checked
every 6 months7
Dose
The adult dose for oral administration starts at 3 –4 mg/kg/day. The
daily dose is increased if necessary in 25-mg increments, with a
minimum interval between dose changes of 7 –10 days, until the
therapeutic effect is achieved or toxic effects manifest. Dosage must
be individualised because there is wide interpatient variability in
phenytoin serum concentration from equivalent doses.1
In adults in status epilepticus who are not normally maintained on
oral phenytoin, a loading dose of phenytoin 15 –20 mg/kg (the BNF
recommends 20 mg/kg to a maximum of 2 g5 ) should be injected
slowly intravenously. The rate should not exceed 1 mg/kg/minute
to a maximum rate of 50 mg/minute, although the slower rate of
25 mg/minute reduces the likelihood of hypotension. Cardiac
monitoring is advised because of the risk of serious arrhythmias. Rate
of administration should be further reduced in the elderly or those
with heart disease. Blood levels may be checked 2 hours after giving
the loading dose to ensure they are in the correct range. The loading
dose should be followed by maintenance doses orally or intravenously
every 6 –8 hours, and serum concentration monitored.2
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Phenytoin: management and monitoring 347
Administration
Injection
Phenytoin can be administered as an intravenous injection or as an
intravenous infusion. The intravenous injection route is preferred.
Each injection must be preceded and followed by an injection of 5 mL
sodium chloride 0.9% through the same needle (this reduces venous
irritation due to the alkalinity of the solution). N.B.: Rapid
intravenous administration can cause hypotension; ECG and blood
pressure monitoring must be carried out. The patient must also be
observed for any signs of respiratory depression. It is not
recommended to give phenytoin as an intramuscular injection
because it may crystallise in the tissue, resulting in very unpredictable
absorption. If the intramuscular route is to be used, dose adjustment
is essential.
● Intravenous injection: withdraw the required dose through a
5 micron filter needle. Replace the filter needle with a large-gauge
needle, or intravenous catheter, and inject slowly into a large vein
at a rate not exceeding 50 mg/min for adults (but see Dose above
for more detail).
● Intravenous infusion: the infusion must be given through an in-line P
filter (0.22 –0.50 microns) as there is a risk of precipitation. If the
solution is hazy it must not be used. The injection is diluted with
sodium chloride 0.9% so that the final concentration does not
exceed 10 mg/mL. The infusion is only stable for 1 hour and should
k be used immediately. It is infused into a large vein at a rate not
k
exceeding 50 mg/min for adults (but see Dose above for more
detail), via a large-gauge needle or intravenous catheter.2
Switching forms
The capsule and injection forms contain phenytoin sodium and the
suspension form contains phenytoin base, so when switching between
formulations, doses should be changed accordingly (Table P10).1 – 3
TABLE P10
Bioequivalent doses of phenytoin formulations
Injection Capsule Suspension
100 mg 100 mg 92 mg*
*N.B.: this relates to molecular weight equivalence, and does not necessarily represent
biological equivalence – care should be taken when switching between formulations.
Enteral feeding – phenytoin interaction

Continuous enteral feeds reduce absorption of phenytoin. To avoid
this, the feed should be stopped 2 hours before the phenytoin is
administered, and recommenced 2 hours after the administration.
The nasogastric (NG) tube should be flushed before and after
administration. The suspension is thixotropic and cannot be
administered under gravity; it has a viscosity 40 times greater than
standard enteral feed. Therefore, for NG administration phenytoin
k
k
348 Phenytoin: management and monitoring
suspension should be mixed with an equal volume of a suitable

diluent, e.g. water. Even with appropriate flushing and a feeding
break, phenytoin is still not well absorbed via the NG route and high
doses or alternative agents may need to be considered.
Overdose
The initial symptoms are nystagmus, ataxia and dysarthria. Other
signs are tremor, hyperreflexia, lethargy, nausea and vomiting. The
patient may become comatose and hypotensive. If death occurs it is
due to respiratory and circulatory depression.
Seek specialist advice from the National Poisons Information
Service (http://www.toxbase.org). There is no antidote and general
supportive measures should be used.1–3
Interactions1–3
● Drugs that may increase phenytoin serum levels include:
amiodarone, antifungal agents (e.g. amphotericin, fluconazole,
ketoconazole, miconazole, itraconazole), chloramphenicol,
chlordiazepoxide, diazepam, diltiazem, disulfiram, fluoxetine,
H2-antagonists, halothane, isoniazid, methylphenidate, nifedipine,
P omeprazole, oestrogens, phenothiazines, salicylates,
sulphonamides, tolbutamide and trazodone.
● Drugs that may decrease phenytoin serum levels include: folic acid,
rifampicin, sucralfate, theophylline, vigabatrin and St John’s wort.
k ● Drugs that may either increase or decrease phenytoin serum levels k
include: carbamazepine, phenobarbital, valproic acid, sodium
valproate, antineoplastic agents and ciprofloxacin.
● The effect of phenytoin on the serum concentration of
carbamazepine, phenobarbital, valproic acid and sodium valproate
is unpredictable.
● Acute alcohol intake may increase phenytoin serum levels, whereas
chronic alcoholism may decrease serum levels.
● Tricyclic antidepressants and phenothiazines may precipitate
seizures in susceptible patients and phenytoin dosage may need to
be adjusted.
● Drugs whose effect is impaired by phenytoin include: antifungal
agents, antineoplastic agents, calcium-channel antagonists,
clozapine, corticosteroids, ciclosporin, digitoxin, doxycycline,
furosemide, lamotrigine, methadone, neuromuscular blockers,
oestrogens, oral contraceptives, paroxetine, quinidine, rifampicin,
theophylline and vitamin D.
● The effect of phenytoin on warfarin is variable and the patient’s
INR should be monitored closely.
REFERENCES
1 SPC (2014). Phenytoin Sodium Flynn Hard Capsules 25 mg, 50 mg, 100 mg and
300 mg. www.medicines.org.uk (accessed 19 January 2015).
2 SPC (2012). Epanutin Ready-mixed Parenteral. www.medicines.org.uk (accessed
19 January 2015).
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Phosphate 349
3 SPC (2013). Epanutin 30 mg/5 mL Oral Suspension. www.medicines.org.uk

4 Dollery C (ed.) (1999). Therapeutic Drugs (2nd edn). Edinburgh: Churchill Living-
stone.
6 Crawford P (1999). Monitoring requirements with antiepileptic drugs. Prescriber
19: 122–123.
7 Dyfed Powys Primary Care Effectiveness Team (2004). Drug Monitoring Booklet.
Dyfed Powys: National Public Health Service for Wales.
Phosphate
Overview
Normal range 0.8–1.5 mmol/L
Local range
Background ● The total plasma phosphate concentration is approximately
3.9 mmol/L in adults.1
● Two-thirds is organic phosphate, e.g. phospholipids, and one-third is
inorganic (the form usually assayed by clinical chemistry
laboratories).2
P
● Phosphate is found primarily in bone and soft tissue, with less than
1% of the total body store in the extracellular fluid3
Recom- The average diet provides 1000–2000 mg phosphorus daily,4 of
k k
●
mended which 60–80% will be absorbed from the gut.5

nutrient ● Dietary sources of phosphorus include: meat, fish, grains, dairy
intake products, seeds, nuts, eggs, most fruits and vegetables and soft
drinks
Hypophosphataemia
Symptoms ● Usually asymptomatic
● Levels <0.5 mmol/L can produce clinical symptoms
Symptoms are non-specific:
● Musculoskeletal symptoms – myalgia, muscle weakness,
osteomalacia and rhabdomyolysis
● Pulmonary symptoms – respiratory failure
● Cardiovascular symptoms – acute heart failure
Causes Internal redistribution
● The most common cause of hypophosphataemia, resulting from an
acute shift from the extracellular to the intracellular compartment
● Associated clinical conditions: acute respiratory alkalosis, increased
insulin concentration during glucose administration, recovery from
diabetic ketoacidosis and the refeeding syndrome associated with
feeding of malnourished patients (see Parenteral nutrition entry)
● These conditions stimulate glycolysis, leading to the formation of
phosphorylated glucose compounds and an intracellular shift of
phosphate
● Rapid cell turnover as a result of malignancy or hungry-bone
syndrome can lead to low serum phosphate levels
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350 Phosphate
Increased renal excretion

● Acquired and inherited disorders of the renal tubules as well as some
drugs may lead to an increase in the renal excretion of phosphate
● Patients with primary hyperparathyroidism have decreased renal
tubular reabsorption, resulting in low serum phosphate levels
● Inherited disorders of vitamin D metabolism may also cause
hypocalcaemia and consequently hypophosphataemia
● Some drugs that may cause an increase in renal excretion of
phosphate include diuretics, chemotherapy agents, antivirals,
antibiotics and antiepileptics
Decreased intake and reduced intestinal absorption
● Dietary phosphorus restriction will only result in hypophosphataemia
if the restriction is severe and prolonged or if intestinal absorption is
reduced by the long-term use of phosphate binders
● Chronic diarrhoea may also reduce phosphate absorption
● Alcohol misusers may have a prolonged poor intake of phosphate
Assessment ● Mild: 0.65–0.84 mmol/L
● Moderate: 0.32–0.64 mmol/L
● Severe: <0.32 mmol/L
Treatment* Mild hypophosphataemia
● Asymptomatic: no treatment
P ● Symptomatic: Phosphate-Sandoz tablets 2–4 tablets a day for 7–10
days*
Moderate hypophosphataemia
● Asymptomatic: Phosphate-Sandoz tablets 4–6 tablets a day for
k ●
7–10 days*
Symptomatic and oral route does not provide an adequate rate of
k
symptom relief: parenteral replacement
Severe hypophosphataemia
● Parenteral replacement
Adminis- ● Tablets should be taken orally. The dose should be divided equally to
tration prevent gastrointestinal side effects
● Intravenous phosphate: 9 mmol to be infused over 12 hours, which
can be repeated as required
● In critically ill patients, the phosphate dose can be increased to
500 micromol/kg (max. 50 mmol) infused over 6–12 hours.6
Monitoring ● Serum magnesium and potassium: hypomagnesaemia and
hypokalaemia promote excessive phosphate excretion
● Serum calcium: hypocalcaemia is a common complication of
phosphate therapy
Hyperphosphataemia5
Symptoms ● Hypocalcaemia
● Tetany
Causes Renal failure
● Phosphate is cleared through glomerular filtration
● 80–95% of the filtered phosphate is reabsorbed by the proximal
tubule
● Despite maximal suppression of phosphate reabsorption, when
glomerular filtration rate falls below 20–25 mL/min, urinary
excretion cannot counterbalance the dietary intake
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Phosphate 351
Increase in renal phosphate reabsorption

● Can occur in the following conditions: hypoparathyroidism, vitamin
D toxicity, familial tumoral calcinosis and acromegaly
Massive acute phosphate load
● Endogenous or exogenous
● Endogenous causes result from tissue breakdown, leading to the
release of intracellular phosphate into the extracellular fluid.
Includes: severe tissue necrosis due to tumour lysis syndrome and
rhabdomyolysis. Other causes include lactic acidosis and diabetic
ketoacidosis.
● Exogenous causes include the ingestion of phosphate-containing
laxatives
Treatment Acute hyperphosphataemia
● Cleared rapidly if renal function normal
● Increase renal phosphate excretion using a sodium chloride 0.9%
infusion to expand the extracellular volume
Chronic hyperphosphataemia
● Restrict dietary intake
● Reduce intestinal absorption using phosphate-binding agents
● Binding agents are split into two categories: calcium-based (e.g.
calcium acetate) and calcium-free (e.g. magnesium carbonate or
sevelamer) P
● In patients with renal failure, calcium salts are preferred;
otherwise aluminium may accumulate to toxic levels
Adminis- ● Phosphate-binding agents should be taken with meals to achieve
k tration
●
maximal phosphate-binding effect
For dosing of individual preparations, see BNF
k
Monitoring ● Phosphate levels
● Calcium levels
● Renal function
*The use of Phosphate-Sandoz in hypophosphataemia is unlicensed. The licensed
indications are hypercalcaemia: up to 6 tablets daily, adjusted according to response, and
vitamin D-resistant hypophosphataemic osteomalacia: 4–6 tablets daily. Diarrhoea is a
common side effect and should prompt a reduction in dosage.6,7
TABLE P11
Phosphate content of various preparations6
Product Phosphate content
Phosphate-Sandoz 16.1 mmol/tablet
(also contains Na+ 20.4 mmol and K+ 3.1 mmol)
Addiphos 40 mmol/20 mL
(also contains K+ 30 mmol, Na+ 30 mmol – due to the
concentration of potassium in Addiphos, availability should be
restricted as for strong potassium solutions: see Potassium entry)
Phosphate Polyfusor 50 mmol/500 mL
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352 Postoperative nausea and vomiting
REFERENCES
1 Patel R et al. (2013). Management of hypophosphatemia. Br J Hosp Med 74:
C66–C70.
2 Crook M (1994). Phosphate: an abnormal anion? Br J Hosp Med 52: 200–203.
3 Koda-Kimble MA et al. (eds) (2004). Applied Therapeutics: The clinical use of drugs.
London: Lippincott, Williams and Wilkins.
4 European Food Safety Authority (2006). Tolerable Upper Intake Levels for Vitamins
and Minerals. http://www.efsa.europa.eu/en/ndatopics/docs/ndatolerableuil.pdf
5 Malberti F (2013). Hyperphosphataemia: treatment options. Drugs 73: 673–688.
7 Electronic Medicines Compendium (2014). Summary of Product Characteristics
Phosphate-Sandoz Effervescent Tablets. https://www.medicines.org.uk/emc
/medicine/811 (accessed 4 October 2014).
Postoperative nausea and vomiting

Postoperative nausea and vomiting (PONV) is defined as nausea
and/or vomiting occurring within 24 hours of surgery.1 It affects
20 –30% of patients undergoing surgery and the consequences can be
P
severe and include:2
● aspiration of vomit with depressed consciousness and laryngeal
reflexes
k ● delayed administration of opioid analgesia k
● wound disruption after abdominal surgery
● bleeding
● dehydration and electrolyte imbalance
● interference with nutrition
● delayed discharge from theatre recovery
● impact on day surgery and increased nursing time
● general delay in mobilisation and recovery
● patient discomfort, distress and fear about future
surgery/anaesthesia.
The cause of PONV is not always clear but is likely to be multifactorial.
The assessment of risk can be categorised into those relating
specifically to the patient, the type of surgery and the anaesthetic.
When deciding to administer prophylaxis or wait until treatment is
required, the decision is based on the balance between efficacy of
prevention and the incidence of side effects. No single drug is 100%
effective in all cases. The use of prophylactic antiemetics in all cases is
therefore not always necessary. The use of a high-risk identification
tool can be beneficial. A risk stratification method, such as the Apfel
score, can be used to determine the likelihood of PONV for each
patient. This is a simplified method that includes four positive factors:
female gender, non-smoking, history of PONV or motion sickness and
postoperative use of opioids. Each of these factors is supposed to
elevate the risk by 20%.3 Local guidelines should be consulted.
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Postoperative nausea and vomiting 353
Patient factors
The most important risk factors include:
● gender – females are at higher risk of PONV
● previous PONV
● motion sickness, vertigo or Ménière’s disease
● PONV in children is usually twice as common as in adults.
Types of surgery
An increased duration of surgery can lead to an increase in PONV, as
more drugs are administered to the patient in that time. Each
30-minute increase in duration of surgery increases the risk of PONV
by 60%.1 The following types of surgery increase the risk of PONV:
● major obstetric and gynaecological surgery
● major GI surgery
● ear, nose and throat surgery.
Anaesthetic factors
Anaesthetic factors that have an effect on the incidence of PONV
include:
● method of anaesthesia – general is associated with higher risk than P
either local or epidural
● use of opioids
● etomidate/ketamine
k ● volatile gases (nitrous oxide) associated with higher incidence than k
intravenous anaesthetics
● anticholinesterases
● preoperative drug treatment:
● opioids
● cancer chemotherapy
● prostaglandins.
Non-pharmacological intervention
Ensure that:
● the patient is adequately hydrated (which may necessitate
intravenous infusion)
● pain is under control with minimal use of opioids
● preoperative fasting recommendations are complied with.
Other methods include psychological techniques, such as
suggestion and hypnosis, acupuncture, eating or sucking ginger or
mint, and the use of pressurised wristbands, however, there is little
evidence to support their use.
Pharmacological intervention
Cyclizine
Cyclizine is a cheap, commonly used drug. Its use is based on
anecdotal evidence and, interestingly, there are no real scientific
reasons behind its huge use. It has antimuscarinic and antihistamine
properties and the few side effects (sedation and dry mouth) and
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354 Postoperative nausea and vomiting
cautions (in glaucoma and heart failure) are related to this

mechanism of action.
Dose
The dose is oral/intravenous/intramuscular 50 mg up to three times
daily. Cyclizine does not need to be administered strictly every
8 hours and can be given after 4 –6 hours if the patient requires,
provided the daily maximum of 150 mg is not exceeded.
5HT3 antagonists
Ondansetron, granisetron, tropisetron and dolasetron are specific
5HT3 antagonists that block 5HT3 receptors in the GI tract and in the
central nervous system. They are licensed for the treatment and
prophylaxis of PONV and in practice are usually recommended
second line after cyclizine.
The dosing for each drug is guided by whether it is treatment or
prophylaxis; higher doses are given for prophylaxis.
5HT3 antagonists have few side effects, including headache,
transient raised LFTs and constipation due to reduced lower-bowel
motility. Patients with signs of subacute intestinal obstruction should
be monitored following administration and caution should be taken if
P the patient is receiving opioids or has a new stoma formed
postoperatively.
Dolasetron and tropisetron are reported to have the potential to
increase the QT interval and caution should be taken when
k administering with other drugs that may cause arrhythmias. k
Ondansetron and granisetron SPCs do not report this interaction;
however, in a patient with unstable arrhythmias, antiemetic therapy
may be worth considering as a contributory factor.
Metoclopramide
At a 10-mg dose, metoclopramide has been reported as no better than
placebo in the management of PONV4 and is therefore considered to
be ineffective for PONV prophylaxis. A treatment dose of 50 mg
intravenously would be required to show any reduction in the rate of
PONV, but the side effect profile is unsatisfactory.1
Its GI motility stimulation properties mean that it is a useful agent
as a prokinetic. It can be used in patients who are at risk of developing
a postoperative ileus (reduction or lack of peristalsis within the
bowel, resulting in poor GI absorption). Due to such properties, care
must be taken not to use metoclopramide in patients with a suspected
bowel obstruction.
Recent guidance from the MHRA recommends that metoclo-
pramide should be used for no longer than 5 days due to the risks of
extrapyramidal disorders and tardive dyskinesia.5
Prochlorperazine
There are few clinical studies advocating its use; however, it remains
widely used in the prevention and treatment of PONV.
Prochlorperazine is only indicated for treatment, and then only as a
single dose; however, in some enhanced recovery programmes the
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Potassium 355
use of the buccal formulation is recommended, with a typical regimen

being 3 mg three times a day for 5 days post-op.
Dexamethasone
Corticosteroids have been shown to be effective in the prophylaxis of
PONV, although their mechanism of action remains unclear.
Combination with 5HT3 antagonists may enhance their efficacy.
Doses of dexamethasone range from 150 micrograms/kg/24 hours in
children up to 8 mg/24 hours in adults.
If the patient is at high risk of PONV, numerous studies have
demonstrated that using more than one antiemetic, with differing
modes of action, is usually more effective and results in fewer side
effects than simply using and increasing the dose of one agent.6
Clinical trials have shown that the combination of 5HT3 and
dexamethasone is the most effective therapy in the prevention of
PONV.1
REFERENCES
1 McCracken G et al. (2008). Guidelines for the Management of Post-Operative
Nausea and Vomiting. SOGC Clinical Practice Guideline 209. http://sogc.org/wp-
content/uploads/2013/07/gui209CPG0807E.pdf (accessed 15 May 2015).
2 UK Key Advances in Clinical Practice Series (2003). The effective prevention and
management of post-operative nausea and vomiting. 2nd edition, 2003. London: P
Aesculapius Medical Press.
3 Pierre S, Whelan R (2013). Nausea and vomiting after surgery. Continuing educa-
tion in anaesthesia. Crit Care Pain 13: 28–32.
4 Henzi ML et al. (1999). Metoclopramide in the prevention of postoperative nausea
k and vomiting: a quantitative systematic review of randomized placebo-controlled k
studies. Br J Anaesth 85: 761–771.
5 MHRA (2013). Metoclopramide: Risk of neurological adverse effects – restricted dose
and duration of use. http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate
/CON300404 (accessed 13 January 2013).
6 Chandrakantan A, Glass P (2011). Multimodal therapies for post-operative nausea
and vomiting and pain. Br J Anaesth 107(1): i27–i40.
Potassium
Overview
Normal range 3.5–5.0 mmol/L1
Local range
Background Potassium is the major intracellular electrolyte. Where an imbalance
occurs with the extracellular (serum) concentration, it is important to
look at serum concentration over a period of time rather than at an
isolated result (a patient may be apparently well, despite having an
anomalous high or low potassium serum concentration).
Blood samples are sometimes haemolysed (the blood cells have
disintegrated and released their intracellular contents), and this will
result in a falsely high potassium serum concentration. Laboratories
highlight this problem, and the potassium result from this sample
should be ignored and a further blood sample should be taken. Where
close monitoring of potassium levels is crucial, a new sample should be
taken as soon as the problem is recognised.
k
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356 Potassium
Patients receiving treatment for acute hyperkalaemia or hypokalaemia

should ideally have their potassium level checked at least daily, to check
that treatment remains appropriate
Recom- The reference nutrient intake is 90 mmol/day; however, 40–50 mmol/day
mended is considered adequate for an adult
nutrient
intake
Hypokalaemia
Symptoms ● Symptoms include muscle weakness, paralysis, respiratory
insufficiency, ECG abnormalities and ileus. Chronic hypokalaemia
may lead to renal tubular damage. The risk of digoxin toxicity is
increased in hypokalaemia
Causes ● GI losses due to diarrhoea, a fistula, persistent vomiting or laxative
abuse
● Mineralocorticoid excess, e.g. hyperaldosteronism and Cushing’s
syndrome (see Cushing’s syndrome entry)
● Glucocorticoid therapy, e.g. prednisolone because of
mineralocorticoid side effects
● Metabolic alkalosis
● Drugs, including: aminoglycosides, amphotericin, bicarbonates,
P corticosteroids, furosemide, insulin, laxatives, levodopa, high-dose
penicillins, salbutamol (intravenous), theophylline and thiazides1
Assessment ● Renal function and electrolytes (Ur, Cr, K, Na)
● Severe hypokalaemia is <2.5 mmol/L
k ● Mild hypokalaemia is >2.5 mmol/L k
Treatment ● Severe hypokalaemia requires intravenous therapy; for mild
hypokalaemia, oral supplements will normally be sufficient unless
vomiting is a problem or the oral route is not available.
● Intravenous potassium treatment may involve giving a limited
number of infusions to correct a short-term imbalance (e.g.
postsurgical) or may be protracted (e.g. as a component of
parenteral nutrition). Modest hypokalaemia may require only a
single dose of 20–40 mmol of potassium pending the availability of
the oral route, whilst a patient with serious potassium losses (e.g. GI
fistula) may require 100–200 mmol per day.
● The recommended maximum dose of potassium is 2–3 mmol/kg in
24 hours2
Adminis- Intravenous potassium chloride
tration ● Always use a volumetric infusion pump for infusion of potassium.
● In general clinical areas, when given via a peripheral vein, infusion
rates in adults should not usually exceed 10 mmol/hour and no more
than 20 mmol/hour in emergencies. Administration rates above
20 mmol/hour require cardiac monitoring.2 Ready-prepared infusion
bags containing 20 or 40 mmol/L are available, but solutions above a
concentration of 30 mmol/L are associated with an increased risk of
phlebitis. As a general principle, ready-prepared bags should be used
in preference to preparing bags from concentrated potassium
chloride solutions.
k
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Potassium 357
● In critical care areas (e.g. intensive care units) faster infusion rates or
more concentrated solutions may be employed. Because of the risk
of thrombophlebitis, more concentrated infusions are generally given
via the largest vein available, and ideally by means of a central line.
The infusion site should be checked at least every 4 hours for
inflammation.2
● Infusion rates above 20 mmol/hour require ECG monitoring, whilst
infusion rates above 40 mmol/hour present a risk of asystole.
● Concentrated parenteral potassium chloride solutions in ampoules
are potentially lethal. Numerous drug errors have occurred with
these products, largely because of their availability in clinical areas.
For instance, potassium chloride ampoules have been accidentally
used in place of sodium chloride 0.9% injection for reconstitution of
antibiotic bolus injections. Rapid administration of potassium
chloride may be fatal.
● Where infusions have to be prepared using potassium chloride
concentrate solution, it is vital to mix the product with vigorous
agitation to ensure that additive has dispersed throughout the
diluent. It is advised to squeeze and invert the bag 10 times.2 Failure
to do this may result in inadvertent administration of a potassium
chloride bolus to the patient, as undispersed concentrated solution
will sink towards the outlet of the bag.
● Additions must never be made to an infusion container that has P
already been connected to a giving set.
● The National Patient Safety Agency issued a Patient Safety Alert on
this topic in July 2002, which contained a number of safety measures
for implementation in NHS trusts. The key measures were:3
k ● Restriction of potassium chloride concentrate solutions to k
pharmacy departments and critical care areas
● Introduction of a controlled drug-style system for requisition and
storage of the product in critical care areas
● Utilisation of commercially available diluted solutions wherever
possible
Familiarise yourself with the policies for control of use of parenteral
potassium chloride in your hospital and the range of products in use
locally . Death or harm resulting from a potassium-containing
solution is an MHRA ‘never event’.4
Oral potassium therapy
● Sando-K is typically given as 2 tablets three or four times a day; if
serum potassium levels are in the range 2–3 mmol/L, then up to
16 tablets/day may be given5
● Liquid and effervescent preparations are preferred. If Slow-K tablets
are used, counsel the patient to swallow whole with a full glass of
water and remain upright for a few minutes after taking (as this
reduces the likelihood of oesophageal ulceration). ‘Ghost tablets’
may appear in stools6
● The potassium content of the various oral preparations available is
listed in Table P12 for comparison
TABLE P12
Potassium content of various oral preparations
Product Potassium content
Sando-K 12 mmol/tablet
Slow-K 8 mmol/tablet
Kay-Cee-L syrup 1 mmol/mL
k
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358 Potassium
Monitoring Monitor serum potassium concentration at least daily and stop

treatment when serum potassium levels return to the normal range
Hyperkalaemia
Symptoms ● Include ECG abnormalities, ventricular arrhythmias, and cardiac
arrest.
● There may also be neuromuscular dysfunction, e.g. muscle weakness
and paralysis
Causes ● Excessive intake, e.g. overuse of Lo-Salt (a salt alternative containing
66.6% potassium chloride and 33.4% sodium chloride),
inappropriate use of parenteral solutions
● Decreased elimination, e.g. in renal failure
● Metabolic acidosis
● Drugs, e.g. those acting on the renin–angiotensin–aldosterone
system: aliskiren, angiotensin-converting enzyme inhibitors,
angiotensin II receptor antagonists, aldosterone antagonists,
potassium-sparing diuretics, potassium salts, indometacin,
trimethoprim, heparins, ciclosporin, tacrolimus1
Assessment ● Renal function and electrolytes (Ur, Cr, K, Na), Mg, Ca
● A serum potassium concentration of >6.5 mmol/L will usually
require urgent treatment, as will those with ECG changes
P Treatment ● Give 10 mL calcium gluconate 10% intravenously over 2–3 minutes
to stabilise cardiac muscle. N.B.: this does not change serum
potassium levels. Repeat as necessary within 5–10 minutes if no
effect, dependent on ECG. Duration of action is usually
k 30–60 minutes so further doses may be necessary if serum k
potassium remains raised.7
● Rapidly lower the potassium serum level by giving soluble insulin,
e.g. Actrapid insulin 10 units in glucose 50%.8 The insulin causes
uptake of potassium from the extracellular fluid into cells, lowering
the level, while the glucose limits the hypoglycaemic effect of the
insulin. Higher doses of insulin carry an increased risk of
hypoglycaemia.
● Nebulised salbutamol (10–20 mg) can also be used in conjunction
with the above measures, but should not be used as monotherapy
for severe hyperkalaemia.7 This also moves potassium into the cells.
● Dialysis may be an option if these measures are ineffective.
● After emergency treatment, or if initial potassium is in the range
5.1–6.4 mmol/L, if possible treat the cause of the hyperkalaemia.
This includes stopping any implicated drugs and treating underlying
medical conditions.
● Calcium Resonium or Resonium A resin may be given but should be
stopped when serum potassium concentration falls to 5 mmol/L
Adminis- Administration of insulin and glucose
tration ● Draw up 50 mL of glucose 50% into a 50 mL syringe from a vial or a
500 mL infusion bag. Infusion bags are preferred to Minijets as they
are easier to handle, maintain aseptic technique and are cheaper.
● Draw up the prescribed amount of insulin using an insulin syringe
(usually 10 units) and add to the 50 mL syringe. Cap the syringe and
mix well to disperse the insulin thoroughly. Failure to do this may
result in unexpected hypoglycaemia.
● Place the syringe in a syringe driver and give intravenously over
5–15 minutes (slower administration reduces thrombophlebitis).
Effects are observed within 15–30 minutes and last for 4–6 hours.
k
k
Potassium 359
Oral/rectal therapy for hyperkalaemia

Continuing treatment with either Calcium Resonium or Resonium A may
be appropriate.
● Calcium Resonium should be avoided in patients who have
conditions associated with hypercalcaemia.9
● Resonium A should be avoided in patients at risk from an increase in
sodium load. Neither product should be given if the patient has
obstructive bowel disease.10
● Both resins can affect the body’s balance of magnesium and calcium,
and patients should be monitored for disturbances in these
electrolytes.
● Antacids and laxatives containing cations, such as magnesium and
aluminium, should be avoided during treatment.
● Absorption of lithium and levothyroxine may be reduced.9,10
● In the initial stages of treatment of hyperkalaemia, administration by
the rectal route as well as orally may help to achieve a rapid
lowering of the serum potassium level. If both routes are used
initially, it is probably unnecessary to continue rectal administration
once the oral resin has reached the rectum.
Oral therapy
● The dose of both Calcium Resonium and Resonium A resins is 15 g
three or four times daily.
● Mix the powder with a little water, or mix to a paste with a P
sweetening vehicle, e.g. jam or honey (do not use fruit squash
because of high potassium content).
● Treatment may need to be continued for several days or long-term.7
k Rectal administration
● Both forms can be given daily as an enema (30 g resin in 150 mL
k
water or 10% dextrose, and retained for at least 9 hours (this may be
tricky), and the colon irrigated to remove the resin).
● Some local manufacturing units supply ready-made kits.
● Faecal impaction can sometimes occur with the enema, and
lactulose may be used to resolve this. If clinically significant
constipation occurs, treatment should be stopped until normal bowel
movement returns
Monitoring Very frequent monitoring of serum potassium level is crucial (every few
hours), particularly during the early stages of treatment of severe
hyperkalaemia
REFERENCES
2 UK Medicines Information (2012). How Should Intravenous Potassium Chloride
be Administered in Adults? NHS: UKMi Medicines Q&A. www.evidence.nhs.uk
3 NPSA (2002). Potassium Chloride Concentrate Solutions – Patient safety alert.
http://www.nrls.npsa.nhs.uk/resources/?entryid45=59882 (accessed 17 January
2015).
4 NHS England (2014). The Never Events List: 2013/14 update. NHS England:
Patient safety domain team. http://www.england.nhs.uk/wp-content/uploads/
2013/12/nev-ev-list-1314-clar.pdf (accessed 14 July 2014).
5 SPC (2014). Sando-K. www.medicines.org.uk (accessed 17 January 2015).
k
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360 Prescription charge exemptions
6 SPC (2014). Slow-K. www.medicines.org.uk (accessed 17 January 2015).

7 Renal Association (2012). Treatment of Acute Hyperkalemia in Adults.
www.renal.org (accessed 14 July 2014).
9 SPC (2014). Calcium Resonium. www.medicines.org.uk (accessed 17 January
2015).
10 SPC (2014). Resonium A. www.medicines.org.uk (accessed 17 January 2015).
Prescription charge exemptions and

prepayment certificates
Prescription charge exemptions on medical grounds
People are eligible for free NHS prescriptions if they suffer from
specific medical conditions and they hold a valid medical exemption
certificate. In NHS England, the specified medical conditions are
currently:1
● a permanent fistula (for example, caecostomy, colostomy,
laryngostomy or ileostomy) that needs continuous surgical
P dressing or an appliance
● a form of hypoadrenalism (for example, Addison’s disease) for
which specific substitution therapy is essential
● diabetes insipidus and other forms of hypopituitarism
k ● diabetes mellitus, except where treatment is by diet alone k
● hypoparathyroidism
● myxoedema (that is, hypothyroidism that needs thyroid hormone
replacement)
● epilepsy that needs continuous antiepileptic therapy
● a continuing physical disability, which means you cannot go out
without the help of another person
● cancer: undergoing treatment; the effects of cancer; or the effects
of cancer treatment.
Such individuals are exempt from all prescription charges, not just for
items prescribed for the condition specified. There is variation across
other parts of the UK where, for instance, in Wales all prescriptions
are free.
Medical exemption certificates are valid for 5 years. Application
forms are available at general practitioner surgeries and must be
completed and signed by the patient and doctor. The general
practitioner sends the completed form directly to:
NHS Help With Health Costs
Medical Exemption
Bridge House
152 Pilgrim Street
Newcastle Upon Tyne
NE1 6SN
UK.
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Protamine 361
Prepayment certificates
These can be bought for 4- or 12-month periods, and their current
price is listed in the Drug Tariff .2 Application forms can be obtained
from pharmacies and surgeries, or completed online using the
following link: https://apps.nhsbsa.nhs.uk/ppcwebsales/patient.do.
Some community pharmacies may sell certificates directly.
REFERENCES
1 NHS England (2014). Help with Health Costs. http://www.nhsbsa.nhs.uk
/HealthCosts/Documents/HealthCosts/HC11 April 2014.pdf (accessed 23
February 2015).
2 Drug Tariff Online (updated monthly). http://www.ppa.org.uk/ppa/edt intro.htm
Protamine
Protamine sulfate is used to reverse or neutralise the anticoagulant
effect of unfractionated and, to a lesser extent, low-molecular-weight
heparin (LMWH). It is derived from fish sperm, and acts by binding
with heparin to form a salt. 1 mg protamine neutralises 100 units of
heparin.1 P
Neutralisation of heparin given by intravenous infusion
Stop the heparin infusion. To calculate the amount of protamine
needed, consider the amount of heparin given in the last 2 hours. This
k is due to the short (60 –90 minutes) half-life of heparin. For example, k
if a patient is receiving 1500 units/hour of heparin and requires
reversal, give 30 mg protamine intravenously. This should be given no
faster than 5 mg/min, as the risk of severe hypotension and
anaphylaxis is increased at faster administration rates. No more than
50 mg protamine should be given in one dose. Protamine has a shorter
half-life than heparin (7 minutes), so repeated doses may be required.
Neutralisation of heparin given by subcutaneous
injection
As the absorption from subcutaneous injection is slower, the total
dose of protamine required is calculated from the total dose of
subcutaneous heparin given. Protamine 25 –50 mg is given as a slow
intravenous bolus, then the remainder is infused over 8 –16 hours.2,3
Neutralisation of LMWH
For LMWH, the usual recommendation is 1 mg protamine to 100 units
LMWH. The anti-Xa activity may not be completely reversed. If the
LMWH has been given up to 8 hours prior to the requirement for
reversal, protamine in the dose described above can be used. If more
than 8 hours has elapsed, lower doses of protamine may be tried.
Doses may need to be repeated due to the longer half-life of LMWH.
Risk of allergy
Some patients have an increased risk of allergy to protamine and must
be monitored carefully or given antihistamines or corticosteroids
pretreatment. These include: previous protamine exposure, patients
k
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362 Prothrombin complex concentrates
with diabetes treated with protamine insulin, patients with a fish

allergy, men with a vasectomy or infertile who may have protamine
antibodies.
The reason for the caution with fish sensitivity and vasectomised
males is as follows. When undergoing elective vasectomy, antibodies
develop against natural nucleoprotamines (a normal component of
human sperm cells) in 22 –33% of patients. These antibodies have
been shown to cross-react with medicinal protamines, which are
extracted commercially from the testes of salmon and certain other
fish. There is an increased risk of an allergic reaction developing if
these individuals are later exposed to protamine as a medication as
cross-reactivity can occur.4
REFERENCES
1 SPC (2010). Protamine Sulphate 10mg/ml Solution for Injection. http://www.
medicines.org.uk/emc/medicine/13567 (accessed 19 November 2014).
2 American College of Chest Physicians (2012). Antithrombotic Guidelines (9th edn).
http://www.chestnet.org/Guidelines-and-Resources/Guidelines-and-Consensus-
Statements/Antithrombotic-Guidelines-9th-Ed (accessed 19 November 2014).
3 British Committee for Standards in Haematology (2012). Guidelines: Managing
bleeding with anti-thrombotic agents. http://onlinelibrary.wiley.com/store/10.1111
/bjh.12107/asset/bjh12107.pdf;jsessionid=2023AF04077F18258798B59461144
P C9A.f03t01?v=1&t=i2p54js1&s=ba9775e3ebf44b5e80d9e066460d19d1a2f67f4e
4 Watson RA et al. (1983). Allergic reaction to protamine: a late complication of elec-
tive vasectomy? Urology 22: 493–495.
k k
Prothrombin complex concentrates
The two main 4-factor prothrombin complex concentrates (PCC) in
use in the UK are Beriplex and Octaplex.1 They are used for the
reversal of bleeding caused by vitamin K antagonists, and for patients
bleeding or due for surgery who have a congenital deficiency in the
vitamin K-dependent coagulation factors II and X when the specific
factors are not available. They contain the vitamin K-dependent
clotting factors II, VIII, IX and X, protein C and protein S. The two
products differ slightly in the amounts of the factors they contain. As
most of the amounts can vary within a range, it is only the factor X
that is significantly higher in Beriplex. Both contain small amounts of
heparin as an excipient.
They are both blood products (derived from human plasma), so
local guidelines on the use of blood products should be followed, with
records made of batch number and expiry. They should be used when
rapid correction of clotting is required, such as for bleeding or
emergency surgery – not for elective surgery or in response to a high
INR with no bleeding. The dose of PCC required is based on units of
factor IX and is dependent on the INR and the patient’s weight.
● Octaplex: a single dose should not exceed 3000 units (120 mL)
intravenously at a starting rate of not more than 1 mL/min,
increasing to 2 –3 mL/min. Higher rates, up to 10 mL/min, have
k
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CPPC V2 - 11/18/2015 1:56 P.M. Page 363
been used, according to the Medusa drug administration guide, but

this is not licensed.2
● Beriplex: a single dose should not exceed 5000 units given
intravenously at a rate of not more than 3 units/kg/min up to a
maximum of 210 units/min (approximately 8 mL/min).
It is essential that no blood flows into the syringe containing the

product during administration as there is a risk of formation of
fibrin clots.
The effect of PCC on coagulation can take up to 30 minutes, but the
INR can quickly start to increase again due to the short half-life of the
factors. Vitamin K (phytomenadione) 5 mg is therefore given at the
same time and this takes effect within 4 –6 hours when given
intravenously.3
The INR should be monitored regularly throughout treatment.
Many patients on warfarin will have an underlying hypercoagulable
state; PCC can exacerbate this and a thrombus can develop.
Disseminated intravascular coagulation (DIC) can also develop as a
side effect.3 PCCs can cause allergy and anaphylaxis and, as they
contain heparin, should not be used in patients with a history of HIT,
and can actually cause HIT. Other side effects include headache and P
pyrexia.
Both PCCs can be tried in cases of life-threatening bleeding with
the novel oral anticoagulants: dabigatran (a direct thrombin
k inhibitor), rivaroxaban and apixaban (direct factor Xa inhibitors). k
There are no extensive trials in patients but there are data from
animal and healthy human studies and case reports suggesting they
may be of some effect.
The use of the products for patients with a congenital deficiency of
any of the vitamin K-dependent coagulation factors is detailed in the
SPC.
REFERENCES
1 eMC (2014). www.medicines.org.uk (accessed 1 November 2014).
2 Injectable Medicines Guide (2014). http://www.injguide.nhs.uk/?ID=
cb046ef7dab14de7ec7a81755f2f71f01305 (accessed 9 November 2014).
3 Keeling D et al.(2011). Guidelines on oral anticoagulation with warfarin – 4th
edition. Br J Haematol 154: 311–324.
Pulmonary function tests

PFTs are non-invasive tests that provide measurable feedback about
the function of the lungs. PFTs have both diagnostic and therapeutic
roles.
Peak expiratory flow rate
The peak expiratory flow rate (PEFR) is measured using a portable,
hand-held peak flow meter, and is the rate at which the air is expelled
forcefully from the lungs. PEFR is a useful measure of airway calibre
in the management of asthma and is ideally expressed as a percentage
k
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364 Pulmonary function tests
For use with EU/EN13826 scale PEF meters only

680
660
640
620
600
580
560
PEF (Vmin) EU scale
540
520
500
Height
480 Men
460 190 cm (75 in)
183 cm (72 in)
440 175 cm (69 in)
420 167 cm (66 in)
160 cm (63 in)
400
380 Height
Women
360 183 cm (72 in)
P 340 175 cm (69 in)
167 cm (66 in)
320 160 cm (63 in)
300 152 cm (60 in)
15 20 25 30 35 40 45 50 55 60 65 70 75 80 85
k Age (years) k
Adapted by Clement Clarke for use with EN13826 / EU scale peak
flow meters from Nunn AJ Gregg I, Br Med J 1989:298;1068-70
FIGURE P1 Peak expiratory flow rate – normal values
of the patient’s previous best value. In the absence of a previous best

result, the PEFR as a percentage of the predicted value is an
approximate guide (Figure P1).
When taking a reading, the patient performs three maximum
forced expirations, and the best of these three results is recorded on a
peak flow chart. Trends in PEFR are used to determine the progression
of the disease or the success of treatment.
In acute asthma, PEFR is one of the measures used to determine
the severity of the attack (Table P13).
TABLE P13
Severity of asthma as determined by peak expiratory
flow rate (PEFR)
PEFR Severity
50–75% of best or predicted Moderate
33–50% of best or predicted Acute severe
<33% of best or predicted Life-threatening
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FVC
4 Normal
3 FEV1
Volume (L)
Obstructive
2
0
0 1 2 3 4 5 6 7
Time (s)
FIGURE P2 An example of a spirometer recording (a spirogram)
PEFR measurement is used by some patients as part of a

self-management plan, e.g. if PEFR drops below a certain percentage
of normal (e.g. <50%), they may have been given instructions to take
a course of oral steroids. P
Spirometry
Spirometry is an assessment of lung function by measurement of rate
and volume of air forced out from the lungs immediately after a
k maximum inspiration. It is used to differentiate between obstructive k
airways disorders (e.g. asthma, COPD) and restrictive disorders (e.g.
interstitial lung diseases).
Relative contraindications for spirometry include haemoptysis of
unknown origin, pneumothorax, unstable angina pectoris, recent
myocardial infarction, thoracic, cerebral or abdominal aneurysms,
recent eye surgery (within 2 weeks due to increased intraocular
pressure during forced expiration), recent abdominal or thoracic
surgical procedures, and patients with a history of syncope associated
with forced exhalation.
Spirometers are the devices used to measure these parameters.
They either produce a spirogram, which is a graph of flow–volume
against time, or they will show the values on a digital display. An
example of a spirogram is shown in Figure P2. Interpretation of
spirometry results should begin with an assessment of test quality.
Failure to meet performance standards can result in unreliable test
results and possible incorrect diagnosis. Reproducibility of the forced
vital capacity (FVC) and the forced expiratory volume (FEV1 ) helps
ensure that the results truly represent the patient’s lung function.1
The main measures obtained by spirometry are as follows:
● FEV1 is the volume of air that the patient can exhale in the first
second of forced expiration.
● FVC is the total volume of air that the patient can forcibly exhale in
one breath.
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366 Pulmonary function tests
● FEV1 /FVC gives an indication of airflow limitation. It is the ratio of

FEV1 to FVC, expressed as a percentage.
The FEV1 and FVC are expressed as a percentage of the predicted

normal rate for a person of the same sex, ethnicity, age and height.
Tables P14 and P15 contain the reference values for FEV1 and FVC.
TABLE P14
Predicted values of forced vital capacity (FVC) and forced
expiratory volume in 1 second (FEV1 ) in men
Male Height
5 3 5 5 5 7 5 9 5 11 6 1 6 3
160 cm 165 cm 170 cm 175 cm 180 cm 185 cm 190 cm
Age 38–41 FVC 3.81 4.10 4.39 4.67 4.96 5.25 5.54
years FEV1 3.20 3.42 3.63 3.85 4.06 4.28 4.49
42–45 FVC 3.71 3.99 4.28 4.57 4.86 5.15 5.43
years FEV1 3.09 3.30 3.52 3.73 3.95 4.16 4.38
46–49 FVC 3.60 3.89 4.18 4.47 4.75 5.04 5.33
years FEV1 2.97 3.18 3.40 6.61 2083 4.04 4.26
50–53 FVC 3.50 3.79 4.07 4.36 4.65 4.94 5.23
P years FEV1 2.85 3.07 3.28 3.50 3.71 3.93 4.14
54–57 FVC 3.39 3.68 3.97 4.26 4.55 4.83 5.12
years FEV1 2.74 2.95 3.17 3.38 3.60 3.81 4.03
58–61 FVC 3.29 3.58 3.87 4.15 4.44 4.73 5.02
k years FEV1 2.62 2.84 3.05 3.27 3.48 3.70 3.91 k
62–65 FVC 3.19 3.47 3.76 4.05 4.34 4.63 4.91
years FEV1 2.51 2.72 2.94 3.15 3.37 3.58 3.80
66–69 FVC 3.08 3.37 3.66 3.95 4.23 4.52 4.81
years FEV1 2.39 2.60 2.82 3.03 3.25 3.46 3.68
These values apply to Caucasians and should be reduced by 7% for Asians and by 13%
for Afro-Caribbeans.
COPD is diagnosed if the postbronchodilator FEV1 /FVC is <70% and

the patient has symptoms and risk factors for developing COPD. The
severity of the airflow obstruction is determined by the variation of
FEV1 from the predicted, and is classified as mild, moderate, severe or
very severe depending on the degree of the reduction of FEV1 from
the predicted value. In a restrictive disorder, the spirometry would
show FEV1 <80% and FVC <80%, but the FEV1 /FVC ratio would be
normal (>70%).
Figure P3 gives an example of how spirometry can work in practice.
Reversibility measurements
When airway obstruction is identified on spirometry, reversibility
testing is useful in cases of diagnostic doubt, especially to help
identify people with COPD or asthma. Response is assessed
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TABLE P15
Predicted values of forced vital capacity (FVC) and forced
expiratory volume in 1 second (FEV1 ) in women
Female Height
4 11 5 1 5 3 5 5 5 7 5 9 5 11
150 cm 155 cm 160 cm 165 cm 170 cm 175 cm 180 cm
Age 38–41 FVC 2.69 2.91 3.13 3.35 3.58 3.80 4.02
years FEV1 2.30 2.50 2.70 2.89 3.09 3.29 3.49
42–45 FVC 2.59 2.81 3.03 3.25 3.47 3.69 3.91
years FEV1 2.20 2.40 2.60 2.79 2.99 3.19 3.39
46–49 FVC 2.48 2.70 2.92 3.15 3.37 3.59 3.81
years FEV1 2.10 2.30 2.50 2.69 2.89 3.09 3.29
50–53 FVC 2.38 2.60 2.82 3.04 3.26 3.48 3.71
years FEV1 2.00 2.20 2.40 2.59 2.79 2.99 3.19
54–57 FVC 2.27 2.49 2.72 2.94 3.16 3.38 3.60
years FEV1 1.90 2.10 2.30 2.49 2.69 2.89 3.09
58–61 FVC 2.17 2.39 2.61 2.83 3.06 3.28 3.50
years FEV1 1.80 2.00 2.20 2.39 2.59 2.79 2.99
62–65 FVC 2.07 2.29 2.51 2.73 2.95 3.17 3.39
years FEV1 1.70 1.90 2.10 2.29 2.49 2.6 2.89
66–69 FVC 1.96 2.18 2.40 2.63 2.85 3.07 3.29 P
years FEV1 1.60 1.80 2.00 2.19 2.39 2.70 2.79
These values apply to Caucasians and should be reduced by 7% for Asians and by 13%
for Afro-Caribbeans.
k k
A 47-year-old woman, 5’5” (165 cm), has an FEV1 of 1.48 litres and an FVC
of 2.6 litres.
reading (1.48)
FEV1 = × 100 = 55% of predicted normal
predicted (2.69)
reading (2.6)
FVC = × 100 = 82.5% of predicted normal
predicted (3.15)
FEV1 reading (1.48)

= × 100 = 56.9%
FVC reading (2.6)
This patient has moderate airflow obstruction (FEV1 between 50% and 80% of
predicted and FEV1/FVC is <70%). The patient could have either COPD or
asthma, and the diagnosis will be dependent on clinical features, history and,
if required, bronchodilator reversibility.
FIGURE P3 An example of spirometry interpretation
10 –15 minutes after inhalation of a therapeutic dose of salbutamol

(four inhalations each of 100 micrograms) administered through a
valved spacer device. Asthma can usually be identified if the following
are found:
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368 PH and PAH
● FEV1 and FEV1 /FVC ratio returns to normal with drug therapy
● a very large (>400 mL) FEV1 response to bronchodilators, or to
30 mg oral prednisolone daily for 2 weeks
● serial peak flow measurements showing significant (20% or
greater) diurnal or day-to-day variability.
REFERENCE
1 Bellamy D (2005). Spirometry in Practice: A practical guide to using spirometry in
primary care (2nd edn). London: BTS COPD Consortium.
Pulmonary hypertension and

pulmonary arterial hypertension
Our understanding of pulmonary hypertension (PH) has been
transformed in recent years. The ‘face’ of the PH patient has been
transformed from a young female (the classic pulmonary arterial
hypertension (PAH) patient) having few treatment options and a
dismal survival, to an older demographic with numerous
comorbidities,1 and elevated pulmonary pressures, which can
P complicate a variety of cardiac and respiratory disorders.
Understanding of the common pathological processes in certain
classes of the disease has led to the development of targeted
treatments. It is crucial that pharmacists understand the roles and
k limitations of specialised drugs and how use of these agents fits into k
general supportive care. Numerous interactions and adverse effects
complicate the use of these specialised treatments.
Diagnostic classification
The diagnostic classification of PH2 can be seen in Table P16.3
TABLE P16
Clinical classification of pulmonary hypertension4
Classification group Sample causes Comment
Group 1 Pulmonary ● Idiopathic PAH Causes in group 1 and group 1’
arterial hypertension ● Heritable PAH – some (PAH) share a common
(PAH) genotypes have been pathophysiology and have
identified proven benefit from therapy
● Drug- and toxin-induced, acting on the endothelin, nitric
e.g. anorexigens oxide and prostacyclin
● Associated with: connective pathways
tissue disease, HIV infection,
portal hypertension,
congenital heart diseases,
schistosomiasis,
lymphangioleiomyomatosis
Group 1’ ● Pulmonary veno-occlusive
disease
(Continued)
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PH and PAH 369
TABLE P16
(Continued)
Classification group Sample causes Comment
Group 2 Pulmonary ● Left ventricular dysfunction In group 2, pulmonary
hypertension (PH) ● Valvular disease vasodilators may worsen
due to left heart ● Congenital/acquired left pulmonary oedema and in
disease heart inflow/outflow tract group 3, ventilation/perfusion
obstruction and congenital mismatching may be worsened
cardiomyopathies by these agents. Targeted
therapy should generally not be
used. Treatment should be
directed at managing
underlying cause. Congenital
heart disease may have
consequent PAH or PH,
depending on the exact nature
of the disease and any repair.
Some of these patients (PAH)
may be suitable for targeted
therapies
Group 3 PH due to ● Chronic obstructive
lung disease and/or pulmonary disease P
hypoxaemia ● Interstitial lung disease
● Sleep-disordered breathing
Group 4 Chronic ● Approximately 4% of For CTEPH: a pulmonary
thromboembolic PH patients with pulmonary endarterectomy can be
k (CTEPH) embolism can develop curative. A recent trial of k
CTEPH. Ventilation riociguat in inoperable CTEPH
perfusion scan is an showed benefit5
important part of the
work-up for PH
Group 5 PH with ● Haematological disorders
unclear multifactorial ● Systemic disorders:
mechanism sarcoidosis, pulmonary
histiocytosis,
lymphangioleiomyomatosis
PAH is defined as a mean pulmonary artery pressure ≥25 mmHg and

pulmonary capillary wedge pressure ≤15 mmHg on right heart
catheterisation with exclusion of other causes.6 If these values are
found, further tests are performed to find the underlying cause.
During the right heart catheterisation, vasodilator testing with either
nitric oxide or epoprostenol will be carried out. The (rare)
‘responders’ to this test are treated with high-dose nifedipine or
diltiazem (depending on heart rate).4 Non-responders will be treated
with specialised treatments with choice based on functional class,
ability to comply with complex regimens and methods of
administration, interactions and comorbidities (see below).
Disease severity
Disease severity is classified using the New York Heart Association
(NYHA) (heart failure) classification.4 Registry data have shown that
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370 PH and PAH
treatments leading to improvement or maintenance in functional

class translate into improved survival, whilst progression on
treatment is associated with worse outcome.7 The aim of treatment is
that the patient improves to class II symptoms; for patients with group
1 PAH the initial choice of targeted therapy will be made depending
on the NYHA class (Table P17).
TABLE P17
Functional class and evidence-based targeted therapy
Functional Proportion of Symptoms Recommendations for
class patients at targeted therapy1
presentation (UK
and Irish registry)
Class I 15% Does not limit physical Nil
activity
Class II 15% Comfortable at rest but Ambrisentan, bosentan,
slight limitation of sildenafil, tadalafil,
physical activity riociguat
Class III 67% Comfortable at rest but Ambrisentan, bosentan,
marked limitation of sildenafil, intravenous
P physical activity epoprostenol, inhaled
iloprost, tadalafil,
treprostinil, riociguat
Class IV 18% Unable to carry out any Intravenous epoprostenol,
physical activities without ambrisentan, bosentan,
k symptoms and may be sildenafil, inhaled or k
symptomatic at rest intravenous iloprost,
subcutaneous, intravenous
or inhaled treprostinil
Initial combination
therapy
Supportive care
For all types of PH, the importance of supportive treatment cannot be
overstated:
1 optimal management of any underlying cause or aggravating

factor, e.g. hypothyroidism, infection (particularly pneumonia),
anaemia, pulmonary embolism, arrhythmia, non-adherence
2 heart failure management with fluid restriction, salt restriction,
diuretics etc.
3 oxygen therapy may be appropriate
4 warfarin is widely used in PAH, with a target INR of approximately
1.5 –2 (unless higher is indicated, e.g. in atrial fibrillation). Most of
the evidence predates the advent of specialised treatments
5 vaccination (influenza and pneumococcal)
6 physiotherapy
7 psychosocial support/support group network
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PH and PAH 371
8 agents to avoid (particularly in class III and IV PAH):

● pregnancy (50% postpartum mortality)
● oestrogen-containing contraceptives are unsuitable (N.B.:
bosentan increases clearance of the contraceptive pill)
● cyclizine: anecdotal risk of hypotension and falls
● beta-blockers: may be used if compelling indication in PH
● platelet transfusions
● precipitating medications – anorexigens.
Specialised treatments
Once diagnosis of PAH is confirmed, any reversible factors have been
addressed and fluid balance has been optimised, targeted therapy can
be instigated. There is a common pathology underlying PAH,
involving endothelin, nitric oxide and prostacyclin pathways.
Pharmacological agents have been developed to target each of these
pathways. Clinical trials have shown the benefit of various
combinations; however, the cost means that combinations of more
than two agents are not routine practice in the UK.
Phosphodiesterase type-5 (PDE-5) inhibitors
These work on the nitric oxide pathway. Headache and flushing
P
usually subside and hypotension can be avoided by careful titration.8
Sildenafil has more interaction potential than tadalafil. CYP3A4
inducers and inhibitors have an important effect on sildenafil and
slightly less effect on tadalafil kinetics. Bosentan reduces the sildenafil
k area under the curve by >60%; however, this combination is widely k
used in practice. Doses used in practice and clinical trials have been
≥80 mg three times a day, although the licensed dose is substantially
lower than this.8 The combination of tadalafil and bosentan has not
been as extensively studied. The recently licensed riociguat acts on
the same pathway and concomitant use with PDE-5 inhibitors is
contraindicated.8 Nitrates are contraindicated with all of these
agents.
Endothelin receptor antagonists
Bosentan, ambrisentan and macitentan block the endothelin
receptors A and B in differing ratios.8 The significance of this
difference is not currently fully understood. The main toxicities of
these agents are hepatotoxicity and anaemia. The hepatotoxicity of
bosentan and ambrisentan is thought to be due to their effects on the
bile efflux pump; this is not affected by macitentan.8 Monthly LFTs
(and pregnancy test, where appropriate) are required while on these
agents8 (sitaxentan was withdrawn due to hepatotoxicity). These
agents are teratogenic, and effective contraception methods must be
used. Bosentan lowers the effectiveness of the oral contraceptive pill.8
Prostacyclin analogues
These are complex and demanding therapies, requiring involved
administration schedules using sophisticated delivery devices.8
Iloprost is nebulised up to six times daily using a breath-activated
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372 PH and PAH
nebuliser. Epoprostenol, iloprost and treprostinil (unlicensed) may be

given by continuous intravenous infusion. It is also possible to give
treprostinil by continuous subcutaneous infusion; this route has the
disadvantage of severe site pain, which is not related to dose. The
demands of complying with these treatments (including line care)
mean that comparatively few patients can benefit from these
treatments.
REFERENCES
1 Peacock A (2013). Clinical year in review – pulmonary hypertension. Eur Resp Rev
22: 20–25.
2 Simonneau G et al.(2013). Updated clinical classification of pulmonary hyperten-
sion.. J Am Coll Cardiol 62(Suppl): D34–D41.
3 Ghofrani HA et al. (2013). Riociguat for the treatment of chronic thromboembolic
pulmonary hypertension.. N Engl J Med 369: 319–329.
4 Barst RJ et al. (2011). Impact of functional class change on survival in patients with
pulmonary arterial hypertension in the reveal registry. Am J Respir Crit Care Med
183: A5941.
5 Simonneau G et al. (2013). Riociguat for the treatment of Chronic Thromboembolic
Pulmonary Hypertension (CTEPH): 1-year results from the CHEST-2 long-term
extension study. Chest 144(4 Meeting Abstracts): 1023A.
6 Galie N et al. (2009). Guidelines for the diagnosis and treatment of pulmonary
P hypertension. Eur Respir J 34: 1219–1263.
7 Ling Y et al. (2012). Changing demographics, epidemiology and survival of incident
pulmonary arterial hypertension: Results from the Pulmonary Hypertension Reg-
istry of the United Kingdom and Ireland. Am J Respir Crit Care Med 186: 790–796.
8 eMC (2014). https://www.medicines.org.uk/emc/ (accessed 30 August 2014).
k k
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Quinine for muscle cramps 373
Q
Quinine for muscle cramps
Cramp is a transient, involuntary episode of pain due to muscle
spasm, continuing for up to 10 minutes. One-third of people over 60
years suffer from leg cramps: 40% have three or more attacks per
week.1
Evidence for use of quinine
Mechanism of action is unknown but muscle excitability appears
reduced. Quinine has modest efficacy: 25% reduction in frequency,2,3
although patient response varies. There is no evidence for long-term
use. Q
Choice of treatment
k Rule out secondary causes: k
● pregnancy
● exercise
● medication – diuretics, salbutamol, raloxifene, nifedipine,
phenothiazines, penicillamine, nicotinic acid and statins may
aggravate cramps. Review and discontinue or reduce dose if
possible
● identify and treat disease, e.g. Baker’s cyst, deep-vein thrombosis,
dystonia, myoclonus, parkinsonism, metabolic problems.1
Reassure patient: idiopathic cramps are common, have no real
cause, tend to resolve on their own and won’t lead to any serious
complications.
Provide advice on self-care measures, such as stretching exercises
and massaging the affected area.1 Simple analgesia can alleviate
post-cramp pain.
Consider quinine only if cramps are very painful, frequent enough
to affect quality of life or self-care measures have failed.4 Prescribe
only after weighing up the risks of serious adverse effects versus the
benefits to the patient.
If appropriate, prescribe 200 –300 mg quinine sulfate at bedtime
for 4 –6 weeks.
Monitor effect by using a sleep or cramp diary. Stop if benefit is not
seen. If the patient experiences benefit, continue treatment for
another 3 months and review.
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374 Quinine for muscle cramps
If long-term treatment is required, interrupt every 3 –6 months to

assess for continued effectiveness and ongoing need.1,2,4,5
Key prescribing points
● State salt when prescribing: quinine sulfate 200 mg ∼ = quinine
bisulfate 300 mg.
● For low-dose therapy, no dosage adjustment is required for renal
impairment.6
● Patients should not have quinine-containing drinks, such as tonic
water or bitter lemon.
● Adverse effects are unlikely at these doses but stop treatment if
tinnitus, impaired hearing, headache, gastrointestinal symptoms or
disturbed vision are experienced. Thrombocytopenia is rare but
advise patients to report unexplained bleeding or unusual bruising.
● In overdose, quinine can cause irreversible blindness and death.
Quinine drug interactions
●Quinine may increase risk of ventricular arrhythmias with
antipsychotics, antiarrhythmics and moxifloxacin.
●Quinine may increase digoxin levels.
●Antivirals may increase quinine levels.
Q REFERENCES
1 NICE (2014). Clinical Knowledge Summaries. Leg cramps. http://cks.nice.org.uk/
leg-cramps (accessed 20 August 2014).
k 2 Joint Formulary Committee (2014). British National Formulary (67th edn). k
3 El-Tawil S et al. (2010). Quinine for muscle cramps. Cochrane Database of Systemat
Rev Issue 12: (accessed 20 August 2014).
4 MHRA (2010). Quinine: Not to be used routinely for nocturnal leg cramps. Drug
Safety Update. http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/
CON085085 (accessed 20 August 2014).
5 SPC (2014). Quinine Sulphate Tablets BP 200mg. Actavis UK Limited (accessed 20
August 2014).
6 Ashley C, Currie A (eds) (2009). The Renal Drug Handbook (3rd edn). Oxford:
Radcliffe Medical Press.
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R
Rapid tranquillisation
Rapid tranquillisation is a pharmacological strategy that is used over
brief intervals of time to help manage acute behavioural disturbance
in patients who are unable otherwise to maintain the safety of
themselves, others or their environment.1,2
Treatment goals
The primary aim is “to anticipate and reduce the risk of violence and
aggression”. It may be used to avoid or allow cessation of other
management strategies, such as seclusion or physical intervention.3
R
Other aims are to reduce the suffering of the service user and to
k intervene without causing harm (by prescribing safely and k
monitoring appropriately).2
Considerations
The available evidence base is poor. Guidance is based on a mix of
evidence and clinical experience and therefore varies across settings
and organisations.2 Person-centred care, including effective risk
assessment and risk management strategies should be used to predict
and prevent disturbed behaviour where possible.3
Risk factors for disturbed behaviour can relate to the service user
(e.g. history of disturbed behaviour/trauma, presence of trigger
factors/stressors), clinical factors (e.g. effect of alcohol/substances/
medication, active mental illness) and the situation itself (e.g.
freedom being restricted).3
Rapid tranquillisation should only be considered once other
management strategies, such as verbal de-escalation, have been
ineffective. De-escalation techniques should continue to be used
throughout.3 Clinical need, safety of service users and staff, and
advance directives should be considered when deciding which
management strategy is indicated, and it must be a proportionate
response to the risk posed by the service user.3
Identification and treatment of any underlying illness/condition
(e.g. psychosis, delirium) should occur alongside rapid
tranquillisation, and total daily doses and the possibility of additive
adverse effects should be borne in mind.2
k
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376 Rapid tranquillisation
The medication chosen for rapid tranquillisation is not dictated by

any underlying illness; someone with active psychosis may receive an
agent other than an antipsychotic for rapid tranquillisation.2
Arrangements for review of the effect of the medication used and the
presentation of the service user should be made in advance.3
Staff should be trained to the appropriate resuscitation level, and
resuscitation equipment (including oxygen) and medical support
must be quickly available if required.3 Consent and capacity issues
must be covered in line with relevant legislation; the Mental Health
Act Code of Practice should be followed and any departures from this
clearly documented along with rationale.3
A physical examination and history (including ECG), and medica-
tion and substance history should be carried out prior to undertaking
rapid tranquillisation, whenever possible.1 Privacy and dignity must
be maintained for the service user as much as possible. The service
user should be debriefed regarding the reasons for the intervention
as soon as possible after the event and encouraged to document his
or her account of what occurred in the clinical record if s/he wishes.3
Medication
The main agents used are benzodiazepines, antipsychotics and
antihistamines. Doses need to be individualised to the service user,
and will generally be lower in older adults or those with medical
R comorbidities than those quoted below.3
The oral route is preferable; the intramuscular route may be
k indicated when oral medication is ineffective or has been refused, or
k
where previous experience would suggest it is preferred. Only in
exceptional circumstances should the intravenous route be used;
senior clinician expertise should be sought prior to doing so.3
If the intramuscular route is to be used, lorazepam is the agent of
choice if the person is antipsychotic naı̈ ve or there is evidence of
cardiovascular disease, a prolonged QT interval, or no recent ECG
available. Otherwise, a combination of haloperidol and promethazine
is recommended;3 it allows lower doses of both agents to be used, but
risks adverse effects from both agents.2,3
Prescription considerations:3
● Prescribe oral and intramuscular doses separately.
● Do not use two medications from the same class.
● Do not mix medication in the same syringe.
Bioequivalence needs to be borne in mind (e.g. 10 mg of oral
haloperidol is approximately equivalent to 6 mg of intramuscular
haloperidol). N.B.: BNF and SPC doses may not always match.1
Specific SPC cautions, contraindications and requirements (e.g.
the need for a baseline ECG prior to use of parenteral haloperidol)
should be borne in mind. If medicines are being used off-license, the
prescriber should take full responsibility, informed consent should be
obtained and documented, and relevant professional guidance should
be followed.3
k
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Sufficient time should be allowed between doses to elucidate effect

(generally 45 –60 minutes for oral and 30 –60 minutes for
intramuscular; but see Table R1), prior to repeating the dose or
TABLE R1
Medication used in rapid tranquillisation2 –4
Medication Adult dose Comments
Oral medication
Lorazepam 1–2 mg Recommended to be used in
combination with an antipsychotic if
psychosis is the underlying cause.
Does not accumulate with repeated
doses or in hepatic impairment1
Olanzapine 10 mg Not licensed. Slow onset of effect
Risperidone 1–2 mg Not licensed
Haloperidol 5 mg SPC recommends a pretreatment ECG
and to avoid using concomitantly with
other antipsychotics
Promethazine 25 mg Not licensed. Not recommended by
NICE due to lack of UK evidence
Short-acting intramuscular injections
Lorazepam 2 mg, repeated after May need to be diluted before use
6 hours depending upon the brand used.
Caution in the young/older adults/those
with brain damage as disinhibition is
R
more likely
k Olanzapine 5–10 mg (usually NICE does not recommend currently due k
10 mg), repeated after to a lack of UK marketing authorisation.
2 hours. Maximum of Intramuscular lorazepam should not be
three injections/day and used within 1 hour of intramuscular
20 mg/day (including all olanzapine, and vice versa
formulations)
Aripiprazole 9.75 mg (range Less hypotension than olanzapine but
5.25–15 mg) repeated may be less effective
after 2 hours. Maximum
of three injections/day
and 30 mg/day
(including all
formulations)
Haloperidol 5 mg (range 2–10 mg), NICE recommend as the first-line
repeated after 4 hours. antipsychotic combination with
Maximum of 18 mg/day promethazine
Promethazine 50 mg (may be repeated Not licensed. NICE recommend as the
once after 1–2 hours) first-line agent in combination with
haloperdol. May be especially useful
if service user is tolerant to
benzodiazepines
Intermediate-acting intramuscular injections
Zuclopenthixol See SPC See comments above regarding
acetate indications
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378 Rapid tranquillisation
considering moving from oral to intramuscular (only if two doses fail

or the person or others are at significant risk), or intramuscular to
intravenous administration.2,3
The availability of ‘rescue’ medication needs to be considered.
If using an antipsychotic, oral and parenteral forms of an
antimuscarinic (e.g. procyclidine) should be quickly available. If
using a benzodiazepine, flumazenil should be quickly available.3
On occasion, prescribers may elect to use doses exceeding the
licensed maximum. In this scenario, specific rationale and risk
assessment should be documented; consultation with expert peers
may be useful. Monitoring should be more frequent and extensive.3
The newer antipsychotics are less likely to cause extrapyramidal
adverse effects compared to haloperidol.2
Zuclopenthixol acetate is not recommended for rapid
tranquillisation due to the delay to onset of effect and the long
duration of action, nor in those who are antipsychotic-naı̈ ve or who
are accepting oral medication, but it can be considered for use in the
following circumstances:3
● There is a previous history of repeated parenteral administration
without resolution.
● The service user has responded to zuclopenthixol acetate
previously.
R ● An advance directive is in place indicating this is a preferred
k management strategy. k
Risks
Risks include extrapyramidal adverse effects (especially acute
dystonia), oversedation (leading to loss of consciousness/alertness),
loss of airway, cardiovascular/respiratory collapse, seizures,
neuroleptic malignant syndrome, sudden death, interaction with
other medication/substances, issues with comorbidities, injury to the
service user/staff and a negative effect on the therapeutic
relationship.1,3
Cautions
Cautions include pre-existing comorbidities (e.g. QTc prolongation,
respiratory issues), hypo-/hyperthermia, stress/extreme emotions,
dehydration or extreme physical exertion.3
Monitoring
Monitoring should include pulse, blood pressure, temperature,
respiratory rate, hydration and consciousness levels.3
Parameters should be monitored every 10 minutes initially and
then half-hourly until the service user is ambulatory. Any issues
detected should prompt increased monitoring, withholding of
additional medication and early medical referral.2
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If consciousness is lost, monitor as if general anaesthesia has been

used, including continuous pulse oximetry.2,3
If service users refuse to accept monitoring, or remain too
behaviourally disturbed for monitoring to be safely undertaken, this
should be documented in the clinical record along with any available
proxy measures (e.g. being ambulatory, vocalising, looking flushed,
becoming unbalanced when standing) used instead.
REFERENCES
1 Bazire S (2014). Psychotropic Drug Directory: The professionals’ pocket handbook and
aide memoire. Dorsington: Lloyd-Reinhold.
2 Taylor D et al. (2015). The Maudsley Prescribing Guidelines in Psychiatry (12th edn).
3 NICE (2015). Violence and aggression: short-term management in mental health,
health and community settings (NG10) http://www.nice.org.uk/guidance/ng10
4 eMC (2014). https://www.medicines.org.uk/emc/ (accessed 25 August 2014).
Renal disease: assessment of renal function

Renal function is measured either in terms of creatinine clearance
(CrCl) or estimated glomerular filtration rate (eGFR). Serum
creatinine alone is not an accurate measure of renal function, as it is
affected by factors independent of renal function, including age, R
gender, race and body size.
k Measuring the clearance of an exogenously administered renally k
cleared marker (e.g. radiolabelled EDTA) is the gold standard in renal
function estimation; however, this is expensive and impractical for
everyday situations. For this reason, prediction equations using serum
creatinine are commonly used to estimate renal function in practice.
Creatinine clearance
The most commonly used method for determining CrCl is the
Cockcroft and Gault equation:1
F × (140 – age) × weight (kg)∗
CrCl (mL/ min) =
serum creatinine (micromol/L)
where F = 1.23 for men, 1.04 for women.
*The use of Cockcroft and Gault in any patient where the patient’s actual body
weight is not reflective of a normal muscle mass always needs to be interpreted
with caution. If the patient is obese (>20% of ideal body weight (IBW)), IBW must
be used because fatty tissue does not produce creatinine:
● for men : IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet
● for women : IBW (kg) = 49 kg + 1.7 kg for each inch over 5 feet.
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380 Renal disease: assessment of renal function
In patients with oedema or ascites, IBW should be used, whereas

for patients who weigh significantly less than their IBW, actual body
weight should be used. In all of these situations there is some degree
of inaccuracy.
Renal function gradually declines with age; however, this may not
result in an elevated serum creatinine due to a concurrent reduction
in muscle mass.
The following examples illustrate why CrCl is a more precise
indicator of renal function than serum creatinine alone:
1 70-year-old female, IBW = 45 kg, serum creatinine =
149 micromol/L
2 30-year-old male, IBW = 75 kg, serum creatinine =
149 micromol/L.
Both have the same serum creatinine, but the 70-year-old female has
a CrCl of 22 mL/min, whereas the 30-year-old male has a CrCl of
68 mL/min.
eGFR
The Modification of Diet in Renal Disease (MDRD)2 formula uses
serum creatinine in combination with age, sex and race to give an
eGFR that is normalised for a body surface area of 1.73 m2 . As eGFR
does not require knowledge of the patient’s weight, it can easily be
R reported by laboratories along with serum creatinine, and forms the
basis of the classification system for chronic kidney disease.
k More recently, NICE3 has recommended the use of the Chronic k
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation4 for
determining eGFR. The CKD-EPI equation is based on the same four
variables as the MDRD equation, but is proposed to be more accurate
at higher eGFR values.
Which method to use for drug dosing?
Most recommendations for dose adjustment in patients with renal
impairment are based on CrCl calculated using Cockcroft and Gault.
However, eGFR is increasingly being used for the purposes of drug
dosing,5 and it is important to recognise the limitations of this
approach: eGFR has not yet been validated for drug dose calculations.
Although CrCl and eGFR are not interchangeable, in practice, for
most drugs and for most adults of average build and height, eGFR can
be used to determine dosage adjustments in place of CrCl. Exceptions
to this include:
● toxic drugs with a narrow therapeutic index, where Cockcroft and
Gault should be used in addition to therapeutic drug and clinical
response monitoring
● patients at extremes of weight, where either Cockcroft and Gault or
the absolute GFR may be used for drug dosing (N.B.: both methods
still have limitations in this setting).
k
k
An individual’s absolute GFR can be calculated from the eGFR as

follows:
Individual s body surface area (m2 )
GFR absolute = eGFR ×
1.73
It is extremely important that caution should be used when
calculating drug doses in renal impairment, particularly where
estimations of renal function using MDRD rather than Cockcroft and
Gault would alter a dose recommendation. The risks of drug toxicity
or therapeutic failure in an individual patient must always be
considered and neither method is validated in acutely unwell patients.
Limitations
Limitations of prediction equations, such as Cockcroft and Gault and
MDRD that are based on serum creatinine, include use in:
● extremes of age (not validated)
● extremes of body size
● severe malnutrition or obesity
● oedematous states
● amputation
● disease of skeletal muscle, muscle wasting
● paraplegia or quadriplegia
● pregnancy (not validated)
● rapidly changing serum creatinine, e.g. acute kidney injury (AKI). R
k k
Measuring CrCl from a serum creatinine concentration and a timed
urine collection may be used to estimate renal function in situations
where prediction equations may be inaccurate. A single serum
creatinine measurement is taken and urine collected over a fixed
period of time, usually 24 hours. The following equation is then
applied:
CrCl (mL/ min) = UCr × V
PCr × t
U Cr = urine creatinine concentration (micromol/L); V = volume of
urine (mL); PCr = plasma creatinine concentration (micromol/L);
t = time (minutes).
N.B.: pay close attention to units and remember that there are
1440 minutes in 24 hours.
The accuracy of a timed urine collection depends on the accurate
collection of urine over the time period, which many patients find
difficult and inconvenient. Incomplete collection will result in
underestimation of renal function.
REFERENCES
1 Cockcroft DW, Gault MH (1976). Prediction of creatinine clearance from serum
creatinine. Nephron 16: 31–41.
k
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382 Renal impairment and renal replacement therapy
2 Levey AS et al. (2006). Using standardized serum creatinine values in the Modifi-
cation of Diet in Renal Disease Study equation for estimating glomerular filtration
rate. Ann Intern Med 145: 247–254.
3 NICE (2014). Chronic Kidney Disease: Early identification and management of chronic
kidney disease in adults in primary and secondary care. NICE guidelines CG182.
www.nice.org.uk/guidance/CG182 (accessed 7 September 2014).
4 Levey AS et al. (2009). A new equation to estimate glomerular filtration rate. Ann
Intern Med 150: 604–612.
Renal disease: dosing in renal impairment

and renal replacement therapy
The kidney is an important site of excretion for many drugs and/or
their metabolites. Reduction in renal function can significantly
increase serum concentrations of renally excreted drugs and/or
metabolites and cause accumulation and toxicity. A number of other
pharmacokinetic and pharmacodynamic changes also occur in renal
impairment that may alter efficacy and increase the likelihood of
adverse effects.
R Pharmacokinetic changes in renal impairment
k Absorption (generally less significant) k
● Gastrointestinal (GI) oedema may reduce absorption, e.g. oral
furosemide; consider converting to intravenous.
● Prolonged gastric emptying.
● Alterations in GI pH due to uraemia or medication, e.g. reduced
absorption of iron with proton pump inhibitors.
● Vomiting due to uraemia.
● Phosphate binders/ion exchange resins – may chelate drugs and
reduce absorption, e.g. quinolone antibiotics – separate
administration times.
Distribution
● Fluid status, e.g. oedema, use of diuretics. Only significant for

water-soluble drugs with volume of distribution (V d ) <1 L/kg,
e.g. aminoglycosides.
● Reduced protein binding secondary to uraemia and/or low
albumin. Results in increased free (active) drug. Clinically
important for highly protein-bound drugs (>80%) such as
phenytoin and warfarin. Care when interpreting drug levels for
highly protein-bound drugs – need to consider increased free
levels, e.g. phenytoin.
● Reduced tissue binding secondary to uraemia. Results in increased
free (active) drug, e.g. digoxin.
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Renal impairment and renal replacement therapy 383
Metabolism
● Hepatic metabolic pathways are generally unaffected, although
impact of renal impairment on accumulation of renally cleared
active/toxic metabolites needs to be considered.
● Kidneys responsible for activation of vitamin D and metabolism of
insulin.
● In chronic kidney disease (CKD) stages 4/5 use alfacalcidol
(1α-hydroxycolecalciferol) as it only requires activation by the
liver and not kidneys.
● Reduced doses of exogenous insulin are required in diabetics as
renal function declines.
Excretion
The main pharmacokinetic change is seen in CKD. Many
water-soluble drugs and/or metabolites are excreted by the kidney
and renal impairment may lead to reduced excretion, accumulation
and toxicity unless dose and/or frequency are adjusted. Drugs that are
most affected are those with significant renal excretion or active/toxic
renally excreted metabolites. Table R2 illustrates how to manage
some issues of excretion of drugs; dose reduction depends on:
● degree of renal impairment
● proportion of the drug and/or metabolites cleared by renal
excretion R
● toxicity
k ● therapeutic index. k
Pharmacodynamic changes
Uraemia and renal impairment can increase the risk of side effects of
some medications, including:
● increased cerebral sensitivity to sedating medications (even if
excretion unaffected) due to increased permeability of blood–brain
barrier. Start with low doses and titrate carefully
● increased risk of GI bleeding with non-steroidal anti-inflammatory
drugs (NSAIDs) and anticoagulants
● increased risk of hyperkalaemia with potassium-sparing diuretics.
Loading doses
Alterations in V d and/or tissue binding may require alterations in
loading doses, e.g. digoxin may require a lower loading dose in
end-stage renal disease due to reduced V d .
For drugs requiring rapid therapeutic levels that have a prolonged
half-life in renal failure (e.g. vancomycin), a loading dose may be
needed to achieve steady state in a timely manner, and can be
calculated as follows:
Cp × Vd
D=
FS
D = dose; Cp = desired concentration; V d = volume of distribution;
F = bioavailability; S = salt fraction.
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384 Renal impairment and renal replacement therapy
TABLE R2
Drug excretion management issues in renal impairment
Drug characteristics Management in renal impairment
High renal clearance, wide therapeutic ● Likely to accumulate; may require either
index, e.g. penicillins dose reduction or increasing dosing
interval
High renal clearance, narrow therapeutic ● Significant potential for accumulation
index, e.g. aminoglycosides, lithium, and toxicity; use alternative where
digoxin, glycopeptide antibiotics possible
● Adjust dose and perform therapeutic
drug monitoring (TDM)
● Drugs with renally excreted active
metabolites (e.g. morphine) should also
be used with great care or preferably
avoided
Low renal clearance, wide therapeutic ● Generally safe
index, e.g. lansoprazole
Low renal clearance, narrow therapeutic ● Unlikely to be affected, but consider
index, e.g. theophylline, phenytoin impact of other changes in
pharmacokinetics and/or
pharmacodynamics
● Perform TDM
Drugs titrated against a response, e.g. ● Use with caution; start with low doses
atenolol, angiotensin-converting enzyme and titrate against response
inhibitors
R Accumulation unlikely
Stat doses ●
k ● See loading doses section below k

Renal clearance needed for efficacy ● Large doses of furosemide required in
severe renal impairment as reduced
tubular secretion means lower
concentrations at site of action
● Nitrofurantoin ineffective in CrCl
<60 mL/min, as requires urinary
excretion to get to site of action
Drug removal by renal replacement therapy

No renal replacement therapy (RRT) method is as effective as a
normal kidney; drug doses in RRT should never be larger than in
normal renal function.
Factors affecting the removal of a drug by RRT are shown in
Table R3.
Key considerations for drug dosing in CKD and on RRT
● use drugs only when there is a definite indication
● avoid nephrotoxins
● degree of renal impairment
● contribution of residual urine output if on RRT
● proportion of drug normally renally excreted
● presence of renally excreted active metabolites
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Renal impairment and renal replacement therapy 385
TABLE R3
Factors affecting the removal of a drug by renal
replacement therapy
Drug/active Haemodialysis (HD) Peritoneal dialysis Continuous
metabolite venous-venous
characteristic haemofiltration
Molecular ● Clearance by ● Clearance by ● Clearance by
weight1 diffusion diffusion and convection
● <500 Da = likely convection ● Membranes have
to be cleared ● Poor clearance - larger pores than
● 500–20 000 Da: small molecular HD
clearance depends weight more likely ● Increased
on dialysis to be cleared clearance up to
membrane 30 kDa
● Low flux = unlikely
to be cleared
● High flux = more
likely to be cleared
Protein binding ● Low protein binding = more drug available for clearance
● High protein binding = not generally removed
● (N.B.: consider effect of uraemia on binding)
Volume of ● <1 L/kg = mostly contained in plasma, more likely to be
distribution cleared
● >2 L/kg = less contained in plasma, less likely to be cleared
Water/lipid ● Higher water solubility = higher clearance R
solubility Higher lipid solubility = lower clearance
k k
●
Amount ● Higher renal clearance = more likely to be cleared

usually cleared
by kidneys
● proportion of drug and/or metabolites cleared by non-renal routes

(e.g. hepatic metabolism)
● toxicity – wide or narrow therapeutic index
● drug removal by RRT
● use TDM where possible
● monitor for effectiveness and toxicity
● available references sources for drug dosing:
● BNF: limited; little information on RRT
● SPC (www.medicines.org.uk): more detailed information, but
only includes licensed uses. Limited RRT information
● Renal Drug Handbook:2 detailed, specialist information,
including RRT. Includes common practice/off-licence uses.
Caution required, as not frequently updated.
k
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386 Renal disease: chronic kidney disease
REFERENCES
1 UK Medicines Information (UKMi) Q&A 168.5 (2013). What Factors Need to be
Considered When Dosing Patients on Renal Replacement Therapies? https://www
.evidence.nhs.uk/Search?q=What+factors+need+to+be+considered+when+
dosing+patients+on+renal+replacement+therapies%22 (accessed 15 May 2015).
2 Ashley C, Currie A (2009). The Renal Drug Handbook (3rd edn). Oxford: Radcliffe
Publishing.
Renal disease: chronic kidney disease

Overview
Definition Diagnosed when there is either impaired kidney function (estimated
eGFR <60 mL/min/1.73 m2 ), evidence of kidney damage or structural
abnormality of the kidney, present for >90 days.1
Markers of kidney damage include leakage of protein (proteinuria)
and/or blood (haematuria) into the urine.
Structural abnormalities include renal stones or prostatic hypertrophy.
Renal impairment in CKD can range from mild, with minimal or no
symptoms, to end-stage renal disease (ESRD) requiring renal replacement
therapy (RRT)
Differential Acute kidney injury (AKI) due to potentially reversible causes, e.g. sepsis,
diagnosis urinary tract obstruction, nephrotoxic drugs.
R
Acute chronic renal failure – may have features of CKD, but also features
k of an acute cause for deterioration of renal function, e.g. urinary tract k
infection
Causes/risk ● Diabetes
factors1 ● Hypertension
● AKI
● Cardiovascular disease (CVD), e.g. ischaemic heart disease,
chronic heart failure, peripheral vascular disease
● Structural renal tract disease, recurrent renal stones or prostatic
hypertrophy
● Multisystem diseases with kidney involvement, e.g. systemic
lupus erythematosus
● Family history of ESRD or hereditary kidney disease
(e.g. polycystic kidney disease)
k
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Classification1 Classified according to:

● Renal function: using serum creatinine and a prediction
equation for eGFR
● Proteinuria: using measurement of urinary albumin:creatinine
ratio (ACR)
Urinary albumin:
creatinine ratio (ACR) (mg/mmol)
<3 3–30 >30
Normal to mildly Moderately Severely
increased increased increased
A1 A2 A3
> 90 G1 No CKD unless

Normal/high other markers of
kidney damage
Increasing risk of adverse outcome

60–89 G2
Mild reduction in
young adult
eGFR (mL/min/1.73m2)
45–59 G3a
Mild–moderate
reduction
30–44 G3b R
Moderate–severe
k reduction k
15–29 G4
Severe reduction
<15 G5
End-stage renal
disease
The darker the shading, the greater the risk of an adverse outcome,
e.g CKD progression, AKI, all-cause mortality and cardiovascular events
’G’ is used to denote the GFR category and ’A’ for the ACR category, e.g.:
● A person with an eGFR of 25 mL/min/1.73 m2 and an ACR of
15 mg/mmol has CKD stage G4A2
● A person with an eGFR of 50 mL/min/1.73 m2 and an ACR of
35 mg/mmol has CKD stage G3aA3
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Clinical The kidney regulates fluid and electrolyte balance, stimulates bone
features marrow red blood cell production through production of erythropoietin,
and helps maintain calcium and phosphate balance by activating vitamin
D. It is also responsible for excreting waste products of metabolism
(e.g. urea, creatinine, uric acid) and medications.
During the early stages of CKD patients are often asymptomatic;
however, as renal function declines, changes to all of these functions
occur with the following results:
● Hypertension: may cause, or be caused by, CKD. Activation of the
renin–angiotensin system occurs in CKD in an attempt to increase
renal perfusion. This leads to sodium and fluid retention and
hypertension.
● Proteinuria: leakage of protein into urine may occur when the
glomeruli of the kidney are damaged. Proteinuria is a significant risk
factor for progression of CKD and cardiovascular morbidity and
mortality.
● Fluid overload: due to sodium and fluid retention.
● Cardiovascular disease: hypertension and chronic fluid overload
can lead to left ventricular hypertrophy and cardiac dysfunction.
● Uraemia: accumulation of waste products such as urea can cause
nausea, fatigue, itching, restless-leg syndrome and anorexia.
● Hyperkalaemia: due to reduced potassium excretion. May be
exacerbated by medications, e.g. angiotensin-converting enzyme
inhibitors (ACEIs) and angiotensin receptor blockers (ARBs).
Anaemia due to:
R ●
● Reduced erythropoietin production

k ● Iron deficiency (poor intake, poor absorption, increased losses) k
● Renal bone disease: vitamin D from diet and sunlight
(colecalciferol) requires hydroxylation by the liver and kidneys to
become active (1,25-dihydroxycolecalciferol, calcitriol). Low levels of
active vitamin D reduce calcium absorption from the gut. The
resulting hypocalcaemia stimulates the production of parathyroid
hormone (PTH), which increases calcium release from bones.
Untreated, high PTH levels lead to increased bone loss (renal bone
disease) and an increased risk of fractures.
● Hyperphosphataemia due to reduced phosphate excretion. Reduces
calcium absorption from the gut and causes itching.
● Acidosis: the kidney regulates acid balance through reabsorption of
bicarbonate and production of other buffers to remove hydrogen ions.
Metabolic acidosis can occur when the kidney is unable to perform
these functions.
● Bleeding complications: uraemia increases the risk of
gastrointestinal (GI) bleeding and can cause platelet dysfunction
Diagnostic ● U&Es, FBC, LFTs, albumin, bicarbonate

tests ● Folate, vitamin B12 , iron, ferritin and % transferrin saturation
● Serum calcium, phosphate and PTH
● GFR estimation – usually eGFR
● Plasma glucose (detect undiagnosed diabetes or assess diabetic
control)
● Urine dipstick for haematuria
● Urinary ACR
● Renal ultrasound (where appropriate)
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Treatment ● Early diagnosis and treatment of CKD can delay progression to ESRD,
goals hence screening of at-risk patients is crucial
● Establish cause of CKD, particularly if it is treatable (e.g. urinary tract
obstruction, nephrotoxic drugs)
● Minimise risk factors, e.g. tight glycaemic and blood pressure control.
CVD is the most common cause of death in CKD, with CVD-associated
mortality risk increasing proportionally with decline in GFR
● Slow progression
● Manage complications
● Appropriate planning for RRT
● End-of-life care
Treatment Pharmacological treatments: most common interventions used to
options relieve symptoms, replace functions of failing kidneys and slow
progression.
Lifestyle advice: exercise, weight loss, smoking cessation.
Dietary intervention: restrict/limit potassium, phosphate, salt and fluid
intake where appropriate. Supplements may be required in poor intake.
RRT in ESRD
Blood ● Aim to keep systolic blood pressure <140 mmHg (120–139 mmHg)
pressure and diastolic blood pressure <90 mmHg.1
control ● In CKD and diabetes, and in people with an ACR of ≥70 mg/mmol, R
aim to keep systolic blood pressure <130 mmHg (120–129 mmHg)
k and diastolic blood pressure <80 mmHg.1 k
First-line choice of antihypertensive agent in CKD
A1 A2 A3 ACR >70
ACR <3 ACR 3-30 ACR >30 mg/mmol
mg/mmol mg/mmol mg/mmol
Non- Renin–
diabetic angiotensin
normotensive system
†
antagonist*
Non- Follow National Institute of

diabetic Renin–angiotensin system
Health and Care Excellence
hypertensive (NICE) clinical guideline 1272 antagonist*†
Diabetic
Renin–angiotensin system antagonist,
normotensive Follow NICE †
irrespective of blood pressure*
diabetes
Diabetic pathway 3
hypertens Renin–angiotensin system antagonist*†
*ACEIs, ARBs or direct renin inhibitors (e.g. aliskiren). ARBs should be used if ACEIs are
not tolerated.
†
Caution if serum potassium >5.0 mmol/L.
Use of ACEI/ARBs is beneficial in CKD, as they reduce renin–angiotensin
system activation (a consequence of CKD)
k
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Proteinuria ● ACEIs/ARBs provide additional renoprotective effects (above blood

pressure control) by reducing protein leak, and may be used in
patents with proteinuria irrespective of initial blood pressure
Fluid ● Diuretics (may require large doses of loop diuretics in low GFR)
overload ● Fluid restriction
Cardio- ● Follow NICE clinical guideline 1814 for use of statins in CKD – start
vascular risk at a low dose and increase slowly.
management ● Offer antiplatelet medication where appropriate, but be aware of
increased risk of bleeding
Uraemia ● Itching: control phosphate and calcium levels; hydrate skin with
topical moisturisers; sedating antihistamines
● Restless-leg syndrome: correct iron deficiency; clonazepam;
haloperidol; ropinirole
● Nausea: antiemetics such as metoclopramide or prochlorperazine
● Gout: allopurinol
Hyper- ● Low-potassium diet
kalaemia ● Review medications, i.e. ACEIs/ARBs, potassium-sparing diuretics
● Insulin/glucose infusion, sodium bicarbonate and/or nebulised
salbutamol are all used in acute hyperkalaemia to increase
potassium uptake into cells. May also require calcium gluconate to
prevent arrhythmias (see Potassium entry)
● Ion exchange resins, e.g. Calcium Resonium, exchange calcium ions
for potassium ions as it passes through the gut. Always give with a
laxative as very constipating.
R ● RRT
k Anaemia5 In CKD, defined as haemoglobin <110 g/L (<11 g/dL) k
● Optimise iron levels: often involves intravenous iron due to reduced
absorption of oral iron (see Iron entry)
● Correct folate or vitamin B12 deficiencies
● Use of an erythropoiesis-stimulating agent to maintain stable
haemoglobin 10–12 g/dL (higher levels lack additional benefit and
increase risk of harm)
Bone ● Low-phosphate diet
metabolism ● Phosphate binders,6 taken with food to bind phosphate in the gut
and prevent absorption. Commonly used phosphate binders
include calcium acetate, calcium carbonate, aluminium hydroxide,
sevelamer and lanthanum
● Vitamin D supplementation: initially with colecalciferol or
ergocalciferol if vitamin D-deficient. If GFR <30 mL/min/1.73 m2 ,
use alfacalcidol (1-alpha hydroxycolecalciferol), which does not
require activation by kidneys (but still requires activation by liver)1
● Tertiary (uncontrolled) hyperparathyroidism may require use of
calcimimetics, such as cinacalcet and paricalcitol. If severe, surgical
removal of the parathyroid glands (parathyroidectomy) may be
necessary
Metabolic ● Consider oral sodium bicarbonate if serum bicarbonate
acidosis <20 mmol/L. Common dose 500 mg–1 g three times a day
Stress ● Altered gastric pH in uraemia increases risk of GI bleeding
ulceration ● Consider prophylaxis with H2 -antagonist or proton pump inhibitor
k
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Assess ● Type of renal impairment (e.g. acute or chronic)
● Severity of renal impairment: eGFR routinely available, calculate
creatinine clearance where possible
● RRT method (if applicable)
● Residual urine output if on RRT
● Choice and dose of medications (see below)
Essential Choice of drug in CKD
intervention ● Avoid nephrotoxic agents in predialysis patients and patients on RRT
with residual renal function
● Determine pharmacokinetic and pharmacodynamic effects of renal
impairment on drug choice (see Renal impairment and renal
replacement therapy – drug dosing entry)
● Consider using medicines that are metabolised to inactive compounds
or excreted by non-renal routes
● Renally cleared medicines with a narrow therapeutic index (e.g.
aminoglycosides and vancomycin) require careful monitoring and
dose adjustment – avoid where possible
● Consider reduced efficacy, e.g. nitrofurantoin ineffective in CrCl
<60 mL/min, as requires urinary excretion to work
Essential Drug dosing in CKD
intervention ● Consider proportion that is normally renally cleared
● Presence of renally cleared active metabolites
● Proportion of drug and/or metabolites cleared through non-renal
routes (e.g. hepatic metabolism) R
k ●
●
Toxicity – wide or narrow therapeutic index
Drug removal by RRT (see individual Renal replacement therapy
k
entries for more information)
● Changes in volume of distribution that may require alterations in
loading doses (e.g. digoxin)
Essential Therapeutic drug monitoring
intervention ● Renally cleared, narrow-therapeutic-index medications (e.g.
aminoglycosides and vancomycin) require therapeutic drug
monitoring and dose adjustment
● Caution interpreting levels for highly protein-bound drugs – reduced
protein binding due to uraemia will increase amount of unbound
(active) drug, e.g. phenytoin
Essential Cardiovascular risk management
intervention ● Assess in same way as people without CKD; however, some
medications (e.g. statins) may require dose modification
● Consider increased risk of bleeding with antiplatelets/anticoagulants
● Ensure good glycaemic and blood pressure control
● Non-pharmacological interventions, e.g. stop smoking, weight
management, healthy eating, exercise
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Essential Commencing an ACEIs/ARBs1

intervention ● Check baseline potassium, creatinine and eGFR
● Repeat 1–2 weeks after starting and after each dose increase
● If decrease in eGFR of ≥25% or increase in creatinine ≥30%,
investigate other causes (volume depletion, concurrent medication,
e.g. non-steroidal anti-inflammatory drugs (NSAIDs)). If no other
cause found, stop ACEIs/ARBs or reduce to previously tolerated dose
● Stop if serum potassium ≥6.0 mmol/L
● Titrate to maximum dose where possible
Secondary Timing of medications
intervention ● Avoid taking phosphate binders at same time as oral iron or some
antibiotics (e.g. quinolones) – binds in gut and prevents absorption
● Counsel patient and annotate timings on drug chart
Secondary Polypharmacy
intervention ● May take >10 medications/day
● Potential for interactions is very high
● Review unnecessary medications/rationalise
● Consider adherence aids (or referral to community or domiciliary
pharmacy services for assessment)
Secondary Fluid restriction
intervention ● Polypharmacy may mean a considerable amount of fluid is needed for
medication taking, which has an impact on daily fluid allowance
● Some medications require addition of fluid, e.g. Movicol/Laxido
● Fluid content of intravenous medications
R Secondary Analgesia in CKD
k intervention ● Caution with NSAIDs: ↓GFR and ↑GI bleeding risk. Avoid topical use k
as some systemic absorption occurs.
● Paracetamol is generally safe.
● Many opiates are renally cleared, therefore accumulation may occur,
which may lead to increased cerebral sensitivity – start with low
doses and titrate
● Impact of renally cleared metabolites, e.g. codeine/morphine have
highly active renally cleared metabolites with prolonged half-lives
Secondary Over-the-counter medications
intervention ● Avoid NSAIDs
● Impact of calcium/magnesium in antacids on bone disease control
● Some vitamins accumulate in renal disease; also consider vitamin D
content
● Electrolyte content, e.g. high sodium content in effervescent tablets,
potassium content in potassium citrate
● Cough/cold remedies containing sympathomimetics in hypertension
Secondary Vaccinations
intervention ● Annual influenza and 5-yearly pneumococcal vaccination
recommended in all patients
● All patients on, or being considered for, RRT should be vaccinated
against hepatitis B
● Caution with live vaccines if on immunosuppressant
medications/renal transplant
Further Jogia P, O’Brien M (2009). How to approach prescriptions for patients
reading with renal impairment. Clin Pharmacist 179–183.
Morlidge C, Richards T (2001). Renal disease (2): managing chronic renal
disease. Pharm J 266: 655–657.
k
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REFERENCES
1 NICE (2014). Chronic Kidney Disease: Early identification and management
of chronic kidney disease in adults in primary and secondary care. CG182.
2 NICE (2011). Hypertension: Clinical management of primary hypertension in
adults. NICE guidelines CG127. www.nice.org.uk/Guidance/CG1277 (accessed
7 September 2014).
3 NICE (2014). Diabetes Pathway. www.pathways.nice.org.uk/pathways/diabetes
4 NICE (2014). Lipid Modification: Cardiovascular risk assessment and the modification
of blood lipids for the primary and secondary prevention of cardiovascular disease.
CG181. www.nice.org.uk/guidance/CG181 (accessed 7 September 2014).
5 NICE (2011). Anaemia Management in People with Chronic Kidney Disease. CG114.
6 NICE (2013). Hyperphosphataemia in Chronic Kidney Disease: Management of hyper-
phosphataemia in patients with stage 4 or 5 chronic kidney disease. NICE guideline
CG157. www.nice.org.uk/guidance/CG157 (accessed 7 September 2014).
Renal replacement therapy: haemodialysis

Overview
Setting Haemodialysis (HD) can be used either acutely in acute kidney injury to rest
the kidneys, or longer term in the treatment of end-stage renal disease.
HD can be provided: R
k ● In the hospital setting, usually for acutely unwell patients k
● In satellite units with reduced medical cover
● In the patient’s home, after careful patient selection and training
Vascular Access to the patient’s blood stream for HD is achieved by one of the
access following methods:
Arteriovenous fistula (‘fistula’): the radial or brachial artery is surgically
joined to an adjacent vein. The higher-pressure arterial blood causes the vein
wall to thicken and the lumen to get bigger, creating a vessel of sufficient
size and blood flow for dialysis to occur.
Two needles are usually inserted into the fistula for dialysis – one for the
arterial line (taking blood out of the patient) and one for the venous line
(returning blood to the patient).
A fistula may take 3–6 months to be usable, therefore must be planned in
advance of the need for dialysis. Complications include stenosis, thrombosis,
infection and aneurysm.
Central venous catheter (CVC or ‘line’): usually placed in the internal
jugular vein either temporarily or permanently (tunnelled under the skin).
CVCs usually have an arterial lumen and a venous lumen.
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394 Renal replacement therapy: haemodialysis
Disadvantages include:
● Relatively narrow calibre, limiting blood flow and dialysis adequacy.
● High risk of infection and thrombosis. Locking with an anticoagulant ±
antibiotic solution (e.g. heparin/vancomycin) may reduce this risk. If
CVCs become blocked, locks/infusions of urokinase or alteplase may be
used.
Graft: a plastic tube connects the artery to the vein and is used for dialysis.
This may be used almost immediately. Disadvantages include an increased
infection and thrombosis risk, and a life span of only a few years.
Ideally patients should dialyse with a fistula because they are more durable
and less likely to become infected;1 however, a CVC will be needed if a
fistula is not ready or is impossible to create. Grafts are only used if other
options have failed
Technology HD works through a combination of:
● Diffusion (movement of solutes from fluid with a high to a low
concentration across a semipermeable membrane)
● Ultrafiltration (movement of fluid under pressure across a
semipermeable membrane)
Blood is removed from the patient via the arterial line of the fistula or CVC
and pumped through the dialysis machine via the dialyser or ‘kidney’. The
patient is usually anticoagulated with either low-molecular-weight heparin
or unfractionated heparin to prevent blood from clotting in the dialysis
machine.
R The dialyser contains thousands of hollow fibres made of a semipermeable
membrane. Blood is pumped through the fibres, whilst a crystalloid solution
k (dialysate) is pumped in the opposite direction outside the fibres. The k
opposing blood and dialysate flow directions increase the amount of
diffusion and ultrafiltration that occurs. Different dialysate compositions are
used depending on the patient’s requirements.
Waste products such as urea and creatinine and solutes such as potassium
are removed from the blood by diffusion into the dialysate along a
concentration gradient (from high to low).
Essential minerals (e.g. calcium and bicarbonate) are replaced in the blood
by diffusion from the dialysate along a concentration gradient (high in the
dialysate, lower in the blood).
Excess fluid is removed from the blood by ultrafiltration, with the dialysate
compartment having a higher osmolality and being kept at a lower pressure
relative to the blood compartment. The dialysed blood is then returned to
the patient via the venous line of the fistula or CVC
Common Hypotension, infection, electrolyte disturbance, blood loss, restless-leg
complica- syndrome, cramps, nausea and vomiting, headache, angina, arrhythmias
tions
Other Length of HD session is gradually increased to 3–5 hours three times a
informa- week. Patients are assigned a ‘dry weight’, equivalent to their weight
tion without excess fluid or hypotension, and are weighed before and after
dialysis, with the post weight being as close to their dry weight as possible
k
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Pharmaceutical care for non-specialist pharmacists

Drug dosing Equations for assessment of estimated glomerular filtration rate
on HD (eGFR)/creatinine clearance (CrCl) cannot be used in HD patients.
Even though drug clearance during HD may be good, as it is an
intermittent process performed for a few hours every 2–3 days, drugs are
usually dosed for a CrCl of <10 mL/min unless other information is
available.1,2
Drug removal by HD is hard to quantify, but is influenced by:3
● Duration of session (longer session = more clearance)
● Flow rate (higher flow rate = more clearance)
● Dialysate composition
● Dialyser porosity (‘high-flux’ dialysers provide greater clearance than
standard dialysers)
If a drug is likely to be removed by HD it should be given after the
session; otherwise it could be removed before it has time to act fully
HD anticoag- Caution in patients prescribed anticoagulants for other indications, i.e.
ulation venous thromboembolism prophylaxis, warfarin, new oral
anticoagulants, fondaparinux.
Review in patients with bleeding complications or new contraindications
to anticoagulation (i.e. recent stroke) – anticoagulant-free dialysis may
be needed.
Patients may develop heparin-induced thrombocytopenia requiring use of R
different anticoagulants
k k
Fluid HD patients usually restrict their fluid intake to 500–1000 mL/day,
restriction depending on residual urine output. Consider the impact of oral
medications needing to be swallowed with fluid and volumes of
intravenous medications
REFERENCES
1 eMC (2015). www.emc.medicines.org.uk. (accessed 9 February 2015).
Publishing.
3 UK Medicines Information (UKMi) Q&A 168.5: What Factors Need to be Con-
sidered When Dosing Patients on Renal Replacement Therapies? Date prepared:
January 2013. http://www.ukmi.nhs.uk/activities/specialistServices/default.asp?
pageRef=5 (accessed 14 May 2015).
k
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396 Renal replacement therapy: haemofiltration
Renal replacement therapy:

haemofiltration
Overview
Setting Haemofiltration (HF) is used in the management of severe acute kidney
injury in patients who are haemodynamically unstable, e.g. patients with
multiple organ failure or shock or requiring vasopressors. For this reason
it is usually provided in the critical care setting. It can be either
continuous or intermittent depending on the stability of the patient,
although continuous is best for very unstable patients.
The main advantage of continuous HF over intermittent HD is the ability
to remove large volumes of fluid over a longer time period, minimising
the risk of hypotension
Vascular Most HF methods in use are veno-venous. A temporary double-lumen
access CVC is placed in the femoral, subclavian or internal jugular vein
Technology HF works through a combination of:
● Convection (movement of solutes in fluid across a semipermeable
membrane under pressure)
● Ultrafiltration (movement of fluid under pressure across a
semipermeable membrane)
The most common method used is continuous veno-venous
haemofiltration (CVVHF), where blood is removed from the patient via
R one lumen of a venous line and pumped through the dialysis circuit to a
semipermeable membrane (the filter).
k k
The filters used for HF contain thousands of hollow fibres made of a semi-
permeable membrane that are very permeable to fluids and solutes (high
flux).
Unlike in HD, dialysate is not used. Instead, a positive hydrostatic
pressure created on the blood side of the filter drives water and solutes
across the filter membrane into the filtrate compartment. Molecules that
are small enough to pass through the membrane (<30 kDa) are dragged
across the membrane with the water by the process of convection. The
ultrafiltration rate (fluid removal) is controlled by pump speed.
The filtrate is discarded and an isotonic replacement fluid (haemofiltra-
tion fluid) is added to the blood to replace fluid volume and electrolytes.
Different haemofiltration fluid compositions are used depending on the
patient’s requirements and can either be added before the filter (pre-
dilution) or after (postdilution). The postdilution method is most common
and allows a more accurate fluid balance, but has problems with clotting
if the blood becomes too concentrated at the filter. The blood is then
returned to the patient via the second lumen of the venous line.
Advantages of continuous HF over intermittent HD include:
● Ability to remove larger volume of fluid (up to 3–6 L/day), as it is
carried out over a longer time interval
● Better control of blood pressure and reduced hypotension
● Better control of fluid balance and reduced hypovolaemia
● Slower fluid shifts and a more gradual change in electrolytes
Disadvantages include:
● Cost
● Increased complexity and staff training
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Renal replacement therapy: haemofiltration 397
Anti- Methods of anticoagulation on HF include:

coagulation ● a prefilter infusion of unfractionated heparin (easily reversed by
protamine if needed). Activated partial thromboplastin time (APTT)
monitoring is required
● infusion of prostaglandins (e.g. epoprostenol)
● prefilter infusion of citrate
Common CVC-related infection and thrombosis, haemodynamic instability, blood
complica- loss, electrolyte imbalances, hypothermia, effects of anticoagulation
tions (bleeding or specific side effects of the anticoagulant used, e.g.
heparin-induced thrombocytopenia)

Drug dosing Equations for assessment of eGFR/CrCl cannot be used in HF patients.
on HF Continuous HF generally gives better drug clearance than intermittent
HD. During CVVHF drugs are usually dosed for a CrCl of 10–20 mL/min
unless other information is available.1,2
Because HF uses convection rather than diffusion, it has a higher rate of
removal of larger molecules (up to 30 kDa) compared to HD,3 as larger
molecules have a slower diffusion rate. Therefore, drugs such as
vancomycin (molecular weight 1449 Da) have higher clearance on HF
than HD.
Drug removal by HF is hard to quantify, but is influenced by:3
● permeability of filter membrane
● system pressure (pump speed)
As HF is a continuous process, timing of medication administration in
R
k relation to dialysis is not crucial. k
It is important to know whether HF is currently being performed or has
stopped (i.e. due to clotting, or because renal function is improving) and
consider the effect this will have on drug clearance
HF anti- Use of anticoagulation for HF should be avoided in:
coagulation ● coagulopathy
● raised international normalised ratio or APTT
● thrombocytopenia
● high risk of bleeding
● new contraindications to anticoagulation (i.e. recent stroke)
Caution in patients prescribed anticoagulants for other indications, i.e.
warfarin, fondaparinux.
Patients may develop heparin-induced thrombocytopenia requiring use of
different anticoagulants
Fluid Fluid restriction in CVVHF is less of an issue than in intermittent HD, as
restriction fluid removal is continuous and larger volumes can be removed
REFERENCES
1 eMC (2014). www.emc.medicines.org.uk (accessed 26 April 2015).
Publishing.
3 UK Medicines Information (UKMi) Q&A 168.5: What Factors Need to be Considered
When Dosing Patients on Renal Replacement Therapies? Date prepared: January
2013. http://www.ukmi.nhs.uk/activities/specialistServices/default.asp?pageRef=5
k
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398 Renal replacement therapy: peritoneal dialysis
Renal replacement therapy:

peritoneal dialysis
Overview
Setting Peritoneal dialysis (PD) is not as aggressive as haemodialysis (HD) and is
performed at home, allowing patients greater flexibility. It is useful for
patients likely to have vascular access problems (e.g. diabetics) and
people with unstable cardiovascular disease.
PD requires greater patient involvement than HD, and motivation and
home circumstances are important when deciding on patient suitability
Access Requires intraperitoneal access via a soft flexible catheter (Tenckhoff
catheter), inserted surgically into the peritoneum.
PD catheters have a cuff that promotes fibrous tissue development to
secure the catheter and reduce the risk of infection.
The catheter cannot be used for 2 weeks after insertion to allow healing
and reduce the risk of leakage and infection
Technology PD uses the patient’s peritoneal membrane as a semipermeable
membrane, and works through a combination of:
● diffusion
● osmosis (movement of water from a less concentrated solution to a
more concentrated solution through a semipermeable membrane)
● convection (movement of solutes in fluid across a semipermeable
R membrane under pressure).
k Most dialysates use glucose as the osmotic agent and come in three
strengths, weak, medium and strong, with strong solutions providing
k
more fluid removal.
The dialysate also contains solutes such as sodium, potassium, calcium
and magnesium.
Diffusion and convection of solutes occur between capillary blood and
the dialysate, and fluid is removed from blood by osmosis.
There are two types of PD:
Continuous ambulatory peritoneal dialysis (CAPD)
● Most commonly used.
● Dialysate is warmed to body temperature and instilled into the
peritoneal cavity via the catheter by gravity (∼10 minutes).
● Volume of dialysate depends on body size, but is usually 2–3 litres.
● Dialysate remains in peritoneum for ∼4 hours (‘dwell time’), after
which the patient connects the catheter to an empty bag and the
dialysate is drained out (∼10–20 minutes).
● This ‘exchange’ process is repeated up to 4–5 times per day.
● A dwell time of 8–12 hours is used overnight.
Automated peritoneal dialysis (APD)
● Follows the same principles as CAPD, except that ∼6 exchanges of
1.5–3 litres dialysate are performed overnight by a machine and a
12–15-hour dwell time is used in the daytime
● Patients have more freedom during the day, but the machine inhibits
night-time mobility.
k
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Renal replacement therapy: peritoneal dialysis 399
Maintaining sterile technique is critical to prevent infection.

Ways to enhance PD adequacy include:
● increasing bag volumes for CAPD
● increasing frequency of exchanges for CAPD
● increasing the strength of the bag
● increasing dwell time
Common ● Peritonitis and catheter exit-site infection. Symptoms and signs of
complica- peritonitis include abdominal pain, cloudy peritoneal fluid, fever,
tions nausea and tenderness to palpation. Intraperitoneal administration of
antibiotics is often utilised in the treatment of PD peritonitis.
Repeated peritonitis episodes can cause dialysis failure due to
fibrosis of the peritoneal membrane and formation of adhesions.
● Catheter flow or drainage problems, often due to constipation, also
caused by catheter misplacement, migration or kinking or fibrin
deposition.
● Dialysate leakage, hyperglycaemia (due to glucose in dialysate),
hernias

Drug dosing Equations for assessment of estimated glomerular filtration
on PD rate/creatinine clearance (CrCl) cannot be used in PD patients.
In general, PD provides minimal drug removal and drugs are usually
dosed for a CrCl of <10 mL/min unless other information is available.1,2
Drugs that are small, unbound, uncharged and with a small volume of
distribution may have some clearance on PD. R
k Drug removal by PD is influenced by:3 k
● dialysate volume
● dialysate to plasma osmotic gradient
● dwell time
● peritoneal perfusion
● membrane porosity.
Drug clearance is enhanced in patients receiving APD compared to CAPD,
and also in those with residual urine output compared to anuric patients.
As PD is a continuous process, timing of medication administration in
relation to dialysis is not crucial.
With PD peritonitis, when an antibiotic that is strongly protein-bound
(e.g. teicoplanin) is given intravenously, the amount reaching the
peritoneum is low because only unbound drug can be transported into
the dialysate. In this situation, administration by the intraperitoneal route
is preferred over the intravenous route
Constipation Constipation can cause catheter flow or drainage problems, and all PD
patients should be prescribed regular laxatives. Consider increasing
laxatives if constipating medications are prescribed
Fluid Tends to be less strict than on HD as PD patients usually still pass some
restriction urine and dialysis is continuous. However, it is still important to consider
the impact of oral medications needing to be swallowed with fluid and
volumes of intravenous medications if the patient has poor residual urine
output
k
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400 Rheumatoid arthritis: DMARDs
REFERENCES
1 Electronic Medicines Compendium (2014). www.emc.medicines.org.uk (accessed
14 October 2014).
Publishing.
3 UK Medicines Information (UKMi) Q&A 168.5: What Factors Need to be Considered
When Dosing Patients on Renal Replacement Therapies? https://www.evidence.nhs.
uk/Search?q=What+factors+need+to+be+considered+when+dosing+patients+
on+renal+replacement+therapies%22 (accessed 15 May 2015).
Rheumatoid arthritis: drugs suppressing

the disease process
Traditionally these drugs have been used following NSAID and steroid
treatment. Increasingly they are being introduced much earlier in the
disease process to prevent irreversible damage despite the potential
for adverse effects.
They can be divided into two categories:
1 disease-modifying antirheumatic drugs (DMARDs)
2 cytokine inhibitors, mainly comprising tumour necrosis factor α
antagonists (anti-TNFs), which are sometimes called ‘biologics’.
All require baseline measurements to be taken prior to
R commencement, and routine monitoring of various parameters to
k ensure safe and efficacious use. Disease progression and efficacy of k
therapy are monitored, typically monthly, by measurement of
C-reactive protein and erythrocyte sedimentation rate, amongst
others. Any beneficial effect of DMARDs is not usually seen for several
months after initiation, whereas anti-TNFs can produce beneficial
effects after just a few doses.
It should be noted that many patients suffering from rheumatoid
arthritis may have reduced manual dexterity. Assessment of their
needs regarding packaging and labelling should be carried out. It may
be necessary for them to use larger containers or have easy-to-open
lids that aid compliance and discourage the patient from decanting
doses into inappropriate containers at home.
The following summarises key information for the common drugs,
including dose, common side effects, monitoring requirements and
pharmaceutical care issues to facilitate counselling.
Disease-modifying antirheumatic drugs (Tables R4–R11)

Azathioprine pharmaceutical care considerations
● Warn patient to tell doctor immediately if persistent fever, sore
throat, bruising, bleeding or other signs of myelosuppression occur.
● Live vaccines should be avoided in patients taking azathioprine.
Pneumococcal vaccine and an annual influenza vaccine should be
given. Varicella-zoster immunoglobulin should be considered for
passive immunisation in non-immune patients if exposed to
chickenpox or shingles.1
k
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Rheumatoid arthritis: DMARDs 401
TABLE R4
Azathioprine1,2
Dose ● 1 mg/kg daily, increasing after 4–6 weeks to
2–3 mg/kg daily. Use lower doses if there is significant
renal or hepatic impairment. If allopurinol is
coprescribed, the dose of azathioprine must be
reduced by 75%
Examples of possible ● Nausea, flu-like symptoms, hepatitis, cholestatic
side effects jaundice, bone marrow suppression, leucopenia,
increased susceptibility to infections
Baseline monitoring ● FBC (including platelets), LFTs, U&Es (including serum
creatinine)
Routine monitoring ● FBC (including platelets) and LFTs once a week for 6
weeks, then every fortnight until the dose stabilises for
6 weeks, then once a month thereafter.
● After each dose, change FBC: LFTs should be repeated
after 2 weeks.
● U&Es (including serum creatinine) should be monitored
every 6 months
Pharmaceutical care ● Warn patient to tell doctor immediately if persistent
considerations fever, sore throat, bruising, bleeding or other signs of
myelosuppression occur.
● Live vaccines should be avoided in patients taking
azathioprine. Pneumococcal vaccine and an annual
influenza vaccine should be given. Varicella-zoster R
immunoglobulin should be considered for passive
k immunisation in non-immune patients if exposed to k
chickenpox or shingles.1
● Patients should be warned to avoid excessive exposure
to the sun and ultraviolet rays due to possible
increased risk of skin cancer. Patients should have their
skin examined at regular intervals.2
● To help avoid problems with GI disturbances patients
can be advised to take azathioprine in divided doses or
with meals2
TABLE R5
Ciclosporin1,2
Dose ● 2.5 mg/kg daily in two divided doses. The dose is increased after 6
weeks in 25 mg increments (to a maximum of 4 mg/kg/day) every
2–4 weeks if necessary until clinically effective
Examples of ● Hirsutism, gingival hyperplasia, hypertension, renal impairment
possible
side effects
Baseline ● FBC, LFTs, lipids, U&Es (including serum creatinine) and blood
monitoring pressure. These should be measured on two separate occasions prior
to commencement
(Continued )
k
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TABLE R5
(Continued)
Routine ● U&Es (including serum creatinine) should be measured fortnightly
monitoring until the dose has been stable for 3 months, then monthly thereafter.
FBC and LFTs should be measured monthly until the dose has been
stable for 3 months, then 3-monthly thereafter.
● Serum lipid profile is measured every 6 months.
● Blood pressure should be measured every time the patient attends
the monitoring clinic
Pharmaceutical ● The total daily dose should be taken in two divided doses. Grapefruit
care consid- or grapefruit juice should be avoided (bioavailability may be
erations increased by up to 45%).
● To improve the taste of the solution form, it can be mixed with orange
juice (or squash), apple juice or water immediately before taking (and
the container rinsed with more to ensure the total dose is taken). The
medicine measure provided with the solution must be kept away from
other liquids (including water). After use, the outside of the measure
should be wiped with a dry tissue only.2
● Ciclosporin is contraindicated in patients with abnormal renal
function or uncontrolled hypertension. NSAIDs should be used with
caution if concomitantly prescribed, and in particular the dose of
diclofenac should be halved if given with ciclosporin.1
● Live vaccines should be avoided. The annual influenza vaccine should
be given.1,2
Prescribing of ciclosporin should always be brand-specific due to
R
●
possible differences in bioavailability

k k
TABLE R6
Gold, intramuscular (sodium aurothiomalate)1 – 3
Dose ● Before commencing therapy a 10-mg test dose must be
given, and the patient observed for 30 minutes for signs of
allergy. If no adverse effects are observed a dose of 50 mg
weekly is given until a significant response is seen.
● Thereafter the dose can be reduced to 50 mg fortnightly
until full remission occurs, when the dosing interval can be
slowly increased to 6-weekly.
● If, after a total dose of 1 g has been administered, no
response has occurred, then treatment should be stopped3
Examples of ● Rashes, pruritus, anaphylaxis, bone marrow suppression,
possible side proteinuria
effects
(Continued )
k
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TABLE R6
(Continued)
Baseline ● FBC, urinalysis, U&Es (including serum creatinine), LFTs
monitoring
Routine monitoring ● FBC and urinalysis (for proteinuria) at each injection. The
result of the previous FBC should be reviewed before giving
the next injection. The patient’s skin should be inspected for
rashes before each injection
Pharmaceutical ● Warn patients to tell their doctor immediately if any of the
care considerations following develops: sore throat, fever, infection,
unexplained bleeding and bruising, mouth ulcers, metallic
taste, rashes, menorrhagia, diarrhoea, breathlessness or
cough.2,3
● Live vaccines should be avoided1
TABLE R7
Hydroxychloroquine2,3
Dose ● Initially 200 mg twice a day, then maintenance of
200–400 mg daily (maximum dose is 6.5 mg/kg ideal
body weight daily, and not more than 400 mg daily)
Examples of possible ● GI disturbances, headache, rashes, pruritus, visual
disturbances, hypoglycaemia
side effects R
Baseline monitoring Assessment of eye sight (see BNF: antimalarials 10.1.3
k k
●
for full guidance)3

● LFTs, U&Es, FBC
Routine monitoring ● FBC periodically
● Assessment of eye sight annually
Pharmaceutical care ● Warn patient to report any visual disturbances.
considerations ● Avoid antacids for 4 hours before or after a dose.3
● Patients need to be counselled to recognise the possible
symptoms of hypoglycaemia and what action to take if
symptoms occur2
TABLE R8
Leflunomide1 – 3
Dose ● A loading dose of 100 mg daily for 3 days is given, then
10–20 mg daily. In practice, some rheumatologists do not give
a loading dose
Examples of ● GI disturbances, alopecia, weight loss, liver abnormalities,
possible side hypertension, bone marrow suppression, headache, dizziness,
effects dry skin, tenosynovitis, rash, mouth ulcers, pruritus
(Continued )
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TABLE R8
(Continued)
Baseline ● FBC, LFTs, U&Es, weight and blood pressure
monitoring
Routine monitoring ● FBC and LFTs fortnightly for the first 6 months, then every 8
weeks. Weight and blood pressure should be assessed every
time the patient attends monitoring clinic
Pharmaceutical ● The recommendation of leflunomide SPC is that it should not
care considerations be used in conjunction with other DMARDs in routine clinical
practice. Leflunomide may inhibit the metabolism of warfarin,
phenytoin and tolbutamide. It has an extremely long
elimination half-life and interactions with these drugs and
with other DMARDs may occur even after leflunomide has
been discontinued.2
● For both women and men, effective contraception should be
exercised throughout treatment and for women a 2-year
period should elapse following cessation of leflunomide
before a planned conception (3 months for men). Blood
concentrations of its active metabolite should be measured
after the discontinuation period before pregnancy occurs.
Alternatively the leflunomide washout procedure may be
considered (see below), followed by active metabolite
monitoring.1
● If alanine transaminase (ALT) level is raised between two and
three times the upper limit of normal (ULN), the dose should
R
be reduced from 20 mg to 10 mg and LFTs must be monitored
k weekly. If the ALT level remains raised at more than twice the k
ULN, or if a level more than three times the ULN occurs,
leflunomide must be stopped and washout procedures
initiated. The washout procedure should also be initiated if
any severe undesirable side effect of leflunomide occurs or if
for any other reason rapid removal of its active metabolite is
required.2
● Leflunomide increases susceptibility to infections, which
should be treated promptly. Live vaccines are
contraindicated.1
● Leflunomide is supplied in a plastic bottle with a desiccant in
the lid, and should be supplied to the patient in its original
container.
Leflunomide washout procedure

Washout is achieved by administering cholestyramine 8 g three
times daily for 11 days. Alternatively, 50 g of activated powdered
charcoal may be given four times daily for 11 days. Monitoring of
liver enzymes must be maintained after discontinuation until liver
enzyme levels have normalised.3
It should be noted that the washout procedure is likely to
affect the absorption of concurrent drug therapy adversely
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TABLE R9
Methotrexate1
Dose ● The usual starting dose is 5–10 mg as a single weekly
dose; this is increased by 2.5–5 mg every 2–6 weeks as
tolerated until the disease stabilises (up to a usual
maximum of 25 mg). Lower doses should be used in the
frail elderly or if there is significant renal impairment.
● Regular folic acid supplements are thought to reduce
some side effects. The usual dose of folic acid is 5 mg
weekly, often taken the day after the methotrexate,
although this varies with local practice.
Check your local policy . . . . . . . . . . . . . . . . . . . . . . .
Methotrexate is sometimes given subcutaneously or
intramuscularly if the oral route is not available, if a patient
develops GI side effects or if poor absorption is suspected.
The dose is usually the same as that given orally, although
bioavailability is slightly higher
Examples of possible ● See notes below regarding the patient monitoring
side effects booklet
Baseline monitoring ● FBC, U&Es, LFTs and a chest X-ray
Routine monitoring ● U&Es, FBC and LFTs fortnightly until 6 weeks after the
last dose increase. Providing the measurements are
stable, they can be performed monthly thereafter
Pharmaceutical care If methotrexate is prescribed with NSAIDs or aspirin, the
considerations dose may require careful monitoring as excretion may be R
reduced; local practice may vary as some rheumatologists do
k not think the interaction is significant. Patients should be k
advised to avoid self-medicating with over-the-counter
aspirin or NSAID therapies.3
In July 2004, the National Patient Safety Agency issued a
safety alert regarding methotrexate.4 It was prompted by
several safety incidents in which patients died or came to
serious harm. The alert concerned agreeing local risk
reduction strategies: providing a pretreatment leaflet and a
patient handheld monitoring and dosage book; ensuring
prescribing and dispensing software were updated to include
methotrexate alerts and prompts; and a review of
purchasing to ensure the 2.5 mg and 10 mg tablets are of a
visually distinguishable shape. Some hospitals only use the
2.5 mg strength.5
The locally produced patient monitoring booklet will vary in
presentation and content from hospital to hospital, and it is
worth familiarising yourself with your local version, but there
will be a core content that remains constant. The key points
that can be used to aid patient counselling are listed below.
● The importance of taking methotrexate on the same day
each week should be emphasised and this day should be
recorded in the booklet. If the dose is missed, it can be
taken on one of the two following days, but must not be
taken if more than 3 days have elapsed. In either case,
the next dose should be taken on the patient’s usual day.
(Continued )
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TABLE R9
(Continued)
● Patients should speak to their doctor if they have:
● any infections, including fever, chills or a sore throat
● an unexplained skin rash, ulcerations or soreness of
skin
● yellowing of the skin/eyes or generalised itching
● bleeding gums, black tarry stools or unexplained
bleeding or bruising
● chest pain, difficulty breathing or a dry, persistent
cough
● sore mouth or mouth ulcers
● severe and continuous diarrhoea, vomiting or
stomach pains.
● If they come into contact with someone with
chickenpox or shingles and they have not had the
illness themselves they may need special treatment.
● Excess alcohol should be avoided, although an occasional
drink may not be expected to cause significant side
effects, e.g. well within the national daily limits.
● Read food labels carefully, as foods made from
unpasteurised milk, e.g. soft cheese, and uncooked
meats, e.g. pâté, may be a source of bacteria, which
could increase the risk of infection.
● Methotrexate can reduce fertility in men and women. It is
R teratogenic and must be avoided in pregnancy and
breastfeeding. For both women and men effective
k contraception should be exercised throughout treatment k
and at least a 3-month period should elapse following
cessation of methotrexate before a planned conception.
● Live vaccines should be avoided but the annual influenza
vaccination and the pneumococcal vaccine should be
given.
● Co-trimoxazole and trimethoprim should not be given
concomitantly as serious side effects and fatalities have
occurred.
Calcium folinate is a specific antidote for methotrexate and
following accidental overdose (see Methotrexate: calcium
folinate rescue regimen entry).
TABLE R10
Penicillamine1,2,3
Dose ● 125–250 mg daily, increasing by 125 mg every 4 weeks to
500 mg daily in divided doses. If no response has occurred
after a further 3 months, a dose increase to 750 mg daily
could be considered (although a dose of 1.5 g daily is
licensed). For patients with renal impairment, therapy
should be initiated at a low dose, with intervals between
each dose increase of at least 12 weeks
Examples of ● Rashes, urticaria, fever, taste disturbance, nausea,
possible side proteinuria, bone marrow suppression
effects
(Continued )
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TABLE R10
(Continued)
Baseline ● FBC, U&Es (including serum creatinine) and urinalysis (for
monitoring proteinuria and haematuria)
Routine monitoring ● FBC and urinalysis fortnightly until the dose has been stable
for 3 months, then monthly for both thereafter. Patients
should be asked about the presence of rash or oral
ulceration every time they attend the monitoring clinic
Pharmaceutical ● Penicillamine should be taken on an empty stomach at least
care considerations half an hour before meals or at bedtime.2
● Warn patients to tell their doctor immediately if a sore
throat, fever, unexplained bleeding or bruising, purpura,
mouth ulcers, metallic taste or rashes develop.3
● Penicillamine should be used with caution in patients who
have had adverse reactions to gold. Concomitant treatment
with gold should be avoided.2
● If oral iron, digoxin or antacid therapy is coprescribed, a
2-hour administration gap should be left.2
● NSAIDs and other nephrotoxic drugs may increase the risk
of renal damage.2
● Although cross-reactivity is rare, a patient who is allergic to
penicillin may also react to penacillamine2
TABLE R11 R
k Sulfasalazine1 – 3 k
Dose ● Initially 500 mg daily, increasing by 500 mg at weekly
intervals to 2–3 g daily in three to four divided doses
Examples of ● Nausea, headache, rash, loss of appetite, insomnia,
possible side stomatitis, hepatitis, bone marrow suppression
effects
Baseline ● FBC, U&Es and LFTs
monitoring
Routine monitoring ● FBC and LFTs every 4 weeks for the first 12 weeks, then
12-weekly thereafter. If, during the first year of treatment,
blood results have been stable, 6-monthly tests will suffice
for the second year and thereafter monitoring of blood for
toxicity could be discontinued. After a dose change, FBC
and LFTs should be repeated after 4 weeks.
● Patients should be asked about the presence of rash or oral
ulceration at each clinic appointment.
● U&Es, including urinalysis, should be monitored 4-weekly
for 12 weeks
Pharmaceutical ● Warn patients to tell their doctor immediately if persistent
care considerations fever, sore throat, unexplained bruising or bleeding occurs.
● Urine and tears may be discoloured orange and contact
lenses may be stained.3
● Macrocytosis or pancytopenia due to folic acid deficiency
can be reversed by administration of a folic acid
supplement2
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Cytokine inhibitors
The NICE guidelines set out eligibility criteria for treatment with
anti-TNFs; to comply, the patient must:5
1 have active rheumatoid arthritis determined by a disease activity
score (DAS28) measured at two points 1 month apart, recording a
score >5.1 to confirm ongoing active disease.
2 have trialled at least two standard DMARD therapies (one of which
must be methotrexate, unless contraindicated). Trials should have
lasted at least 6 months, with 2 months at the recommended
maintenance dose, unless toxicity or intolerance required the
treatment to be withdrawn or the dose to be limited.
NICE may recommend that additional requirements are met
dependant on the drug of choice.
There may be circumstances when other DMARDs are relatively
contraindicated, so anti-TNF therapy may be considered very early in
the course of the disease and in patients in whom methotrexate has
not been used.
Safety of the anti-TNF therapies is unknown or has not been
established in pregnancy or lactation and it is recommended that:
● pregnancy should be avoided whilst on cytokine inhibitors and

effective contraception is strongly recommended to prevent
R
pregnancy in women of childbearing potential (both sexes should
k have a washout period before a planned conception) k
● the decision to breastfeed should take into consideration the
individual circumstances and drug
● consideration should be given to stopping anti-TNF therapy if a
patient becomes pregnant whilst on treatment.6
All patients should be screened for tuberculosis prior to initiating
treatment and monitored for mycobacterial infection during
treatment and for 6 months after stopping.6
Live vaccines should not be given. It is recommended that juvenile
chronic arthritis patients are brought up to date with all
immunisations if possible, in agreement with current immunisation
guidelines, before starting therapy.
As this is an ever-developing area of treatment, please refer to the
latest NICE guidance for current recommendations. Tables R12 –R14
refer to three of the first-line anti-TNFs.
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TABLE R12
Adalimumab2,3
Dose ● 40 mg every other week by subcutaneous injection in
combination with methotrexate (in monotherapy, the
frequency may be increased to weekly depending on
response)
Examples of ● Injection site pain, respiratory, urinary tract and other
possible side infections, headache, dizziness, GI disturbances, rash,
effects pruritus, hyperlipidaemia, worsening heart failure
Baseline ● Assess for infections or risk factors for infections, especially
monitoring tuberculosis
● Hepatitis B virus should be tested for in patients with risk
factors
● FBC
Routine monitoring ● Observe for injection site reactions. FBC monitoring
Pharmaceutical ● Patients should tell their doctor immediately if the following
care considerations occur: persistent fever, sore throat, weight loss, bruising or
bleeding, as these symptoms can be suggestive of blood
disorders.3
● Patients should also be aware to monitor for symptoms of
tuberculosis, such as persistent cough, fever or weight loss,
and to report these immediately to their doctor.3
● Patients should carry the relevant alert card provided on
initiation of treatment2
R
k k
TABLE R13
Etanercept2,3
Dose ● 25 mg twice weekly, or 50 mg weekly by subcutaneous
injection; it may be given in combination with methotrexate
or as monotherapy if methotrexate is contraindicated or not
tolerated
Examples of ● Injection site reactions, respiratory and other infections,
possible side fever, pruritus, worsening heart failure
effects
Baseline ● Assess for infections or risk factors for infections
monitoring ● Patients should be screened for hepatitis B virus
● FBC
Routine monitoring ● Observe for injection site reactions. FBC monitoring
disorders.3
● Patients should be provided with the appropriate patient
alert card
k
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TABLE R14
Infliximab2,3
Dose ● 3 mg/kg as an intravenous infusion at weeks 0, 2, and 6 and
then every 8 weeks thereafter. If the response is inadequate
after 12 weeks, refer to product literature for advice on how
the dose may be increased.
● Infliximab must be given in combination with methotrexate
when used for rheumatoid arthritis
Examples of ● Injection site reactions, respiratory and other infections, fever,
possible side pruritus, rash, headache, vertigo, flushing, GI disturbances,
effects fatigue, tachycardia and worsening heart failure
Baseline ● Assess for infections or risk factors for infections, especially
monitoring tuberculosis
● Patients should be screened for hepatitis B virus
● FBC
Routine monitoring ● Observe for injection site reactions, including anaphylaxis
(observe patient for 2 hours after infusion). FBC monitoring
disorders.3
The dose is given as an infusion, which must be prepared in an
R ●
aseptic suite. An infusion set should be used with an in-line,

k sterile, non-pyrogenic, low protein-binding filter (pore size 1.2 k
microns or less).2
● Patients should be provided with the patient information
leaflet and alert card
REFERENCES
1 BSR/BHPR (2008). BSR/BHPR guideline for disease modifying anti-rheumatic drug
(DMARD) therapy in consultation with the British association of Dermatologists.
http://www.rhuematology.org.uk (accessed 23 August 2014).
2 Electronic Medicines Compendium (2014). http://www.medicines.org.uk/emc/
4 NPSA (2006). Improving Compliance with Oral Methotrexate Guidelines.
http://www.nrls.npsa.nhs.uk/ (accessed 23 August 2014).
5 NICE (2009). Rheumatoid Arthritis – The Management of rheumatoid arthritis in
adults. CG79. https://www.nice.org.uk/guidance/cg79 (accessed 5 January 2015).
6 BSR/BHPR (2010). BSR and BHPR Rheumatoid Arthritis Guidelines on Safety of
Anti-TNF Therapies. http:// www.rheumatology.org.uk (accessed 23 August 2014).
k
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Rockall score for gastrointestinal bleed 411
Rockall score for gastrointestinal bleed

Overview
Background ● Designed to predict death based on clinical and endoscopic findings1

● Also used to predict rebleeding risk
SCORING SYSTEM1
Age <60 years 0
Age 60–79 years 1
Age ≥80 years 2
Shock: ‘no shock’, systolic blood pressure (SBP) ≥100 mmHg, pulse <100 0
beats/min
Shock: ‘tachycardia’, SBP ≥100 mmHg, pulse ≥100 beats/min 1
Shock: ‘hypotension’, SBP <100 mmHg 2
Comorbidity: no major comorbidity 0
Comorbidity: cardiac failure, ischaemic heart disease, any major comorbidity 2
Comorbidity: renal failure, liver failure, disseminated malignancy 3
Diagnosis: Mallory–Weiss tear, no lesion identified and no stigmata of recent 0
haemorrhage
Diagnosis: all other diagnoses 1
Diagnosis: malignancy of upper GI tract 2 R
k Major stigmata of recent haemorrhage: none, or dark spot only 0
k
Major stigmata of recent haemorrhage: blood in upper GI tract, adherent clot, 2
visible or spurting vessel
Interpretation1,2
Initial pre-endoscopic score (derived from age, score, comorbidity):
● 0: a score of 0 identifies 15% of patients with an acute upper GI bleed at presentation
who have an extremely low risk of death (0.2%) and rebleeding (0.2%), and who may
be suitable for early discharge or non-admission
● If the initial (pre-endoscopic) score is above 0, there is a significant mortality and
endoscopy is recommended for full assessment of bleeding risk:
● 1: predicted mortality 2.4%
● 2: predicted mortality 5.6%
The full Rockall score comprises the initial score plus additional points for endoscopic
diagnosis:
<3: low risk of rebleeding or death and should be considered for early discharge and
outpatient follow-up.
>8: high risk of mortality
REFERENCES
1 SIGN (2008). Management of Acute Upper and Lower Gastrointestinal Bleeding. NHS
Scotland: SIGN. http://www.sign.ac.uk/pdf/sign105.pdf (accessed 31 July 2014).
2 NICE (2012). Acute Upper Gastrointestinal Bleeding. National Clinical Guideline
centre: NICE. http://www.nice.org.uk/guidance/cg141/resources/cg141-acute-
upper-gi-bleeding-full-guideline2 (accessed 31 July 2014).
k
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412 Sarcoidosis
S
Sarcoidosis
Overview
Definition Sarcoidosis is a condition caused by granulomatous inflammation and can
affect virtually any organ.1 The most commonly affected organs are the
lungs (≈80% of patients), the lymph nodes, the eyes and the skin.
Granulomas are seen in a number of other conditions and are a collection
of immune cells usually formed in response to the presence of an antigen.
Sarcoidosis may resolve spontaneously, probably representing clearance
of the antigen. In some patients, treatment may be required to bring
about resolution or to reduce the damage caused by local inflammation,
which may otherwise progress to fibrosis.
k S It is likely that a range of antigens may result in sarcoidosis and it is not k
thought to result from either an infectious or autoimmune process. The
pattern of disease and its natural history are thought to represent
interplay between: the precipitating antigen, human leukocyte antigen
(HLA) class II molecules and T-cell receptors
Risk factors Sarcoidosis predominantly affects people between the ages of 25 and
40 years. There is a slightly higher incidence in women (male to female
ratio of 1:1.2).
Sarcoidosis is more common in Afro-Caribbeans and in this population
more likely to follow a chronic course (the incidence is ≈3-fold higher and
prevalence ≈10-fold higher).
Sarcoidosis has been known to develop during treatment with antitumour
necrosis factor (anti-TNF) agents or following chemotherapy
Differential Given the range of organs affected there is considerable scope for initial
diagnosis misdiagnosis.
Non-specific constitutional symptoms, such as fever, fatigue (which may
be very severe), malaise and weight loss, may also be present.
Granulomas are seen in a number of conditions, including tuberculosis,
berylliosis, cat-scratch disease (caused by Bartonella henselae), vasculitis
and hypersensitivity pneumonitis.
Pulmonary sarcoidosis may present with bilateral hilar lymphadenopathy
(where lymphoma is an important differential), patch infiltrates or
pulmonary fibrosis (where interstitial lung disease is an important
differential)
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Sarcoidosis 413
Diagnostic ● The presence of granulomas in a biopsy sample of affected tissue, with

tests the exclusion of other causes of granulomatous inflammation, is
desired for diagnosis. Biopsy may not be required if the presentation is
peculiar to sarcoidosis, where obtaining the sample would represent
an undue risk or where there is sufficient radiological and clinical
evidence to support a diagnosis of sarcoidosis confidently.
● Serum angiotensin-converting enzyme (sACE) may be elevated in
≈60% of patients. An elevated level is supportive of a diagnosis but is
neither sensitive nor specific. sACE levels do not reflect disease activity
and are of limited value in monitoring progression.
● Serum immunoglobulin G (IgG) may be elevated in ≈50% of patients.
Decreased IgG concentration is uncommon and suggests an
alternative diagnosis.
● Lymphopenia due to relocation of circulating lymphocytes to the site of
active disease may occur.
● Granulomas can produce 1-α hydroxylase, catalysing the conversion of
ergocalcitriol to calcitriol and precipitating hypercalcaemia and/or
hypercalciuria. Increased urinary calcium concentrations may result in
renal stones and renal dysfunction. Ergocalciferol (vitamin D2 )
concentration may be low despite elevated calcitriol (vitamin D3 )
levels. Assays routinely only measure ergocalciferol levels and should
be interpreted cautiously.
● Pulmonary involvement most commonly presents with a restrictive
pattern of spirometry but obstructive patterns may also be seen.
Interstitial inflammation or fibrosis will impair gas transfer, with a
reduced diffusing capacity of the lung for carbon monoxide (DLCO) or
transfer factor for carbon monoxide (TLCO, which provides an estimate
k of the lung’s ability to diffuse gases). S k
● Staging based on the appearance of the chest X-ray has been
proposed (Scadding stage)
Treatment ● Sarcoidosis may resolve spontaneously in some patients and watchful
goals waiting may be appropriate. If the likelihood of spontaneous
resolution is low or the risk of organ damage high (for example,
sarcoidosis involving the central nervous system, eyes or heart) then
immunosuppressive treatment may hasten resolution. In some
patients, sarcoidosis will not resolve despite treatment and in these
patients ongoing immunosuppression is required to reduce the rate of
progression.
● Chronic anterior uveitis may develop without significant symptoms
and may be sight-threatening. Routine eye examination is commonly
advised in patients suffering with sarcoidosis (recommendations
typically 6–12-monthly).
● Cardiac sarcoidosis is an uncommon complication but can be
life-threatening. Some specialists therefore recommend periodic ECGs
to identify the development of cardiac abnormalities during follow-up
Treatment ● There are no licensed therapies in sarcoidosis.
options2 ● Corticosteroids are the initial treatment in the majority, typically
starting at 20–40 mg prednisolone daily and tapering 1–3 months
after initiation to a maintenance dose of 10–20 mg daily. If resolving,
treatment will be continued for a period of 6–12 months and then
tapered to a stop. Intravenous methylprednisolone (500–1000 mg) is
sometimes used for short-course (3–5 days) induction.
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414 Sarcoidosis
● Topical corticosteroids (usually potent ones) may be appropriate for

some presentations.
● Higher doses of corticosteroids, i.e. 1 mg/kg prednisolone, or
initial dosing with 3–5 days’ intravenous methylprednisolone
(500–1000 mg) has been used in acutely unwell patients.
● In patients in whom a maintenance dose <10 mg prednisolone
cannot be achieved then azathioprine or methotrexate are
commonly used as steroid-sparing agents.
● Hydroxychloroquine may be useful in some patients but use is
generally limited to mild presentations.
● There is limited experience with other immunosuppressive agents,
such as leflunomide and mycophenolate mofetil.
● Some evidence supports the use of adalimumab or infliximab in
patients with chronic sarcoidosis (>2 years) and
treatment-refractory sarcoidosis3
Assess ● Is sarcoidosis an adverse reaction to current treatments (particularly
anti-TNF-α agents)?
● Which organs are affected and how will this affect monitoring of
response to, or adverse effects from, treatment?
Corticosteroids ● Relatively long courses with relatively high doses of corticosteroids
may be required. Patients should be advised not to stop therapy
abruptly and of potential side effects.
● Where osteoporosis prophylaxis is indicated, the potential to
precipitate or worsen hypercalcaemia or hypercalciuria should be
k S considered and calcium/vitamin D supplementation avoided in k
some patients or used cautiously in others
Methotrexate4 ● Methotrexate is the most commonly used steroid-sparing agent in
sarcoidosis, typically at doses of 5–20 mg weekly with folic acid
5 mg the following day or 1–5 mg every day apart from the day of
treatment to reduce the severity of side effects. It may take up to
6 months for treatment to demonstrate effectiveness and this
should be considered when assessing efficacy.
● Monitoring of FBC, LFTs and U&Es is consistent with its use in other
indications but potential sarcoidosis-related complications should
be considered when reviewing blood results, i.e. baseline
lymphocytosis reflecting disease activity and potential hepatic
dysfunction in hepatic sarcoidosis
Azathioprine ● Azathioprine is possibly as efficacious as methotrexate in
sarcoidosis and typically used in the range 50–200 mg daily.
● Myalgia, flu-like symptoms and pancreatitis may complicate
treatment.
● Azathioprine is metabolised by thiopurine S-methyltransferase and
high or low levels of activity may predispose to treatment failure or
toxicities, respectively. Pretreatment measurement of enzyme
activity may be useful.
● As with methotrexate, monitoring is consistent with its use in other
indications
k
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Management of malignant pleural effusions 415
Hydroxychloro- ● Gastrointestinal side effects are relatively common and may resolve
quine on dose reduction.
● Hydroxychloroquine may cause haemolytic anaemia in patients
deficient in glucose-6-phosphate-dehydrogenase (G6PD). G6PD
deficiency primarily affects those of African or Mediterranean
descent and pretreatment measurement of enzyme activity may be
useful.
● Ocular toxicity can occur and may be irreversible. The risk is higher
in patients with compromised renal or hepatic function and appears
to be related to cumulative dose, with a higher risk in those
receiving >6.5 mg/kg/day (hydroxychloroquine has a low volume
of distribution and lean body weight should be used if less than
actual) or treatment >5 years. Patients should be advised of the
need for a baseline eye examination and to seek advice if they
experience visual disturbances, especially changes in colour
vision, blurred vision, sensitivity to light or the presence of haloes
around lights.
● Hypoglycaemia may occur during treatment and patients should be
aware that feeling faint or fainting may be a symptom of this.
In diabetic patients antidiabetic therapies may need to be adjusted
in light of this
REFERENCES
1 Joint Statement of the ATS/ERS/WASOG (1999). Statement on sarcoidosis Am J
Respir Crit Care Med 160: 736–755.
2 Baughman RP et al. (2012). Therapy for sarcoidosis: evidence-based recommenda-
k tions. Exp Rev Clin Immunol 8: 95–103.
S k
3 Drent M et al. (2014). Practical eminence and experience-based recommenda-
tions for use of TNF-α inhibitors in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis
31: 91–107.
4 Cremers JP et al. (2013). Multinational evidence-based World Association of
Sarcoidosis and Other Granulomatous Disorders recommendations for the
use of methotrexate in sarcoidosis: integrating systematic literature research
and expert opinion of sarcoidologists worldwide. Curr Opin Pulm Med 19:
545–561.
Sclerosants for the management of

malignant pleural effusions
Pleurodesis is a treatment to eliminate the space between the tissues
in the chest cavity and the pleural membranes to prevent the build-up
of fluid. Chemical pleurodesis with a sclerosing agent (i.e. an agent
that promotes fibre formation between the pleural membranes) may
be used in the management of malignant pleural effusions.
Sterile talc is the chemical sclerosant of choice for pleurodesis.
Historically, other agents – bleomycin, doxycycline, tetracycline and
minocycline – have been used in the UK for intrapleural
administration. Sterile talc is available as an unlicensed product.
It has a success rate of approximately 90%.1
An intercostal tube is inserted and the pleural effusion is drained.
A chest radiograph is then performed to ensure complete lung
expansion and to confirm the position of the tube.
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416 Serotonin syndrome
Intrapleural administration of sclerosing agents may be painful.

A premedication, for example, an anxiolytic, should be administered
prior to commencing chemical pleurodesis. After the premedication
has been administered, lidocaine solution (3 mg/kg up to a maximum
of 250 mg) is instilled via the intercostal tube into the pleural space,
followed by the sterile talc. To prepare the talc slurry, 2 –5 g of
sterile talc is mixed with 40 mL of sterile water in a bladder syringe
and instilled. Sterile talc is also available as Steritalc PF Puffer
(see instructions below). The tube should then be clamped for 1 hour.
The patient will need to change position several times during the
procedure to allow dispersion of the talc. After 1 hour, the clamp is
released and the fluid is drained off. Common side effects include
chest pain and fever. Rare side effects (<1%) include acute
respiratory failure.
In practice, some clinicians advise that non-steroidal
anti-inflammatory drugs, cyclooxygenase-2 inhibitors and
corticosteroids should not be administered to patients for 48 hours
before and for up to 5 days after the procedure because of a possible
reduction in the inflammatory reaction of the pleura to the sclerosant.
If using Steritalc PF Puffer, which is a medical device containing
4 g sterile talc, it can be administered directly into the pleural cavity
as follows:
1 Fix the silicone connector (included) on the internal nozzle of the
puffer.
k S 2 Screw the male Luer lock connector to its maximum on the cannula k
while holding it firmly.
3 Hold the cannula and the puffer together and press smoothly
several times on the puffer to spray Steritalc homogeneously into
the pleural space.
REFERENCE
1 Roberts ME et al. (2010). Management of a malignant pleural effusion. British
Thoracic Society Pleural. Guidelines 2010. Thorax 65(Suppl. 2): ii32–ii40.
Serotonin syndrome
Serotonin syndrome is a rare, but potentially life-threatening,
condition caused by excess serotonergic agonism. It can develop when
serotonergic drugs are given in combination, when switching
between serotonergic drugs, upon overdose and also with therapeutic
doses. Serotonin syndrome usually occurs within hours of initiation
or dose change. Very rarely mild symptoms may recur over a period of
weeks prior to the development of more severe symptoms.
Diagnosis
Serotonin syndrome is diagnosed if precipitating drugs are identified,
no other cause is likely, and at least three of the following symptoms
are present:1
● mental state changes
● fever
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Serotonin syndrome 417
● shivering
● sweating
● agitation/restlessness
● diarrhoea
● myoclonus
● hyperreflexia (more commonly of the lower limbs)
● tachycardia
● ataxia
● tremor.
The Hunter criteria may also be used for diagnosis.2
Management
●Discontinue serotonergic agents.
●Seek specialist advice from the National Poisons Information
Service.3
●Carry out supportive care to normalise vital signs.
●Consider:
benzodiazepines, e.g. 1 –2 mg lorazepam by slow intravenous
●
injection every 30 minutes

serotonin antagonists, e.g. cyproheptadine orally 4 –8 mg every
●
2 –4 hours (max. 0.5 mg/kg/day).

Symptoms often resolve within 24 –36 hours with adequate
supportive care but may persist following agents with long half-lives
or those with active metabolites.
k S k
Managing risk
The risk of serotonin syndrome developing is reduced by avoiding the
use of serotonergic drugs in combination (Table S1). Care must be
taken when switching, especially between selective serotonin
reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors
(MAOIs).
Tramadol may cause serotonin syndrome, particularly when it is
used at high doses (patients with low weight should use 0.7 mg/kg
body weight4 ) or in combination with other drugs increasing
serotonin concentrations.
TABLE S1
Drug combinations to be avoided or used with caution
due to increased risk of serotonin syndrome developing5
Drug Interacting combination Comment
Almotriptan Lithium or other 5-HT1B/1D agonists Some combinations
contraindicated by
MAOIs Bupropion, pethidine, rizatriptan,
manufacturers
sumatriptan, SSRIs, tramadol
MAOIs Tricyclic antidepressants, venlafaxine Avoid due to severe cases
of serotonin syndrome
St John’s wort Psychotropic drugs (e.g. SSRIs), triptans
reported
Lithium MAOIs, SSRIs, sumatriptan, tricyclic Use with caution and
antidepressants, tramadol, venlafaxine monitor closely for
symptoms of serotonin
SSRIs Tramadol, triptans
syndrome
Venlafaxine Fluoxetine, paroxetine
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418 SIRS due to sepsis scoring system
REFERENCES
1 Sternbach H (1991). The serotonin syndrome. Am J Psychiatry 148: 705–713.
2 Dunkley EJ et al.(2003). The Hunter serotonin toxicity criteria: simple and accurate
diagnostic decision rules for serotonin toxicity. QJM 96: 635–642.
3 National Poisons Information Service. http://www.toxbase.org (accessed 16
September 2015).
4 SPC (2015). Tramadol. http://www.medicines.org.uk (accessed 2 January 2015).
5 Neil K (2003). Drug interactions and serotonin syndrome: tramadol with MAOIs.
Prescriber 19: 18–24.
Systemic inflammatory response syndrome

due to sepsis scoring system
Background
Systemic inflammatory response syndrome (SIRS) is the term given to the inflammatory
process seen in response to an insult, which can be either infectious or non-infectious in
origin. Causes of SIRS can include infection, trauma and ischaemia. The term SIRS does not
necessarily mean an infection is present
SCORING SYSTEM – SIRS (TWO OR MORE OF THE FOLLOWING)

Temperature <36◦ C or >38◦ C 1
Heart rate >90 beats/min 1
k S Respiratory rate>20 breaths/min or PaCO2 <4.2 kPa 1 k
White cell count <4 or >12 × 109 /L 1
Definition of SIRS plus sepsis1

Infection (suspected or diagnosed) plus any of the following:
● Temperature <36◦ C or >38◦ C

● Heart rate >90 beats/min
● Respiratory rate >20 breaths/min or PaCO2 <4.2 kPa
● White cell count <4 or >12 × 109 /L
● Blood pressure <90 mmHg or mean <65 mmHg
● O2 saturations <90% on air or oxygen
● Creatinine >175 micromol/L or urine output <0.5 mL/kg/hour for 2 hours despite
adequate fluid resuscitation
● Abnormal LFTs
● Platelets <100 × 109 /L or coagulopathy (INR >1.5)
● Lactate >1 mmol/L
● Decreased capillary refill
● Ileus
● Acutely altered mental state
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SIRS due to sepsis scoring system 419
Interpretation2
Guidelines for the management of sepsis, severe sepsis and septic shock have been
developed by the Surviving Sepsis Campaign, and include the following in the first 6 hours:
1 Initial resuscitation:
i. central venous pressure 8–12 mmHg
ii. mean arterial pressure ≥65 mmHg
iii. urine output ≥0.5 mL/kg/hour.
2 Diagnosis:
i. obtain appropriate cultures in order to identify causative organism before
antibiotics are administered (e.g. respiratory secretions, cerebrospinal fluid, wound
swabs, urine)
ii. at least two blood cultures (sample peripherally and centrally if vascular access
device is in place)
iii. imaging where appropriate.
3 Antibiotic therapy:
i. initial intravenous antibiotics within 1 hour of recognition of severe sepsis
ii. consider spectrum of activity, penetrations and local formulary when starting
empiric antibiotics
iii. review antibiotics every 24 hours against received culture and sensitivity results and
consider de-escalation to a narrow-spectrum agent
iv. stop antibiotics if SIRS subsequently deemed to be due to a non-infectious cause.
4 Source control:
i. consider source of infection and possible control measures, e.g. abscess drainage,
removal of vascular access device.
5 Fluid therapy:
i. use crystalloid for initial fluid resuscitation
k ii. do not use hydroxyethyl starches for fluid resuscitation S k
iii. consider albumin in patients requiring large volumes of crystalloid.
6 Vasopressors:
i. use noradrenaline first-line
ii. add vasopressin to noradrenaline to raise mean arterial pressure or in an attempt to
reduce noradrenaline doses.
7 Inotropes:
i. dobutamine may be added to vasopressors when myocardial dysfunction is present.
8 Corticosteroids:
i. do not use steroids if fluid resuscitation and vasopressors have achieved
haemodynamic stability
ii. if hydrocortisone is appropriate, give 200 mg/day via continuous infusion.
9 Venous thromboembolism (VTE) prophylaxis:
i. ensure VTE risk assessed and prophylactic doses of low-molecular-weight heparin
prescribed as appropriate
ii. if pharmacological methods are contraindicated, consider mechanical prophylaxis.
10 Stress ulcer prophylaxis:
i. give either a proton pump inhibitor (preferably) or H2 antagonist.
REFERENCES
1 Dellinger RP et al. (2013). Surviving sepsis campaign: international guidelines for
management of severe sepsis and septic shock. Crit Care Med 41: 580.
2 Townsend S et al. (eds) (2005). Implementing the Surviving Sepsis Campaign. Mount
Prospect: Society of Critical Care Medicine.
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420 Sodium
Sodium
Overview
Normal range 135–146 mmol/L
Local range
Background Sodium is the major extracellular electrolyte and its role and
metabolism are closely related to the body’s water balance
Reference 70 mmol/day (1.6 g sodium, or about 4 g sodium chloride)
nutrient intake1
Hypernatraemia
Symptoms Thirst, reduced salivation and lacrimation, fever, tachycardia,
hypertension, headache, dizziness, restlessness, irritability and
weakness. Hypernatraemia can lead to central nervous system
dehydration, manifesting as somnolence, confusion, convulsions,
coma, respiratory failure and death
Causes ● Fluid loss with inadequate water intake, e.g. diarrhoea, vomiting,
burns, coma
● Incorrect fluid replacement in patients dependent on intravenous
therapy
● Osmotic diuresis, e.g. diabetic ketoacidosis
● Excessive fluid loss due to diabetes insipidus
● Primary aldosteronism
k S ● Drugs that can cause hypernatraemia include: demeclocycline,
clonidine, corticosteroids, lactulose, methyldopa, oestrogens,
k
oral contraceptives and sodium bicarbonate
Treatment If due to dehydration or there is only mild sodium excess,
rehydrating the patient should correct this and sodium intake may
be restricted. Water given orally is the preferred route
If hypernatraemia is severe, intravenous fluids may be needed. There
is some debate as to whether to use glucose 5% or sodium chloride
0.9% (sodium chloride 0.9% can cause less marked fluid shifts and
is relatively hypotonic to a hypernatraemic individual).
If the hypernatraemia is drug-induced, discontinuing or changing
the drug therapy may alleviate the condition
Hyponatraemia
Classification The severity of hyponatraemia can be classified by the serum
sodium concentration:2
● Mild hyponatraemia: serum sodium concentration is
125–134 mmol/L.
● Moderate hyponatraemia: serum sodium concentration is
115–124 mmol/L.
● Severe hyponatraemia: serum sodium concentration is
<115 mmol/L
Symptoms ● Dilutional hyponatraemia can be asymptomatic but headache,
confusion, nausea, vomiting, somnolence and weakness can
manifest. If there is plasma volume contraction as well as
sodium depletion, postural hypotension and circulatory
insufficiency may occur
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Sodium 421
Causes ● Reduced water excretion, e.g. in renal impairment

● SIADH, which may be drug-induced (see Syndrome of
inappropriate secretion of antidiuretic hormone entry)
● Excessive oral fluid intake
● Inappropriate intravenous administration of hypotonic fluids
● Certain disease states, e.g. nephrotic syndrome, heart failure,
liver cirrhosis, renal failure, adrenocortical insufficiency and
acquired immunodeficiency syndrome
● Drugs that can cause hyponatraemia include: amphotericin,
angiotensin-converting enzyme inhibitors, carbamazepine,
cyclophosphamide, desmopressin, diuretics, heparin, lithium,
non-steroidal anti-inflammatory drugs (NSAIDs), selective
serotonin reuptake inhibitors (SSRIs), opioids, tolbutamide and
vasopressin3
Treatment Fluid restriction is often all that is necessary.
If due to SIADH, the hyponatraemia may be drug-nduced.
Sodium chloride supplementation is sometimes used. If sodium
depletion is mild or moderate, e.g. in salt-losing bowel or renal
disease, Slow Sodium is used at doses of 4–8 tablets daily
(40–80 mmol or 2.4–4.8 g). In severe cases up to 20 tablets daily
(200 mmol or 12 g) have been used. For control of muscle cramps
during routine maintenance haemodialysis, 10–16 tablets per
dialysis is usual. Patients should swallow each tablet whole with at
least 70 mL water/tablet, and be counselled about ‘ghost’ tablets
appearing in their stools.4
k Acute symptomatic hyponatraemia (water intoxication), where

serum sodium concentration falls below 120 mmol/L, is treated
S k
aggressively with intravenous hypertonic or isotonic sodium chloride
solution. Furosemide is often given, especially if fluid overload is
likely to be a problem. The aim is for the patient to be asymptomatic,
and to achieve a sodium serum concentration of 120–130 mmol/L.
Care should be taken to increase sodium levels gradually, as central
nervous system toxicity can occur if correction is too rapid. It is
important to avoid the development of hypernatraemia
TABLE S2
Sodium content of various preparations
Product Sodium content3
Slow Sodium MR tablets 600 mg (approx. 10 mmol)
Sodium chloride 0.9% intravenous infusion 9 g/L (150 mmol)
Sodium chloride 0.18% and glucose 4% 30 mmol/L
Sodium chloride 0.45% and glucose 2.5% 75 mmol/L
Sodium chloride 0.45% and glucose 5% 75 mmol/L
Ringer’s solution 147 mmol/L
Sodium lactate intravenous infusion, compound 131 mmol/L
(Hartmann’s solution for injection, Ringer’s lactate
solution for injection)
Sodium bicarbonate capsules 500 mg (6 mmol)
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422 Sterile larvae
REFERENCES
2 NICE (2011). Hyponatraemia – CKS. http://cks.nice.org.uk/hyponatraemia
4 Summary of Product Characteristics (2014). Slow Sodium. http://www.medicines
.org.uk (accessed 1 November 2014).
Sterile larvae
Larval therapy (also known as ‘maggot therapy’ or ‘biosurgery’) is a
method of wound debridement that, after having been used for
centuries, has been reintroduced relatively recently into modern
medicine by doctors and wound care specialists.1 It can be used as a
bridge between debridement procedures, or for debridement of
chronic wounds when surgical debridement is not available or cannot
be performed.2 Larval therapy can be used for debridement of acute
or chronic necrotic, infected or sloughy wounds and has been used in
the treatment of pressure ulcers, chronic venous ulceration and
diabetic ulcers.2 It can also be used to maintain a clean wound after
debridement if the wound is considered prone to resloughing.1
In the UK, the maggots used in larval therapy are the live sterile
larvae of Lucilia sericata, also known as the common greenbottle fly.
k S Outside of the UK, Lucilia cuprina, also known as the Australian sheep k
blow fly, are used as well.2
Mode of action
The sterile larvae work by releasing a mixture of natural proteolytic
enzymes and components that break down the necrotic tissue
(healthy tissue is left unharmed) into a liquid form that they can then
easily remove and digest.3 During this process the larvae also take up
bacteria, particularly Gram-positive bacteria, which are then
destroyed within their gut.1 Larval therapy has been shown to be
successful at eliminating MRSA from wounds1 and the movement of
the larvae is also thought to accelerate wound healing by promoting
the formation of granulation tissue.4
Disadvantages of larval therapy
Some patients experience an increased amount of wound pain and
this may be particularly so for those patients with poor circulation.1
Pain associated with the therapy may limit its use in about 20% of
patients.2 It has also been suggested that maggots should not be
applied to wounds that have a tendency to bleed easily or that
communicate with a body cavity or any internal organ.3
Availability
In the UK, larval therapy is prescribable on the NHS; however, it
should be noted that randomised trials have not found consistent
reductions in the time to wound healing compared with standard
wound therapy.2
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Sterile larvae 423
In the UK, larval therapy is produced by a company called

Biomonde. Larvae are available as either a Biobag dressing or loose
within a retention system.
The advantage of the Biobag dressing is that the larvae remain
sealed within the dressing throughout the treatment, making the
application and removal of larvae significantly easier for clinicians
and also allowing for inspection of the wound during treatment.1
The loose larvae are particularly useful when the exact extent of
the wound is unknown (e.g. the depth).
It has been demonstrated that loose and Biobag larvae are equally
effective in terms of debriding the wound.1 The quantity of larvae
required to treat a wound effectively is dependent on the area of the
wound and the amount of slough, which is expressed as a percentage
of the wound area covered. Once these two factors have been assessed
a ‘larvae calculator’5 is used to calculate the quantity of sterile larvae
necessary.4
Practical points
There are some important practical points to remember regarding
larval therapy.
● Metronidazole is known to kill larvae and so it is important to

ensure that, for at least 2 days prior to larval therapy being
initiated, it is not administered to the patient.4
Larval therapy has a 3- or 4-day treatment cycle (depending on the
k S k
●
preparation of larvae used) and so care must be taken to ensure

that subsequent supplies are ordered the day before needed so that
they can be reared and delivered in time for optimum application.
This is ideally
◦
on the day of delivery; however, they may be stored
at 6 –25 C for 24 hours.
● Any dressings used to secure the sterile larvae in place must not be
occlusive, as the larvae need a constant oxygen supply to survive.
● When the larvae are removed from a wound they should be bagged
as clinical waste and incinerated according to local policy.1,4
● Full guidance and instructions on all aspects of treatment with
larvae therapy can be found at the Biomonde website.1
REFERENCES
1 Biomonde (2015). http://biomonde.com/en/ (accessed 30 January 2015).
2 Up To Date (2014). Principles of Wound Debridement. http://www.uptodate.com/
contents/basic-principles-of-wound-management?source=machineLearning&
search=principles+of+wound+debridement&selectedTitle=1%7E150&
sectionRank=2&anchor=H55268712#H55268712 (accessed 30 January 2015).
4 Thomas S, McCubbin P (2002). Use of maggots in the care of wounds. Hosp Pharm
9: 267–271.
5 Biomonde Sizing Ordering Guide (2015). http://biomonde.com/attachments/
article/7/BM48 EN 08 0914 IP.PDF (accessed 21 February 2015).
k
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424 Stroke and transient ischaemic attack
Stroke and transient ischaemic attack

Overview
Definition: Stroke is defined by the WHO as a clinical syndrome consisting of
stroke ‘rapidly developing clinical signs of focal (at times global) disturbance
of cerebral function, lasting more than 24 hours or leading to death
with no apparent cause other than that of vascular origin’.1 The
‘stroke of God’s hande’ was the phrase physicians used in the late 16th
century to describe what is now simply called a stroke or a
cerebrovascular accident (CVA)
Definition: A transient ischaemic attack (TIA) is defined as stroke symptoms and
TIA signs that resolve within 24 hours.2 However, in the majority of TIAs
the symptoms usually resolve within minutes, or a few hours at the
most, and anyone with continuing neurological signs when first
assessed should be presumed to have had a stroke
Classification Broadly, a stroke can be classified as either ischaemic or haemorrhagic.
Ischaemic stroke: about 70% of strokes are ischaemic and are
caused by a blood clot formed as a result of either cardioembolic or
atherosclerotic vascular disease.
Haemorrhagic stroke: results from the rupture of blood vessels in the
brain with the leakage of blood, causing damage. The most common
cause is primary intracerebral haemorrhage (PIH), which accounts for
about 10% of all patients presenting with acute stroke. Subarachnoid
haemorrhage (SAH) accounts for approximately 5%, with an overall
k S survival rate of about 50%3 k
Assessment All people with suspected stroke should be admitted directly to a
specialist acute stroke unit following initial assessment, either from
the community or from the Accident and Emergency department. The
unit is staffed by a coordinated multidisciplinary team (MDT) with a
special interest in stroke care.4 Pharmacists are part of this MDT and
should contribute to regular MDT meetings that occur for goal setting
Diagnostic ● Face Arm Speech Test (FAST) is a common validated tool used to
tests screen for a diagnosis of stroke or TIA outside the hospital setting.
A stroke should be suspected if a person exhibits any of these
symptoms.
● Recognition Of Stroke In Emergency Room (ROSIER).4 A stroke is
likely if a person scores >0 in the absence of hypoglycaemia.
● Non-contrast CT scanning is quick and can easily identify
haemorrhagic stroke, which is of use when identifying patients who
may be suitable for thrombolysis. A CT scan, however, is not
sensitive for early ischaemic stroke (less than 6 hours from onset)
or small areas of ischaemia.
● MRI is more sensitive than CT to early stroke and small strokes but
is expensive and takes longer to perform and process the results.
● Carotid imaging (Doppler ultrasound) – about 80% of TIAs require
scanning of the arteries around the throat, which provide blood
supply to the brain.5,6 This is due to carotid artery stenosis (CAS),
which may be a cause of ischaemic stroke. ‘Carotid imaging’ is the
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most common way of assessing the blood flow in the carotid

arteries and diagnosing CAS. If blood flow is sufficiently impaired,
patients will be referred to the vascular team and offered surgery
(carotid endarterectomy) to improve carotid blood flow.
● ECG monitoring – used for identification of atrial fibrillation (AF),
which is a risk factor for stroke and to establish if the stroke is
cardioembolic in origin (see Atrial fibrillation entry)
Treatment goals Time is the most important factor in the treatment of stroke. There is
evidence that rapid treatment improves outcomes after stroke.
Thrombolysis with alteplase in acute ischaemic stroke has been
shown to reduce the risk of permanent disability from a stroke
significantly7
Treatment of acute ischaemic stroke
Thrombolysis ● Intravenous thrombolysis uses the recombinant human tissue
plasminogen activator alteplase.
● Licensed indication: treatment of acute ischaemic stroke in adults
if treatment is started as early as possible within 4 1/2 hours of
onset of stroke symptoms and intracranial haemorrhage (ICH)
has been excluded by appropriate imaging techniques (e.g. CT).7
● Dose: 0.9 mg alteplase/kg body weight (maximum of 90 mg)
intravenously over 60 minutes with 10% of the total infused dose
administered as an initial intravenous bolus. The treatment effect
is time-dependent; therefore, earlier treatment increases the
probability of a favourable outcome. Beyond 4 1/2 hours after
onset of stroke symptoms there is a negative benefit–risk ratio
k associated with alteplase administration (increased risk of ICH) S k
and so it should not be administered.8
● If patients wake from sleep with stroke symptoms, then they will
generally be excluded as it is nearly impossible to say at which
point during their sleep they had a stroke.
● Contraindications: <18 and >80 years of age. Other exclusion
criteria are mainly related to patients who have an increased risk
of haemorrhage. These include the prior use of all anticoagulants,
including the novel oral anticoagulants (NOAC) drugs
Aspirin and ● Once a diagnosis of PIH has been excluded by CT scan, all
anticoagulant patients with an acute stroke should be given aspirin 300 mg
treatment orally or, if dysphagic, this can be given rectally or via an enteral
feeding tube. This should be continued until 2 weeks after the
onset of stroke symptoms, at which time long-term secondary
prevention should be initiated.
● Anyone who is allergic to, or genuinely intolerant of, aspirin,
should be given an alternative antiplatelet agent (e.g. clopidogrel
300 mg as a single loading dose and then continued at 75 mg
daily). If there is a history of dyspepsia associated with aspirin, a
proton pump inhibitor (PPI) should be given in addition to the
aspirin.3,4
● Anticoagulation treatment should not be used routinely for the
treatment of acute stroke
Anticoagulation ● For patients in AF, anticoagulation should be deferred for 2
for comorbidities weeks after onset of symptoms of stroke and replaced with
300 mg aspirin daily during this period.
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● In people with prosthetic heart valves, and who are at significant

risk of haemorrhagic transformation, anticoagulation treatment
should be stopped for 1 week after onset of stroke and
substituted with aspirin 300 mg daily.
● Patients with stroke and symptomatic proximal deep-vein
thrombosis (DVT) or pulmonary embolism (PE) should receive
anticoagulation treatment in preference to treatment with aspirin
unless there are other contraindications to anticoagulation4
Statin therapy ● Immediate initiation of a statin is not recommended in people
with acute stroke and the consensus is that it is safe to start one
after 48 hours. People already taking a statin may continue with
their treatment4
Blood pressure ● Antihypertensive treatment is only recommended in acute stroke
(BP) control if there is a hypertensive emergency (BP >220/120 mmHg) or for
people suitable for thrombolysis but who need a reduction in
their BP to ≤185/110 mmHg.1,4 If treatment is indicated,
intravenous antihypertensive drugs with a short half-life should
be used, e.g. glyceryl trinitrate or labetalol. BP should be reduced
cautiously and abrupt lowering is to be avoided
Thrombo- ● Heparins are not routinely used in the treatment of acute stroke,
prophylaxis due to the increased risk of ICH3
Treatment of haemorrhagic stroke
Cessation of ● Following brain imaging confirmation of PIH, all antiplatelets or
antiplatelets/ anticoagulants should be discontinued. A baseline full blood
k S anticoagulants count and clotting screen should be done and clotting levels in k
those receiving anticoagulation treatment (and who have an
elevated INR) should be returned to normal as soon as possible.
Reversal is usually achieved using a combination of prothrombin
complex concentrate and intravenous vitamin K.4
● At present, there is no antidote for the NOACs, so patients
admitted with PIH taking these drugs need to be managed with
supportive care.3
● Patients with haemorrhagic stroke and symptomatic DVT or PE
should be treated with either anticoagulants or a caval filter4
Statin therapy ● Is not recommended routinely as there may be an increased risk
of ICH in patients being treated with statins.9 Current practice is
only to use statins where the risk of further ischaemic vascular
events outweighs the risk of further haemorrhage, but even then,
only once the haemorrhage has resolved1
SAH ● Patients diagnosed as having an SAH should be referred to a
tertiary neuroscience centre. For prevention of ischaemic
neurological deficits, patients may be started on oral nimodipine
60 mg every 4 hours (within 4 days of onset of SAH) and
continued for 21 days unless there are specific
contraindications3,10
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Treatment of TIA
Assessment ● People experiencing a TIA should be assessed rapidly in order to
minimise the chances of a full stroke occurring. It is crucial that
these people are referred for further investigation within a
specialist TIA clinic since the risk of subsequent stroke is greatest
in the first few days.3,5
● The risk of subsequent stroke is made using a validated scoring
system, such as ABCD2 (see ABCD2 scoring system entry)
Secondary prevention of stroke and TIA
Pharmacists have an opportunity to improve patients’ adherence in taking their
secondary prevention medication and should counsel patients on the importance of
adherence with drug treatment and how to take their medicines. Changes in lifestyle are
also important and people should be given both written and verbal information on
smoking cessation, alcohol consumption, diet and exercise
Antiplatelet Antiplatelet medicines used in secondary prevention are usually
therapy started 2 weeks after the acute event and should be continued
lifelong. Occasionally, they may be started earlier if the patient is
discharged from hospital within this time period.
● Aspirin, modified-release (m/r) dipyridamole and clopidogrel are
the three current treatment options used in secondary prevention
following TIA or ischaemic stroke.
● After the 2-week course of aspirin 300 mg daily, patients who
have experienced an ischaemic stroke should receive clopidogrel
75 mg daily, to be continued indefinitely. For people in whom
k clopidogrel is either contraindicated or not tolerated, the
combination of aspirin 75 mg daily and dipyridamole m/r 200 mg
S k
twice daily should be used.11
● Clopidogrel is not licensed for the management of TIA but many
stroke units will also use clopidogrel in TIA patients for the
secondary prevention of stroke.5,12 Others will follow NICE
guidance, which recommends the combination of aspirin 75 mg
daily and dipyridamole m/r 200 mg twice daily for this
indication.11 For people who have a contraindication or
intolerance to aspirin, dipyridamole MR alone is recommended as
a treatment option
PPIs ● There is pharmacological evidence that omeprazole and
esomeprazole may reduce the efficacy of clopidogrel, so the
combination should be avoided and an alternative PPI, e.g.
lansoprazole, used if needed.12
Anticoagulation ● Patients who have had a cardioembolic stroke (e.g. patients with
AF) should be anticoagulated after imaging to exclude ICH,
unless contraindicated. This is usually not until 14 days after the
onset of stroke symptoms, as there is a concern that
anticoagulation may increase the risk of haemorrhagic
transformation of the initial infarct. Treatment can be started
earlier, especially in minor or non-disabling strokes, at the
discretion of the stroke physician. Anticoagulation may be with
an NOAC (e.g. apixaban, dabigatran, rivaroxaban) or a vitamin K
antagonist (e.g. warfarin).
k
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● In patients with AF, aspirin 300 mg daily should be continued

until warfarin has been started and the INR is in therapeutic
range (usually 2–3); then the aspirin can be stopped. The NOACs
have the advantage of fast onset of action and aspirin can be
stopped on their initiation.
● The decision of starting treatment with an oral anticoagulant
should be made after an informed discussion between the
clinician and the patient, and a comparison should be made
regarding the risks and benefits of the different NOACs available
and warfarin.13 – 15
● Risk stratification is important to determine which patients have
a stroke risk that is significant enough to justify the bleeding risk
associated with oral anticoagulants. The CHA2 DS2 -VASc is a
validated tool, used to score people in non-valvular AF and
assess their risk of stroke16
See CHA2 DS2 -VASc and HAS-BLED scoring, below
Hypertension ● Hypertension is the single most important modifiable risk factor
for stroke. A target BP of <130/80 mmHg should be aimed for in
all patients with stroke or TIA. Poststroke hypertension is
common and in most cases a patient’s BP will return to baseline
in the first 4–10 days after stroke. Ideally, BP-lowering treatment
should be initiated after stroke or TIA prior to hospital discharge
or at 2 weeks, whichever is the soonest.3
● In the PROGRESS trial, BP lowering using the combination of
perindopril and indapamide in patients with a history of stroke or
TIA was shown to reduce the incidence of both recurrent stroke
k S and major vascular events.17 k
● Hypertensive patients <55 years old and not of African or
Caribbean origin should be started on an ACE inhibitor, e.g.
perindopril, or an angiotensin-II receptor blocker if an ACE
inhibitor is not tolerated.
● For patients >55 years old and African or Caribbean patients of
any age, first-line treatment should be with a calcium-channel
blocker, such as amlodipine, or a thiazide-like diuretic, such as
indapamide17
Lipid-lowering ● All patients who have had an ischaemic stroke or TIA should be
therapy prescribed a statin, irrespective of cholesterol level.18 Evidence
suggests that the vasoprotective effects of statins extend further
than just cholesterol reduction. In the Heart Protection Study, the
addition of simvastatin 40 mg daily, irrespective of initial
cholesterol levels, was shown to reduce the risk of ischaemic
stroke by 25%.19 Note that the dose of simvastatin may need
halving if coprescribed with some drugs, e.g. certain
calcium-channel antagonists. In the SPARCL study, atorvastatin
80 mg daily was also shown to reduce the risk of stroke.9
● The first-line treatment often used is therefore simvastatin 40 mg
daily, but high-intensity statins, e.g. atorvastatin 80 mg daily, can
be used if target cholesterol levels are not achieved, i.e. total
cholesterol <4.0 mmol/L and low-density lipoprotein cholesterol
<2.0 mmol/L.3
● The SPARCL study also showed that the risk of haemorrhagic
stroke was increased for those on a statin; therefore, statins are
not routinely used for secondary prevention in patients with a
history of PIH3
k
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Rehabilitation and long-term management

In addition to knowing what secondary prevention measures are required for patients
who have had a stroke, pharmacists should also be aware and be able to advise on how
medications will be administered. Patients may now need help in taking their medicines,
so it is important to review this prior to discharge, e.g. if there are dexterity problems a
patient may need a compliance aid, such as easy-open tops or a monitored-dosage
system. Patients may also now be unable to take their medicines in the same form as
before their stroke due to difficulties in swallowing
Dysphagia ● The majority of patients who develop swallowing difficulties
(dysphagia) following a stroke will recover; however, a
proportion will have persistent abnormal swallowing problems
that may become chronic.3 Patients may require enteral feeding
tubes to ensure that they receive adequate fluid and nutrition.
● Aspiration pneumonia is a major risk in patients with dysphagia,
and so to administer medicines safely to patients with dysphagia
it is important to find out what the patient’s swallowing status is.
Speech and language therapists assess patients to check for safe
swallowing. They may ask for patients to be kept nil-by-mouth
(NBM) if patients have an unsafe swallow or advise for patients
to be tried on thickened fluids/modified diets. If NBM, medicines
would need to be given by other routes, e.g. topically, rectally or
parenterally.
● Most of the secondary prevention medicines used in stroke,
however, are in tablet/capsule form and very few are available as
either liquids or dispersible preparations. There is therefore little
choice and many tablets will need to be crushed and dispersed in
k water for administration via a nasogastric tube or mixed with S k
food/thickened fluids. Any change to a drug’s licensed
formulation will deem the medicine off-licence, as there is a risk
of increased side effects and potential differences in
bioavailability. There is also a possibility for interactions between
enteral feeds and medication (e.g. with perindopril, a gap of
2 hours should be left before and after feeds), so pharmacists
should liaise with the dietician to organise times for feeding and
medicine administration to cause the least disruption.
● Pharmacists should help to rationalise and tailor drug therapy to
the patient’s swallowing requirements by endorsing prescription
charts/discharge letters with information for nurses/carers on the
safest method of administering a patient’s medications.
Pharmacists should be familiar with the resources available to
check whether a drug can be safely crushed or if a suitable
alternative can be recommended
Sialorrhoea and ● Sialorrhoea (drooling or excessive saliva secretion) can increase a
xerostomia patient’s risk of aspiration. The drug options for treating
sialorrhoea are limited and most are unlicensed for this use.
Antimuscarinics, such as hyoscine and glycopyrronium, are
generally prescribed and preparations are available for topical,
oral and parenteral use.
● A large proportion of stroke patients will develop xerostomia (dry
mouth) and this can lead to oral infections and contribute to
dysphagia. Administration of an artificial saliva spray may help to
reduce any discomfort
k
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Spasticity and ● Patients with poststroke general spasticity can be managed with
spasms skeletal muscle relaxants, such as baclofen, tizanidine or
gabapentin, but they all have the disadvantage of causing
drowsiness so should be started at a low dose and titrated up
according to response.
● Patients with focal spasticity affecting one or more joints should
be treated where appropriate with intramuscular botulinum
toxin in conjunction with weeks of rehabilitation therapy from a
specialist MDT service3
Depression and ● Mood disturbance is common after stroke and may present as
anxiety depression or anxiety. All patients entering stroke rehabilitation
should be screened for depression using a validated tool and
observed regularly for mood changes.3 It is important to manage
and treat poststroke depression, especially during rehabilitation,
as if left untreated this may impact on a patient’s recovery.
● At present there is no evidence to determine the choice of drug
treatment but in practice most experience poststroke is with the
use of SSRIs. Patients started on an SSRI should be prescribed a
low dose initially and monitored regularly for improvement in
mood and any adverse effects
Pain ● Pain symptoms poststroke may be due to different causes, e.g.
neuropathic, musculoskeletal, spasticity and depression. A
patient’s pain should initially be assessed using a validated tool
and regularly monitored thereafter.3
● Neuropathic pain should be treated in accordance with the
recommendations from the NICE guidance on neuropathic pain.
k S A choice of amitriptyline, gabapentin or pregabalin should be k
offered as initial treatment, starting with low doses and titrating
to the maximum tolerated dose that controls the patient’s pain. If
satisfactory pain reduction is not achieved with first-line
treatment, another drug should be used instead of, or in
combination with, the original drug.20
● Shoulder pain is common and is the most important specific
musculoskeletal pain problem after stroke. It is often associated
with subluxation of the joint and, in the later stages, spasticity.
Treatment with simple analgesic drugs taken regularly should be
tried first-line if needed
CHA2 DS2 -VASc score (risk of stroke in valvular atrial fibrillation)
Background ● CHADS2 was replaced in practice in 2011 with CHA2 DS2 -VASc
(pronounced ‘chads-two-vasc’) as a scoring system used to
determine the long-term risk of stroke in valvular AF, the name
coming from an acronym for the risk factors shown in the table
(see below).21 The subscript ‘2’ is used for criteria that score 2.
● The scoring system was increased, with three additional risk
factors, as the revised system was found to be more sensitive.
Patients with a CHA2 DS2 -VASc score of 0 were found to be less
likely to have a thromboembolic event than those with a CHADS2
score of 0, and those with a CHA2 DS2 -VASc score of 1 were also
less likely to have a thromboembolic event than those with a
CHADS2 score of 1
k
k
TABLE S3
CHA2 DS2 -VASc scoring
Congestive heart failure or left ventricular dysfunction 1
Hypertension 1
Age ≥ 75 years 2
Diabetes mellitus 1
Stroke or TIA or thromboembolism 2
Vascular disease (prior myocardial infarction, peripheral artery disease or 1
aortic plaque)
Age 65–74 years 1
Sex category (i.e. female gender) 1
Maximum score 9
Interpretation
CHA2 DS2 -VASc score Recommended antithrombotic therapy
0 Either aspirin 75–325 mg daily or no antithrombotic therapy.
Preferred: no antithrombotic therapy rather than aspirin
1 Either oral anticoagulant or aspirin 75–325 mg daily.
Preferred: oral anticoagulant rather than aspirin
≥2 Oral anticoagulant
A vitamin K antagonist, e.g. warfarin, is first-line oral anticoagulant with INR range
k 2.0–3.0 (target 2.5). NOAC drugs may be considered if warfarin is not suitable; the risk of S k
bleeding needs to be considered when considering the choice and dose of a NOAC
(see HAS-BLED score, below).
HAS-BLED score
Atrial fibrillation increases the risk of stroke by fivefold, and anticoagulant therapy reduces
the risk of stroke and all-cause mortality, although there is a bleeding risk associated with
anticoagulant therapy.21 The HAS-BLED tool can be used to assess and score an individual’s
bleeding risk in patients with AF who are starting, or have started, anticoagulation.22 It
can be used to support a clinical decision to commence antithrombotic therapy, in
conjunction with the CHA2 DS2 -VASc score to estimate risk of stroke in AF versus the risk of
a bleed23 (see CHA2 DS2 -VASc, above).
HAS-BLED is an acronym, with a score of 1 given to each measure in Table S4. Scores
range from 0 to 9; scores of ≥3 indicate a high risk of bleeding, for which caution and
regular review of the patient are recommended.24
TABLE S4
HAS-BLED scoring
Scores
Hypertension (uncontrolled systolic blood pressure >160 mmHg) 1
Abnormal liver and/or renal function: 1
Liver: cirrhosis, bilirubin >2 × upper limit of normal (ULN) with
aspartate transaminase/alanine transaminase/alkaline phosphatase
>3 × ULN
Renal: chronic dialysis, renal transplant, serum creatinine ≥2.3 mg/dL 1
(200 micromol/L)
(Continued )
k
k
TABLE S4
HAS-BLED scoring (Continued)
Stroke – previous history 1
Bleeding history or predisposition 1
Labile INRs (therapeutic time in range <60%) 1
Elderly (age >65 years) 1
Drugs and/or alcohol usage: 1
Drugs: other antiplatelet agents or NSAIDs 1
Alcohol: >8 units/week
Maximum score 9
REFERENCES
1 SIGN (2008). A National Clinical Guideline: Management of patients with stroke
or TIA: assessment, investigation, immediate management and secondary preven-
tion. 108. www.sign.ac.uk (accessed 13 May 2015).
2 Aho K et al. (1980). Cerebrovascular disease in the community: results of a WHO
collaborative study. Bull WH O 58: 113–130.
3 Intercollegiate Stroke Working Party, Royal College of Physicians (2012).
National Clinical Guideline for Stroke (4th edn). www.sign.ac.uk (accessed 13 May
2015).
4 NICE (2008). Stroke: Diagnosis and initial management of acute stroke and tran-
sient ischaemic attack (TIA). Clinical guideline 68. https://www.nice.org.uk/
guidance/cg68 (accessed 13 December 2014).
5 NICE (2013). ESUOM23: Transient ischaemic attack: clopidogrel.
k S http://www.nice.org.uk/advice/esuom23/resources/non-guidance-transient- k
ischaemic-attack-clopidogrel-pdf (accessed 13 December 2014).
6 Department of Health (2007). National Stroke Strategy. http://clahrc-
gm.nihr.ac.uk/cms/wp-content/uploads/DoH-National-Stroke-Strategy-2007.pdf
(accessed 13 December 2014).
7 NICE (2012). Technology appraisals (TA264). Alteplase for treating
acute ischaemic stroke (review of technology appraisal guidance 122).
https://www.nice.org.uk/guidance/ta264 (accessed 13 December 2014).
8 SPC (2014). Actilyse. https://www.medicines.org.uk/emc/medicine/308
9 The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
(2006). Investigators high-dose atorvastatin after stroke or transient ischaemic
attack. N Engl J Med 355: 549–559.
10 SPC (2014). Nimotop. https://www.medicines.org.uk/emc/medicine/8086
11 NICE (2010). Technology appraisal (TA210). Clopidogrel and Modified-
release Dipyridamole for the Prevention of Occlusive Vascular Events.
http://www.nice.org.uk/guidance/ta210 (accessed 13 December 2014).
12 SPC (2014). Plavix. https://www.medicines.org.uk/emc/medicine/24207
13 NICE (2013). Technology appraisal (TA275). Apixaban for the Prevention of
Stroke and Systemic Embolism in People with Non-Valvular Atrial Fibrillation.
http://www.nice.org.uk/guidance/ta275 (accessed 13th December 2014).
14 NICE (2012). Technology appraisal (TA249). Dabigatran Etexilate for
the Prevention of Stroke and Systemic Embolism in Atrial Fibrillation.
15 NICE (2012). Technology appraisal (TA256). Rivaroxaban for the Prevention
of Stroke and Systemic Embolism in People with Atrial Fibrillation.
k
k
Suppositories 433
16 NICE (2014). Clinical guideline (CG180). Atrial Fibrillation: The management

of atrial fibrillation. http://www.nice.org.uk/guidance/cg180 (accessed
13 December 2014).
17 Progress Collaborative Group (2001). Randomised trial of a perindopril based
blood pressure lowering regimen among individuals with previous stroke or TIA.
Lancet 358: 1033–1041.
18 NICE (2011). Clinical guideline (CG127) Hypertension: Clinical management of pri-
mary hypertension in adults. http://www.nice.org.uk/guidance/cg127 (accessed
13 December 2014).
19 Heart Protection Study Collaborative Group (2002). MRC/BHF heart protec-
tion study of cholesterol lowering with simvastatin in high-risk individuals: a
randomised placebo-controlled trial. Lancet 360: 7–22.
20 NICE (2013). Clinical guideline CG173 Neuropathic Pain – Pharmacological
management: the pharmacological management of neuropathic pain in adults
in non-specialist settings. https://www.nice.org.uk/guidance/cg173 (accessed
13 December 2014).
21 Camm AJ et al. (2010). Guidelines for the management of atrial fibrillation. The
Task Force for the Management of Atrial Fibrillation of the European Society of
Cardiology (ESC). Eur Heart 31: 2369–2429.
22 You JJ et al. (2012). Antithrombotic therapy for atrial fibrillation: antithrom-
botic therapy and prevention of thrombosis, 9th edn: American College of Chest
Physicians evidence-based clinical practice guidelines. Chest 141: e531S–e575S.
23 NICE (2014). Atrial Fibrillation: The management of atrial fibrillation. Clinical
Guideline 180. Available at: www.nice.org.uk/guidance/CG180 (accessed 6 May
2015).
24 Pisters R et al. (2010). A novel user-friendly score (HAS-BLED) to assess one-year
risk of major bleeding in atrial fibrillation patients: the Euro Heart Survey. Chest
k 138: 1093–1100.
S k
Suppositories
If the rectal route is selected for administration of medication, it is
useful to be aware of current thought on which way round a
suppository should be inserted.
Traditionally the pointed or round end is inserted first, and most
patient information leaflets provided by manufacturers use this
method in their explanation to patients. If one is self-administering,
this may be the easiest way to insert. The rationale is that the round
end enters the anal sphincters more easily than the blunt end, and the
flat end is easier to push against.
In hospital most suppositories are inserted by nurses. Many nursing
textbooks advocate insertion of suppositories blunt-end first, on the
basis of a single study that suggested retention was better, with less
need to introduce a finger into the anal canal.1 However, the change
in practice has been more recently criticised in that it was based on
the results of a single small study, with no statistical analysis.2
It may not make a great deal of difference which way round the
suppository enters the rectum, as long as it is retained there long
enough to dissolve. It is probably easier to self-administer round end
first, and it is equally easy for a nurse to administer either way round.
Caution must be exercised when administering suppositories post
colorectal surgery, as there is a risk of perforating anastomoses. Some
consultants will not consider the rectal route even after minor
colorectal surgery.
k
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434 Surgical pharmacy
REFERENCES
1 Abd-el-Maeboud KH et al. (1991). Rectal suppository: commonsense and mode of
insertion. Lancet 338: 798.
2 Kyle G (2012). Practice questions: Should a suppository be inserted with the blunt
end or the pointed end first, or does it not matter? Nurs Times 105: 16.
Surgical pharmacy
The role of the pharmacist in surgery should not be underestimated.
The multidisciplinary care of patients who come into hospital for
surgical procedures should always include pharmaceutical input.
The key areas for the pharmacist to be involved in are:
● management of long-term medication in the perioperative period
● postoperative nausea and vomiting
● pain control
● thromboprophylaxis
● antibiotic prophylaxis.
The pharmacist should become integrated as part of the multidiscipli-
nary team and be prepared to accept responsibility for writing
protocols, procedures and guidelines for use by the nursing and
medical staff. These protocols should then be reinforced on the wards
and audited in practice.
When beginning work on the surgical wards, it is important to
k S
become familiar with the different surgical procedures and
k
understand the principles of the terminology. Examples of commonly
used suffixes and meanings are:
−oscopy = to view using scope (colonoscopy)
−ectomy = the surgical removal of (nephrectomy)
−otomy = the surgical incision of (laparotomy)
−ostomy = to create a hole, also referred to as stoma, surgically.
e.g. laparoscopic cholecystectomy is the removal of the gallbladder
(cholecyst) using a surgical scope method.
It is important to understand the surgical procedure that the
patient is undergoing to identify any implications for changes in
medication, e.g. stopping alpha-blocker therapy post transurethral
resection of the prostate.
The importance of an accurate medicines reconciliation
The pharmacy team is responsible for patients’ medication
throughout the admission, which starts with ensuring an accurate
drug history before surgery. The optimum place to take the drug
history is the preadmission clinic and now more pharmacists have a
key role in this area. This allows time before the patient goes to
theatre to advise on stopping, withholding or changing long-term
medication. Ideally, the documentation should be available for the
anaesthetist and surgeon prior to the procedure.
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The important details to find out are: name of medicine, form,

strength, dose, frequency and, if known, the indication for its use.
This should be established for all routinely taken medication,
including over-the-counter, herbal and homeopathic medicines. Use
of illegal drugs should also be documented if possible. Find out if any
medicines have been recently stopped or changed; e.g. prior to
surgery it is important to know if a long course of steroids has only
recently stopped as replacement with intravenous hydrocortisone
may still be required.
If the medication history has been recorded in the preadmission
clinic, it is important to check that nothing has changed in the time
between the clinic and admission.
Once all this information is established the management of the
medicines throughout the perioperative period can be planned and
tailored to meet the patient’s ongoing needs and to prepare for a safe
and effective discharge (see ‘Nil-by-mouth’ – management of long-term
medicines during surgery entry).
Many surgical specialties have now adopted the enhanced recovery
after surgery (ERAS) approach.1 This encompasses perioperative
pathways as part of a multidisciplinary approach to improve patient
outcomes of surgery.2 Pharmacists can play an important role in this,
particularly in terms of medicines optimisation, pain management
and fluid management.
Thromboprophylaxis
k S k
Patients undergoing surgical procedures are at an increased risk of a
VTE. There is a vast amount of literature to support the routine use of
prophylaxis, which reduces the risk of DVT and PE. Equally, there are
data to reassure that the use of anticoagulants at the time of surgery
causes little or no increase in the rate of clinically important
bleeding.3,4 It should be noted that the combination of NSAIDs and
prophylactic heparin is a common necessity in surgical patients;
however, consideration should always be given to the patient’s risk of
bleeding and renal dysfunction.
Surgical units should have thromboprophylaxis protocols which
are easy to apply in practice and which take into consideration:
● acute and chronic clinical risks

● previous thromboembolic episodes
● risk associated with type of surgery
● assessment of the risk of VTE versus bleeding.3
The risk of VTE should be viewed as two separate categories: patient

risk and surgical risk.
Patient risks
● age over 60 years
● active cancer or cancer treatment
● dehydration
● immobility (pre-existing/postoperative)
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● hypercoagulable state – this includes all the thrombophilic

diseases, such as low coagulation inhibitors (antithrombin, protein
C or S); activated protein C resistance (factor V Leiden); high
coagulation factors (I, II, VIII, IX, XI); antiphospholipid syndrome
or high homocysteine. Any patients undergoing surgery with these
conditions are usually discussed with the haematologist to ensure
appropriate prophylaxis
● obesity – if the body mass index is greater than 30 kg/m2 , the risk
of VTE is three times greater
● pregnancy – the risk of VTE postpartum within 6 weeks or through
pregnancy is increased by 10 times
● oestrogen therapy – the use of the combined oral contraceptive pill
(COCP), hormone replacement therapy, raloxifene or tamoxifen
confers an additional VTE risk. Stopping the COCP can be
considered and discussed with the patient; however, the risk of
becoming pregnant and using less effective contraception must be
taken into account. The perioperative use of these drugs should be
in accordance with local policy, combined with appropriate
thromboprophylaxis. There is no evidence that low-dose
progestogens increase the risk and therefore they do not need to be
stopped prior to surgery
● coexisting illness (heart failure, myocardial infarction, sepsis) –
medical patients have an increased risk of DVT even without
undergoing a surgical procedure, so it is important to increase the
k S level of the thromboprophylaxis in these patients. k
Surgical risk
● Surgical procedure lasting longer than 90 minutes.
● Acute surgical admission.
● Pelvic or lower-limb surgery – the risk can be increased by up to
30%.
● Major abdominal surgery, including gynaecological and colorectal.
Extended thromboprophylaxis may be indicated in patients for up to

35 days postprocedure following hip or knee replacements and
abdominal surgery for cancer treatment.5
Thromboprophylaxis should be considered in terms of both
pharmacological and mechanical methods. Only after assessing each
individual patient’s risks should the appropriate therapy be
prescribed.
Mechanical prophylaxis
The choice should be based on individual factors. It is important to be
aware of the contraindications of use. Mechanical prophylaxis is
recommended as first-line, with pharmacological methods used as an
adjuvant in higher-risk patients.
● antiembolic stockings/graduated compression stockings. If
correctly sized and fitted, VTE risk can be reduced by up
to 50%.
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● intermittent pneumatic compression devices and foot pumps

increase the venous outflow in the lower limbs and hence reduce
venous stasis.
Pharmacological prophylaxis
The choice should be based on local policy, licensed indication and
individual factors.
Heparins and fondaparinux
Low-molecular-weight heparins (LMWH) are the agents most
commonly used, as they require once-a-day administration, as
opposed to unfractionated heparin, which is administered three times
daily. The timing of administration needs to be considered,
particularly if patients are to have surgery under a spinal or epidural
anaesthetic because there is a risk of spinal haematoma. To avoid this
risk, the LMWH is administered in the evening. Removal of an
epidural catheter should be delayed for 10 –12 hours
postadministration of the LMWH, and the administration of LMWH
should not be within 6 hours of the insertion or removal of an
epidural catheter.
The duration of treatment is variable. It is an unfortunate paradox
that most patients are continued on LMWH until discharge, when in
reality they may go home to a state of immobility, or they may be back
to a fully mobile state well before discharge (see Low-molecular-weight
heparin entry). Fondaparinux sodium is a synthetic pentasaccharide
k that inhibits activated factor X. It is licensed for prophylaxis in S k
patients undergoing major orthopaedic surgery of the legs. It has
more recently been superseded by the NOACs. However, it still has a
useful role in patients where heparins are contraindicated.
NOACs
NOACs include direct thrombin inhibitors (dabigatran) and factor Xa
inhibitors (rivaroxaban and apixaban). Currently all agents are only
licensed for use as prevention of VTE in patients undergoing hip or
knee replacements.6 Dose and duration of course are dependent on
patient factors and type of surgery. Timing and initiation of therapy
must be considered due to the associated bleeding risk. NOACs can be
used after LMWHs to complete the recommended course if a patient is
nil-by-mouth following surgery.
Antibiotic prophylaxis
Refer to your local guidelines that should be in place to ensure
appropriate prescribing of antibiotics for surgical procedures, which
take into account local antibiotic resistance patterns. Antibiotic
prophylaxis presurgery is important in the prevention of surgical site
infections (SSIs), which are a type of healthcare-associated infection.
At least 5% of patients undergoing a surgical procedure develop
SSIs.7 Other factors may predispose the patient to an increased risk of
postoperative infections, most commonly, urinary tract infections and
chest infections.
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The risk factors for postoperative infection include:
● the patient’s overall state of health (respiratory comorbidities

increase the risk of chest infections and so patients should be
highlighted for postoperative physiotherapy)
● age
● decreased blood supply to the operation site (e.g. in diabetic
patients postamputation)
● foreign material in the wound
● concomitant medication (long-term antibiotics and
corticosteroids)
● operative and environmental factors (these include the surgeon’s
skill and theatre cleanliness).
Antibiotics should not routinely be used to prevent such infections but

precautions should be in place to reduce this risk, i.e.:
● early mobilisation
● adequate hydration
● chest physiotherapy
● medicines optimisation (e.g. review of opioid use to allow adequate
mobilisation).
Operations are classified into ‘clean’ (elective, no trauma, no break in

technique), ‘clean contaminated’, ‘contaminated’ or ‘dirty – infected’
k S (the latter may include spillage from the GI tract and traumatic k
emergency). Usually antibiotic prophylaxis is given to patients in the
clean contaminated category and further doses that constitute
treatment may be given for contaminated or dirty surgery.8
The choice of antibiotic is related to the bacteria that would most
likely be found at the site of surgery. Generally a broad-spectrum
antibiotic that covers both anaerobic and aerobic bacteria is
recommended.
The timing of administration of antibiotics is important to ensure
optimum blood levels at the time of incision. The route of choice is
usually intravenous to ensure adequate serum antibiotic
concentration is achieved. However, it is common practice to give a
dose of oral ciprofloxacin 1 or 2 hours before an endoscopic
retrograde cholangiopancreatography. ‘Stat’ doses of antibiotics
should have minimal adverse effects on the patient, and should be
clearly documented in the anaesthetic records. Care must be taken to
review the appropriateness of the antibiotic agent used and the
duration of therapy should be kept to a minimum (a single dose is
usually sufficient).6
Pain management
When managing pain postoperatively, use the World Federation of
Societies of Anaesthesiologists analgesic ladder (see Pain
management entry). Begin with a strong opioid and step down as the
patient’s pain improves, adding in adjuvant therapies as necessary.
k
k
Regular analgesia initially is better than when required as acute pain

is much more difficult to manage if it becomes out of control.9
An extensive review of postoperative pain and pain relief after major
surgery indicates that about 1 in 5 patients experienced severe pain
and only poor or fair pain relief after surgery.10
Many procedures will use an epidural or patient-controlled opioid
analgesia immediately postoperatively. These two methods have
good evidence to support their use, both in patient compliance and
in reducing length of hospital stay and improving outcomes
(see Patient-controlled analgesia and Epidural analgesia in the
postoperative period entries).
The efficacy of analgesics in acute pain is documented in greater
detail in the Oxford league table of analgesic efficacy, where the
analgesics are graded according to their number needed to treat
(NNT: i.e. number of patients who need to receive the active drug for
one to achieve at least 50% relief of pain compared with placebo over
a 4 –6-hour treatment period). More information can be found on the
Bandolier website: http://www.medicine.ox.ac.uk/bandolier.
The most effective drugs have a low NNT of just over 2. A combination
of a simple analgesic with weak opioids improves the NNT and this
theory should be put into practice by administering coanalgesics such
as paracetamol and NSAIDs.
Oral administration of medication may not be practical
perioperatively; therefore, use of intravenous paracetamol or
k suppositories may be appropriate. Suppositories should be used with S k
caution when patients have had colorectal surgery as the anastomosis
(surgical join between two sections of bowel) may be low in the GI
tract, or the anatomy of the bowel may have changed. Check that
rectal administration is an accepted local policy in these cases. The
intravenous COX-2 inhibitor parecoxib is also licensed for short-term
treatment of postoperative pain; however, caution needs to be taken
in patients with impaired renal function and
cardiovascular/cerebrovascular risk factors.
As soon as the patient is able to tolerate oral medicines, the
epidural or patient-controlled analgesia can be changed to oral strong
opioids or stepped down to a weak opioid, with the continued use of
the NSAID and paracetamol as appropriate.
REFERENCES
1 ERAS Society (2014) http://www.erassociety.org (accessed 27 November 2014).
2 Niranjan N et al. (2014). Enhanced Recovery After Surgery – Current trends in
peri-operative Care. Update in anaesthesia. www.anaesthesiology.org (accessed
7 October 2014).
3 SIGN (2014). Prophylaxis of Venous Thromboembolism. www.sign.ac.uk (accessed
7 October 2014).
4 Geerts WH et al. (2004). Prevention of venous thromboembolism. The seventh
4. ACCP conference on antithrombotic and thrombolytic therapy. Chest 126:
338S–400S.
5 NICE (2010). Venous Thromboembolism: Reducing the risk. www.nice.org.uk/
guidance/cg92 (accessed 7 October 2014).
k
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440 Synacthen (tetracosactide) tests
6 Electronic Medicines Companion (2014). www.medicines.org.uk/emc/ (accessed

7 October 2014).
7 NICE (2008). Surgical Site Infection: Prevention and treatment of surgical site
infection. www.nice.org.uk/guidance/cg74 (accessed 7 October 2014).
8 Rahman MH, Anson J (2004). Perioperative antibacterial prophylaxis. Pharm J
272: 743–745.
9 Millen S, Sheikh C (2003). Anaesthesia and surgical pain relief. Hosp Pharmacist
10: 442–450.
10 Dolin S et al. (2002). Effectiveness of acute postoperative pain management:
I. Evidence from published data. BMJ Anaesth 89: 409–423.
Synacthen (tetracosactide) tests

Synacthen contains tetracosactide acetate, which consists of the first
24 amino acids in natural adrenocorticotrophic hormone (ACTH),
and displays the same physiological properties as ACTH.
Synacthen can provoke hypersensitivity or an anaphylactic
reaction, and is contraindicated in patients with allergic disorders,
e.g. asthmatics. If a reaction occurs, it is most likely within 30 minutes
of the injection, so the patient should be closely monitored during this
time and staff prepared to respond as appropriate to the situation.
The short Synacthen test
The short Synacthen test or 30-minute Synacthen diagnostic test is
k S used: k
● to check the ability of the adrenal cortex to respond to an acute
maximal ACTH stimulus
● in the investigation of Addisonian disorders (see Addison’s disease
entry)
● to check for hypopituitarism.
Dose
Table S5 shows the dose for adults and children.
TABLE S5
Dose of tetracosactide for the short Synacthen test
Age Dose
Adults 250 micrograms
Children Standard test: 145 microgram/m2 (max. 250 microgram)1,2
Low-dose test: 300 ng/m2
Procedure
A blood sample is taken to measure the baseline plasma cortisol
concentration and then the tetracosactide injection is given by
intravenous or intramuscular injection.1 Another blood sample is
taken exactly 30 minutes after the injection. In tests for
hypopituitarism, a further blood sample is taken at 60 minutes
postinjection.
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Synacthen (tetracosactide) tests 441
Adrenocortical function can be regarded as normal if the

postinjection plasma cortisol concentration rises by 200 nmol/L
(70 micrograms/L) or more, but check local policy.
Long Synacthen tests
Long Synacthen tests may be used in the investigation of
adrenocortical insufficiency:
● following inconclusive results of the ‘short’ 30-minute test
● to check whether adrenal failure is primary or secondary
● following unilateral adrenalectomy for Cushing’s syndrome
● following long-term steroid therapy.
In practice, long Synacthen tests may offer little additional
information that cannot be obtained from a short Synacthen test.
Synacthen depot is not licensed for children under 3 years of age due
to the presence of benzyl alcohol in the formulation.
Procedure
A blood sample is taken to measure the baseline plasma cortisol
concentration and then 1 mg tetracosactide depot intramuscular
injection is given.3 Further blood samples are taken at 30 minutes, 1,
2, 3, 4 and 5 hours after the injection.
If adrenocortical function is normal, baseline plasma cortisol
(normally >200 nmol/L) doubles in the first hour and then continues
to rise slowly, as shown in Table S6.
k S k
TABLE S6
Anticipated cortisol serum concentrations
following a long Synacthen test
Time nmol/L
1st hour 600–1250
2nd hour 750–1500
3rd hour 800–1550
4th hour 950–1650
5th hour 1000–1800
If plasma cortisol rises more slowly than indicated above, this may be
the result of Addison’s disease, secondary adrenocortical insufficiency
due to a disorder of hypothalamopituitary function or overdose of
corticosteroids.
A 3-day test is sometimes performed with 1 mg tetracosactide
depot intramuscular injection given each day. If the plasma cortisol
level is >500 nmol/L at the end of the test, then adrenal insufficiency
is likely to be secondary rather than primary.
REFERENCES
1 SPC (2011). Synacthen Ampoules 250 mcg. www.medicines.org.uk (accessed 13 May
2015).
2 BNFC (2014). London: British Medical Association and Royal Pharmaceutical
Society of Great Britain.
3 SPC (2011). Synacthen Depot. www.medicines.org.uk (accessed 13 May 2015).
k
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442 SIADH
Syndrome of inappropriate secretion of

antidiuretic hormone
Overview
Definition Hyponatraemia is defined as an excess of water in relation to sodium in
the extracellular fluid. It is the most common electrolyte imbalance in
hospital inpatients, with 15–20% showing sodium serum concentrations
of <135 mmol/L. Syndrome of inappropriate secretion of antidiuretic
hormone (SIADH) is the most frequent cause of euvolaemic
hyponatraemia
Risk factors The risk of SIADH rises with increasing age. There are also a myriad of
causes that can be categorised as related to malignant diseases,
pulmonary diseases and disorders of the central nervous system. In
addition, a variety of drugs can stimulate the release of arginine
vasopressin or potentiate its action. These include:
● SSRIs and tricyclic antidepressants
● carbamazepine
● NSAIDs
● antipsychotics
Differential The differential diagnoses of SIADH include other hyponatraemic
diagnosis conditions, which can be divided into those that cause impairment in
urinary water excretion and those in which renal handling of water is
normal. All patients with hyponatraemia should have a plasma osmolality
k S measured to confirm hypo-osmolality. Other possibilities include: k
● acute renal failure
● chronic renal failure
● addison’s disease and adrenal crisis
● diabetic ketoacidosis
● hypothyroidism and myxoedema coma
Diagnostic ● Low plasma Na+ (<135 mmol/L)
tests ● Low plasma osmolality (<275 mOsmol/L)
● Submaximally dilute urine osmolality (>100 mOsmol/kg)
Treatment ● Return to normal plasma sodium range (135–145 mmol/L)
goals
Treatment ● Fluid restriction
options ● Demeclocycline
● Tolvaptan
Assess The treatment of SIADH and the rapidity of correction of hyponatremia
depend on the degree of hyponatraemia, on whether the patient is
symptomatic and on whether it is acute (<48 hours) or chronic1
Essential Emergency (symptomatic, severe and acute <48 hours): The goal is to
intervention correct hyponatraemia at a rate that does not cause neurological
complications. The objective is to raise serum Na+ levels by
0.5–1 mEq/hour, and not more than 10–12 mEq in the first 24 hours.
Administration of hypertonic sodium chloride 3% is used (2.7% is more
widely available in the UK), but its use should be restricted to emergency
circumstances, and both neurological symptoms and serum Na+ should
be monitored frequently to achieve the desired target and to prevent
overcorrection2
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Water restriction. The degree of restriction depends on the prior water

intake, the expected ongoing fluid losses, and the degree of
hyponatraemia. Water restriction to about 500–1500 mL/day is usually
prescribed. The main drawback of fluid restriction is poor compliance due
to an intact thirst mechanism.2
Secondary Demeclocycline is a tetracycline derivative that causes a partial
intervention nephrogenic diabetes insipidus. Its limitations include a slow onset of
action (2–5 days) and an unpredictable treatment effect. It is used
off-licence; however, it is cheap and easy to administer and therefore is the
first-line choice for medical therapy. The dose is initially 0.9–1.2 g, given
daily in divided doses, reduced to 600–900 mg daily for maintenance3
Secondary Tolvaptan is a selective vasopressin V2 -receptor antagonist (there are
intervention usually excessive levels of vasopressin in the pathophysiology of most
types of SIADH). Tolvaptan aims to prevent the excess water absorption
that causes hyponatraemia by blocking these effects. When taken orally
there is an increase in urine excretion, resulting in decreased urine
osmolality and increased serum sodium concentrations.4 The dose is
15 mg once daily, increased as required to max. 60 mg daily.3
Due to the expense of ‘vaptans’, the need to start in the hospital and a
lack of clear long-term benefit, they are only recommended when
traditional measures, such as fluid restriction, have been unsuccessful.
Continued ● Plasma Na+
monitoring ● Volume status
REFERENCES
k 1 Ellison DH, Berl T (2007). The syndrome of inappropriate diuresis. N Engl J Med S k
356: 2064–2072.
2 Thomas CP (2014). Syndrome of Inappropriate Antidiuretic Hormone Secretion.
Medscape. http://emedicine.medscape.com/article/246650-overview (accessed
19 November 2014).
4 Verbalis J et al. (2011). Efficacy and safety of oral tolvaptan therapy in patients with
the syndrome of inappropriate antidiuretic hormone secretion. Eur J Endocrinol
163: 725–732.
Syringe pumps
Syringe pumps are portable, battery-operated devices for delivering
medicines by continuous subcutaneous infusion. The most common
clinical use for syringe pumps is in the palliative care setting where
the administration by this route can be helpful in the management of
symptoms when the oral route cannot be used (Tables S7 and S8).
Typically patients may present with one or more of the following:
● intestinal obstruction
● difficulty swallowing
● persistent nausea with or without vomiting
● mouth, throat and oesophageal lesions
● unconsciousness or fluctuating consciousness
● malabsorption
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444 Syringe pumps
TABLE S7
Potential advantages and disadvantages of using a
syringe pump in palliative care
Advantages Disadvantages
Ability to control more than one symptom Reliance on trained health professionals
through a single infusion
Reduces need for when required bolus Site discomfort
injections
Stability of medication doses over 24 hours Risk of psychological dependence
Reduces oral medication burden Portable – but adds practical burden
Portable device Stigma of being associated with dying
TABLE S8
Preferred sites to insert a subcutaneous needle for a
syringe pump
Preferred sites Sites to avoid
Chest wall Active radiotherapy sites
Outer thighs Broken, inflamed or
infected skin
Upper arms Lymphoedematous limbs/
ascites
Abdomen Near bony prominence/
joints
k S Scapula (consider if the k
patient is agitated and
may pull the infusion out)
● an unsatisfactory response to oral medications, for example,

intractable pain despite upwards titration of analgesia, and where
the rectal, sublingual or transdermal routes of administration are
inappropriate.
In 2010, the National Patient Safety Agency issued guidance on the

technical standards that syringe pumps had to comply with in order to
improve their safety in clinical practice.1 The commonly used Graseby
syringe drivers (MS16a and MS26) were not compliant with these
standards and have now been replaced by other models. One of the
most popular is the CME Medical T34 (formerly known as the
McKinley T34).
Ask your palliative care team for a copy of their syringe pump
clinical guidelines for more information.
Clinically screening the prescription
Medicines used together in a syringe pump should be checked for
compatibility. Combinations may be compatible only at certain
concentrations; therefore, the concentration of each medication in
the syringe should be compared with compatibility data, not the dose.
Standard reference sources include The Syringe Driver2 and the
Palliative Care Formulary3 and online at: http://www.pallcare.info/.
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Syringe pumps 445
The BNF carries some limited information about compatibilities in the

section ‘Prescribing in palliative care’.4 Consider the following when
there is a lack of compatibility data:
● Medicines with a similar pH are more likely to be compatible.
● Medicines commonly used in a syringe pump are acidic in solution;
therefore more alkaline medications such as dexamethasone,
diclofenac, furosemide, ketorolac and phenobarbital can cause
compatibility problems if added. A second syringe pump should be
considered to administer such medicines.
● Exposure of the syringe mixture to extremes of temperature and
light can affect stability and should be avoided where possible.
● In general, medications tend to be more stable in lower
concentrations in solution. Therefore, use a larger syringe with
more diluent where possible.
● Medications with long durations of action can be given equally well
as a bolus subcutaneous or intravenous injection once or twice
daily, for example dexamethasone and levomepromazine. This
avoids the need to add to a continuous subcutaneous infusion that
may affect stability.
● Skin irritation around the needle site, poor symptom control or an
unexpected loss of symptom control may result from medications
becoming unstable when mixed together. Frequent checks of the
syringe pump contents for precipitation or discoloration, as well as
the patient’s condition, are essential.
k S k
Medicines are commonly prescribed for pain, nausea and/or
vomiting, agitation and distress, and respiratory tract secretions. If a
range of doses is prescribed, the lowest possible dose of medication
should be used to control the symptom. Bolus subcutaneous doses of
medicines should be prescribed for ‘when required’ use to treat
breakthrough of any of the patient’s symptoms. It is also good practice
to anticipate symptoms and prescribe medications in case of future
need. Patients with evidence of abnormal renal or liver function, as
well as frail, elderly patients may require dose adjustments. The
prescription should be reviewed daily in light of any ‘when required’
bolus doses given and the dose of the medicines in the syringe pump
adjusted accordingly. Patients must be referred to the palliative care
team where symptoms remain uncontrolled.
Medicines doses and their frequencies may vary between
organisations; ask your palliative care team for a copy of their syringe
pump clinical guidelines for more information, and make contact
with your local palliative care pharmacist for support.
Preparing and monitoring the syringe pump
The preparation of a syringe pump is a complex process that is
undertaken by healthcare professionals who are trained to do so, for
example nurses and doctors.
Pharmacy staff can offer help in some basic aspects of monitoring
of the syringe pump while it is in use, including:
● the needle is firmly in place and there are no signs of skin
inflammation
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446 Syringe pumps
● the solutions in the syringe and line are clear

● the battery light is flashing green
● the pump is silent; there is no alarm sounding.
The palliative care team must be contacted urgently if there is a
concern that the pump may be malfunctioning.
Offering general advice to the patient and relative/carer
Pharmacy staff can offer the following advice:
● Avoid spilling liquids on the syringe pump, or dropping it, and
report if the battery light stops flashing green or the alarm sounds.
● Support the syringe pump when mobile, for example carry it in a
pocket or holster.
● Do not lose the syringe pump; most palliative care teams have
arrangements for returning pumps that are no longer required.
● Check the patient and relative/carer have been offered an
information leaflet by their palliative care team.
Medicines reconciliation of syringe pumps

There is a substantial body of evidence that shows when patients
move between care providers that risk of miscommunication and
unintended changes to medicines remain a significant problem.5 This
is particularly challenging for patients receiving medicines via a
syringe pump. Routine sources of information used to reconcile
medicines, e.g. discharge letters and discharge medication labels,
k S
may not be helpful as they will often state doses as a range, and they
k
may not distinguish medicines currently being administered from
those prescribed in case of future anticipatory needs. This can lead to
medication errors, a failure in symptom control and the possibility of
readmission.
Pharmacists should check with their palliative care team what
arrangements are in place to facilitate medicines reconciliation and
identify how they may be able to help; for example, encouraging the
patient and relative/carer to carry important information about their
medications if they have to move.
REFERENCES
1 National Patient Safety Agency (2010). Rapid Response Report. NPSA/2010/RRR019
2010 www.nrls.npsa.nhs.uk (accessed 13 May 2015).
2 Dickman A, Schneider J (eds) (2011). The Syringe Driver: Continuous subcutaneous
infusions in palliative care (3rd edn). Oxford: Oxford University Press.
3 Twycross R et al. (eds) (2011). Palliative Care Formulary (4th edn). Palliative-
drugs.com. Oxon: Radcliffe Press.
5 Royal Pharmaceutical Society (2012). Keeping Patients Safe When they Transfer
Between Care Providers – Getting the medicines right. http://www.rpharms.com/
previous-projects/getting-the-medicines-right.asp (accessed 11 December 2014).
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Theophylline 447
T
Theophylline
Theophylline is a xanthine derivative, which exerts its therapeutic
effect by relaxing bronchial smooth muscle and is used to manage
reversible airways obstruction. Theophylline also stimulates the
central nervous system and cardiac muscle, and acts on the kidneys to
produce diuresis.1
Different brands of modified-release theophylline have differing
release characteristics and bioavailabilities, therefore patients should
not swap brands without supervision.2
The difference in bioavailability of modified-release formulations
can be up to 20%. Twice-daily dose regimens of theophylline achieve
peak plasma levels between 4 and 8 hours. Theophylline is 40 –60%
k bound to plasma proteins.1,3 k
Theophylline is metabolised in the liver and many diseases, drugs T
and even dietary preferences can affect the rate of elimination. These
factors are important because theophylline has a narrow therapeutic
range.1,3
Pharmacokinetic variations between individuals, such as age, disease,
smoking status, diet and drug interactions, all affect serum
concentration levels of theophylline. Doses should be adjusted for
patients individually and serum concentration monitored to avoid
toxicity and ensure effectiveness (see Table T1).1
Theophylline may have a bronchodilator effect at ‘subtherapeutic’
serum concentrations; ensure the patient is being treated rather than
serum levels meeting the therapeutic range.2
Serious toxicity is related to high serum theophylline
concentrations; the patient may not present with any minor
symptoms first.1
Dose
The adult dose of oral theophylline is initiated with a modified-release
preparation. Doses range from 175 mg to 500 mg twice daily, adjusted
according to clinical response and serum concentration levels.2
Table T2 provides guidance for any action from a given plasma
concentration, but local policy should always be followed.
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448 Theophylline
TABLE T1
Half-life1 Adult (healthy): 7–9 hours (elderly: 10 hours, smokers:
4–5 hours)
Children: 3–5 hours
Pretreatment Liver function tests (LFTs), smoking status, weight (and height
measures2 for obese patients to calculate ideal body weight)
Also consider age and assess for cor pulmonale and heart failure
Therapeutic range 10–20 mg/L (55–110 micromol/L)2
Sampling time of Initiation of oral treatment: after 5 days
plasma theophylline Dose adjustments to oral treatment: after at least 3 days
concentrations2 (Oral theophylline levels should be taken 4–6 hours postdose).
Intravenous (aminophylline):
1 Prior to infusion (if the patient has been taking theophylline
or aminophylline orally); if possible, wait for results.
2 After infusion initiation: 4–6 hours, then every 24 hours
TABLE T2
Action to be taken based on plasma theophylline
concentration3
Plasma level (mg/L) Result Action
<5 Too low Increase dose by 25%
5–20 Correct Maintain dose providing patient is clinically responding
k 20–25 Too high Decrease dose by 10% k
25–30 Too high Miss next dose and decrease subsequent doses by 25%
T
>30 Too high Miss next two doses and decrease subsequent doses
by 50%
Administration of intravenous aminophylline

Aminophylline (a mixture of theophylline and ethylenediamine) is
given intravenously to relieve bronchospasm in asthma and chronic
obstructive pulmonary disease.3
A loading dose of 250 –500 mg (5 mg/kg) aminophylline may be
given if the patient has not been treated previously with oral
theophylline. This is given by slow intravenous injection over a
minimum of 20 minutes. This can be followed by a maintenance
infusion.2
No loading dose is required for patients who have been receiving
oral theophylline; after checking levels, commence a maintenance
infusion.
The maintenance aminophylline infusion should be given at a rate
of 500 –700 micrograms/kg/hour (300 micrograms/kg/hour in the
elderly, in cor pulmonale, heart failure or liver disease). The rate can
be adjusted according to plasma theophylline concentration.2
To prevent overdosing in obese patients the ideal body weight
based on the patient height should be used to calculate the dose.2
k
k
Theophylline 449
It is useful to recommend the use of a standard-strength solution,

e.g. 500 mg aminophylline in 500 mL of glucose 5% or sodium
chloride 0.9%.2 The rate of infusion can be adjusted according to
response and concentration levels.
Toxicity
Side effects are common, e.g. nausea, vomiting, diarrhoea and
palpitations, and can occur even when the serum concentration is
within the normal range.1
At higher serum concentrations, more serious side effects are
observed, such as tremor, cardiac arrhythmias and seizures.
Hypokalaemia may also occur and can be exacerbated by other
hypokalaemic drugs.1,2
Treatment
Seek specialist advice from the National Poisons Information Service
(http://www.toxbase.org). The stomach should be emptied. It may be
necessary to give repeated doses of activated charcoal. Monitor the
ECG and maintain fluid balance. Check serum theophylline
concentration every 4 hours after ingestion and at 4 –12-hourly
intervals thereafter if symptoms are severe.1,3
Interactions
Examples of drugs that increase serum concentration of theophylline
include:
k ● allopurinol, cimetidine, ciprofloxacin, diltiazem, erythromycin, k
fluconazole, interferon-alfa, oral contraceptives, nifedipine, T
norfloxacin, verapamil.2
Examples of drugs that decrease serum concentration of theophylline
include:
● barbiturates, carbamazepine, phenytoin, rifampicin, ritonavir,
sulfinpyrazone, St John’s wort, tobacco smoking.2,4
When ciprofloxacin or erythromycin is added to the prescription of a
patient receiving theophylline it is a recommended precaution to
reduce the dose of theophylline by 25 –50% for the duration of the
antibiotic course.4
A pragmatic approach with a modified-release preparation is to
omit either the morning or the nighttime dose if each individual dose
cannot be halved. Remember to reinstate the original theophylline
dose when the interacting drug is withdrawn.
Avoid concomitant use of theophylline and fluvoxamine. If this is
not possible, the dose of theophylline should be halved.2
Smoking tobacco and cannabis can cause a reduction in
theophylline levels. Patients who stop smoking should have plasma
theophylline levels monitored carefully.4
REFERENCES
1 Brayfield A (ed.) (2014). Martindale: The complete drug reference. www.medicines
complete.com (accessed 25 November 2014).
k
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450 Thyroid function
3 eMC (2014). www.medicines.org.uk/emc (accessed 25 November 2014).
4 Baxter K, Preston CL (eds) (2014). Stockley’s Drug Interactions. www.medicines
complete.com (accessed 25 November 2014).
Thunderclap headache
Thunderclap headaches are very severe and have a sudden onset;
typically they peak within 60 seconds. The pain may fade after
60 minutes but some headaches can last for several days.
Thunderclap headaches may be primary or secondary. There are
many causes1 and treatment will depend on the cause of the
headache. Patients presenting with a thunderclap headache should
be referred urgently to an emergency department for consideration of
a secondary cause, as it may be caused by a subarachnoid
haemorrhage.2
Some of the common causes of a thunderclap headache are:3
● subarachnoid headache
● reversible cerebral vasoconstriction syndrome: there is no
evidence-based treatment, patients should rest, and all vasoactive
substances should be stopped and avoided. Nimodipine has been
used in an unlicensed capacity to treat this, although evidence is
k scarce. A suggested dose is 30 –60 mg orally every 4 hours or k
T 0.5 –2 mg/hour intravenously if the oral regimen fails or images
showed cerebral vasospasm.4
Less common causes include: intracerebral haemorrhage, cerebral

venous sinus thrombosis, arterial dissection, pituitary apoplexy,
infection.
REFERENCES
1 Devenney E et al. (2014). A systematic review of causes of sudden and severe
headache (thunderclap headache): should lists be evidence based? J Headache Pain
15: 49.
2 SIGN Guideline 107 (2008) Diagnosis and Management of Headache in Adults.
http://www.sign.ac.uk/guidelines/fulltext/107/ (accessed 18 November 2014).
3 Ducros A et al. (2013). Clinical review: thunderclap headache. BMJ 346: e8557.
4 Lu SR et al. (2004). Nimodipine for treatment of primary thunderclap headache.
Neurology 62: 1414–1416.
Thyroid function
The thyroid gland produces hormones that are essential for the
function and maintenance of all body systems. Since disorders of
thyroid function are common (especially in women) it is important
for pharmacists to be aware of the monitoring requirements.
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Thyroid function tests

Table T3 shows the ranges of the markers used to measure thyroid
function, although there may be some local variations depending on
the assay used by the laboratory.
TABLE T3
Normal ranges of thyroid hormones1
Hormone Range
Thyroid-stimulating hormone (TSH) 0.3–4.2 munits/L
Free triiodothyronine (T3 ) (FT3 ) 3–9 picomol/L
Free levothyroxine (T4 ) (FT4 ) 10–26 picomol/L
Total serum T3 (TT3 ) 1.3–3.1 nanomol/L
Total serum T4 (TT4 ) 66–174 nanomol/L
Hypothyroidism
There are three types of hypothyroidism:
1 primary hypothyroidism: failure of the thyroid gland to produce
thyroid hormone, due to disease (usually autoimmune)
2 secondary hypothyroidism: failure of the anterior pituitary gland to
produce TSH
3 tertiary hypothyroidism: failure of the hypothalamus to produce
thyroid-releasing hormone (TRH).
k Monitoring therapy k
Table T4 indicates the monitoring requirements for patients treated T
for hyperthyroidism. In hypothyroidism expect to see the following
biochemical results:2,3
● TSH: raised
● FT4 : lowered.
TABLE T4
Monitoring in hypothyroidism3
Half-life 7 days4
Pretreatment Prior to commencing therapy with levothyroxine, an ECG is useful
measures because changes induced by hypothyroidism may be confused
with evidence of ischaemia
Sampling time Monitoring should be 6–8 weeks after a dose change, and once
stable, should be checked annually. The blood sample may be
collected at any time of the day
Other monitoring Monitor for side effects, and correction of signs and symptoms of
hypothyroidism.
Toxicity symptoms include diarrhoea, tachycardia, insomnia and
tremors
Treatment of hypothyroidism
Oral levothyroxine (T4 ) is the treatment of choice for primary
and secondary hypothyroidism. The normal starting dose is
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452 Thyroid function
50 –100 micrograms (or 25 micrograms in the elderly and patients

with ischaemic heart disease). The dose can be increased by 25 –50
microgram increments every 6 –8 weeks according to response.
The tablets should be taken 30 minutes before breakfast as a single
daily dose because the presence of food can affect the absorption of
levothyroxine. Similarly, if patients are also taking calcium
supplements they should allow a 4-hour gap between the T4 dose and
the calcium preparation.
Liothyronine sodium injection is used to treat severe
hypothyroidism and hypothyroidism myxoedema coma. It has also
been used to maintain organ viability (unlicensed) in brain-dead
organ donors (a dose of 0.6 micrograms/kg has been given
approximately 2 hours before harvesting from heart donors).5,6
Oral liothyronine is rarely used, but can be useful when a rapid
response is needed. It has a similar action to levothyroxine, but is
more rapidly metabolised. It can precipitate arrhythmias and so must
be used with caution in the elderly.
20 micrograms liothyronine ≡ 100 micrograms levothyroxine7
Hyperthyroidism
In hyperthyroidism expect to see the following biochemical results:3
● TSH: significantly lowered
● TT4 : raised
k ● TT3 : raised k
FT4 : raised
T ●
● FT3 : raised.
The most common cause of hyperthyroidism is Graves’ disease
(caused by antibodies developing to TSH receptors). Other causes
include:
● toxic nodular goitre
● thyroiditis
● iodine-induced hyperthyroidism
● amiodarone-induced hyperthyroidism
● TSH-secreting pituitary adenoma (rare).
Treatment of hyperthyroidism
Treatment involves giving an antithyroid agent that blocks the
production of thyroid hormones. The treatment of choice is
carbimazole, which is given as a single daily oral dose at a dose
titrated to reduce FT4 levels.
Some endocrinologists use a block-replacement regimen. In this
case a carbimazole dose of 40 –60 mg daily is given to block
production of endogenous T4 , and supplemental levothyroxine is
given to prevent hypothyroidism. This strategy cannot be used in
pregnancy because T4 does not cross the placenta, whereas
carbimazole does, therefore fetal hypothyroidism can develop.8
k
k
Monitoring
Table T5 indicates the monitoring requirements for patients treated
for hyperthyroidism.
If oral carbimazole is not tolerated (usually if the patient develops
a rash or pruritus), propylthiouracil is given orally in divided doses.
The usual starting dose is 150 –400 mg daily and the maintenance
dose is 50 –100 mg daily.
Carbimazole and propylthiouracil may be used in pregnancy,
although they both cross the placenta and should be used in the
lowest possible dose after assessing the mother’s needs against the
risk to the foetus.9
Carbimazole and propylthiouracil may cause agranulocytosis and
patients should be warned to report any signs of infection, especially
a sore throat. The estimated incidence of agranulocytosis is 0.3 cases
per 1000 patient-years of treatment in European populations.10
TABLE T5
Monitoring in hyperthyroidism3
Pretreatment Consider a baseline white blood cell count for patients at risk of
agranulocytosis, e.g. the elderly, patients taking other drugs that
may cause agranulocytosis
During treatment ● Thyroid function test: periodically.
● Creatine kinase (CK) if myalgia occurs.
● LFTs: if hepatic side effects occur.
● White blood cells: if signs of neutropenia or agranulocytosis
k occur, e.g. sore throat, mouth ulcers, bruising, fever or exercise k
tiredness
T
Radioactive iodine (131 I)
If this treatment is being used then carbimazole and propylthiouracil
should be stopped at least 4 days before the dose of 131 I (as sodium
iodide solution) is given and restarted at least 3 days after treatment.5
Thyrotoxicosis
Long-acting beta-blockers, such as atenolol, propranolol or nadolol
may be used to relieve many of the symptoms of thyrotoxicosis,
especially palpitations, tremor and anxiety.
Beta-blocker treatment is short-term, usually for 2 –6 weeks, until
the antithyroid agent is effective and the symptoms have resolved.5
REFERENCES
1 British Thyroid Association (2008). Diagnosis and Management of Primary
Hypothyroidism. http://www.british-thyroid-association.org/news/Docs/
hypothyroidism statement.pdf (accessed 25 April 2015).
2 NHS Lanarkshire Acute Division (2005). Thyroid Function Tests. http://
www.show.scot.nhs.uk/monklands/index.htm?/monklands/ClinicalServices/
labServices/Biochem/notes/TFTS.html (accessed 18 August 2005).
3 Dyfed Powys Primary Care Effectiveness Team (2004). Drug Monitoring Booklet.
Dyfed Powys: National Public Health Service for Wales.
Livingstone.
5 MacFarlane I (2000). Endocrinology – thyroid disease. Pharm J 265: 240–244.
6 Jeevanandam V et al. (1994). Reversal of donor myocardial dysfunction by
triiodothyronine replacement therapy. J Heart Lung Transplant 13: 681–687.
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454 Tinzaparin dosing in pulmonary embolism

8 SPC (2014.) NeoMercazole Tablets. http:// emc.medicines.org.uk/ (accessed
13 August 2014).
9 SPC (2014). Propylthiouracil Tablets, Cell-tech. http://emc.medicines.org.uk/
10 CSM/MHRA (1999). Reminder: agranulocytosis with anti-thyroid drugs. Curr
Probl Pharmacovig 25: 3.
Tinzaparin dosing in pulmonary embolism

and deep-vein thrombosis
Dose
Tinzaparin is a low-molecular-weight heparin (LMWH) licensed for
the treatment of DVT and PE. It is administered by subcutaneous
injection at a dose of 175 units/kg body weight once a day. Peak
activity is seen around 4 hours postdose and its effects last for 24
hours. If a patient presents acutely unwell, requiring urgent
anticoagulation, and an accurate weight and renal function cannot be
obtained, the first dose of tinzaparin can be prescribed and
administered without knowing an exact weight or renal function. For
subsequent doses it is important to know an accurate weight and
renal function using creatinine clearance (CrCl) to ensure the correct
dose is used.
k Patients with a CrCl as low as 20 mL/min can use the standard k
T dose of tinzaparin and, although antifactor Xa monitoring is
recommended for patients with CrCl between 20 and 30 mL/min, it
frequently does not happen in practice. There are no data on the use
of tinzaparin at CrCl below 20 mL/min and its use below this level is
therefore unlicensed.
Preparations
Preparations containing tinzaparin 20 000 units/mL are used to
deliver treatment doses (the lower-strength 10 000 units/mL
preparations are used for prophylactic doses). Graduated syringes are
available as 10 000 units in 0.5 mL, 14 000 units in 0.7 mL and 18 000
units in 0.9 mL. There is also a 2 mL multidose vial of 20 000
units/mL, but this does contain benzyl alcohol so should not be used
for premature babies or neonates and use should be avoided in
children under 3 years and pregnant and breastfeeding women.1
Administration
Doses should be rounded to the nearest 1000 units for ease of
measurement, especially if patients are self-administering. There is an
air bubble in the syringe and this should be left in if administering the
whole syringe, but will need to be expelled if only a portion of the
syringe is required – this can be the cause of much discussion amongst
nurses but the bubble is insignificant and should not cause concern.
Larger patients may need to administer the contents of more than
one syringe to get the required dose. When checking prescriptions for
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these patients it is important to check what syringes they have been

using and what volume from each they have been administering to
avoid dosing errors.
Duration of treatment
Some patients will remain on tinzaparin for the duration of their
treatment course, usually 3 –6 months for a first DVT or provoked PE,
as detailed in NICE CG144.2 These would include active intravenous
drug users, where warfarin is not considered safe; pregnant patients,
where warfarin may cause damage to the fetus; and patients with
cancer, where LMWH has been shown to be superior to warfarin.
Warfarin initiation
Warfarin can be initiated at the same time as tinzaparin using an
appropriate loading regimen (see Warfarin treatment and monitoring
entry). Tinzaparin should be continued for at least 6 days and until
the INR is >2 on two subsequent occasions. This is due to the
hypercoagulable state that warfarin, in high doses, induces in its first
few days. Stopping the tinzaparin too early can lead to an extension of
the existing thrombus.
REFERENCES
1 SPC (2014). Innohep 20,000 IU/mL and Innohep Syringe 20,000 IU/mL.
http://www.medicines.org.uk/emc/medicine/5176 (accessed 18 September 2015).
2 NICE (2012). Venous Thromboembolic Diseases: The management of venous throm-
boembolic diseases and the role of thrombophilia testing. http://www.nice.org.uk/
k guidance/cg144 (accessed 19 November 2014). k
T
Tobramycin: monitoring and management
Tobramycin is an aminoglycoside antibiotic produced by Streptomyces
tenebrarius. It is used clinically as the sulfate salt.1 It has a similar
spectrum of activity to gentamicin and is particularly active against
Gram-negative organisms, and inhibits bacterial growth through
inhibition of protein synthesis. Like other aminoglycosides, it is not
active against anaerobic bacteria; it has no activity against
mycobacteria, including Mycobacterium tuberculosis. It has the
advantage of having a greater intrinsic activity against Pseudomonas
aeruginosa and can therefore be used to treat some
gentamicin-resistant Pseudomonas strains.1
Tobramycin has a very poor oral bioavailability and is therefore given
intravenously or by intramuscular injection. It is distributed
throughout bodily fluids and tissues in a similar manner to gentamicin
and is excreted via the kidneys, with high concentrations in the urine.
Tobramycin crosses the placenta. It is not known to be harmful in
pregnancy, but it is recommended only where the benefits clearly
outweigh the risks. It is excreted into breast milk and is therefore not
recommended in breastfeeding mothers.2
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456 Tobramycin: monitoring and management
Dose
Initial dosing is based on a patient’s weight and renal function. CrCl,
calculated using the Cockcroft and Gault equation, should be used to
estimate renal function. As with other aminoglycosides, actual body
weight is used in calculations, except for those patients who are obese
(see Gentamicin entry). Like gentamicin, dosing is either as a
multiple-daily-dosing regimen or a once-daily (unlicensed) dosing
regimen. It is important to follow your local policy.
Multiple daily dosing
For adult patients with normal renal function, the dose is 3 –5 mg/kg
in three divided doses; it is recommended that the higher dose is used
in life-threatening infections.3 Table T6 shows the initial doses in
renal impairment.
TABLE T6
Recommended doses in renal impairment
CrCl (mL/min) Recommended dose4
20–50 1–2 mg/kg, then according to serum levels
10–20 1 mg/kg, then dose according to serum levels
<10 1 mg/kg, then dose according to serum levels
Subsequent doses can be adjusted by either reducing the dose

administered every 8 hours (Table T7) or by increasing the dosage
k interval (Table T8). k
T TABLE T7
Tobramycin dose adjustment in renal impairment2
CrCl (mL/min) Adjusted dose at 8-hourly intervals
50–60 kg 60–80 kg
>70 60 mg 80 mg
40–69 30–60 mg 50–80 mg
20–39 20–25 mg 30–45 mg
10–19 10–18 mg 15–24 mg
5–9 5–9 mg 7–12 mg
<4 2.5–4.5 mg 3.5–6 mg
Predose (trough) and peak serum concentrations should be checked

around the third or fourth dose and dose adjustments made
accordingly.
Once-daily dosing
Many hospitals use once-daily dosing regimens. In patients with cystic
fibrosis, 10 mg/kg once a day up to a maximum dose of 660 mg is
recommended.5 Levels should be checked before the second dose,
and then doses adjusted accordingly (Table T9).
k
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TABLE T8
Dose frequency adjustment of tobramycin in renal
impairment
CrCl (mL/min) Normal dose at prolonged interval
50–60 kg: dose is 60 mg
60–80 kg: dose is 80 mg
>70 Every 8 hours
40–69 Every 12 hours
<4 Every 48 hours (when dialysis is not performed)
TABLE T9
Therapeutic range Multiple daily dosing: peak: <10 mg/L3
Pre-dose (trough): <2 mg/L3
Once-daily dosing: pre-dose <1 mg/L
Sampling time Peak: 60 minutes post-dose (required for multiple daily dosing
only)
Trough: pre-dose
k Other monitoring U&Es at least 2–3 times a week, urine output, consideration of k
auditory monitoring in those receiving repeated courses
T
Administration
Tobramycin may be given by intravenous infusion, intravenous bolus
over 3 –5 minutes or by intramuscular injection. If given as an
infusion (recommended for once-daily dosing), tobramycin should be
diluted in 50 –100 mL sodium chloride 0.9% or glucose 5% and given
over 20 –60 minutes.2,6
Overdose
Specialist advice should be sought.7 Most common features are
nephrotoxicity, ototoxicity and neuromuscular blockade as well as
electrolyte imbalance (e.g. hypocalcaemia, hypokalaemia).
Nephrotoxicity may be reversible. Ototoxicity may be irreversible and
may present as hearing loss or deafness or as vestibular toxicity
(dizziness, vertigo). U&Es, aminoglycoside concentrations and
assessment of auditory and vestibular function should be undertaken.
Haemodialysis should be considered in those with acute renal failure.
As onset of nephrotoxicity and ototoxicity may be delayed, patients
should be reviewed at 48 hours and 1 week.7
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458 Travel recommendations
Drug interactions2,3
The risk of ototoxicity is increased by use with loop diuretics and
vancomycin. Tobramycin is known to potentiate the actions of
warfarin and enhance the effects of non-depolarising muscle
relaxants. Use of tobramycin with general anaesthetics
(e.g. succinylcholine, tubocurarine) may potentiate neuromuscular
blockade and cause respiratory paralysis. Tobramycin antagonises the
effects of pyridostigmine and neostigmine.
REFERENCES
1 Grayson M et al. (eds) (2010). Kucers’ The Use of Antibiotics (6th edn). London:
Hodder Arnold.
2 eMC (2014). SPC Tobramycin 40 mg/mL Injection. http://www.medicines.org.uk/
emc (accessed 24 August 2014).
4 Ashley C, Dunleavy A (2014). Renal Drug Database. https://www.renaldrugdata
base.com (accessed 23 August 2014).
5 Cystic Fibrosis Trust (2009). Antibiotic Treatment for Cystic Fibrosis (3rd edn).
https://www.cysticfibrosis.org.uk/media/82010/CD Antibiotic treatment for CF
May 09.pdf (accessed 7 January 2015).
6 Gray A, Wright J, Goodey V, Bruce L. (eds) (2011). Injectable Drugs Guide. London:
7 National Poisons Information Service (2014). Toxbase. http://www.toxbase.org
k k
T Travel recommendations
An increase in easier, cheaper and more readily available
international travel has led to ever more patients seeking advice on
travel health. The following list identifies validated sources of travel
health information; the list is not comprehensive, and links may be
subject to change.
For patients
● Comprehensive disease-specific prevention (including vaccination)
and general travel health advice from NHS Scotland: http://
www.fitfortravel.nhs.uk/home.aspx.
● Country-specific clinical information and health risks: http://
www.nathnac.org/ds/map world.aspx.
● General travel information from NHS Choices: http://www.
nhs.uk/livewell/travelhealth.
● Healthy holidays section of NHS Choices (with a focus on UK
holidays): http://www.nhs.uk/LiveWell/Healthyholidays/Pages/
Healthyholidayshome.aspx7.
● General advice on travelling in pregnancy: http://www.nhs.uk/
Conditions/pregnancy-and-baby/Pages/travel-pregnant.aspx.
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Tuberculosis 459
For healthcare professionals

● Comprehensive resource, including general and disease-specific
information, regular clinical updates, country-specific advice and
outbreak surveillance: http://nathnac.org/pro/ (non-24-hour
telephone advice also available on 020 3447 5943).
● Travel vaccination and malaria prophylaxis: http://www.mims.
co.uk/TravelTables (free registration required).
● Full travel health information: http://www.travax.nhs.uk/
(requires registration, for which a fee may be payable).
● Country and patient subgroup-specific information (e.g. disaster
relief workers) on travel diseases and prevention, including patient
counselling points and a ‘healthy travel packing list’:
http://wwwnc.cdc.gov/travel/.
Other useful resources

● Public Health England: Immunisation against Infectious Disease
(The Green Book): https://www.gov.uk/government/
collections/immunisation-against-infectious-disease-the-green-
book.
● Information on the European Health Insurance Card (EHIC) and
link to the online application: http://www.nhs.uk/nhsengland/
Healthcareabroad/pages/Healthcareabroad.aspx.
● Home Office advice on travelling abroad with controlled drugs:
k https://www.gov.uk/travelling-controlled-drugs. k
T
Tuberculosis
Tuberculosis (TB) is an infectious disease, usually caused by the
bacillus Mycobacterium tuberculosis, which most commonly affects the
lungs but may affect almost any part of the body. The disease is spread
in the air by people with active pulmonary TB infection. In general, a
relatively small proportion of people infected with M. tuberculosis will
develop TB disease; however, the probability of developing TB is
much higher among people infected with HIV. Untreated disease has
a high mortality rate and remains a major global health problem.1
In the UK, the incidence of notified cases is 12.3/100 000 and is
concentrated in deprived areas and people born abroad.2 People
suffering from any form of active TB must be notified to the ‘proper
officer’ under Public Health Law (usually the Consultant in
Communicable Disease in England and Wales, or the equivalent in
Scotland and Northern Ireland) within 3 working days.3
The management of TB should be undertaken by expert clinicians
and specialist nurses. Pharmacists need to be aware of the issues
surrounding the treatment of TB and must be able to give advice on
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460 Tuberculosis
the monitoring requirements of the medication used to treat this

disease. Patient adherence to the medicine regimen is vital for
successful treatment outcomes and pharmacists can play an
important role.
Diagnosing active tuberculosis
Diagnosing pulmonary TB is usually made on a clinical and
microbiological basis. Typical signs and symptoms include:4
● cough – with or without mucus
● haemoptysis
● breathlessness – gradual increase
● weight loss – gradual
● anorexia
● fever – often with night sweats
● malaise
● cachexia.
Chest X-ray
Often this is the first indication of the presence of TB because the
symptoms may be non-specific. Chest X-ray appearance suggestive of
TB should lead to further diagnostic investigation.5
Microbiological investigations6
Culturing M. tuberculosis is the gold standard for diagnosing TB and
k multiple sputum samples should be sent to the microbiology k
laboratory.
T
1 Initially a smear test is performed, which will provide results within
24 hours, and identify patients who are ‘smear-positive’
(mycobacteria present in sputum), and who are thought to be the
most infectious.
2 Sputum is incubated to culture and identify the specific myco-
bacteria present – it may take several weeks for a positive result.
3 Susceptibility testing on positive cultures is performed to identify
strains resistance to antitubercular drugs – this may require
multiple weeks for a result.
4 Nucleic acid amplification (molecular) tests may be used to provide
considerably more rapid detection and susceptibility testing from
specimen or culture but are comparatively expensive and not
offered routinely for all patients – a decision is made on clinical
and epidemiological grounds.
Treatment of active tuberculosis
The aim of treatment is to eradicate the infection in the individual and
to control the spread of the disease. The recommended drug regimens
in the UK are listed in the BNF section 5.1.9.7 The standard
unsupervised 6-month regimen for adults is summarised in
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Tables T10 and T11. Combination preparations are commonly used to

improve adherence, unless one of the components cannot be given
because of resistance or tolerance. Drugs may also be given as
individual components if liquid formulations are required.
TABLE T10
Standard adult unsupervised 6-month tuberculosis
treatment regimen using combination preparations
Initial phase, 2-month period only
Drug Adult dose
Rifater (rifampicin, isoniazid and Body weight <40 kg: 3 tablets daily
pyrazinamide) Body weight 40–49 kg: 4 tablets daily
Body weight 50–64 kg: 5 tablets daily
Body weight ≥65 kg: 6 tablets daily
Ethambutol (may be omitted if the 15 mg/kg daily
risk of isoniazid resistance is low)
4-month continuation phase
Drug Adult dose
Rifinah (rifampicin and isoniazid) Body weight <50 kg: 3 tablets daily of Rifinah 150
following initial treatment with Body weight ≥50 kg: 2 tablets daily of Rifinah 300
Rifater
Longer treatment courses are required for meningeal TB and infection

with resistant organisms.
k k
Monitoring therapy T
Before treatment commences the following should be established:
● body weight of the patient – this is vital to ensure the correct dose
is prescribed
● hepatic function (LFTs) – a pretreatment baseline is required
● renal function (U&Es): the dose of ethambutol and pyrazinamide
should be adjusted in renal impairment
● visual acuity: ethambutol can cause optic neuropathy. This is more
common in the elderly and renally impaired. Advise the patient to
report changes in colour vision and visual field.
During treatment LFTs should continue to be monitored frequently in
high-risk patients, e.g. weekly for 4 weeks, then monthly thereafter.
● Rifampicin commonly causes a transient rise in hepatic enzymes,
usually within the first 8 weeks of therapy; however, less than 1%
lead to hepatotoxicity.
● Pyrazinamide can cause hepatotoxicity; this tends to be
dose-related.
● Isoniazid commonly causes an asymptomatic rise in hepatic
enzymes, usually within the first 8 weeks, but less than 5% develop
hepatitis, the risk increasing with patient age.9
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462 Tuberculosis
TABLE T11
Standard adult unsupervised 6-month tuberculosis
treatment regimen if combination preparations are
not appropriate
Initial phase, 2-month period only
Drug Paediatric dose Adult dose Common side effects8
Isoniazid 10 mg/kg daily 300 mg daily Transient rise in LFTs,
(max. dose peripheral neuropathy
300 mg)
Rifampicin <50 kg: 15 mg/kg Body weight GI upset, transient rise
daily (max. dose <50 kg: 450 mg in LFTs, reddish
450 mg) daily discoloration of bodily
Body weight fluids, ‘influenza-like’
≥50 kg: 600 mg syndrome
daily
Pyrazinamide <50 kg: 35 mg/kg Body weight Nausea, vomiting,
daily (max. dose <50 kg: 1.5 g daily arthralgia. Transient rise
1.5 g) Body weight in LFTs (leading to
≥50 kg: 2 g daily hepatotoxicity), rash
Ethambutol 20 mg/kg daily 15 mg/kg daily Optic neuritis, red/green
(may be omitted colour blindness
if the risk of
isoniazid
resistance is low)
4-month continuation phase
k k
Drug Paediatric dose Adult dose
T Isoniazid 10 mg/kg daily 300 mg daily
(max. dose
300 mg)
Rifampicin <50 kg: 15 mg/kg Body weight <50 kg: 450 mg daily
daily (max. dose Body weight ≥50 kg: 600 mg daily
450 mg)
If the AST/ALT level exceeds five times the ULN or if the bilirubin
level rises, treatment with rifampicin, isoniazid and pyrazinamide
should be stopped. If the patient is not unwell, wait until the patient’s
liver function returns to normal, then rechallenge with the drugs one
at a time. The following regimen may be used:10
1 Isoniazid 50 mg/day, increasing daily to 300 mg/day after
2 –3 days. If there is no reaction after a further 2 –3 days, rifampicin
should be added.
2 Rifampicin 75 mg/day, increasing to 300 mg/day after 2 –3 days,
and then to 450 mg/day (for patients <50 kg) or 600 mg/day (for
patients ≥50 kg). If there is no reaction after a further 2 –3 days,
pyrazinamide should be added.
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Tuberculosis 463
3 Pyrazinamide 250 mg/day, increasing to 1 g/day after 2 –3 days

and then to 1.5 g/day (for patients <50 kg) or 2 g/day (for patients
≥50 kg).
If there is a reaction, the offending drug should be withdrawn and
consideration should be given to an alternative regimen. If the patient
is unwell or infectious and the AST/ALT exceeds five times the ULN
then, provided they are not clinically contraindicated, streptomycin
and ethambutol may be given whilst the process of rechallenge is
undertaken as before.
Drug interactions
Potential clinically significant drug interactions to consider include:7
● rifampicin: antiarrhythmics, various antiretroviral agents, azole
antifungals, antacids, oral anticoagulants, phenytoin, lamotrigine,
calcium-channel blockers, immunosuppressants, oral
contraceptive pill, corticosteroids
● isoniazid: carbamazepine.
Adherence
Patient adherence to their drug regimen is necessary to ensure
successful treatment. The following should be considered:
● patient counselling about medication, including potential side
effects, duration of therapy, taking rifampicin on an empty stomach
and the importance of adherence
k ● use of combination products, e.g. Rifinah and Rifater
k
● intermittent dosing at higher doses three times a week. Doses are T
listed in BNF section 5.1.9
● supervised treatment (directly observed therapy or DOT) for
non-compliant patients. Patients are dosed three times weekly as
above, but the administration is supervised.
Multidrug-resistant tuberculosis
Multidrug-resistant tuberculosis (MDR-TB) is defined as resistance to
at least isoniazid and rifampicin.11 The proportion of TB cases with
MDR-TB in the UK has remained stable over the last few years at
1.6%, with the large majority of patients born outside the UK.2
Patients with MDR-TB will require a different combination of drugs
and a longer period of treatment. Five different drug types are
generally used to treat MDR-TB and usually include:
● a first-line oral agent to which the isolated organism is sensitive
● an injectable second-line (or reserve) drug, typically an
aminoglycoside
● a quinolone
● two other second-line drugs, unless it is possible to substitute one
of these for pyrazinamide or ethambutol, depending on sensitivity
results.
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464 Tuberculosis
Table T12 gives details of drugs used in MDR-TB.
TABLE T12
Drugs used in multidrug-resistant tuberculosis12
Drug Paediatric dose Adult dose TDM Common side effects
Amikacin 15 mg/kg 15 mg/kg intravenously Yes Ototoxicity and
intravenously daily nephrotoxicity
daily (maximum dose 1 g (increased risk with
daily) prolonged exposure),
neuromuscular
blockade, electrolyte
abnormalities
Bedaquiline Not currently 400 mg orally daily for No Arthralgia, chest pain,
recommended 2 weeks, then 200 mg nausea, headache,
three times a day for haemoptysis, QTc
22 weeks interval prolongation in
patients at risk
Capreomycin 15 mg/kg 15 mg/kg No Ototoxicity and
intramuscularly intramuscularly daily nephrotoxicity
daily (maximum dose 1 g (increased risk with
daily) prolonged exposure),
eosinophilia
Clarithromycin See BNFC dose 500 mg twice daily No Nausea, diarrhoea,
for respiratory (orally or intravenously) vomiting, abdominal
infections13 pain, headache, taste
k perversion, QTc interval k
prolongation in
T patients at risk
Clofazimine 1 mg/kg orally 100–200 mg orally No Red skin discolouration,
daily13 daily (up to 300 mg GI upset, ichthyosis and
daily) dry skin, pruritus, rash,
photosensitivity
reactions
Co-amoxiclav See BNFC dose 1.2 g intravenously or No Rash, urticaria, GI
for respiratory 625 mg orally 8-hourly upset, candidiasis
infections
Cycloserine 10–20 mg/kg/ 250–500 mg orally Yes Confusion, dizziness,
day orally in two twice daily somnolence
divided doses
(maximum daily
dose 1 g)
Delamanid Not currently 18–64 years: 100 mg No Dermatitis, urticaria, GI
recommended orally twice daily for upset, dizziness,
24 weeks insomnia,
>65 years: no data paraesthesias, tremor,
available haemoptysis, QTc
interval prolongation in
patients at risk
k
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Tuberculosis 465
TABLE T12
(Continued)
Imipenem/ 20–40 mg/kg >50 kg: 1 g No Rash, urticaria, GI
cilastatin (maximum dose intravenously 12-hourly upset,
2 g) <50 kg: 15 mg/kg thrombophlebitis,
intravenously intravenously 12-hourly eosinophilia, transient
8-hourly rise in LFTs, transient
rise in serum
urea/creatinine
Levofloxacin >5 years: 500–1000 mg Yes Nausea, vomiting,
10 mg/kg once intravenously or orally diarrhoea, dizziness,
daily once daily headache, transient rise
<5 years: in LFTs, QTc interval
7.5–10 mg/kg prolongation in
once daily patients at risk
Both
intravenously or
orally
Linezolid 10 mg/kg three 600 mg intravenously Yes GI upset, headache,
times daily in or orally once daily transient rise in LFTs,
children up to candidiasis,
11 years of age myelosuppression and
and 10 mg/kg neuropathy with
(maximum dose prolonged use
600 mg) twice
k daily in older k
children13 T
Both
intravenously or
orally
Meropenem 1 month to 1 g intravenously No Rash, pruritus, GI upset,
12 years: 8-hourly (with thrombocytopenia,
10–20 mg/kg co-amoxiclav) headache, transient rise
intravenously in LFTs
8-hourly.
If >50 kg use
adult dose
Moxifloxacin 7.5–10 mg/kg 400 mg intravenously Yes Nausea, vomiting,
orally once daily or orally once daily headache, dizziness,
taste perversion,
transient rise in LFTs,
QTc interval
prolongation in
patients at risk
Ofloxacin 15–20 mg/kg 400 mg intravenously Yes Nausea, vomiting,
orally once daily or orally twice daily headache, dizziness,
(maximum dose taste perversion,
400 mg) transient rise in LFTs,
QTc interval
prolongation in
patients at risk
(continued )
k
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466 Tuberculosis
TABLE T12
(Continued)
Para- 50 mg/kg/day 150 mg/kg/day orally, No GI upset,
aminosali- orally (maximum usually 8–12 g/day in hypersensitivity
cylate sodium dose 12 g) in two to four divided reactions, including
two to four doses fever and rash
divided doses.
Higher doses
have been used
Protionamide 15–20 mg/kg 15–20 mg/kg orally No GI upset, including
orally once daily once daily nausea, vomiting,
(maximum dose (max. dose 1 g) diarrhoea, anorexia,
1 g) excessive salivation,
metallic taste,
stomatitis, abdominal
pain and transient rise
in LFTs
Rifabutin 5 mg/kg orally 300–450 mg orally Yes GI upset, neutropenia,
once a day once daily uveitis, transient rise in
LFTs, rash, reddish
discolouration of bodily
fluids
Streptomycin 15 mg/kg 15 mg/kg Yes Nephrotoxicity,
intramuscularly intramuscularly once ototoxicity, rashes and
once daily daily (maximum dose urticaria, eosinophilia
k (maximum dose 1 g daily) initially, then k
T 1 g daily) initially reduce to thrice weekly.
then reduce to If >59 years: 10 mg/kg
thrice weekly once daily (maximum
dose 750 mg daily)
initially, then reduce to
15 mg/kg thrice weekly
Thiacetazone No information 150 mg daily No GI upset, dizziness,
rash. Contraindicated if
HIV-positive
Diagnosis of latent tuberculosis14

Latent TB may reactivate in later life, often associated with a
weakened immune system due to disease, drugs or older life. The
Mantoux (tuberculin skin) test and interferon-gamma release assay
(IGRA) are used to identify individuals with latent TB.
The Mantoux test involves injecting tuberculin purified protein
derivative (PPD) intradermally and measuring the individual’s skin
reaction 48 –72 hours after injection. The greater the reaction, the
more likely an individual is infected with TB. In the UK, the standard
strength of tuberculin PPD used is 2 TU/0.1 mL, with 0.1 mL injected
per test. Reading the test involves measuring the diameter of the area
k
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Tuberculosis 467
of induration (not erythema) in millimetres with a ruler.

Interpretation of the result is described in Table T13. It is possible to
obtain a false-negative result due to immunosuppression, viral illness
or live viral vaccines. The Mantoux does not provide the ability to
distinguish between previous bacillus Calmette-Guérin (BCG)
vaccination and latent TB, and requires an experienced operator to
perform the test and the individual to return for a second visit.
TABLE T13
Interpretation of the Mantoux test
Diameter of induration Positivity Interpretation
Less than 6 mm Negative No previous TB infection or BCG
vaccination
>6 mm, but <15 mm Positive Previous TB infection or BCG vaccine or
exposure to non-tuberculous bacteria
≥15 mm Strongly positive Suggests TB infection or disease
There are currently two IGRA tests commercially available and both
involve stimulating an individual’s blood with a synthetic antigen and
measuring the amount of interferon-gamma produced by T cells or
the number of active T cells. IGRAs can be used to diagnose latent TB
alone or in a two-step strategy after a Mantoux test.15 IGRAs are more
expensive than the Mantoux and are not readily available in all areas;
however, they do not require an individual to return for a second visit
for interpretation. IGRAs provide the ability to distinguish between
k previous BCG vaccination and latent (or active) TB infection and can
k
reduce the number of individuals offered chemoprophylaxis when T
there is no vaccination record or scar.
Treatment of latent tuberculosis
Chemoprophylaxis should be offered, consisting of isoniazid for
6 months or a combination of isoniazid and rifampicin for 3 months.
Doses are as for the treatment regimen described in Table T11. If
there is a high risk of exposure to MDR-TB, seek specialist advice.
Miscellaneous points
Pregnancy and breastfeeding
Standard treatment is compatible with pregnancy and breastfeeding.
Streptomycin and other aminoglycosides should be avoided as they
may be ototoxic in the foetus. For second-line drugs consult specialist
literature.
Unconscious patients16
● Rifampicin and isoniazid may be given intravenously or via a
nasogastric tube.
● Pyrazinamide tablets may be crushed and dispersed in water
(unlicensed) and given via a nasoenteric tube.
● Ethambutol tablets may be crushed and dispersed in water
(unlicensed) and given via a nasogastric tube.
● Streptomycin may be given intramuscularly.
k
k
468 Tuberculosis
Isoniazid
Isoniazid may cause peripheral neuropathy and pyridoxine 10 mg
daily should be prescribed for patients at high risk, e.g. those who are
alcoholics, diabetics, HIV-positive, in chronic renal failure or the
malnourished.
REFERENCES
1 WHO (2013). Global Tuberculosis Report 2013. http://apps.who.int/iris/bitstream/
10665/91355/1/9789241564656 eng.pdf (accessed 13 September 2014).
2 Public Health England (2014). TB in the UK 2014 Report. https://www.gov.uk/
government/publications/tuberculosis-tb-in-the-uk (accessed 13 September
2014).
3 Public Health England (2014). Tuberculosis and Other Mycobacterial Diseases:
Diagnosis, screening, management and data. https://www.gov.uk/government/
collections/tuberculosis-and-other-mycobacterial-diseases-diagnosis-screening-
management-and-data (accessed 13 September 2014).
4 Campbell IA, Bah-Sow O (2006). Pulmonary tuberculosis: diagnosis and manage-
ment. BMJ 332: 1194–1197.
5 NICE (2011). Clinical guideline 117. Tuberculosis: Clinical diagnosis and
management of tuberculosis, and measures for its prevention and control.
http://www.nice.org.uk/guidance/cg117 (accessed 13 September 2014).
6 Health Protection Agency (2013). Molecular Diagnosis of Tuberculosis (TB):
Information for health care professionals. https://www.gov.uk/government/
publications/tuberculosis-tb-molecular-diagnosis (accessed 13 September 2014).
8 eMC (2014). http://www.medicines.org.uk/emc/ (accessed 1 November 2014).
k 9 Larson ASM, Graziani AL (2014). Isoniazid Hepatotoxicity. Up to date 2014. k
http://www.uptodate.com/contents/isoniazid-hepatotoxicity?source=see link
T (accessed 21 October 2014).
10 Pozniak AL et al. (2011). British HIV Association guidelines for the treatment of
TB/HIV coinfection 2011. HIV Med 12: 517–524.
11 Lange C et al. (2014). Management of patients with multi-drug resis-
tant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus
statement. Eur Respir J 44: 23–63.
12 Potter JL, Capstick T (2014). TB drug monographs. A UK based resource to sup-
port the monitoring and safe use of anti-tuberculosis drugs and second line treat-
ment of multidrug-resistant tuberculosis. http://www.tbdrugmonographs.co.uk/
13 Paediatric Formulary Committee (2014). British National Formulary 2014–15.
London: BMJ Group and Pharmaceutical Press.bWHO (2014). Companion Hand-
book to the WHO Guidelines for the Programmatic Management of Drug-resistant
Tuberculosis. Available at: http://apps.who.int/iris/bitstream/10665/130918/1/
9789241548809 eng.pdf?ua=1 (accessed 11 May 2015).
14 Public Health England (2011). The Green Book: Tuberculosis; Chapter 32. https://
www.gov.uk/government/publications/tuberculosis-the-green-book-chapter-32
k
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kc19.tex V2 - 11/18/2015 1:57 P.M. Page 469
Tuberculosis 469
15 Public Health England (2011). Health Protection Agency Position Statement on the
Use of Interferon gamma Release Assay Tests for Tuberculosis: Draft interim guidance.
https://www.gov.uk/government/publications/tuberculosis-tb-interferon-gamma-
release-assay-tests (accessed 13 September 2014).
16 Pharmaceutical Press (2014). Handbook of Drug Administration via Enteral Feed-
ing Tubes. https://www.medicinescomplete.com/mc/tubes/current/index.htm
k k
T
k
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470 Vancomycin
V
Vancomycin
Vancomycin is a glycopeptide antibiotic with bactericidal activity
against aerobic and anaerobic Gram-positive bacteria. It is usually
reserved to treat resistant staphylococcal infections (in particular,
methicillin-resistant Staphylococcus aureus (MRSA)) in patients who
have not responded or are allergic to penicillins/cephalosporins.1
Check your local antibiotic policy to see when vancomycin is used in
your hospital.
Vancomycin is absorbed poorly from the gastrointestinal (GI) tract
and therefore is given as an intravenous infusion. The exception is for
the treatment of Clostridium difficile and enterocolitis, where
vancomycin is given orally, acting locally in the GI tract.2
Pharmacokinetic properties
Vancomycin readily diffuses into most tissues. However, it does not
k penetrate into the cerebrospinal fluid in a healthy patient. In k
meningitis, where the meninges are inflamed, therapeutic
V concentrations may be achieved. Vancomycin is excreted renally.1
Early impure formulations of vancomycin resulted in high levels of
ototoxicity and nephrotoxicity. Therapeutic drug monitoring was
recommended on the basis that toxicity could be avoided if serum
concentrations were below 40 mg/L.3 Due to the increased
prevalence of MRSA and other resistant bacteria, monitoring is now
aimed at ensuring drug levels are therapeutic to prevent treatment
failure.4
Dosing
Practice varies with regard to dosing of intravenous vancomycin;
consult your local guideline. Dosing recommendations made here are
based on a newer method of dosing devised to reach therapeutic
concentrations rapidly.4
Loading dose
To reach therapeutic concentrations rapidly, a loading dose of
vancomycin should be given irrespective of renal function. This
is dose-banded with regard to the body weight of the patient
(Table V1).
k
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Vancomycin 471
TABLE V1
Vancomycin loading dose guidance4
Patient’s actual body weight (kg) <60 60–90 >90
Loading dose 1000 mg 1500 mg 2000 mg
Maintenance dose
After the loading dose, a maintenance dose is needed based on the
patient’s renal function, with the patient’s creatinine clearance
calculated using the Cockcroft and Gault equation (see Renal
function – assessment entry). In patients who are at the extremes of
weight, anuric or in acute renal failure, creatinine clearance is less
accurate and clinical judgement is needed. If a patient’s creatinine is
less than 60 mmol/L use 60 mmol/L in the equation to avoid
overestimating renal function.
In obese patients calculate creatinine clearance using a maximum
body weight, which is the ideal body weight (IBW) × 1.2.
● For men: IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet
● For women: IBW (kg) = 49 kg + 1.7 kg for each inch over 5 feet
Table V2 shows suggested maintenance doses.
Monitoring and dose adjustment
k Fluid balance should be monitored along with at least twice-weekly k
urea and electrolytes. It is now common practice to monitor only
trough levels (pre-dose) of vancomycin and the timing of this first
level is shown in Table V2. V
The BNF recommends a trough serum concentration of
10–15 mg/L vancomycin for most infections and 15–20 mg/L in
more resistant or deep-seated infections or less sensitive MRSA
strains.5
If the vancomycin assay is in the desired range, continue with the
current dose and repeat another pre-dose level after 3 –4 days
provided renal function remains stable. If the assay is not in the
desired range, refer to Table V3 for further information.
Side effects of vancomycin
Vancomycin has an infusion rate-related side effect known as
‘red-man syndrome’, which exhibits as flushing of the skin and a
potentially dangerous drop in blood pressure. This usually can be
avoided by administering vancomycin no faster than 10 mg/min.
Ototoxicity and nephrotoxicity are recognised side effects of
vancomycin associated with higher doses of vancomycin.
k
k
V
TABLE V2
Vancomycin maintenance dose guidance4
Calculated creatinine Maintenance dose Time after loading dose Recommended infusion fluid Advised duration Time of first
clearance to start maintenance volume for each dose (either of infusion for dose vancomycin
dose sodium chloride 0.9%* or pre-dose level
472 Vancomycin
glucose 5%)
>110 mL/min 1.5 g every 12 hours† 12 hours 500 mL 150 minutes Before fourth dose
90–110 mL/min 1.25 g every 12 hours 12 hours 250 mL 150 minutes Before fourth dose
75–89 mL/min 1 g every 12 hours 12 hours 250 mL 120 minutes Before fourth dose
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55–74 mL/min 750 mg every 12 hours 12 hours 250 mL 90 minutes Before fourth dose
k
kc20.tex
10–19 mL/min 500 mg every 48 hours 48 hours 100 mL 60 minutes Before second dose
<10 mL/min oliguric or Check levels 48 hours after loading dose. Only redose when levels 250 mL 120 minutes 48 hours after dose
anuric Redose with 1 g when levels <15 mg/L <15 mg/L
*Be mindful of patient’s sodium requirements (each 100 mL of sodium chloride 0.9% contains 15 mmol of sodium).
†
Patients under 45 kg should be given a maximum starting dose of 1.25 g every 12 hours.
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k
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Vancomycin 473
TABLE V3
Vancomycin dose adjustment guidance
Pre-dose (trough) Adjustment needed to maintenance dose When to take
serum concentration subsequent level
Less than 5 mg/L Increase the dose by two dosing levels Before fourth dose
from current dosing schedule in Table V2
5–10 mg/L Increase by one dosing level in Table V2 Before fourth dose
10–15 mg/L If aiming for 10–15 mg/L: continue at After 3–4 days
current dose
If aiming for 15–20 mg/L: increase by one Before fourth dose
dosing level in Table V2
15–20 mg/L If aiming for 10–15 mg/L: decrease by one Before fourth dose
dosing level in Table V2
If aiming for 15–20 mg/L: continue at After 3–4 days
current dose
20–25 mg/L Decrease by one dosing level in Table V2 Before fourth dose
25–30 mg/L Omit next dose and decrease by two Before fourth dose
dosing levels in Table V2
>30 mg/L Omit any further doses and seek specialist advice
Interactions
Careful monitoring is required if vancomycin is given with other
nephrotoxic drugs, e.g. amphotericin, streptomycin, neomycin,
k gentamicin, kanamycin, amikacin, tobramycin, bacitracin, k
polymyxin B, colistin and cisplatin. Loop diuretics may increase the
risk of ototoxicity.
Anaesthetic drugs given with intravenous vancomycin can cause V
hypersensitivity reactions.5
Counselling
Warn the patient of its offensive taste when given orally.
REFERENCES
1 Summary of Product Characteristics (2014). Vancomycin Hydrochloride 500 mg and
1 g Powder for Concentrate for Infusion. Hospira UK. http://www.medicines.org.uk
2 Summary of Product Characteristics (2014). Vancocin Matrigel Capsules 125 mg.
Flynn Pharma. http://www.medicines.org.uk (accessed 23 August 2014).
3 Tobin CM et al.(2002). Vancomycin therapeutic drug monitoring: is there a consen-
sus view? The results of a UK National External Quality Assessment Scheme (UK
NEQAS) for antibiotic assays questionnaire. Antimicrob Chemother 50: 713–718.
4 Thomson A et al. (2009). Development and evaluation of vancomycin dosage guide-
lines designed to achieve new target concentrations. Antimicrob Chemother 63:
1050–1057.
5 Joint Formulary Committee (2014). British National Formulary (online). London:
BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com
(accessed on 23 August 2014).
k
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474 Vitamins and minerals
Venofer
Overview1 (see also Iron: guidance on parenteral dosing and administration
entry)
Form Iron (III) (as iron (III)–hydroxide sucrose complex)
● Total dose required (mg iron)
Dose
= [body weight (kg) × (target haemoglobin (Hb) – actual Hb (g/L))
× 0.24] + X
iron stores (or depot iron) and is only applicable for patients 35 kg and
above. The target Hb for these patients is 150 g/L. For patients with a
body weight below 35 kg, a 15 mg/kg dose should be used for X and
the target Hb is 130 g/L. The dose should be rounded down to the
nearest 5 mg.
● Total single dose should not exceed 200 mg of iron
● Should not be administered more than three times a week
● If total dose exceeds maximum allowed single dose, the
administration should be split
Adminis- Intravenous drip Intravenous instalments Intramuscular
tration infusion
routes Yes Yes No
Administration ● Dilute in sodium ● Administer by slow
chloride 0.9% intravenous injection
k ● Each 50 mg of iron at not more than 20 mg k
should be diluted in a (1 mL) per minute
maximum of 50 mL of
sodium chloride 0.9%
V
● Administer at a rate of
100 mg of iron in at
least 15 minutes
hypersensitivity reactions during and following each administration2
each injection
REFERENCE
1 eMC (2014). Summary of Product Characteristics Venofer (Iron Sucrose).
https://www.medicines.org.uk/emc/medicine/24168 (accessed 27 August 2014).
reactions: strengthened recommendations. https://www.gov.uk/drug-safety-
Vitamins and minerals

Many patients are interested in dietary supplements. When dealing
with queries, it is useful to be aware of the current recommended
daily amounts (RDA) of these substances and also what is considered
the maximum safe dose if patients are taking non-prescribed vitamins
and minerals (Table V4).
k
k
TABLE V4
Role, sources and recommended daily amounts of vitamins and minerals1 (reproduced by kind permission of
the Food Standards Agency)
Supplement Role Natural sources Adult RDA FSA, maximum recommended
safe daily amount
Beta-carotene See vitamin A. Kidney, liver, eggs, some fruit and N/A No more than 7 mg
(precursor of Beta-carotene’s importance to an individual vegetables, especially dried mixed fruit
vitamin A) depends upon the level of preformed vitamin A
in the diet
Boron Boron’s function is unknown but it may be Green vegetables, fruit and nuts 1–13 mg No more than 6 mg
involved in the utilisation of various elements
(including calcium, copper, magnesium), glucose,
triglycerides, reactive oxygen and oestrogen
Calcium Calcium provides rigidity in the form of calcium Milk, cheese and other dairy foods, 700 mg No more than 1500 mg
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phosphate in bones, is a component in the green leafy vegetables (e.g. broccoli,
k
maintenance of cell structure, is a cofactor for cabbage and okra, but not spinach),
many enzymes (e.g. lipase) and it has a role in soya bean products, nuts, bread and
kc20.tex
the blood-clotting mechanism. Changes in the anything made with fortified flour, fish
concentration of intracellular calcium, in where the bones are eaten, e.g.
response to a physiological stimulus, e.g. a sardines and pilchards
neurotransmitter, can act as an intracellular
signal causing events such as cell aggregation,
muscle contraction and cell movement,
secretion, transformation and cell division
Chromium It has been shown to potentiate insulin action Trace element found in the air, water 25 microgram No more than 10 mg
and thereby affect metabolism of carbohydrate, and soil, plants and animals
475
lipids and protein

(continued )
V
V2 - 10/30/2015 11:45 A.M. Page 475
k
k
V
TABLE V4
(Continued)
safe daily amount
Cobalt It is an essential trace element, being an integral Fish, nuts, green leafy vegetables, e.g. Daily amount obtained No more than 1.4 mg
part of vitamin B12 . broccoli, spinach and cereals, e.g. oats from vitamin B12
Copper It is involved in the function of several enzymes, Nuts, shellfish and offal, e.g. liver 1.2 mg No more than 3 mg
e.g. monoamine oxidase. It is thought to be
required for infant growth, host defence
mechanisms, bone strength, red and white blood
cell maturation, iron transport, cholesterol and
glucose metabolism, myocardial contractility
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and brain development

Fluoride It contributes to the formation of strong teeth As a trace element, it is present in all It is not clear how much Supplementation is not
k
and increases resistance to tooth decay animals, plants and water. Fish and tea fluoride is needed for recommended if fluoride
kc20.tex
are particularly good sources. In some good health concentration of drinking water
parts of the UK fluoride is added to >0.7 ppm (700 microgram/L)
drinking water to improve dental
health
Folic acid Folate coenzymes are involved in phases of Green leafy vegetables, peas, 200 microgram (400 No more than 1 mg
amino acid metabolism, purine and pyrimidine chickpeas, yeast extract, brown rice microgram if pregnant)
synthesis and the formation of and some fruit, e.g. oranges and
S-adenosylmethionine bananas
Germanium It has no known biological function. There is a Beans, tomato juice, oysters, tuna and N/A N/A
suggestion that it may have an involvement in garlic
carbohydrate metabolism
V2 - 10/30/2015 11:45 A.M. Page 476
k
k
Iodine Iodine forms part of the thyroid hormones, Sea fish and shellfish 0.14 mg No more than 0.5 mg
levothyroxine (T4 ) and triiodothyronine (T3 ).
Therefore, it has an involvement in the
maintenance of metabolic rate, cellular
metabolism and integrity of connective tissue
Iron The majority of functional iron is present in Liver, meat, beans, nuts, dried fruit, Male: 8.7 mg No more than 17 mg
haem proteins, e.g. haemoglobin, myoglobin e.g. dried apricots, wholegrains, e.g. Female: 14.8 mg
and cytochromes, which are involved in oxygen brown rice, fortified breakfast cereals,
transport or mitochondrial electron transfer soya bean flour and most dark green
leafy vegetables, e.g. watercress, curly
kale and spinach
Magnesium It is a cofactor for many enzyme systems. It is Green leafy vegetables, e.g. spinach, Male: 300 mg No more than 400 mg
needed for protein synthesis, for both anaerobic nuts, bread, fish, meat and dairy foods Female: 270 mg
and aerobic energy generation and for
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glycolysis. It has a role in cell division. It may be

necessary for the maintenance of an adequate
k
supply of nucleotides. It regulates the movement
kc20.tex
of potassium in myocardial cells. It is involved in

the metabolism of vitamin D, and is essential for
the synthesis and secretion of parathyroid
hormone
Manganese It is a component of a number of enzymes, e.g. Bread, nuts, cereals and green 1–10 mg No more than 10 mg
glycosyltransferases vegetables, e.g. peas and runner
beans, and tea
Molybdenum It is required in metalloenzymes, which exploit Peas, leafy vegetables, e.g. broccoli 0.1–0.3 mg N/A
the variable valency states of molybdenum, e.g. and spinach, and cauliflower
477
xanthine oxidase and sulfite oxidase

(continued )
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k
k
V
TABLE V4
(Continued)
safe daily amount
Nickel Nickel influences iron absorption and Lentils, oats and nuts N/A N/A
metabolism and may be an essential component
of the haemopoietic process
Phosphorus It is required for phospholipids that are major Red meat, dairy foods, fish, poultry, 550 mg No more than 2400 mg
constituents of most biological membranes, and bread, rice and oats
for nucleotides and nucleic acids. Phosphorus is
involved in carbohydrate, fat and protein

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metabolism and is essential for bone health.
k
Most metabolic processes derive their energy
from the phosphate bonds of adenosine
kc20.tex
triphosphate and other high-energy phosphate

compounds.
Phosphorus intake influences the
parathyroid–vitamin D axis, which maintains
the body’s calcium balance
Potassium Together with sodium, it is needed to maintain Fruit, e.g. bananas, vegetables, pulses, 3.5 g No more than 3.7 g
normal osmotic pressure within cells. nuts and seeds, milk, fish, shellfish,
Extracellular potassium concentration is a critical beef, chicken, turkey, liver and bread
determinant of neuromuscular excitability.
Potassium is also a cofactor for numerous
enzymes, and is required for secretion of insulin
V2 - 10/30/2015 11:45 A.M. Page 478
k
k
Selenium The biologically active form of selenium is Brazil nuts, bread, fish, meat and eggs Male: 75 microgram No more than 350 microgram
selenocysteine that is incorporated into Female: 60 microgram
selenoproteins. These help protect against
oxidative damage and are involved in the
production of T3 . They are involved in
antioxidant and transport functions, and in the
maintenance of the intracellular redox state
Silicon Silicon is involved in the formation of bone and Grains, e.g. oats, barley and rice N/A No more than 700 mg
connective tissues
Sodium chloride Together with potassium, it is an essential Rock salt 1.6 g No more than 2.3 g
mineral for regulating body fluid balance.
Sodium is the major determinant of extracellular
volume. Chloride is also involved in maintaining
fluid balance as it is a component of gastric and
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intestinal secretions
k
Tin There is no known biological function for tin. Fresh and tinned foods. The amount N/A No more than 13 mg
kc20.tex
There is a suggestion that it may contribute to varies dependent on the amount of tin
the structure and function of metalloenzymes in the soil where the food is grown
Vanadium No specific function has been identified. It may Seafood, meat, dairy foods, cooking N/A N/A
function as an oxidation-reduction catalyst oils, fresh fruit and vegetables
Vitamin A (retinol) It is essential to the processes of vision, Liver, cheese, eggs, oily fish (such as Male: 0.7 mg No more than 1.5 mg. Caution in
reproduction, embryonic development, mackerel), milk, fortified margarine Female: 0.6 mg pregnancy
morphogenesis, growth and cellular and yoghurt
differentiation. Vitamin A metabolites are

involved in the control of gene expression
479
(continued )
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k
k
V
TABLE V4
(Continued)
safe daily amount
Vitamin B1 It is a coenzyme in several enzymatic reactions. Pork, vegetables, milk, cheese, peas, Male: 1 mg No more than 100 mg
(thiamine) It may also be involved in the stimulation of fresh and dried fruit, eggs, wholegrain Female: 0.8 mg
neuronal cells and other excitable tissues, e.g. breads and some fortified breakfast
skeletal muscle cereals
Vitamin B2 It promotes normal growth and assists in the Milk, eggs, fortified breakfast cereals, Male: 1.3 mg No more than 40 mg
(riboflavin) synthesis of steroids, red blood cells and rice and mushrooms Female: 1.1 mg
glycogen. It helps to maintain the integrity of
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mucous membranes, skin, eyes and the nervous

system. It is involved in the production of
k
adrenaline and is thought to aid the absorption
kc20.tex
of iron
Vitamin B3 (niacin) It is the functional factor of two important Beef, pork, chicken, wheat flour, maize Male: 17 mg No more than 500 mg
coenzymes, NAD and NADP, which activate over flour, eggs and milk Female: 13 mg
200 dehydrogenases essential to electron
transport and other cellular respiratory reactions.
It is involved in the oxidation of fats and
carbohydrates, and also the synthesis of steroids
Vitamin B5 It fulfils several roles in cellular metabolism, Chicken, beef, potatoes, porridge, N/A No more than 200 mg
(pantothenic acid) including the synthesis of many essential tomatoes, liver, kidney, yeast, eggs,
molecules broccoli and wholegrains, e.g. brown
rice and wholemeal bread
V2 - 10/30/2015 11:45 A.M. Page 480
k
k
Vitamin B6 It is a cofactor in the metabolism transformation Liver, pork, chicken, turkey, cod, bread, Female: 1.2 mg Between 10 mg and 200 mg for
(pyridoxine) of amino acids. It can modify the action of whole cereals, e.g. oatmeal, Male: 1.4 mg short-term use only is considered
steroid hormones. It is essential for the wheatgerm (found in cereals and safe
manufacture of prostaglandins and the cereal products) and rice, eggs,
formation of red blood cells. vegetables, soya beans, peanuts, milk,
It is involved in cellular replication and antibody potatoes and some fortified breakfast
production. It is necessary for the function of the cereals
nervous system and is involved in the
biosynthesis of several neurotransmitters,
including serotonin, gamma-aminobutyric acid
(GABA), dopamine and noradrenaline and has a
role in the regulation of mental processes and
mood. It is also involved in sodium–potassium
balance, histamine metabolism, the conversion
CPPC
of tryptophan to niacin, absorption of vitamin
k
B12 and the production of hydrochloric acid in
the GI tract
kc20.tex
Vitamin B12 It serves as a cofactor for several enzymes Meat products and certain algae, e.g. 1.5 microgram No more than 2 mg
(cobalamin) required for the cellular import and metabolism seaweed
of folate and even-chained fatty acid synthesis
(continued )
481
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k
k
V
TABLE V4
(Continued)
safe daily amount
Vitamin C (ascorbic It is a reducing agent and an antioxidant, Strawberries, peppers, broccoli, 40 mg No more than 100 mg
acid) involved in prevention of damage from free Brussels sprouts, sweet potatoes,
radicals. It is involved in the synthesis of oranges and kiwi fruit
collagen, neurotransmitters and carnitine. It is
an enzyme cofactor, and increases the GI
absorption of non-haem iron
Vitamin D: It regulates calcium and phosphate metabolism Oily fish, liver and eggs, fortified foods, 10 microgram No more than 25 microgram
vitamin D2 and is involved in the regulation of parathyroid e.g. margarine, breakfast cereals,
(ergocalciferol) and hormone synthesis bread and powdered milk

CPPC
vitamin D3
k
(colecalciferol)
kc20.tex
Vitamin E Current information suggests that the effects of Soya, corn and olive oil, nuts and Male: 4 mg No more than 540 mg (800 units)
(D-α-tocopherol) vitamin E are consistent with an antioxidant seeds, and wheatgerm Female: 3 mg
role. It is thought to have a role in the
maintenance of membrane integrity in virtually
all cells of the body
Vitamin H (biotin/ It is an essential cofactor for enzymes involved Kidney and liver, eggs, some fruit and 0.01–0.2 mg No more than 0.9 mg
coenzyme R) in the synthesis of fatty acids, the catabolism of vegetables, especially dried mixed fruit
branched-chain amino acids and the
gluconeogenic pathway.
It may also have a role in the regulation of gene
expression
V2 - 10/30/2015 11:45 A.M. Page 482
k
k
Vitamin K: It catalyses the carboxylation of a number of Green leafy vegetables, e.g. broccoli 1 microgram No more than 1 mg
vitamin K1 protein factors involved in blood clotting, and spinach, and in vegetable oils and
(phylloquinone) including prothrombin. It is thought to be cereals. Small amounts can also be
Vitamin K2 involved in the limitation of bone growth, and found in meat (such as pork), and dairy
(menaquinone) the mobilisation and deposition of bone calcium. foods, e.g. cheese
Vitamin K3 It may be involved in reabsorption of calcium by
(menadione) the kidney tubules.
Vitamin K4 Vitamin K-dependent proteins are also thought
(menadiol) to have roles in cell signalling and brain lipid
metabolism
Zinc It is required for the synthesis and stabilisation Meat, shellfish, milk and dairy foods, Male: 5.5–9.5 mg No more than 25 mg
of genetic material and is necessary for cell e.g. cheese, bread and cereal products, Female: 4–7 mg
division and the synthesis and degradation of e.g. wheatgerm
carbohydrates, lipids and proteins
CPPC
k
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483
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k
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484 von Willebrand disease
Prescribed doses (e.g. in deficiency states, alcoholic liver disease)

will vary considerably from what is considered necessary for a healthy
lifestyle, i.e. the Food Standards Agency (FSA) maximum
recommended safe daily amount.
For detailed information on this topic, visit the FSA websites at
http://www.food.gov.uk and www.nhs.uk/livewell/healthy-eating.
REFERENCE
1 Food Standards Agency (2003). Safe Upper Levels for Vitamins and Minerals: Report
of the expert group on vitamins and minerals. http://cot.food.gov.uk/sites/default/
files/cot/vitmin2003.pdf (accessed 13 December 2014).
von Willebrand disease

Overview
Definition von Willebrand disease is a bleeding disorder caused by reduced
functioning of von Willebrand factor. von Willebrand factor is a plasma
glycoprotein responsible for normal haemostasis
Diagnosis The disease tends to be diagnosed when patients present bleeding,
usually mucocutaneously, or bleeding more after a surgical procedure or
postdelivery
Treatment ● Stopping or preventing bleeding episodes
goals
k Treatment ● Desmopressin k
options ● Tranexamic acid
● von Willebrand factor
V
Desmopressin1
Desmopressin works by increasing factor VIII levels and von Willebrand factor levels by
causing a release from stores. This usually results in levels 2–5 times the patient’s
pretreatment level
Dose ● Intravenous dose is 0.3–0.4 micrograms/kg body weight diluted in
50 mL sodium chloride 0.9% and infused over 20 minutes depending
on the product used
● One product is licensed for subcutaneous use
● This can be repeated every 12 hours if cover is still required
Side effects ● Include flushing and hypotension, which tend to be harmless. Fluid
retention should be managed by fluid restriction for 24 hours
postdose, usually to around 1 litre
Contra- ● Unstable angina
indications ● Decompensated cardiac insufficiency
Pharmacist ● Pharmacists can ensure the dose of desmopressin is correct based on
interventions a patient’s weight and is given an appropriate time prior to a
procedure, ideally immediately before. The pharmacist should ensure
the patient is aware of potential side effects and knows to restrict
fluid intake. For patients undergoing surgery, ensuring tranexamic
acid is also prescribed is important
k
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von Willebrand disease 485
Tranexamic acid
Tranexamic Tranexamic acid is an antifibrinolytic drug
acid2
Dose The local fibrinolytic dose of 1–1.5 grams (2–3 tablets) 2–3 times a day
is recommended for patients with von Willebrand disease undergoing
surgery, usually starting before surgery. If using the intravenous form,
0.5–1 grams 2–3 times a day is recommended.
Pharmacist ● Pharmacists can ensure that patients know how to take the
interventions medication and what side effects to expect, and ensure a reduced
dose is used in patients with renal dysfunction
von Willebrand disease
von ● If von Willebrand factor is required, there are specific brands that
Willebrand contain the factor alone or brands containing factor VIII and von
factor3 Willebrand factor. The combined product with factor VIII is more
common and should be used for acute bleeding episodes or
emergency surgery according to British Committee for Standards in
Haematology guidance.3
● This should be given on the guidance of a haematologist
REFERENCES
1 SPC (2014). DDAVP/Desmopressin Injection. www.medicines.org.uk (accessed 31
October 2014).
2 SPC (2014). Cyklokapron Tablets and Injection. www.medicines.org.uk (accessed 31
October 2014).
k 3 Laffan MA et al.(2014). The diagnosis and management of von Willebrand disease: k
a United Kingdom Haemophilia Centre Doctors Organization guideline approved by
the British Committee for Standards in Haematology. Br J Haematol 167: 453–465.
V
k
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486 Warfarin treatment and monitoring
W
Warfarin treatment and monitoring
The oral anticoagulant warfarin is the most widely used agent for
long-term anticoagulation in the UK. The other coumarin drugs,
acenocoumarol and phenindione, are used occasionally in people who
cannot tolerate warfarin and the information in this entry (apart from
dosing details) can also be applied to the use of these drugs.
The action of warfarin
Warfarin is a vitamin K antagonist that reduces the hepatic
production of vitamin K-dependent active coagulation factors II, VII,
IX and X, along with the regulatory anticoagulant proteins C and S, in
a dose-related way. This action results in prolongation of the
prothrombin time (‘bleeding time’) and a decreased tendency to form
k blood clots. Warfarin therefore acts to prevent enlargement of k
existing blood clots and formation of new clots. All patients treated
with warfarin require dose titration to achieve a target intensity of
anticoagulation, with dosage determined individually for each
W patient.
Monitoring of warfarin is a pharmacodynamic rather than
pharmacokinetic measure.
Bleeding and the international normalised ratio
The overwhelming treatment risk with warfarin is uncontrolled
bleeding. The desired targets or ranges for intensity of anticoagulation
have been defined for which a highly protective antithrombotic effect
is combined with an acceptable risk of bleeding – the so-called
‘Goldilocks range’ (Table W1). Intensity of anticoagulation is
expressed as the international normalised ratio (INR), which is the
prothrombin time expressed as a ratio (clotting time for patient
plasma divided by the clotting time for control plasma) corrected by a
standardising factor: the higher the INR value, the greater the level of
anticoagulation and the greater the risk of bleeding.
Length of treatment
The recommended initial treatment duration after a first episode of
confirmed VTE is 3 months. Treatment beyond 3 months may be
indicated in patients with unprovoked VTE depending on risk of VTE
recurrence and bleeding.2
k
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TABLE W1
Indications for warfarin and international normalised
ratio (INR) targets1
Indication Target (desired range) INR
Prophylaxis of venous thromboembolism 2.5 (2.0–3.0)
in high-risk patients
Treatment of VTE (including 2.5 (2.0–3.0)
thromboembolism associated with
antiphospholipid syndrome, although
warfarin is contraindicated in pregnancy)
Recurrent VTE whilst receiving warfarin 3.5 (3.0–4.0)
within therapeutic range
Prophylaxis of cardiac thromboembolism
Atrial fibrillation (AF) 2.5 (2.0–3.0)
Heart valve disease (mitral stenosis or 2.5 (2.0–3.0)
regurgitation with a history of systemic
embolism, left atrial thrombus or left atrial
enlargement), cardiomyopathy
Mechanical heart valves – range 2.5–3.5 (2.0–4.0)
dependent on prosthesis thrombogenicity
and patient risk factors for thrombosis1
Bioprosthetic heart valves (some patients) 2.5 (2.0–3.0)
Cardioversion (for 3 weeks before and 2.5 (2.0–3.0)
4 weeks after) To reduce cardioversion cancellations due
k to low INR on the day of the procedure, a k
target of 3.0 (2.5–3.5) can be used prior to
the procedure
Prophylaxis of thrombosis in patients with mechanical heart valves W

and patients with recurrent thromboembolism will be lifelong.
Prophylaxis in patients with AF at risk of stroke (as determined by
the CHA2 DS2 VASc score: see Atrial fibrillation entry) is lifelong,
irrespective of the duration of AF or if sinus rhythm is achieved.3
Warfarin and antiplatelet therapy

The routine combination of warfarin and an antiplatelet agent is not
recommended due to the increased risk of bleeding. However, in
patients with a high cardiovascular thrombotic risk, warfarin plus
aspirin or clopidogrel may be indicated.4 Unless there is a high
bleeding risk, warfarin plus aspirin for at least 12 months is indicated
in patients who have had a myocardial infarction (MI) who otherwise
need anticoagulation and who:
● have had the condition managed medically

● have undergone balloon angioplasty
● have undergone coronary artery bypass grafting (CABG).
For patients who need warfarin and have had an MI and undergone
percutaneous intervention (PCI) with a bare metal stent or
k
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drug-eluting stent, warfarin should be combined with clopidogrel for

at least 12 months.
Patients with mechanical heart valves who have had an embolic
event despite good INR control should also be considered for warfarin
plus antiplatelet therapy.1
Anticoagulation services
The anticoagulation of patients is usually the responsibility of a
consultant haematologist or sometimes a general practitioner. Some
services are hospital-based, whilst others are delivered directly within
primary care under the auspices of the primary care organisation.
Pharmacists are often involved in the management and delivery of
these services. It is important to familiarise yourself with the model of
service delivery in your locality.
Patient education
Patients must understand the implications, risks and benefits of oral
anticoagulation when commencing treatment with warfarin.
A well-informed patient will find it easier to accept the regimen
of clinic appointments, blood tests and the precautions to be
observed.
In the UK, all NHS patients are supplied with the yellow
Anticoagulant Therapy Record booklet (the ‘yellow book’).
The booklet contains a diary for recording INR results, dosing
instructions for the patient, clinic appointment dates and information
k about the safe use of warfarin. k
The following points should be included in discussion with
patients:
W ● the reason for treatment, i.e. their diagnosis

● how warfarin works (delays clotting time), the benefits of
treatment and likely length of treatment
● warfarin tablets – strengths are colour-coded:
● 0.5 mg is white
● 1 mg is brown
● 3 mg is blue
● 5 mg is pink
● explain the need to keep a selection of the available strengths in
order to manage dose changes and make sure patients know they
can use any combination of tablets that provide the required dose
● take the dose at the same time each day, usually around 6 p.m., to
allow dose adjustments to be made on the day of clinic visits
● explain why everybody needs different doses and the likely pattern
of blood tests required (i.e. blood tests daily or on alternate days
initially, decreasing over weeks eventually to every 8 or 12 weeks if
stable)
● the increased risk of bleeding and bruising and the need to see
a doctor urgently if serious bleeding occurs, e.g. uncontrolled
nose bleeds, blood in urine, conjunctival haemorrhage, vaginal
bleeding
k
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● patients should make sure that healthcare professionals are aware

of the anticoagulation prior to any invasive procedures or dental
work
● interactions with medicines – patients should always make
prescribers and pharmacists aware they are taking warfarin and
should seek advice before using any non-prescribed medicinal
substances. The major interaction problems are covered in the
booklet (see Table W4, below)
● the need to maintain a consistent diet should be stressed. Most
dietary sources of vitamin K (e.g. spinach, broccoli, avocado) do
not significantly affect the INR if eaten in moderate quantities.
Cranberry juice should be avoided due to the risk of elevated INR.
Products containing gingko biloba may also increase the risk of
bleeding. St John’s wort, ginseng and garlic may reduce blood
levels of warfarin
● alcohol should be consumed only in moderation according to the
usual recommended safe limits (the Department of Health advises
a maximum of 3 –4 units per day for men and 2 –3 units per day for
women)
● the need for adequate contraceptive measures in women of
childbearing potential.
Initiation of therapy (induction of anticoagulation)

Anticoagulation with warfarin takes 72 –96 hours to develop fully.
k An extremely rapid blockade of clotting factors (and rapid increase in k
INR) can result in a hypercoagulable state due to rapid reduction in
protein C and S levels.
Patients requiring rapid anticoagulation (active VTE, heart valve
insertion, acute-onset AF) should be treated with a parenteral W
anticoagulant until therapeutic anticoagulation is achieved with
warfarin.
Historical 10 mg loading regimens have not been shown to be
superior to 5 mg loading regimens in achieving a stable level of
anticoagulation.1 And in the elderly or in patients without active
thrombosis or in those taking amiodarone, 10 mg loading regimens
do increase the risk of high out-of-range INRs during the initiation
phase.1
A suitable 5 mg loading regimen for elderly patients or those
starting warfarin for stroke prevention in AF is given below.5
● Ensure the baseline INR is <1.4.

● Give 5 mg daily for 4 days.
● Check INR on day 5 and adjust according to Table W2.
● Check INR on day 8 and adjust according to Table W2.
● Check INR on day 15 (or day 12) and make fine dose adjustments
as appropriate.
In patients receiving concomitant amiodarone (particularly in the

elderly), initiation with a 5 mg loading regimen may result in
k
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TABLE W2
Dose adjustments of warfarin following 5 mg induction5
Day 5 INR Dose (day 5–7) Day 8 INR Dose (from day 8)
≤1.7 5 mg ≤1.7 6 mg
1.8–2.4 5 mg
2.5–3.0 4 mg
>3.0 3 mg for 4 days
1.8–2.2 4 mg ≤1.7 5 mg
1.8–2.4 4 mg
2.5–3.0 3.5 mg
3.1–3.5 3 mg for 4 days
>3.5 2.5 mg for 4 days
2.3–2.7 3 mg ≤1.7 4 mg
1.8–2.4 3.5 mg
2.5–3.0 3 mg
3.1–3.5 2.5 mg for 4 days
2.8–3.2 2 mg ≤1.7 3 mg
1.8–2.4 2.5 mg
2.5–3.0 2 mg
3.1–3.5 1.5 mg for 4 days
3.3–3.7 1 mg ≤1.7 2 mg
k 1.8–2.4 1.5 mg
k
2.5–3.0 1 mg
3.1–3.5 0.5 mg for 4 days
>3.5 Omit for 4 days
W >3.7 Omit days 5, 6 and 7 <2.0 1.5 mg for 4 days

2.0–2.9 1 mg for 4 days
3.0–3.5 0.5 mg for 4 days
excessive INRs; close monitoring and dose reduction are advised in

these patients.
For younger patients with active thromboembolism (acute VTE)
who are not taking amiodarone, a 10 mg loading regimen may be
required. An example of such a regimen is given in Table W3.
Some outpatient anticoagulant clinics may initiate with 3 mg daily
for 1 week, followed by dose increases of 1 mg daily at weekly
intervals until a therapeutic INR is achieved. However, this regimen
can delay therapeutic anticoagulation for some weeks and the impact
of this on the patient’s thrombotic risk should be evaluated before it is
employed.
Maintenance doses
The daily dose of warfarin required to achieve an INR within usual
ranges can be anything from 1 mg to 15 mg, although doses above or
below this are sometimes required. Warfarin sensitivity varies widely
k
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TABLE W3
Example of a warfarin induction dosing regimen in
patients with active thrombosis6
Day INR Warfarin dose (mg)
1 <1.4 10
2 <1.8 10
1.8 1
>1.8 0.5
3 <2.0 10
2.0–2.1 5
2.2–2.3 4.5
2.4–2.5 4
2.6–2.7 3.5
2.8–2.9 3
3.0–3.1 2.5
3.2–3.3 2
3.4 1.5
3.5 1
3.6–4.0 0.5
>4.0 0
Predicted maintenance dose
k 4 <1.4 >8
k
1.4 8
1.5 7.5
1.6–1.7 7 W
1.8 6.5
1.9 6
2.0–2.1 5.5
2.2–2.3 5
2.4–2.6 4.5
2.7–3.0 4
3.1–3.5 3.5
3.6–4.0 3
4.1–4.5 Omit the next day’s dose, then give 2 mg
>4.5 Omit the next 2 days’ doses, then give 1 mg
between individuals, and within the same person, due to variables

such as age, diet, diseases and drugs. Intercurrent illness such as
influenza can cause dramatic changes in INR requiring significant
dose adjustment.
Computer software is now widely used for dose prediction. These
programs base predictions on previous response to therapy, although
k
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sound clinical judgement and experience are also required to use

software safely.
Reversal of anticoagulation1
In patients with an elevated INR, the cause should be investigated. In
the case of over anticoagulation (INR >5.0) without bleeding,
warfarin should be withheld for 1 –2 days. In the presence of a very
high INR (>8.0), 1 –5 mg of oral vitamin K should be given. Vitamin K
(1 –5 mg orally) may also be considered in patients with an INR
between 5.0 and 8.0 if they are at increased risk of bleeding.
Correction of INR should be achieved within 24 hours. The INR
should be checked the day after administration of vitamin K in case a
further dose is required. Higher doses of vitamin K should be avoided
when correcting an elevated INR, as they can lead to overcorrection
and resistance to re-anticoagulation.
Patients with major bleeding (limb- or life-threatening bleeding)
should be managed with a four-factor prothrombin complex
concentrate plus 5 mg intravenous vitamin K (see Prothrombin
complex concentrates entry).
Patients with non-major bleeding can be managed with 1 –3 mg
intravenous vitamin K and temporary warfarin omission/dose
reduction. Intravenous vitamin K produces a more rapid correction of
the INR (within 6 –8 hours) compared with oral administration.
It should not be given intramuscularly due to the risk of haematoma
k formation or subcutaneously due to inconsistent correction. k
Intravenous vitamin K can be given as a slow bolus injection over
3 –5 minutes or as an infusion over 20 –30 minutes, diluted in 50 mL
glucose 5%.7,8
W
Drug interactions
Prescription monitoring for interacting medications is essential for
treatment with warfarin. Serious bleeding may result from poorly
managed drug therapy. Table W4 lists commonly interacting drugs,
although this is not exhaustive: if in doubt, consult the BNF9 or
Stockley’s Textbook of Drug Interactions.10
‘When required’ therapy

Regular dosing with interacting drugs may be acceptable if managed
knowingly by the anticoagulant clinic. However, patients should be
strongly warned about the risks of ‘when required’ dosing (e.g.
analgesics), which might cause an increased risk of bleeding.
Pregnancy and lactation

Warfarin must not be taken during pregnancy because the drug is
teratogenic. Subcutaneous low-molecular-weight heparin is used
where treatment or prevention of deep-vein thrombosis/pulmonary
embolism is required. Warfarin is safe when breast-feeding because
the drug does not pass into breast milk. Acenocoumarol and
phenindione should be avoided.
k
k
TABLE W4
Drug interactions with warfarin and suggested action
Drugs to avoid wherever possible
Aspirin ● See section above on warfarin and antiplatelet therapy
Analgesics ● Non-steroidal anti-inflammatory drugs (NSAIDs), ketorolac
(postoperative)
Antifungals and ● Miconazole
antibacterials
Others ● Enteral feeds containing vitamin K
Consider dose adjustment
Ulcer healing ● Cimetidine, omeprazole, esomeprazole
Antiarrhythmics ● Amiodarone, propafenone
Lipid lowering ● Fibrates, fluvastatin
Antiepileptics ● Carbamazepine, phenobarbital, primidone, phenytoin
Dependency ● Disulfiram
Antibiotics and ● Aztreonam, chloramphenicol, ciprofloxacin, clarithromycin,
antifungals co-trimoxazole, erythromycin, griseofulvin, levofloxacin,
metronidazole, neomycin, ofloxacin, rifampicin,
sulphonamides
Thyroid ● Levothyroxine
Gout ● Allopurinol
Others ● Aminoglutethimide, barbiturates, ciclosporin,
mercaptopurine, oral contraceptive steroids
k Monitor INR k
Antiarrhythmics ● Quinidine
Lipid-lowering agents ● Colestyramine, simvastatin, rosuvastatin
Antidepressants ● Selective serotonin reuptake inhibitor
Antibiotics and ● Consult BNF if not listed above W
antifungals
NSAIDs ● All drugs in this class
Others ● Anabolic steroids, corticosteroids, hormone antagonists,
ifosfamide, influenza vaccine, sucralfate
Discontinuation of therapy
It has been demonstrated that, when warfarin is no longer indicated
and the drug is discontinued, dosing may be stopped abruptly
without fear of rebound hypercoagulability.11 Thromboembolism
occurring after cessation of therapy is likely to be due to ongoing
clotting disorder and not cessation of warfarin per se.
REFERENCES
1 Keeling D et al. (2011). Guidelines on oral anticoagulation with warfarin – fourth
edition. Br J Haematol 154: 311–324.
2 NICE (2012). CG 144. Venous Thromboembolic Diseases: The management
of venous thromboembolic diseases and the role of thrombophilia testing.
http://www.nice.org.uk/Guidance/CG144 (accessed 3 September 2014).
k
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494 Wells score for deep-vein thrombosis
3 NICE (2014). CG 180. Atrial Fibrillation: The management of atrial fibrillation.

http://www.nice.org.uk/Guidance/CG180 (accessed 3 September 2014).
4 NICE (2013). CG 172. MI – Secondary Prevention: Secondary prevention in
secondary and primary care for patients following a myocardial infarction.
http://www.nice.org.uk/guidance/CG172 (accessed 3 September 2014).
5 Tait RC et al. (1998). A warfarin induction regimen for out-patient anticoagulation
in patients with atrial fibrillation. Br J Haematol 101: 450–454.
6 Fennerty A et al. (1984). Flexible induction dose regimen for warfarin and predic-
tion of maintenance dose. Br Med J 288: 1268–1270.
7 Summary of Product Characteristics (2012). Konakion MM. http://
www.medicines.org.uk/emc/medicine/1698 last updated 17.08.12 (accessed
3 September 2014).
10 Baxter K and Preston CL (2013). Stockley’s Drug Interactions (10th edn). London:
11 Baglin TP et al. (2005). Guidelines on oral anticoagulation (warfarin):
third edition – 2005 update. Br J Haematol 132: 277–285.
Wells score for deep-vein thrombosis

Background
k The Wells score is a clinical prediction rule for estimating the probability of deep-vein k
thrombosis (DVT) and pulmonary embolism (PE) that looks at various risk factors and
clinical signs associated with thromboembolic disease.
When a patient presents with signs or symptoms of DVT, the patient’s general medical
history should be assessed and a physical examination carried out to exclude other causes.
W If a DVT is suspected, NICE recommends the use of the adapted two-level DVT Wells
score to estimate the clinical probability of DVT1,2
SCORING SYSTEM
Active cancer (treatment ongoing, within previous 6 months or palliative) 1
Paralysis, paresis or recent plaster immobilisation of the lower extremities 1
Recently bedridden for 3 days or more or major surgery within 12 weeks 1
requiring general or regional anaesthesia
Localised tenderness along the distribution of the deep venous system 1
Entire leg swollen 1
Calf swelling at least 3 cm larger than the asymptomatic side 1
Pitting oedema confined to the symptomatic leg 1
Collateral superficial veins (non-varicose) 1
Previously documented DVT 1
An alternative diagnosis is at least as likely as DVT −2
k
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Wells score for pulmonary embolism 495
Interpretation
DVT unlikely – 1 point or less
DVT likely – 2 points or more
The following procedure is then appropriate to confirm diagnosis:
● a proximal leg ultrasound scan carried out within 4 hours of being requested and, if the
result is negative, a D-dimer test
or
● a D-dimer test and an interim 24-hour dose of a parenteral anticoagulant (if a proximal
leg vein ultrasound scan cannot be carried out within 4 hours) and a proximal leg vein
ultrasound scan carried out within 24 hours of being requested.2
NICE provides additional detailed guidance on interpretation of test results, possible

alternative diagnoses and further action that should be taken
REFERENCES
1 Wells PS et al. (2003). Evaluation of D-dimer in the diagnosis of suspected
deep-vein thrombosis. N Engl J Med 349: 1227–1235.
thromboembolic diseases and the role of thrombophilia testing. (CG 144.) http://
www.nice.org.uk/guidance/cg144 (accessed 28 January 2015).
Wells score for pulmonary embolism

k Background k
The Wells score is a clinical prediction rule for estimating the probability of DVT and PE that
looks at various risk factors and clinical signs associated with thromboembolic disease.
When a patient presents with signs or symptoms of PE, the patient’s general medical
history should be assessed and a physical examination and chest X-ray carried out to
exclude other causes.
W
If a PE is suspected, NICE recommends the use of the adapted two-level PE Wells score
to estimate the clinical probability of PE.1,2
SCORING SYSTEM
Clinical signs and symptoms of DVT (minimum of leg swelling and pain with 3
palpation of the deep veins)
An alternative diagnosis is less likely than PE 3
Heart rate >100 beats/min 1.5
Immobilisation for more than 3 days or surgery in the previous 4 weeks 1.5
Previous DVT/PE 1.5
Haemoptysis 1
Malignancy (on treatment, treated in the last 6 months, or palliative) 1
Interpretation
PE unlikely – 4 points or less
PE likely – more than 4 points
k
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496 Wells score for pulmonary embolism
The following procedure is then appropriate to confirm diagnosis:
● an immediate computed tomography pulmonary angiogram (CTPA)

or
● immediate interim parenteral anticoagulant therapy followed by a CTPA if a CTPA
cannot be carried out immediately.2
NICE provides additional detailed guidance on interpretation of test results, possible

alternative diagnoses and further action that should be taken.
REFERENCES
1 Wells PS et al. (2000). Derivation of a simple clinical model to categorize patients’
probability of pulmonary embolism: increasing the models utility with the
SimpliRED D-dimer. Thromb Haemost 83: 416–420.
thromboembolic diseases and the role of thrombophilia testing. (CG 144.)
http://www.nice.org.uk/guidance/cg144 (accessed 28 January 2015).
k k
k
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Y
Yellow Card scheme
In 1964, the UK Committee on Safety of Drugs provided doctors and
dentists with pre-paid yellow postcards with which to report adverse
reactions to drugs, thus creating the Yellow Card scheme. Remodelled
Yellow Cards may now be found in National Health Service
prescription pads, the BNF, and the Monthly Index of Medical
Specialities (MIMS), or may be obtained from the MHRA. Yellow
Cards may also be completed online at https://yellowcard.mhra.
gov.uk. Access to this site and the drug analysis prints (listing all
reactions reported for a particular medicine) can also be found via:
http://www.mhra.gov.uk/Safetyinformation/Reportingsafety
problems/Reportingsuspectedadversedrugreactions/index.htm.
k Action taken by the MHRA k
Once a specific problem has been identified for a medicine, the MHRA
may take action in a number of ways. It may publish the findings and
advice to prescribers in Drug Safety Update, a bulletin used to
disseminate information about ADRs to healthcare professionals.
Analysis of ADR reports received by the MHRA may also result in the Y
withdrawal of drugs from the market or the amendment of product
licences. For example, domperidone was amended from a ‘pharmacy’
medicine to a ‘prescription-only medicine’ in 2014 because of
QT-interval prolongation and arrhythmias.1 The MHRA may also
publish warnings in the BNF to highlight particular aspects of drug
safety.2 Examples include warnings about the use of beta-blockers in
asthmatics, the risks of atypical femoral fractures with
bisphosphonates, and the need for all intravenous iron preparations
to be administered by trained staff with resuscitation facilities
immediately available due to risks of serious hypersensitivity
reactions.
Underreporting of ADRs
Underreporting of ADRs is a consistent problem. It has been
suggested that the incidence of reporting of serious ADRs is at best in
the order of 10% and for non-serious ADRs it is estimated at 2 –4%.3
Even though Yellow Card scheme reporting rates are low in the UK,
k
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498 Yellow Card scheme
they compare favourably with schemes in other countries. The data

obtained through the Yellow Card scheme are therefore incomplete
and indeed, many serious and fatal reactions are never brought to the
attention of the regulatory authorities. Factors considered to dissuade
potential reporters from completing an ADR report include:4 – 6
● the reaction not being considered severe enough

● the reaction is well known
● familiarity with the suspect drug concerned
● concern over potential legal implications
● the reaction may be predictable or expected
● ignorance of how to report an ADR
● lack of time, lethargy or complacency
● lack of feedback following previous reports
● failure to identify the presence of an ADR
● guilt because of patient suffering and lack of confidence in making
a report.
The concept of a fee has been proposed as a method of stimulating

reporting and research has shown that a fee-based incentive can
increase reporting rates, but upon withdrawal of the fee, reporting
rates fall substantially.7
The data collected in the Yellow Card scheme are also open to
significant bias and caution should be exercised in their
k interpretation. Reports of reactions appearing in the medical or lay k
press may result in numerous similar reports being submitted via the
Yellow Card scheme. In turn, this may result in a ‘false-positive’ or
‘true-positive’ sign that a problem exists. An example of a
‘false-positive’ is the association of autism with measles, mumps and
rubella (MMR) vaccination.
Y The lessons of the practolol-induced oculomucocutaneous
syndrome, from the 1970s, are worth noting. Following publication of
a report on this syndrome in the medical press, over 200 reports of a
similar nature were subsequently submitted via the Yellow Card
scheme. Prior to the publication of the first report only one report had
been made to the MHRA in 4 years.4 This suggests that either
practitioners had failed to associate a serious syndrome with a
patient’s drug therapy, or that they had, but were unwilling to report
it either because it was unrecognised or for other reasons.
Intensive monitoring of medicines

The new EU pharmacovigilance legislation has introduced a
Europe-wide ‘additional monitoring’ scheme. Medicines included on
the additional monitoring list are being monitored particularly closely
by regulatory authorities and must have an inverted black triangle
(as previously used in the UK) displayed in their patient information
leaflet and SPCs, together with the following sentence:
This medicinal product is subject to additional monitoring
k
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A medicine is included on the additional monitoring list if:
● it contains a new active substance

● it is a biological medicine, such as a vaccine or a medicine derived
from plasma (blood)
● it has been given a conditional approval (where the company that
markets the medicine must provide more data about it) or approved
under exceptional circumstances (where there are specific reasons
why the company cannot provide a comprehensive set of data)
● the company that markets the medicine is required to carry out
additional studies: for instance, to provide more data on long-term
use of the medicine, or on a rare side effect seen during clinical
trials.
A medicine is included on the list when it is approved for the first time
and could be added at any time during its lifecycle. A medicine
usually remains under additional monitoring for 5 years or until the
EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) is
satisfied that it can be removed from the list.
Black-triangle drugs are identified in the BNF, MIMS and SPC
documents and all promotional materials aimed at healthcare
professionals or patients. A current list of black-triangle drugs is
maintained by the EMA and is available via the MHRA website.8
The limitations of clinical trials mean that the detection of rare
k ADRs, be it due to underlying pathology, drug –drug interactions, k
drug –disease interactions, delayed onset, or to their bizarre or
unexpected nature, may not occur until long after the drug has been
marketed. Reporting of ADRs to newly marketed drugs, i.e. those
marked with a black triangle, is particularly important.
Y
Monitoring of established drugs
Once drugs are no longer under additional monitoring, the black
triangle is removed and the emphasis on ADR surveillance alters.
Relatively minor or well-documented reactions become less
significant and, instead of reporting all reactions, the MHRA requests
that only serious or unusual reactions be reported. Any reaction that is
fatal, life-threatening, disabling, incapacitating or which results in or
prolongs hospitalisation should be reported, even if well recognised.2
These data are especially of value when comparing drugs in the same
class. Examples of ‘serious’ reports that are of particular interest to the
MHRA include anaphylaxis, blood disorders, convulsions, endocrine
disturbances, effects on fertility, haemorrhage from any site, jaundice,
hepatic abnormalities, renal abnormalities, ophthalmic disorders,
severe central nervous system effects and severe skin reactions.
Further information on reporting is available on the MHRA website.9
The MHRA is extremely interested in gathering information about
possible ADRs to herbal medicines and would like all suspected
reactions to be reported.
k
k
500 Yellow Card scheme
ADRs in children
In September 2014, the MHRA introduced new guidance on reporting
suspected adverse drug reactions in children. The advice on which
suspected ADRs to report in children is now the same as for adults
(i.e. you are no longer requested to report all suspected ADRs for
children):
● all suspected ADRs that are serious or result in harm. Serious

reactions are those that are fatal, life-threatening, disabling or
incapacitating, those that cause a congenital abnormality or result
in hospitalisation, and those that are considered medically
significant for any other reason
● all suspected ADRs associated with new drugs and vaccines
(identified by the black-triangle symbol: ).
Problems with MHRA Yellow Card data
Although the data received by the MHRA are of great value to
pharmacovigilance, there are limitations to their use.10 For example,
reporting rates for drugs tend to be at their highest following their
introduction to the market, particularly as they are marked with black
triangles. Furthermore, owing to underreporting and because the
number of patients taking a drug is unknown, it is impossible to
calculate the incidence of specific ADRs and it is only possible to
hypothesise about identified problems. It is not uncommon for
k unusual or unexpected reactions to be reported at the expense of k
well-recognised, albeit more serious, reactions.
Other methods of pharmacovigilance
Whilst the Yellow Card scheme is of great importance, many ADRs
come to light via other routes. Robust and systematic methods
Y employed in pharmacovigilance include case-control studies, cohort
studies and case-registry studies. These methods, rather than relying
on spontaneous reports, focus on individual drugs with the aim of
identifying ADRs. For example:
● the Prescription Event Monitoring (PEM) scheme is run by the

Drug Safety Research Unit in Southampton and is designed to
target particular drugs11
● Clinical Practice Research Datalink, which enables many types of
observational research, including pharmacoepidemiology
studies.12
REFERENCES
1 MHRA (2014). Domperidone (Motilium) can no Longer be Bought without a
Prescription. http://www.mhra.gov.uk/NewsCentre/Whatsnew/CON452545
3 Rawlins MD (1995). Pharmacovigilance: paradise lost, regained or postponed.
J R Coll Phys Lond 29: 41–49.
k
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4 Inman WHW (ed.) (1980). Monitoring for Drug Safety. Lancaster: MTP Press,
pp. 26–27.
5 Belton KJ et al. (1995). Attitudinal survey of adverse drug reaction reporting by
medical practitioners in the United Kingdom. Br J Clin Pharmacol 39: 223–226.
6 Bateman DN et al. (1992). Attitudes to adverse drug reaction reporting in the
northern region. Br J Clin Pharmacol 34: 421–426.
7 Feely J et al. (1990). Stimulating reporting of adverse drug reactions by using a
fee. BMJ 300: 22–23.
8 MHRA (2014). Black Triangle Scheme – New medicines and vaccines subject to
EU-wide additional monitoring. http://www.mhra.gov.uk/Safetyinformation/
Howwemonitorthesafetyofproducts/Medicines/BlackTriangleproducts/index.htm
9 MHRA (2014). The Yellow Card Scheme. http://www.mhra.gov.uk/Safety
information/Howwemonitorthesafetyofproducts/Medicines/TheYellowCard
Scheme/ (accessed 27 November 2014).
10 Edwards JG, Anderson I (1999). Systematic review and guide to selection of
selective serotonin uptake inhibitors. Drugs 57: 527.
11 Drug Safety Research Unit (2014). http://www.dsru.org (accessed 27 November
2014).
12 Clinical Practice Research Datalink (2014). http://www.cprd.com/home/
k k
k
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kc23.tex V2 - 11/18/2015 1:57 P.M. Page 502
502 Zinc
Z
Zinc
Normal range: 10 –24 micromol/L
Local lab range . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The reference nutrient intake per day is 9.5 mg (males) and 7 mg
(females).1
The micronutrient zinc is one of the most important trace elements
in our diet and has an essential role in human physiology. Zinc is
essential for enzyme activities within the body and also contributes to
protein structure and regulates gene expression. It is found in a
variety of foods, such as beef, poultry and grains, and is absorbed
from the GI tract and distributed throughout the body.2
In the body zinc is stored in the prostate and testes (male), muscle,
k liver and kidney, bones and skin (the highest concentrations occur in k
hair, eyes, male reproductive organs and bone). Lower levels are
present in liver, kidney and muscle. In blood 80% is found in
erythrocytes. Plasma zinc levels range from 70 to 110 microgram/dL
and about 50% of this is loosely bound to albumin.3
Individuals who may be at greater risk of zinc deficiency include:
smokers, alcoholics, diabetics, anyone taking large amounts of
Z vitamin B6 and people on non-nutritious or very-low-calorie diet
plans. Zinc levels are also depleted by excessive sweating. Zinc may
accumulate in renal failure.
Zinc deficiency
Symptoms3
Severe deficiency causes skin lesions, alopecia, diarrhoea, increased
susceptibility to infections and failure to thrive in children. Symptoms
of less severe deficiency include distorted or absent perceptions of
taste and smell and poor wound healing.
Causes
Causes include:
● inadequate diet or malabsorption
● parenteral nutrition.4
Excessive loss of zinc can also occur in trauma, burns and
protein-losing conditions.5
k
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Zinc 503
Treatment
Zinc supplements should only be given when there is good evidence
of deficiency (hypoproteinaemia spuriously lowers zinc plasma
concentration).5 Plasma levels are unreliable as they may be low,
e.g. in infection or trauma without deficiency.
Treatment with oral supplements is usual unless the patient is in
the critical care setting. The usual treatment is with Solvazinc,
dosed at:3,5
● adults and children >30 kg: 1 tablet in water 1 –3 times daily
● children 10 –30 kg: 1/2 tablet 1 –3 times daily
● children <10 kg: 1/2 tablet daily.
It is advisable to take with or after food to reduce the adverse effect on
the GI tract. Supplementation continues until clinical improvement
occurs, or it may be ongoing in severe malabsorption, metabolic
disease or non-resolving zinc-losing states.5
Side effects3,5
Side effects of treatment include: abdominal pain, dyspepsia, nausea,
vomiting, diarrhoea, gastric irritation, gastritis, irritability, headache
and lethargy.
Interactions3,5
Zinc reduces the absorption of quinolone antibiotics. The absorption
of tetracycline antibiotics, oral iron, penicillamine and trientine is
k reduced by zinc and the absorption of zinc is reduced by these drugs.
k
When both zinc and tetracycline are being given, an interval of at
least 3 hours should be allowed between preparations.
Preparations
Total parenteral nutrition (TPN) contains zinc within the trace
elements. Baseline zinc requirement in micromoles can be calculated
[0.3 × weight (kg)]. A suggested dose for intravenous nutrition is Z
elemental 6.5 mg zinc (100 micromol) daily.5 Table Z1 shows the zinc
content of available preparations.
Other uses of zinc
The use of zinc in patients with leg ulcers has been assessed in a
systematic review and found to be no better than placebo; therefore,
unless the patient is shown to be deficient, there is no indication for
its use.6
TABLE Z1
Zinc content of various preparations
Product Zinc content5
Solvazinc 125 mg zinc sulfate monohydrate ≡ 45 mg elemental zinc
(0.7 mmol/tablet)
Additrace 10 mL ≡ 100 micromoles of zinc
Zinc sulfate injection 14.6 mg/mL zinc sulfate (1 mL ≡ 50 micromoles elemental
zinc)
k
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504 Zinc
Zinc is an effective treatment for Wilson’s disease.2 Zinc

supplementation has been shown to reduce the duration and severity
of diarrhoea and to prevent subsequent episodes in children in
developing countries.7 It has also been used in combination with
antioxidants to slow the progression of age-related macular
degeneration.2
REFERENCES
1 European Food Safety Authority (2006). Tolerable Upper Intake Levels for Vitamins
and Minerals. http://www.efsa.europa.eu/en/ndatopics/docs/ndatolerableuil.pdf
2 Saper R, Rash R (2009). Zinc: an essential micronutrient. Am Fam Physician 79:
768–772.
3 eMC (2014). Summary of Product Characteristics. Solvazinc Effervescent Tablets.
https://www.medicines.org.uk/emc/medicine/
25407 (accessed 4 October 2014).
6 Wilkinson EAJ, Hawke CI (1998). Does oral zinc aid the healing of chronic leg
ulcers? A systematic literature review. Arch Dermatol 134: 1556–1560.
7 WHO; UNICEF (2004). Clinical Management of Acute Diarrhoea. http://whqlibdoc.
who.int/hq/2004/WHO FCH CAH 04.7.pdf (accessed 4 October 2014).
k k
k
k
CPPC bapp01.tex V2 - 11/18/2015 1:11 P.M. Page 505
Appendix 1 | Glossary of terms 505
Appendix 1
Glossary of terms
ABGs arterial blood gases BNF British National Formulary
ABPA allergic bronchopulmonary BP blood pressure
aspergillosis BSA body surface area
ABW actual body weight BTS British Thoracic Society
ACBS Advisory Committee on BV blood volume
Borderline Substances
Ca calcium
ACE angiotensin-converting enzyme
CABG coronary artery bypass graft
ACE 111 Addenbrookes cognitive
CAPD continuous ambulatory peritoneal
examination 111
dialysis
ACEI angiotensin-converting enzyme
CAS carotid artery stenosis
inhibitor
CBG capillary blood glucose
ACR albumin:creatinine ratio
CCK cholecystokinin
ACTH adrenocorticotrophic hormone
CCR chemokine receptor
ADH antidiuretic hormone
ADR adverse drug reaction CD Crohn’s disease
AF atrial fibrillation CF cystic fibrosis

CFTR cystic fibrosis transmembrane
k AIDS acquired immunodeficiency
syndrome regular k
AIN acute interstitial nephritis CHF congestive heart failure
AKI acute kidney injury CINV chemotherapy-induced nausea
ALP alkaline phosphatase and vomiting
ALT alanine aminotransferase or CIPOLD Confidential Inquiry into

alanine transaminase Premature Deaths of People with
Learning Disabilities
AMD age-related macular degeneration
CK creatine kinase
APD automated peritoneal dialysis
CKD chronic kidney disease
APLS antiphospholipid antibody
syndrome CKD-EPI Chronic Kidney Disease
Epidemiology Collaboration
APS antiphospholipid syndrome
COCP combined oral contraceptive
APTT activated partial thromboplastin
pill
time
COPD chronic obstructive pulmonary
ARB angiotensin receptor blocker
disease
AREDS Age-Related Eye Disease Study
COSHH Control of Substances Hazardous
ART antiretroviral therapy to Health
AST aspartate transaminase COX-2 cyclooxygenase-2
ATN acute tubular necrosis Cr creatinine
AV atrioventricular CrCl creatinine clearance
AVPU alert, voice, pain, unresponsive CRP C-reactive protein
BCG bacillus Calmette-Guérin CSII continuous SC insulin infusion
BHIVA British HIV Association CT computed tomography
BMD bone mineral density CTD-ILD connective tissue
BMI body mass index disease-interstitial lung disease
k
k
506 Appendix 1 | Glossary of terms
CTEPH chronic thromboembolic FAST Face Arm Speech Test

pulmonary hypertension FBC full blood count
CTPA computed tomography pulmonary FDA Food and Drug Administration
angiogram
FEV1 forced expiratory volume in
CVA cerebrovascular accident 1 second
CVC central venous catheter FPG fasting plasma glucose
CVD cardiovascular disease FRAX Fracture Risk Assessment Tool
CVVHF continuous venous-venous FSA Food Standards Agency
haemofiltration
FT3 free triiodothyronine
CYP450 cytochrome P450
FT4 free levothyroxine
DAFNE dose adjustment for normal
FTU fingertip unit
eating
FVC forced vital capacity
DCCT Diabetes Control and
Complications Trial G6PD glucose-6-phosphate-
dehydrogenase
DDW dose-determining weight
GABA gamma-aminobutyric acid
DI diabetes insipidus
GGT gamma-glutamyltransferase or
DIG Digitalis Investigation Group
gamma-glutamyltranspeptidase
DigCl digoxin clearance
GI gastrointestinal
DIP desquamative interstitial
GKI glucose–potassium–insulin
pneumonia
GORD gastro-oesophageal reflux disease
DKA diabetic ketoacidosis
GP general practitioner
DLCO diffusing capacity of the lung for
carbon monoxide Hb haemoglobin
k DM diabetes mellitus HbA1C glycosylated haemoglobin k
DMARD disease-modifying antirheumatic Hct haematocrit
drug HD haemodialysis
DIC disseminated intravascular HDL high density lipoprotein
coagulation HDU High Dependency Unit
DOT directly observed therapy HF heart failure
DSM-V Diagnostic and Statistical Manual HF haemofiltration
of Mental Disorders
HHS hyperosmolar hyperglycaemia
DVLA Driver and Vehicle Licensing state
Agency
HIT heparin-induced
DVT deep-vein thrombosis thrombocytopenia
DXA dual-energy X-ray absorptiometry HIV human immunodeficiency virus
ECF extracellular fluid HLA human leukocyte antigen
ECG electrocardiogram HONK hyperosmotic non-ketotic acidosis
eGFR estimated glomerular filtration HONS hyperosmotic non-ketotic acidosis
rate HP hypersensitivity pneumonitis
EHIC European Health Insurance Card HPA hypothalamic–pituitary–
EMA European Medicines Agency adrenocortical
eMC electronic Medicines HRCT high-resolution computed
Compendium tomography
ERAS enhanced recovery after surgery HSE Health and Safety Executive
ESC European Society of Cardiology hypo hypoglycaemia
ESR erythrocyte sedimentation rate IBD inflammatory bowel disease
ESRD end-stage renal disease IBS irritable bowel syndrome
EWS early warning score IBW ideal body weight
k
k
Appendix 1 | Glossary of terms 507
ICH intracranial haemorrhage MS multiple sclerosis

ICS inhaled corticosteroid NaCl sodium chloride
ICU intensive care unit NBM nil/nothing-by-mouth
IE infective endocarditis NEWS National Early Warning Score
IFCC International Federation of Clinical NG nasogastric
Chemistry NICE National Institute for Health and
Ig immunoglobulin Care Excellence
IGRA interferon-gamma release assay NK1 neurokinin 1
IHD ischaemic heart disease NMDA N -methyl-D-aspartate
IIP idiopathic interstitial pneumonia NMS neuroleptic malignant syndrome
ILD interstitial lung disease NNRTI non-nucleoside reverse
IM intramuscular transcriptase inhibitors
IMCA Independent mental capacity NOAC new oral anticoagulant
advocate NOS nitric oxide synthetase
INR international normalised ratio
NPSA National Patient Safety Agency
IPF idiopathic pulmonary fibrosis
NRT nicotine replacement therapy
IV intravenous
NRTI nucleoside reverse transcriptase
JBDS Joint British Diabetes Societies inhibitor
LABA long-acting beta-2 agonist NSAID non-steroidal anti-inflammatory
LAMA long-acting muscarinic antagonist drug
LDL low-density lipoprotein NSIP non-specific interstitial
LMWH low-molecular-weight heparin pneumonia
k LOLA L-ornithine and L-aspartate NSTEMI non-ST-segment-elevation k
myocardial infarction
LTRA leukotriene antagonist
NTM non-tuberculous mycobacteria
LVSD left ventricular systolic dysfunction
NYHA New York Heart Association
MAOI monoamine oxidase inhibitor
OGTT oral glucose tolerance test
MCV mean corpuscular volume
OTC over-the-counter
MDRD Modification of Diet in Renal
Disease PAH pulmonary arterial hypertension
MDR-TB multidrug-resistant tuberculosis PBC primary biliary cirrhosis
MDT multidisciplinary team PCA patient-controlled analgesia
MEWS medical early warning score PCC prothrombin complex concentrate
MHRA Medicines and Healthcare products PCEA patient-controlled epidural
Regulatory Agency analgesia
MI myocardial infarction PCI percutaneous intervention
MIMS Monthly Index of Medical PCV packed cell volume
Specialities PD peritoneal dialysis
MMR measles, mumps and rubella PE pulmonary embolism
MODY maturity-onset diabetes of the PEFR peak expiratory flow rate
young
PEG percutaneous endoscopic
MRC Medical Research Council gastrostomy
mMRC modified Medical Research Council PEG/J percutaneous endoscopic
MR modified-release gastrostomy-jejunostomy
MRI magnetic resonance imaging PEM Prescription Event Monitoring
MRSA methicillin-resistant Staphylococcus PERT pancreatic enzyme replacement
aureus therapy
k
k
508 Appendix 1 | Glossary of terms
PFT pulmonary function test SPAF stroke prevention in atrial

PI protease inhibitor fibrillation
PIH primary intracerebral SPARCL Stroke Prevention with Aggressive
haemorrhage Reductions in Cholesterol Levels
PLCH pulmonary Langerhans’ cell SPC Summary of Product
histiocytosis Characteristics
PN parenteral nutrition SSRI selective serotonin reuptake
inhibitor
PONV postoperative nausea and
vomiting SVCO superior vena cava obstruction
PPD purified protein derivative T3 triiodothyronine (liothyronine)
PPI proton pump inhibitor T4 thyroxine (levothyroxine)
PRAC Pharmacovigilance Risk TB tuberculosis
Assessment Committee TC topical corticosteroid
PSA prostate specific antigen TCA tricyclic antidepressant
PSC primary sclerosing cholangitis TDM therapeutic drug monitoring
PT prothrombin time TENS transcutaneous electrical nerve
PTH parathyroid hormone stimulation
PV plasma volume TIA transient ischaemic attack
RBC red blood count TIBC total iron-binding capacity
RB-ILD respiratory bronchiolitis- TIPS transjugular intrahepatic
associated interstitial lung disease portosystemic shunt
RCC red cell count TLC total lung capacity
RDA recommended daily amount TLCO transfer factor of the lung for
k ROSIER Recognition Of Stroke In
carbon monoxide k
Emergency Room TOE transoesophageal
echocardiogram
RRT renal replacement therapy
TNF tumour necrosis factor
RSV respiratory syncytial virus
TPMT thiopurine S-methyl transferase
RV residual volume
TPN total parenteral nutrition
SABA short-acting beta-2 agonist
TRH thyroid-releasing hormone
sACE serum angiotensin-converting
enzyme TSH thyroid-stimulating hormone
TTE transthoracic echocardiogram
SAH subarachnoid haemorrhage
TT3 total serum triiodothyronine
SAMA short-acting muscarinic
antagonist TT4 total serum thyroxine
SBP systolic blood pressure U urea
SBP spontaneous bacterial peritonitis U&Es urea and electrolytes

UC ulcerative colitis
SC subcutaneous
UIP usual interstitial pneumonia
SDC serum digoxin concentration
ULN upper limit of normal
SHIFT Systolic Heart failure treatment
with the If inhibitor Ivabradine UPDRS Unified Parkinson’s Disease
Trial Rating Scale
SIADH syndrome of inappropriate UTI urinary tract infection

antidiuretic hormone secretion V/Q ventilation/perfusion
SIGN Scottish Intercollegiate Guidelines VRIII variable-rate intravenous insulin
Network infusion
SIRS systemic inflammatory response VTE venous thromboembolism
syndrome WHO World Health Organization
k
k
Appendix 2 | Laboratory reference ranges 509
Appendix 2
Laboratory reference ranges
Always use the reference ranges quoted by your local laboratory.
Analyte Serum/plasma concentration

Bicarbonate 23–31 mmol/L
Albumin 39–50 g/L
Calcium 2.1–2.6 mmol/L
Creatinine 62–133 micromol/L
Phosphate 0.8–1.5 mmol/L
Potassium 3.6–5.0 mmol/L
Sodium 137–145 mmol/L
Total protein 63–82 g/L
Urea 2.5–7.5 mmol/L
Plasma glucose (fasting) 2 hours after a 3.8–5.5 mmol/L
meal/75 g glucose Maximum 7.8 mmol/L
k Troponin I high sensitivity <50 ng/L k
Troponin T <0.2 microgram/L
Liver enzymes Serum/plasma concentration

Alanine transaminase or alanine 7–56 units/L
aminotransferase (ALT)
Alkaline phosphatase (ALP) 30–300 units/L (adult)
100–390 units/L (ages 3–15 years)
Up to 500 units/L (age 3 years and under,
and growth spurts)
Aspartate transaminase (AST or aspartate 5–40 units/L
aminotransferase)
Bilirubin 3–17 micromol/L
Gamma-glutamyltransferase or 15–73 units/L (male)
gamma-glutamyltranspeptidase (GGT) 12–43 units/L (female)
Enzymes and markers Serum/plasma concentration

Amylase 30–110 units/L
Creatine kinase (CK) Maximum 170 units/L
prostate specific antigen (PSA) <2.5 microgram/L if aged <50 years
<3.5 microgram/L if aged 50–59 years
<4.5 microgram/L if aged 60–69 years
<6.5 microgram/L if aged 70 years or more
k
k
510 Appendix 2 | Laboratory reference ranges
Blood gases and acid–base state (arterial blood) Range

Actual bicarbonate 22–30 mmol/L
Standard bicarbonate 22–26 mmol/L
Base excess –3 to +3 mmol/L
pCO2 4.67–6.0 kPa
pO2 11.3–14.0 kPa
pH 7.35–7.45
Lipids Serum/plasma concentration

Serum cholesterol Desirable <5.0 mmol/L
High-density lipoprotein (HDL) Desirable >0.8 mmol/L
Low-density lipoprotein (LDL) Desirable <4.3 mmol/L
Triglycerides (fasting) Desirable <1.8 mmol/L
Trace elements Serum/plasma concentration

Copper 13–26 micromol/L
Iron Males: 11–28 micromol/L
Females: 7–26 micromol/L
Magnesium 0.6–0.95 mmol/L
k Zinc 10–24 micromol/L

k
Carotene 0.9–5.6 micromol/L
Thyroid function Range

Thyroxine-binding globulin 7.0–18.0 mg/L
Free T4 (thyroxine) 11.8–32.5 pmol/L
Free T3 (triiodothyronine) 2.8–6.6 pmol/L
Thyroid-stimulating hormone (TSH) 0.3–6.0 mu/L
White cells Adults Children Infants

Total count (× 109 /L) 3.0–11.0 4.5–13.5 10.0–26.0
Differential counts
(% and ×109 /L)
Neutrophils 40–75% (2.0–7.5) (2.0–6.0)
Lymphocytes 20–45% (1.5–4.0) (5.5–8.5)
Monocytes 2–10% (0.2–0.8) (0.7–1.5)
Eosinophils 1–6% (0.04–0.4) (0.3–0.8)
Basophils <1.0% (<0.01–0.1) (<0.01–0.1)
k
k
Appendix 2 | Laboratory reference ranges 511
Red cells Men Women Children Infants

Haemoglobin (Hb) 13.0–18 11.5–16.5 3–6 years: 12.0–14.0 13.0–19.5
(g/dL) 10–12 years: 11.5–14.5
Red cell count (RCC) 4.5–6.5 3.8–5.8 3–6 years: 4.1–5.5 4.0–6.0
×1012 /L 10–12 years: 4.0–5.4
Packed cell volume 0.4–0.54 0.37–0.47 3–6 years: 0.36–0.44 0.44–0.64
(PCV) or haematocrit 10–12 years: 0.37–0.45
(Hct) (%)
Mean cell volume 76–100 76–100 3–6 years: 73–89 106 (mean)
(MCV) (femtolitres: fL) 10–12 years: 77–91
Mean corpuscular Hb 27–32 27–32 24–30 24–30
(MCH) (pg)
Mean corpuscular Hb 31–35 31–35 31–35 31–35
concentration (MCHC)
(%)
Red cell distribution 10.9–15.7 10.9–15.7 10.9–15.7 10.9–15.7
width (RDW)
Platelets (×109 /L) 150–400

Plateletcrit (PCT) (%) 0.150–0.320
Mean platelet volume (MPV) (fl) 6.3–10.1
k k
Miscellaneous Range
D-dimer <50 mg/dL
Serum ferritin Male: 28–365 microgram/L
Female: 6–159 microgram/L
Children: 10–150 microgram/L
Serum vitamin B12 193–982 ng/L
Serum folate 3.0–17 microgram/L
Red cell folate 80–727 microgram/L
Erythrocyte sedimentation rate (ESR) Male:
17–50 years: 0–5 mm in first hour
>50 years: 2–10 mm in first hour
Female:
17–50 years: 0–7 mm in first hour
>50 years: 5–15 mm in first hour
Reticulocytes 0–2%
HbA1c 4.6–6 %
k
k
512 Appendix 3 | Imperial–metric height conversion
Appendix 3
Imperial–metric height conversion
Imperial Metric (cm)

4 122
4 2 127
4 4 132
4 6 137
4 8 142
4 10 147
5 152
5 2 157
5 4 163
5 6 168
5 8 173
5 10 178
k 6 183 k
6 2 188
6 4 193
6 6 198
6 8 203
6 10 208
7 213
k
k
Appendix 4 | Imperial–metric weight conversion 513
Appendix 4
Imperial–metric weight
conversion
Imperial Pounds Metric (kg) Imperial Pounds Metric (kg)

6 st 84 38.2 10 st 4 lb 144 65.5
6 st 2 lb 86 39.1 10 st 6 lb 146 66.4
6 st 4 lb 88 40.0 10 st 8 lb 148 67.3
6 st 6 lb 90 40.9 10 st 10 lb 150 68.2
6 st 8 lb 92 41.8 10 st 12 lb 152 69.1
6 st 10 lb 94 42.7 11 st 154 70.0
6 st 12 lb 96 43.6 11 st 2 lb 156 70.9
7 st 98 44.5 11 st 4 lb 158 71.8
7 st 2 lb 100 45.5 11 st 6 lb 160 72.7
7 st 4 lb 102 46.4 11 st 8 lb 162 73.6
7 st 6 lb 104 47.3 11 st 10 lb 164 74.5
k 7 st 8 lb 106 48.2 11 st 12 lb 166 75.5 k
7 st 10 lb 108 49.1 12 st 168 76.4
7 st 12 lb 110 50.0 12 st 2 lb 170 77.3
8 st 112 50.9 12 st 4 lb 172 78.2
8 st 2 lb 114 51.8 12 st 6 lb 174 79.1
8 st 4 lb 116 52.7 12 st 8 lb 176 80.0
8 st 6 lb 118 53.6 12 st 10 lb 178 80.9
8 st 8 lb 120 54.5 12 st 12 lb 180 81.8
8 st 10 lb 122 55.5 13 st 182 82.7
8 st 12 lb 124 56.4 13 st 2 lb 184 83.6
9 st 126 57.3 13 st 4 lb 186 84.5
9 st 2 lb 128 58.2 13 st 6 lb 188 85.5
9 st 4 lb 130 59.1 13 st 8 lb 190 86.4
9 st 6 lb 132 60.0 13 st 10 lb 192 87.3
9 st 8 lb 134 60.9 13 st 12 lb 194 88.2
9 st 10 lb 136 61.8 14 st 196 89.1
9 st 12 lb 138 62.7 14 st 2 lb 198 90.0
10 st 140 63.6 14 st 4 lb 200 90.9
10 st 2 lb 142 64.5 14 st 6 lb 202 91.8
k
k
514 Appendix 4 | Imperial–metric weight conversion
Imperial Pounds Metric (kg) Imperial Pounds Metric (kg)

14 st 8 lb 204 92.7 16 st 10 lb 234 106.4
14 st 10 lb 206 93.6 16 st 12 lb 236 107.3
14 st 12 lb 208 94.5 17 st 238 108.2
15 st 210 95.5 17 st 2 lb 240 109.1
15 st 2 lb 212 96.4 17 st 4 lb 242 110.0
15 st 4 lb 214 97.3 17 st 6 lb 244 110.9
15 st 6 lb 216 98.2 17 st 8 lb 246 111.8
15 st 8 lb 218 99.1 17 st 10 lb 248 112.7
15 st 10 lb 220 100.0 17 st 12 lb 250 113.6
15 st 12 lb 222 100.9 18 st 252 114.5
16 st 224 101.8 18 st 2 lb 254 115.5
16 st 2 lb 226 102.7 18 st 4 lb 256 116.4
16 st 4 lb 228 103.6 18 st 6 lb 258 117.3
16 st 6 lb 230 104.5 18 st 8 lb 260 118.2
16 st 8 lb 232 105.5 18 st 10 lb 262 119.1
k k
k
CPPC
k
bindex.tex V1 - 11/18/2015 1:43 P.M. Page 515
Index 515
Index
5HT3 antagonists, postoperative addiction, nicotine replacement

nausea and vomiting (PONV), therapy (NRT), 282–83
354–55 Addison’s disease, 7–9
6-Item cognitive impairment test — Synacthen (tetracosactide)
(6CIT), 90 tests, 440–41
adrenal function, hypopituitarism,
214
abbreviated mental test score adrenal insufficiency, 7–9
(AMTS), 90 adrenaline
ABCD2 scoring system, 1–2 — nebulised, 9
ABPA. See allergic — phaeochromocytoma,
bronchopulmonary aspergillosis 341–43
absorption of medication, bariatric adrenocorticotrophic hormone
surgery, 55 (ACTH)
absorption, renal impairment, 382 — Cushing’s syndrome, 101–2
ACE inhibitor-induced cough, 3 — hypopituitarism, 213–15
— angiotensin I, 3 — Synacthen (tetracosactide)
— angiotensin II, 3 tests, 440–41
— angiotensin II receptor adverse drug reactions (ADRs),
k blockers, 3
— bradykinin, 3
10–20 k
— at-risk patients, 14
ACE-111. See Addenbrookes — causative agents, 16
cognitive examination 111 — classifying, 10–11
ACEI-related angioedema, 26–27 — complementary medicines, 12
acetylcysteine for nebulisation, 2–3 — de-challenge and re-challenge,
— mucolytic, 3 13
acid-base balance and arterial blood — defining, 10
gases. See arterial blood gases and — documentation and
acid-base balance communication, 14
acidosis — fringe benefits, 15
— chronic kidney disease (CKD), — identifying, 13
388 — information sources, 12
— sodium bicarbonate, 82–83 — iron preparations, 22
ACTH. See adrenocorticotrophic — other medical conditions, 13
hormone — pharmacovigilance, 10
activated charcoal, chloramphenicol — preventing and managing, 15
(systemic), 78 — public’s confidence, 11
acute interstitial nephritis (AIN), 5 — St John’s Wort, 12
acute kidney injury (AKI), 4–9 — Type A reactions/Type B
acute pancreatitis, 328 reactions, 10–11
acute tubular necrosis (ATN), 4 AED. See antiepileptic drugs
adalimumab AF. See atrial fibrillation
— inflammatory bowel disease age-related macular degeneration
(IBD), 219–23 (AMD), nutraceuticals for eye
— rheumatoid arthritis, 400 health, 289–91
Addenbrookes cognitive examination agitation
111 (ACE-111), 91 — antipsychotics, 111
k
CPPC
k
516 Index
agitation (continued) — elemental iron, 22–23

— delirium, 109 — erythropoietin, 24
— rapid tranquillisation, — ferrous salts, 22
375–79 — folate-deficiency anaemia, 23
— sedation, 111 — folic acid, 23–24
agomelatine, depression, 114 — haemoglobin, 22
AIN. See acute interstitial nephritis — haemolytic anaemia, 20
AKI. See acute kidney injury — hydroxocobalamin, 23
alanine aminotransferase (ALT) — investigations, 20–21
alanine transaminase (ALT), liver — iron: parenteral dosing and
function tests (LFTs), 422–29 administration, 238–40
albumin, liver function tests (LFTs), — iron-deficiency anaemia, 21–23
261 — mean corpuscular volume
alcohol (MCV), 21
— appetite stimulation, 36–37 — megaloblastic anaemias, 23–24
— food-drug interactions, — microcytic anaemia, 20
182–83 — red blood cells (RBCs), 20
— pancreatitis, 327–31 — sickle cell disease, 20, 24
aldosterone, Addison’s disease, 8 — thalassaemia, 20
alendronate, osteoporosis, 306 — vitamin B12 deficiency, 23
alkaline phosphatase (ALP), liver analgesia. See also pain management
function tests (LFTs), 259 — epidural analgesia in the
alkalosis, sodium bicarbonate, postoperative period, 156–58
59–60 — opioid partial agonists, 303
allergic bronchopulmonary — pancreatitis, 327–31
aspergillosis (ABPA), 65–66 — patient-controlled analgesia
allergy, antimicrobial. See (PCA), 339–43
k antimicrobial allergy management angina, enoxaparin dosing in k
ALP. See alkaline phosphatase unstable angina, 150–51
ALT. See alanine transaminase angioedema, 25–26
alteplase — ACEI-related angioedema, 26
— stroke, 425 — antihistamines, 26
— transient ischaemic attack — aspirin, 31
(TIA), 424–32 — bradykinin, 26
AMD. See age-related macular — hypersensitivity, 25
degeneration — immediate hypersensitivity
amino transferases, liver function angioedema, 25
tests (LFTs), 260 — immunoglobulin E (IgE), 25
aminoglycosides — NSAID/aspirin-induced
— gentamicin, 185–90 angioedema, 25
— tobramycin, 455–58 — urticaria, 25, 26
aminophylline, theophylline, angiotensin I, ACE inhibitor-induced
449–50 cough, 2
aminosalicylates, inflammatory angiotensin II receptor blockers, ACE
bowel disease (IBD), 220–21 inhibitor-induced cough, 2
amiodarone angiotensin II, ACE inhibitor-induced
— atrial fibrillation (AF), 52 cough, 2
— thyroid function, 452 anhedonia, depression, 112
ammonia, liver disease (chronic), antibiotic choice, 27–28
256 — Clostridium difficile, 27
AMTS. See abbreviated mental test — disease factors, 27
score — methicillin-resistant
anaemias, 20–24 Staphylococcus aureus (MRSA),
— anaemia of chronic disease, 24 27
— defining, 20 — previous history, 28
k
CPPC
k
Index 517
— renal function, 28 antioxidants, nutraceuticals for eye

— reviewing, 28 health, 289–90
— severity of infection, 27 antioxidants, pancreatitis, 327–31
— site of infection, 28 antiphospholipid antibody syndrome
— vancomycin, 27 (APLS). See antiphospholipid
antibiotic prophylaxis, 437–39 syndrome (APS)
antibiotics antiphospholipid syndrome (APS),
— chloramphenicol (systemic), 30–31
76–78 — deep-vein thrombosis (DVT), 30
— gentamicin, 185–90 — pharmaceutical interventions,
— vancomycin, 27 31
anticholinergics, multiple sclerosis, — pulmonary embolism (PE), 30
324 — stroke, 30
anticoagulants — transient ischaemic attack
— atrial fibrillation (AF), 47–52 (TIA), 30
— gastrointestinal bleeding risk — warfarin, 30–31
management, 184–85 antiplatelet therapy
— novel oral anticoagulants — atrial fibrillation (AF), 51
(NOACs), 50 — gastrointestinal bleeding risk
— perioperative period, 284–85 management, 184–85
— protamine, 361–62 — perioperative period, 286
— tinzaparin, 151, 262–63, — protamine, 361–62
454–55 — warfarin, 487
— warfarin, 486–493 antipsychotics
antidiuretic hormone (ADH), — agitation, 110
diabetes insipidus (cranial), 116 — clozapine, 88–90
antiemetic treatment, 324 — delirium, 111
k — apomorphine, 33–36 — neuroleptic malignant k
— chemotherapy-induced nausea syndrome (NMS), 279–80
and vomiting (CINV), 73–75 — rapid tranquillisation, 375–79
antiemetics — sedation, 114
— receptor site affinities, 278 antipsychotics: equivalent doses,
— equivalent, pain management, 32–33
311–18 — depot injections, 33
antiepileptic drugs (AED), — long-acting injections, 33
therapeutic drug monitoring — oral administration, 32
(TDM) of antiepileptics in adults, antiretroviral therapy (ART)
158–66 — drug interactions, 205
antihistamines — human immunodeficiency virus
— ACEI-related angioedema, (HIV) treatment, 206–7
26–27 antithrombotics, protamine, 361–62
— immediate hypersensitivity anti-TNFs, rheumatoid arthritis,
angioedema, 25 400–410
— NSAID/aspirin-induced APD. See automated peritoneal
angioedema, 25–26 dialysis
— rapid tranquillisation, apixaban, atrial fibrillation (AF), 50
375–79 APLS. See antiphospholipid antibody
antimicrobial allergy management, syndrome
28–30 apomorphine, 33–36
— aztreonam, 29 — administration, 35
— carbapenem, 29 — antiemetic treatment, 34
— cephalosporin, 29 — apomorphine challenge,
— penicillin, 29–30 34–35
antimuscarinics, rapid — apomorphine initiation, 34
tranquillisation, 375–79 — monitoring, 35
k
CPPC
k
518 Index
apomorphine, (continued) — long-acting beta-2 agonist

— Parkinson’s disease, 33–34 (LABA), 44
— practical considerations, 35 — peak expiratory flow rate
appetite stimulation, 36–37 (PEFR), 43, 363–65
— alcohol, 36 — pulmonary function tests
— bitters and tonics, 37 (PFTs), 363–68
— corticosteroids, 37 — short-acting beta-2 agonist
— cyproheptadine (Periactin), 36 (SABA), 43–44
— medroxyprogesterone acetate, — spirometry, 365
37 ATN. See acute tubular necrosis
— megestrol acetate, 37 atrial fibrillation (AF)
— mirtazapine, 37 — amiodarone, 52
— progestogens, 37 — antiplatelet therapy, 51
APS. See antiphospholipid syndrome — apixaban, 50
argatroban, low-molecular-weight — beta-blockers, 52
heparins (LMWH), 262–63 — cardioversion, 52
ART. See antiretroviral therapy — CHA2 DS2 -VASc score, 52
arterial blood gases and acid-base — dabigatran, 51
balance, 38–39 — digoxin, 51, 132
— base deficit, 38–39 — HAS-BLED score, 49, 431
— base excess, 38–39 — heart failure, 51, 52
— hypercapnia, 38–39 — novel oral anticoagulants
— metabolic acidosis, 38–39 (NOACs), 50
— oxygen, 38–39 — paroxysmal AF, 52
— respiratory acidosis, 38 — pill in the pocket, 52
— respiratory alkalosis, 39 — rivaroxaban, 51
— sodium bicarbonate, 39 — stroke, 50, 430–31
k artificial saliva — thromboembolism, 48–49 k
— sicca syndrome, 41 — warfarin, 50, 51, 487
— Sjögren’s syndrome, 41 atropine, eye drops: use and care,
— xerostomia, 41 167–70
ascites, liver disease (chronic), automated peritoneal dialysis (APD),
253–54 398
aspartate transaminase (AST), liver azathioprine
function tests (LFTs), 260 — inflammatory bowel disease
aspirin (IBD), 219–22
— NSAID/aspirin-induced — rheumatoid arthritis, 400
angioedema, 25 — sarcoidosis, 414
— stroke, 424–32 aztreonam, antimicrobial allergy
— transient ischaemic attack management, 28–30
(TIA), 424–32
AST. See aspartate transaminase
asthma baclofen, multiple sclerosis, 275
— bronchiolitis, 42 bacteria, antibiotic choice, 27–28
— BTS/SIGN guideline algorithm, banding, liver disease (chronic), 255
43 bariatric surgery, 54–56
— forced expiratory volume — absorption of medication, 54
(FEV1), 365 — bioavailability of medication, 54
— forced vital capacity (FVC), — cost implications, 55
365–66 — formulations of medications, 54
— inhaled corticosteroid (ICS), 43, — pharmacodynamic profiles of
44, 46 medications, 54
— inhaler devices, 223 — pharmacokinetic profiles of
— leukotriene antagonist (LTRA), medications, 54
44 basal bolus insulin regimens, 228
k
CPPC
k
Index 519
base deficit, arterial blood gases and bradykinin

acid-base balance, 38–39 — ACE inhibitor-induced cough,
base excess, arterial blood gases and 2–3
acid-base balance, 38–39 — ACEI-related angioedema, 26
benzalkonium chloride, eye bromocriptine, neuroleptic
ointments: use and care, 172 malignant syndrome (NMS),
benzodiazepines and ‘z’ hypnotics, 279–80
172 bronchiectasis (non-cystic fibrosis),
— equivalence, 58 65–67
— withdrawal, 57 — mucolytics, 66
benzodiazepines, rapid bronchiolitis, asthma, 42
tranquillisation, 375–79 bronchodilators
Beriplex, prothrombin complex — ACE inhibitor-induced cough, 4
concentrates (PCC), 362–63 — theophylline, 447–49
beta-blockers BSA. See body surface area
— atrial fibrillation (AF), 47–52 calculation
— liver disease (chronic), 253–58 buffer, sodium bicarbonate, 59
— phaeochromocytoma, 341–43 buprenorphine
bicarbonate. See sodium bicarbonate — opioid comparative doses,
bile acid binders, liver disease 297–98
(chronic), 257 — opioid misuse management,
bioavailability of medication, 298–302
bariatric surgery, 54 — opioid partial agonists, 303
biochemical monitoring, parenteral
nutrition (PN), 331–33
biologics, rheumatoid arthritis, 400 caffeine, food-drug interactions, 182
biosurgery, 424 calcium
k bipolar disorder, lithium, 249 — hypercalcaemia, 68–69
— hyperparathyroidism, 68
k
bisphosphonates, oncological
emergencies, 296 — hypocalcaemia, 69–70
bitters and tonics, appetite — kidney stones (renal calculi),
stimulation, 37 241–42
Black Triangle scheme, Yellow Card — osteoporosis, 414
scheme, 497–500 calcium acetate, phosphate binding
bladder dysfunction, multiple agent, 351
sclerosis, 275 calcium folinate rescue regimen for
bleeding methotrexate, 270–281
— protamine, 361–62 Calcium Resonium, potassium,
— prothrombin complex 358–59
concentrates (PCC), 362–63 cancer, 319–20, See also oncological
blood glucose monitoring, diabetes emergencies; oncology,
mellitus (DM), 124 neutropenic sepsis
blood glucose units, diabetes mellitus CAPD. See continuous ambulatory
(DM)-monitoring and tests, peritoneal dialysis
123–27 carbamazepine
blood ketone monitoring, diabetes — bioequivalence, 72
mellitus (DM), 125 — drug interactions, 78
blood pressure, — epilepsy, 71–72
phaeochromocytoma, 341–43 — monitoring, 72
body surface area (BSA) calculation, — toxicity, 73
61–64 — pharmacokinetic overview, 76
— Dubois formula, 64 — trigeminal neuralgia, 71
— Mosteller formula, 62, 64 carbapenem, antimicrobial allergy
bosentan, pulmonary hypertension management, 28–30
(PH), 370, 371 carbimazole, thyroid function, 453
k
CPPC
k
520 Index
carbomer, eye ointments: use and chronic kidney disease (CKD),

care, 172 386–93, See also renal
cardiac arrest, sodium bicarbonate, disease-dosing in renal impairment
60–61 and renal replacement therapy
cardioversion — acidosis, 388
— atrial fibrillation (AF), 47–52 — dosing, 391
— warfarin, 487 — haematuria, 386
carvedilol, liver disease (chronic), — hyperkalaemia, 388
255 — hyperphosphataemia, 388
catecholamines, — proteinuria, 388
phaeochromocytoma, 341–42 — renal bone disease, 388
CD4 count, human — uraemia, 388, 390
immunodeficiency virus (HIV) chronic obstructive pulmonary
treatment, 197–98 disease (COPD)
central venous catheters (CVC) — cigarette smoking-calculation of
— haemodialysis (HD), 393–95 pack-years, 86
— parenteral nutrition (PN), 332 — forced expiratory volume
cephalosporin, antimicrobial allergy (FEV1), 235, 366–67
management, 29 — forced vital capacity (FVC), 235,
CHA2 DS2 -VASc score 366–67
— atrial fibrillation (AF), 47–52 — hypoxia, 309–10
— stroke, 424–32 — inhaled corticosteroid (ICS), 81
— warfarin, 487 — inhaler devices, 223–24
checklists, medicines reconciliation, — long-term oxygen therapy
268–70 (LTOT), 309–10
chemotherapy, cytotoxic — long-acting muscarinic
chemotherapy waste, 103–6 antagonists (LAMA), 81
k chemotherapy-induced nausea and — long-acting beta-2 agonist k
vomiting (CINV), 74–75, 278 (LABA), 81
Child –Pugh score — mucolytics, 82
— hepatic impairment, 75 — oxygen, 82, 308–10
— liver function tests (LFTs), 259 — oxygen alert card, 308–9
chloramphenicol (systemic), — oxygen delivery devices, 308
76–78 — peak expiratory flow rate
— activated charcoal, 78 (PEFR), 363–68
— administration, 77–78 — pulmonary function tests
— dose, 77 (PFTs), 363–68
— drug interactions, 78 — pulmonary rehabilitation, 80,
— meningitis, 76 82
— monitoring, 77 — short-acting muscarinic
— overdose, 78 antagonists (SAMA), 81
— pharmacokinetic overview, — short-acting beta-2 agonist
76–77 (SABA), 43, 44
— rickettsial diseases, 77 — smoking/smoking cessation, 87
— septicaemia, 77 — spirometry, 365–68
chloramphenicol, eye drops: use and chronic pancreatitis, 327–28
care, 167–70 ciclosporin, 83–86
cholestasis, liver function tests — administration, 84
(LFTs), 259–62 — dose, 84
cholesterol — drug interactions, 132
— stroke, 424–31 — eczema, 83
— transient ischaemic attack — immunosuppressant, 83
(TIA), 424–31 — monitoring, 83, 84
chronic disease, anaemia of chronic — nephrotic syndrome, 83
disease, 24 — overdose, 85
k
CPPC
k
Index 521
— pharmacokinetic overview, 83 colecalciferol, osteoporosis, 482

— psoriasis, 83 colestyramine, liver disease
— rheumatoid arthritis, 83, 401 (chronic), 493
— transplant, 83 coma, Glasgow Coma Scale (GCS),
— ulcerative colitis (UC), 129–33, 190–191
359–65 co-magaldrox, magnesium, 266
cigarette smoking-calculation of community acquired pneumonia,
pack-years, 86–87 CURB-65 score, 101
cigarette smoking-drug interactions, complementary medicines, adverse
87 drug reactions (ADRs), 12
— clozapine, 88–90 connective tissue, interstitial lung
— CYP1A2, 87 disease (ILD), 234
— insulin, 87 constipation
— nicotine, 87 — faecal softeners, 93
— theophylline, 87 — laxatives, 93–94
CINV. See chemotherapy-induced — palliative and end-of-life care,
nausea and vomiting 318–26
CKD. See chronic kidney disease continuous ambulatory peritoneal
clobazam dialysis (CAPD), 398
— interactions with other continuous subcutaneous infusion,
antiepileptics, 159 syringe pumps, 443
— therapeutic drug monitoring continuous subcutaneous insulin
(TDM) in adults, 158
infusion (CSII), 229
clonazepam
continuous venous-venous
— interactions with other
haemofiltration (CVVHF),
antiepileptics, 159
haemofiltration (HF), 396
— therapeutic drug monitoring
contraception, oestrogen-containing,
k (TDM) in adults, 159
perioperative period, 371 k
clopidogrel
convection, haemofiltration (HF),
— stroke, 425–27
396–97
— transient ischaemic attack
COPD. See chronic obstructive
(TIA), 424–30
Clostridium difficile, antibiotic choice, pulmonary disease
27 corticosteroid oral/intravenous
clozapine, 88–90 equivalence, 94–96
— antipsychotics, 88 — dexamethasone, 95
— cigarette smoking-drug — hydrocortisone, 94–95
interactions, 87 — prednisolone, 94–95
— Parkinson’s disease, 88 corticosteroids
— schizophrenia, 88 — appetite stimulation, 37
Cockcroft and Gault equation — emollients, 96–98, 143–46
— gentamicin, 186 — inhaled corticosteroid (ICS), 45,
— renal function, 456 81
cognitive assessment tools, 90–91 — nil-by-mouth, 288
— 6-Item cognitive impairment — perioperative period, 289
test (6CIT), 90 — sarcoidosis, 414
— abbreviated mental test score — topical corticosteroids (TCs),
(AMTS), 90 96–97
— Addenbrookes cognitive CosmoFer, 98–99
examination 111 (ACE-111), 91 — iron : parenteral dosing and
— dementia, 90–91 administration, 238–39
— mini mental state examination cough
(MMSE), 91 — ACE inhibitor-induced cough,
— Montreal cognitive assessment 2–3
(MoCA), 91 — croup, 9
k
CPPC
k
522 Index
cough (continued) dantrolene, neuroleptic malignant

— interstitial lung disease (ILD), syndrome (NMS), 279–80
233–37 daptomycin, endocarditis, 149, 150
C-peptide, diabetes mellitus D-dimer
(DM)-monitoring and tests, — deep-vein thrombosis (DVT),
123–27 107
cranberry, food-drug interactions, — pulmonary embolism (PE), 108
182–83 debridement, sterile larvae, 422–23
CrCl. See creatinine clearance deep-vein thrombosis (DVT)
C-reactive protein (CRP) — antiphospholipid syndrome
— inflammatory marker, 100 (APS), 30–32
— rheumatoid arthritis, 400 — D-dimer, 107–8
cream, emollients, 143–46 — tinzaparin, 454–55
creatinine clearance (CrCl), renal — warfarin, 492
function, 379–81 — Wells score, 494–95
Creon, pancreatitis, 329 dehydration, hypodermoclysis,
Crohn’s disease (CD). See 211–12
inflammatory bowel disease (IBD) delirium
croup, adrenaline, nebulised, 9
— agitation, 109
CRP. See C-reactive protein
— antipsychotics, 109
cultural issues. See pharmacocultural
— sedation, 110
issues
demeclocycline, syndrome of
CURB-65 score
inappropriate secretion of
— community acquired
antidiuretic hormone (SIADH),
pneumonia, 101
442–43
— pneumonia, 101
dementia, cognitive assessment tools,
Cushing’s syndrome
90–91
k — adrenocorticotrophic hormone
(ACTH), 102 depot injections, antipsychotics: k
— glucocorticoid, 102 equivalent doses, 32–33
— Synacthen (tetracosactide) depression
tests, 438–39 — agomelatine, 114
CVC. See central venous catheters — anhedonia, 112
CVVHF. See continuous — duloxetine, 114
venous-venous haemofiltration — lithium, 249–53
cyclizine, postoperative nausea and — monoamine oxidase inhibitors
vomiting (PONV), 354 (MAOIs), 114
CYP1A2, cigarette smoking-drug — reboxetine, 114
interactions, 87 — selective serotonin reuptake
cyproheptadine (Periactin), appetite inhibitors (SSRIs), 114
stimulation, 36 — trazodone, 114
cytokine inhibitors, rheumatoid — tricyclic antidepressants
arthritis, 408 (TCAs), 113
cytotoxic chemotherapy waste, — venlafaxine, 113–14
spill/spillage, 104–6 desmopressin
— diabetes insipidus (cranial), 116
dabigatran, atrial fibrillation (AF), — Von Willebrand disease,
47–53 484–85
dalteparin dexamethasone
— enoxaparin dosing in unstable — corticosteroid oral/intravenous
angina, 150–151 equivalence, 94–96
— low-molecular-weight heparins — eye drops: use and care, 168–70
(LMWH), 262–63 — postoperative nausea and
danaparoid, low-molecular-weight vomiting (PONV), 355
heparins (LMWH), 262–63 diabetes insipidus (cranial), 116
k
CPPC
k
Index 523
— antidiuretic hormone (ADH), — monitoring, 133

116 — overdose, 136
— desmopressin, 116 dipyridamole
— fluid balance/replacement, 116 — stroke, 424–32
— hyponatraemia, 116 — transient ischaemic attack
— sodium, 116 (TIA), 424–32
diabetes insipidus, hypopituitarism, discrepancies, medicines
214 reconciliation, 268–69
diabetes mellitus (DM), 117–18 disease-modifying antirheumatic
— acute illness, sick-day rules, drugs (DMARDs), 400
196–97 distribution, renal impairment, 382
— classifying, 122 diuretics
— defining, 117 — liver disease (chronic),
— diagnosing, 118 253–54
— laboratory venous haemoglobin — pulmonary hypertension (PH),
A1c (HbA1c ) test, 118 370
— nil-by-mouth, 286 DKA. See diabetic ketoacidosis
— oral glucose tolerance test, 118 DMARDs. See disease-modifying
— pancreatitis, 327–30 antirheumatic drugs
— perioperative period, 286 dobutamine
— type 3 diabetes, pancreatitis, — inotrope, 137
330 — vasodilator, 137
diabetes mellitus (DM) management dolasetron, postoperative nausea and
of hypoglycaemia, 119–121 vomiting (PONV), 354
diabetes mellitus (DM)-monitoring dopamine, inotrope, 138
and tests, 123–27 dose adjustment for normal eating
— blood glucose monitoring, 124 (DAFNE), insulins, 228–29
k — blood glucose units, 124–25 Driver and Vehicle Licensing Agency k
— blood ketone monitoring, 125 (DVLA)
— C-peptide, 126 — advice concerning medication
— glycated haemoglobin (HbA1c ), and medical conditions,
125 140–41
— oral glucose tolerance test — epilepsy, 140
(OGTT), 126–27 — stroke, 140
— urine glucose monitoring, 125 drug history, medicines
— urine ketone monitoring, 125 reconciliation, 268–69
diabetic ketoacidosis (DKA), drug interactions
127–30 — antiretroviral therapy (ART),
— fixed-rate insulin infusion, 129 198
— ketones, 127, 130 — carbamazepine, 72
— perioperative period, 286 — chloramphenicol (systemic), 78
— sodium bicarbonate, 60 — ciclosporin, 83
dialysate, haemodialysis (HD), 394 — digoxin, 133
dialyser, haemodialysis (HD), 394 — gentamicin, 190
diamorphine, opioid comparative — glucosamine, 193
doses, 297–98 — grapefruit juice, 194–96
diffusion, haemodialysis (HD), 394 — lithium, 252
DigiFab, digoxin, 136 — nicotine, 87
digoxin, 131–36 — oranges, 291
— atrial fibrillation (AF), 51, 132 — phenytoin, 463
— DigiFab, 136 — pomelos, 195
— dose, 134–36 — serotonin syndrome, 416–17
— drug interactions, 135–36 — theophylline, 448–49
— formulations, 132–33 — tobramycin, 457–58
— heart failure, 131–32 — tuberculosis, 463
k
CPPC
k
524 Index
drug interactions (continued) — vancomycin, 149, 150

— vancomycin, 470 endocardium, endocarditis, 147
— warfarin, 492 enoxaparin dosing in unstable
drug-induced hepatotoxicity, liver angina, 150–151
function tests (LFTs), 371 — dalteparin, 151
dry eye syndrome, eye ointments: — fondaparinux, 150, 151
use and care, 171–72 — heparin, 151
Dubois formula, body surface area — low-molecular-weight heparins
calculation, 64 (LMWH), 151
duloxetine, depression, 114 — non-ST-segment-elevation
DVLA. See Driver and Vehicle myocardial infarction
Licensing Agency (NSTEMI), 150
DVT. See deep-vein thrombosis — tinzaparin, 151
dysphagia, stroke, 429 enoxaparin, low-molecular-weight
heparins (LMWH), 151, 262, 263
enteral feeding systems and drug
early warning score (EWS), 142–43 administration, 151–56
eczema — blockage management, 155–56
— ciclosporin, 83 — drug administration problems,
— topical corticosteroids (TCs), 96 154–55
eGFR. See estimated glomerular — feeding via enteral feeding
filtration rate tubes, 152, 153
elemental iron, iron-deficiency — flushing, 153, 155, 156
anaemia, 22, 23 — gastrostomy tubes, 152–53
emollients, 143–46 — jejunostomy tubes, 152–53
— choice of product, 144 — nasogastric tubes, 152, 154
— corticosteroids, 96, 97, 143, 146 — pH paper, 152, 154
k — cream, 144–46
— dosing and application, 144,
— pH testing, 154 k
— purpose of enteral feeding
145 tubes, 152
— lotion, 144, 145 — selection of access device,
— ointment, 144–46 152–53
— pharmaceutical care and entry inhibitors, human
counselling points, 146 immunodeficiency virus (HIV)
— psoriasis, 143, 145 treatment, 206
— soap substitutes, 144, 145 epidural analgesia in the
— topical corticosteroids (TCs), postoperative period, 156–58
143, 146 — administration, 157
— types, 144 — adverse effects, 157
encephalopathy, liver disease — contraindications, 157
(chronic), 253, 256 — local anaesthetics, 156, 157
end stage renal disease (ESRD), 383, — medicines used, 157
386, 389, 393 — monitoring, 158
endocarditis, 147–50 — opioid analgesics, 156, 157
— daptomycin, 149 epilepsy
— endocardium, 147 — carbamazepine, 159–65
— gentamicin, 149, 150, 185, 186, — Driver and Vehicle Licensing
189 Agency (DVLA), 140
— infective endocarditis (IE), epilepsy-therapeutic drug
147–49, 185, 186 monitoring (TDM) of antiepileptics
— rifampicin, 149, 150 in adults, 158–66
— transoesophageal — clobazam, 159, 162, 163
echocardiogram (TOE), 148 — clonazepam, 159, 163, 165
— transthoracic echocardiogram — eslicarbazepine, 160
(TTE), 148 — ethosuximide, 160, 163, 165
k
CPPC
k
Index 525
— gabapentin, 160 — chloramphenicol, 168, 170

— lacosamide, 161, 163 — dexamethasone, 170
— lamotrigine, 160–65 — glaucoma, 170
— levetiracetam, 161 — prednisolone, 170
— oxcarbazepine, 162–63 — squint, 170
— perampanel, 162 eye ointments: use and care
— phenobarbital, 159–66 — benzalkonium chloride, 172
— pregabalin, 163 — carbomer, 172
— primidone, 159–61, 164–66 — dry eye syndrome, 171–72
— retigabine, 164 — hypromellose, 172
— rufinamide, 163–65 — Sjögren’s syndrome, 172
— sodium valproate, 161, 165
— tiagabine, 162–63
— topiramate, 160, 162–65 faecal elastase, pancreatitis, 328
— valproic acid, 159–165 faecal softeners, 93, 314
— vigabatrin, 163, 166 falls
— zonisamide, 163, 166 — fragility fractures, 303, 304
epoprostenol, pulmonary — osteoporosis, 174, 175, 303,
hypertension (PH), 370, 372 304
equivalent doses falls: pharmaceutical care
— antipsychotics, 32–33 — medicines, 173–75
— benzodiazepines and ‘z’ — review, 175
hypnotics, 58 — risk assessment, 174–75
erythrocyte sedimentation fatigue, multiple sclerosis, 275
rate (ESR) fat-soluble drugs, LipidRescue,
— polymyalgia rheumatica, 167 248–49
— rheumatoid arthritis, 167 feeding, enteral feeding systems and
k — temporal arteritis, 167 drug administration, 151–56
Ferinject, 177
k
erythropoietin, anaemia of chronic
disease, 24 — iron : parenteral dosing and
eslicarbazepine administration, 238–39
— interactions with other ferrous salts, iron-deficiency
antiepileptics, 160 anaemia, 23
— therapeutic drug monitoring FEV1. See forced expiratory volume
(TDM) in adults, 160 fibrosis, interstitial lung disease
ESR. See erythrocyte sedimentation (ILD), 234–36
rate fingertip unit (FTU), topical
ESRD. See end stage renal disease corticosteroids (TCs), 97
estimated glomerular filtration rate fistula, haemodialysis (HD), 393, 394
(eGFR), renal function, 379–81 fixed-rate insulin infusion, diabetic
etanercept, rheumatoid arthritis, ketoacidosis (DKA), 130
409 fludrocortisone, Addison’s disease, 8
ethosuximide fluid balance, 177–82
— interactions with other — diabetes insipidus (cranial), 116
antiepileptics, 73, 160 — fluid management, 177–78, 180
— therapeutic drug monitoring — fluid physiology, 178–79
(TDM) in adults, 160 — hypodermoclysis, 211–13
EWS. See early warning score — maintenance, 179, 181
excretion, renal impairment, — mannitol, 182
382–84, 421 — NICE fluid guidelines, 179–80
exemption, prescription charge — postoperative fluids, 180–182
exemptions and prepayment — resuscitation, 179, 181
certificates, 360–61 — sodium chloride, 179, 181
eye drops: use and care — vasoconstrictors, 179–81
— atropine, 170 — vasodilators, 180
k
CPPC
k
526 Index
fluid management, fluid balance, fusion inhibitors, human

177–78 immunodeficiency virus (HIV)
fluid physiology, fluid balance, treatment, 198, 206
178–79 FVC. See forced vital capacity
fluid replacement, 60, 128, 129, 209,
210, 232, 420
gabapentin
— diabetes insipidus (cranial), 116
— interactions with other
fluid restriction, syndrome of
antiepileptics, 160
inappropriate secretion of — multiple sclerosis,
antidiuretic hormone (SIADH), 275, 276
421, 442, 443 — therapeutic drug monitoring
flumazenil, rapid tranquillisation, (TDM) in adults, 160
378 gamma-glutamyl transferase (GGT),
flushing, enteral feeding systems and liver function tests (LFTs), 259,
drug administration, 155 261
folate, folate-deficiency anaemia, 20, gamma-glutamyl transpeptidase
21, 23–24 (GGT)
folate-deficiency anaemia, 20, 21, gastric surgery, bariatric surgery, 54
23–24 gastrointestinal bleeding risk
folic acid, folate-deficiency anaemia, management, 184–85
23–24 — anticoagulants, 184
folinate, calcium folinate rescue — antiplatelet therapy, 184
regimen for methotrexate, — Glasgow-Blatchford score,
270–271 185
fondaparinux — HAS-BLED score, 185
— enoxaparin dosing in unstable — non-steroidal anti-inflammatory
k angina, 150–151 drugs (NSAIDs), 184
— Rockall score, 185, 411
k
— low-molecular-weight heparins
(LMWH), 151, 263, 437 — scoring systems, 185, 411
food-drug interactions, 182–83 gastro-oesophageal reflux disease
— alcohol, 182 (GORD), omeprazole, 292
— caffeine, 183 gastrostomy tubes, enteral feeding
— cranberry, 183 systems and drug administration,
152–53
— grapefruit juice, 194–96
GCS. See Glasgow Coma Scale
— tyramine, 183
gelatin, pharmacocultural issues, 344
— vitamin K, 183
gentamicin, 185–90
forced expiratory volume (FEV1)
— administration, 187–90
— chronic obstructive pulmonary
— adult dose, 186–88
disease (COPD), 79
— aminoglycosides, 185
— pulmonary function tests
— Cockcroft and Gault equation,
(PFTs), 365–68 186
forced vital capacity (FVC) — drug interactions, 189, 190
— chronic obstructive pulmonary — endocarditis, 185, 186, 189
disease (COPD), 79 — Hartford regimen, 187–89
— pulmonary function tests — monitoring, 188–89
(PFTs), 365–68 — ototoxicity, 186, 187, 189, 190
formulations of medications, — overdose, 189–90
bariatric surgery, 54, 55 — pharmacokinetic overview, 186
four E’s structure, patient — tobramycin, 187, 188
consultation, 335–37 GGT. See gamma-glutamyl
fragility fractures, osteoporosis, 303, transferase or gamma-glutamyl
304 transpeptidase (GGT)
FTU. See fingertip unit GKI. See glucose-potassium-insulin
k
CPPC
k
Index 527
Glasgow Coma Scale (GCS), — ultrafiltration, 396

190–91 haemofiltration fluid,
Glasgow-Blatchford score, haemofiltration (HF), 396
gastrointestinal bleeding risk haemofiltration, haemofiltration
management, 185 (HF), 396–97
glaucoma, eye drops: use and care, haemoglobin
170 — anaemias, 20–24
glucocorticoid, Cushing’s syndrome, — CosmoFer, 98–99
101 — Ferinject, 176–77
glucosamine — Monofer, 272–73
— drug interactions, 193 — Venofer, 238, 474
— osteoarthritis, 192, 193 haemolytic anaemia, 20, 35, 415
glucose, diabetes mellitus haemorrhagic stroke, 424–32
(DM)-hypoglycaemia, 119–22 haemostasis, von Willebrand disease,
glucose-potassium-insulin (GKI), 484–85
variable rate intravenous insulin Hartford regimen, gentamicin,
infusion (VRIII), 231 187–89
glycated haemoglobin (HbA1c ), HAS-BLED score
diabetes mellitus (DM)-monitoring — atrial fibrillation (AF), 49,
and tests, 125–26 431–32
gold, rheumatoid arthritis, 402 — gastrointestinal bleeding risk
granisetron, postoperative nausea management, 185
and vomiting (PONV), 354 HbA1c . See glycated haemoglobin;
granulomas, sarcoidosis, 412–13 haemoglobin A1c test
grapefruit juice, drug interactions, HD. See haemodialysis
194–96 HE. See hepatic encephalopathy
Graves’ disease, thyroid function, headache, thunderclap headache,
k 453 450 k
growth hormone, hypopituitarism, health coaching, patient
214 consultation, 335
health/hospital passport, learning
haematology, neutropenic disability patients, 247
sepsis, 281 heart failure
haematuria, chronic kidney disease — atrial fibrillation (AF), 47–49,
(CKD), 386, 388 51, 52
haemodialysis (HD) — digoxin, 131–33, 135
— central venous catheters (CVC), heparin-induced thrombocytopenia
393, 394 (HIT), low-molecular-weight
— dialysate, 394, 395 heparins (LMWH), 262–63
— dialyser, 394, 395 heparins. See also
— diffusion, 394 low-molecular-weight heparins
— fistula, 393, 394 (LMWH)
— renal replacement therapy — enoxaparin dosing in unstable
(RRT), 393–95 angina, 150–51
— ultrafiltration, 394 — protamine, 361–62
haemofiltration (HF) hepatic encephalopathy (HE), liver
— continuous venous-venous disease (chronic), 253, 256
haemofiltration (CVVHF), 396, hepatic impairment, 34, 75, 76, 83,
397 259, 293, 377, 401 See also liver
— convection, 396, 397 function tests (LFTs), Child –Pugh
— haemofiltration, 396–97 score
— haemofiltration fluid, 396 herbal medicines, perioperative
— renal replacement therapy period, 285, 435
(RRT), 396–97 HF. See haemofiltration
k
CPPC
k
528 Index
HHS. See hyperosmolar hyperosmolar hyperglycaemia state

hyperglycaemia state (HHS)
HIT. See heparin-induced — insulin, 210
thrombocytopenia — serum osmolality, 208, 209
holiday, travel recommendations, hyperosmolar non-ketotic syndrome
458–59 (HONS or HONK). See
HONK. See hyperosmolar hyperosmolar hyperglycaemia
hyperglycaemia state (HHS) state (HHS)
HONS. See hyperosmolar hyperparathyroidism, 68, 296, 304,
hyperglycaemia state (HHS) 350, 390
hormone replacement therapy hyperphosphataemia
(HRT), perioperative period, — chronic kidney disease (CKD),
285 388
HRT. See hormone replacement — phosphate, 350–351
therapy hypersensitivity, immediate
human immunodeficiency virus hypersensitivity angioedema, 25
(HIV) treatment, 197–207 hypertension
— antiretroviral therapy (ART), — stroke, 424–32
197–207 — transient ischaemic attack
— CD4 count, 197, 198 (TIA), 424–32
— entry inhibitors, 206 hyperthyroidism, thyroid function,
— fusion inhibitors, 206 452–53
— integrase inhibitors, 203–7
hypocalcaemia, 19, 60, 69–70, 190,
— non-nucleoside reverse
265, 333, 388, 457
transcriptase inhibitors
— phosphate, 350
(NNRTIs), 206
hypodermoclysis, 211–13
— nucleoside reverse transcriptase
— dehydration, 211, 212
k inhibitors (NRTIs), 205–6
— fluid balance, 211–13 k
— protease inhibitors (PIs), 206
— hyaluronidase, 212–13
human normal immunoglobulin for
hypoglycaemia, 119–22
intravenous administration,
hypokalaemia
216–18
hyaluronidase, hypodermoclysis, — phosphate, 350
212–13 — potassium, 356–58
hydrocortisone hypomagnesaemia, 264–67
— Addison’s disease, 7–9 — phosphate, 350
— corticosteroid oral/intravenous hyponatraemia
equivalence, 94–96 — diabetes insipidus
hydroxocobalamin, vitamin B12 (cranial), 116
deficiency, 23 — sodium, 420–21
hydroxychloroquine — syndrome of inappropriate
— rheumatoid arthritis, 403 secretion of antidiuretic
— sarcoidosis, 414, 415 hormone (SIADH), 442, 443
hypercalcaemia, 19, 68–69, 116, hypoparathyroidism, phosphate, 351
305, 324–26, 351, 359, hypophosphataemia, 349–51
413, 414 hypopituitarism, 213–14
— oncological emergencies, 296 — adrenal function, 214
hypercapnia, arterial blood gases and — adrenocorticotrophic hormone
acid –base balance, 38–39 (ACTH), 214
hyperkalaemia — diabetes insipidus, 214
— chronic kidney disease (CKD), — growth hormone, 214
388, 390 — hypothyroidism, 214
— potassium, 356, 358–59 — Synacthen (tetracosactide)
hypermagnesaemia, 267 tests, 440
hypernatraemia, sodium, 420–23 — thyroid, 214
k
CPPC
k
Index 529
— thyroid-stimulating hormone inhaler devices in respiratory disease

(TSH), 214 — asthma, 223
hypothyroidism — chronic obstructive pulmonary
— hypopituitarism, 214 disease (COPD), 223
— thyroid function, 451–52 inotropes
hypoxia, 39, 108, 109, 128, 209, 235, — dobutamine, 137–38
236, 308–10 — dopamine, 138–39
hypromellose, eye ointments: use Injectable Drugs Guide, xii
and care, 172 INR. See international normalised
ratio
IBD. See inflammatory bowel disease insulins, 224–30
IBW. See ideal body weight — basal bolus insulin regimens,
ICS. See inhaled corticosteroid 228
ideal body weight (IBW), 216 — cigarette smoking–drug
IE. See infective endocarditis interactions, 87
IgE. See immunoglobulin E — continuous subcutaneous
IGRA. See interferon-gamma release insulin infusion (CSII), 229
assay — diabetes mellitus
ILD. See interstitial lung disease (DM)-hypoglycaemia, 119–22
immediate hypersensitivity — dose adjustment for normal
angioedema, 25 eating (DAFNE), 228–29
immunoglobulin (normal) for — glucose-potassium-insulin
intravenous administration, (GKI), 233
216–18 — hyperosmolar hyperglycaemia
— Kawasaki disease, 218 state (HHS), 208–11
— Vigam, 217, 218 — insulin counselling points, 230
immunoglobulin E (IgE), immediate — insulin injection technique,
k hypersensitivity angioedema, 25 229–30 k
immunosuppressant, ciclosporin, — insulin regimens, 228–29
83–86 — insulin types, 225–27
infection — prescribing insulins, 224–25
— antibiotic choice, 27–28 — sliding scale insulin, 231, 286,
— systemic inflammatory response 333
syndrome (SIRS), 418–19 — subcutaneous (SC) injection,
infective endocarditis (IE), 147–50 229–30
inflammatory bowel disease (IBD), — variable rate intravenous insulin
219–22 infusion (VRIII), 231–33
— adalimumab, 222 integrase inhibitors, human
— aminosalicylates, 220–221 immunodeficiency virus (HIV)
— azathioprine, 221, 222 treatment, 203–7
— infliximab, 222 interactions, drug. See drug
— mercaptopurine, 221 interactions
— mesalazine, 220 interferon-gamma release assay
— methotrexate, 222 (IGRA), tuberculosis, 466–67
— thiopurines, 221 international normalised ratio (INR)
inflammatory marker, C-reactive — prothrombin complex
protein (CRP), 220 concentrates (PCC), 362–63
infliximab — warfarin, 486–93
— inflammatory bowel disease interstitial lung disease (ILD),
(IBD), 222 233–38
— rheumatoid arthritis, 410 — connective tissue, 234, 236, 237
inhaled corticosteroid (ICS) — cough, 235, 236
— asthma, 43–46 — fibrosis, 234–36
— chronic obstructive pulmonary — Medical Research Council
disease (COPD), 81 (MRC) dyspnoea scale, 235, 238
k
CPPC
k
530 Index
interstitial lung disease (ILD), LAMA. See long-acting muscarinic

(continued) antagonists
— pneumonitis, 234 lamotrigine
— sarcoidosis, 234, 412–15 — interactions with other
— spirometry, 235 antiepileptics, 161
intrinsic AKI, 5 — therapeutic drug monitoring
iron: parenteral dosing and (TDM) in adults, 161
administration larval therapy, 422–23
— anaemia, 238–39 latent tuberculosis, 466–67
— CosmoFer, 238–39 laxatives, 92–94, 256, 264–65, 276
— Ferinject, 238–39 learning disability patients, 244–48
— Monofer, 238–39, 272–73 — health/hospital passport, 247
— Venofer, 238–39, 474 — legal obligations, 244
iron preparations — pain management, 246–47
— adverse drug reactions (ADRs), — reasonable adjustments,
22–23 247–48
— CosmoFer, 98–99 leflunomide, rheumatoid arthritis,
— Ferinject, 176–77 403–4
— Monofer, 272–73 legal obligations, learning disability
iron-deficiency anaemia, 21–23 patients, 244
ischaemic stroke, 424–32 leukotriene antagonist (LTRA),
asthma, 44
Jehovah’s Witnesses, levetiracetam
pharmacocultural issues, 344 — interactions with other
jejunostomy tubes, enteral feeding antiepileptics, 161
systems and drug administration, — therapeutic drug monitoring
152–53 (TDM) in adults, 161
k Judaism, pharmacocultural issues, levothyroxine, thyroid function, k
343 450–53
LFTs. See liver function tests
liothyronine, thyroid function,
Kawasaki disease, immunoglobulin
450–53
(normal) for intravenous
LipidRescue
administration, 218
— fat-soluble drugs, 248–49
ketones
— lipophilic drugs, 248–49
— blood ketone monitoring, 125
— overdose, drug, 248–49
— diabetic ketoacidosis (DKA),
lipophilic drugs, LipidRescue,
127–30
248–49
— urine ketone monitoring, 125
lithium, 249–52
kidney, 4–7, See also chronic kidney
— bipolar disorder, 249
disease (CKD); renal
— cardiac function, 250–51
disease-dosing in renal impairment
— counselling, 252
and renal replacement therapy,
— depression, 249
acute kidney injury (AKI)
— dose, 251
kidney stones (renal calculi), 241–42
— drug interactions, 252
— mania, 249
LABA. See long-acting beta-2 agonist — monitoring, 249–52
lacosamide — overdose, 251–52
— interactions with other — perioperative period, 285
antiepileptics, 161 — pharmacokinetic overview,
— therapeutic drug monitoring 249–50
(TDM) in adults, 161 — renal function, 250
lactase, lactose-free medicines, 243 — thyroid function, 250
lactose-free medicines, 243 liver disease (chronic), 253–57
lactulose, liver disease (chronic), 256 — ammonia, 256
k
CPPC
k
Index 531
— ascites, 253–54 long term oxygen therapy (LTOT),

— banding, 255 309–10
— beta-blockers, 255 long-acting muscarinic antagonists
— bile acid binders, 257 (LAMA), chronic obstructive
— carvedilol, 255 pulmonary disease (COPD), 81
— cholestyramine, 257 long-acting beta-2 agonist (LABA)
— diuretics, 253–54 — asthma, 44
— encephalopathy, 256 — chronic obstructive pulmonary
— hepatic encephalopathy (HE), disease (COPD), 81
256 long-acting injections,
— lactulose, 256 antipsychotics: equivalent doses,
— L-ornithine and L-aspartate 33
(LOLA), 256 L-ornithine and L-aspartate (LOLA),
— naltrexone, 257 liver disease (chronic), 256
— norfloxacin, 255 lotion, emollients, 144
— ondansetron, 257 low-molecular-weight heparins
— portal hypertension, 253–55 (LMWH)
— propranolol, 255 — argatroban, 262–63
— pruritus, 257 — dalteparin, 262–63
— rifampicin, 257 — danaparoid, 262–63
— rifaximin, 256 — enoxaparin, 262–63
— sclerotherapy, 255 — enoxaparin dosing in unstable
— spontaneous bacterial angina, 151
peritonitis (SBP), 254–55 — fondaparinux, 262–63
— variceal bleeding, 255–56 — heparin-induced
liver function tests (LFTs), 259–62, thrombocytopenia (HIT),
See also hepatic impairment 262–63
k — alanine transaminase (ALT), — protamine, 361 k
259, 260 — thromboembolism, 262–63
— albumin, 261 — tinzaparin, 262–63, 454–55
— alkaline phosphatase (ALP), 260 — venous thromboembolism
— amino transferases, 260 (VTE), 262–63
— aspartate transaminase (AST), LTOT. See long term oxygen therapy
259, 260 LTRA. See leukotriene antagonist
lutein, nutraceuticals for eye health,
— Child –Pugh score, 259
289–91
— cholestasis, 260, 262
— drug-induced hepatotoxicity,
260, 261 maggot therapy, 422–23
— gamma-glutamyl transferase magnesium
(GGT), 261 — co-magaldrox, 266
— prothrombin time (PT), 262 — hypermagnesaemia, 267
— vitamin K, 262 — hypomagnesaemia, 267
liver impairment, Child –Pugh score, magnesium aspartate, 265
75–76 magnesium carbonate, phosphate
LMWH. See low-molecular-weight binding agent, 351
heparins magnesium glycerophosphate, 265
loading doses, renal impairment, magnesium hydroxide, 265
383–84 maintenance, fluid balance, 179, 181
local anaesthetics, epidural analgesia malaria, travel recommendations,
in the postoperative period, 157 458–459
lofexidine, opioid misuse management of long-term medicines
management, 302 during surgery, 284–89
LOLA. See L-ornithine and mania, lithium, 249
L-aspartate mannitol, fluid balance, 182
k
CPPC
k
532 Index
Mantoux test, tuberculosis, 466–67 — overdose, 270–271

MAOIs. See monoamine oxidase — rheumatoid arthritis, 405–6
inhibitors — sarcoidosis, 414
MASCC, 281 metoclopramide, postoperative
MCV. See mean corpuscular volume nausea and vomiting (PONV), 354
MDR-TB. See multidrug-resistant MEWS. See medical early warning
tuberculosis score
mean corpuscular volume (MCV), microcytic anaemia, 20, 21
anaemias, 21 minerals and vitamins. See vitamins
medical early warning score and minerals
(MEWS), 142 mini mental state examination
Medical Research Council (MRC) (MMSE), 91
dyspnoea scale, interstitial lung mirtazapine, appetite stimulation, 37
disease (ILD), 238 MMSE. See mini mental state
Medicines Optimisation-Refer-to- examination
Pharmacy, xii MoCA. See Montreal cognitive
medicines adherence, patient assessment
consultation, 334–38 monoamine oxidase inhibitors
medicines reconciliation (MAOIs)
— checklists, 268–69 — depression, 114
— discrepancies, 268–69 — perioperative period, 285
— drug history, 268–69 — serotonin syndrome, 417–19
— surgical pharmacy, 434–35 Monofer, 272–73
— transfer of care, 268–69 — iron: parenteral dosing and
medroxyprogesterone acetate, administration, 238–39
appetite stimulation, 37 Montreal cognitive assessment
megaloblastic anaemias, 23–24 (MoCA), 91
k megestrol acetate, appetite morphine, opioid comparative doses, k
stimulation, 37 297–98
meningitis, chloramphenicol Mosteller formula, body surface area
(systemic), 76–78 calculation, 61–64
mercaptopurine, inflammatory bowel mouth ulcers and sore mouths,
disease (IBD), 221 273–74
mesalazine, inflammatory bowel MRC. See Medical Research Council
disease (IBD), 220 (MRC) dyspnoea scale
metabolic acidosis, arterial blood MRSA. See methicillin-resistant
gases and acid –base balance, Staphylococcus aureus
38–39 MSCC. See metastatic spinal cord
metabolism, renal impairment, 383 compression
metastases, oncological emergencies, mucolytics
296–97 — ACE inhibitor-induced cough,
metastatic spinal cord compression 2–3
(MSCC), oncological emergencies, — bronchiectasis (non-cystic
296 fibrosis), 66
methadone, opioid misuse — chronic obstructive pulmonary
management, 299–301 disease (COPD), 82
methicillin-resistant Staphylococcus multidrug-resistant tuberculosis
aureus (MRSA) (MDR-TB), 463–66
— antibiotic choice, 27 multiple sclerosis
— vancomycin, 470–73 — anticholinergics, 276
methotrexate — baclofen, 275
— calcium folinate rescue — bladder dysfunction, 275–76
regimen, 270–271 — fatigue, 275
— inflammatory bowel disease — gabapentin, 275, 276
(IBD), 222 — spasticity, 275
k
CPPC
k
Index 533
— symptomatic management, NMS. See neuroleptic malignant

274–76 syndrome
muscle cramps, quinine, 373–74 NNRTIs. See non-nucleoside reverse
Muslim patients, pharmacocultural transcriptase inhibitors
issues, 344–45 NOACs. See novel oral anticoagulants
myocardial infarction, non-adherence, patient consultation,
non-ST-segment-elevation 337–38
myocardial infarction (NSTEMI), non-nucleoside reverse transcriptase
enoxaparin dosing in unstable inhibitors (NNRTIs), human
angina, 150–51 immunodeficiency virus (HIV)
treatment, 201, 206
non-steroidal anti-inflammatory
naltrexone, liver disease (chronic), drugs (NSAIDs)
257 — gastrointestinal bleeding risk
nasogastric tubes, enteral feeding management, 184
systems and drug administration, — NSAID/aspirin-induced
152, 154 angioedema, 25–26
national early warning score — pain management, 313
(NEWS), 142 non-ST-segment-elevation
nausea and vomiting, 278 myocardial infarction (NSTEMI),
— antiemetic treatment, 278 enoxaparin dosing in unstable
— chemotherapy-induced nausea angina, 150–51
and vomiting (CINV), 73–75, noradrenaline, phaeochromocytoma,
278 341–42
— palliative and end-of-life care, norfloxacin, liver disease (chronic),
318–26 255
— postoperative nausea and novel oral anticoagulants (NOACs)
k vomiting (PONV), 352–55
— receptor sites, 278
— atrial fibrillation (AF), 50, 52 k
— stroke, 424–32
— surgical pharmacy, 434 — transient ischaemic attack
NBM. See nil-by-mouth (TIA), 424–32
nephrotic syndrome, ciclosporin, 83, NRT. See nicotine replacement
85 therapy
neuroleptic malignant syndrome NRTIs. See nucleoside reverse
(NMS) transcriptase inhibitors
— antipsychotics, 279 NSTEMI. See
— bromocriptine, 280 non-ST-segment-elevation
— dantrolene, 280 myocardial infarction
neutropenic sepsis, 280–281 nucleoside reverse transcriptase
— oncological emergencies, inhibitors (NRTIs), human
296–97 immunodeficiency virus (HIV)
NEWS. See national early warning treatment, 205–6
score nutraceuticals for eye health, 289–91
NICE fluid guidelines, fluid balance, — age-related macular
179–80 degeneration (AMD), 289–91
nicotine replacement therapy (NRT), — antioxidants, 289
smoking cessation, 282–83 — lutein, 290–291
nicotine, drug interactions, 87 — zeaxanthins, 290–291
nil-by-mouth (NBM), management of nutrition. See enteral feeding systems
long-term medicines during and drug administration;
surgery, 284–85 parenteral nutrition (PN)
— corticosteroids, 287
— patients with diabetes, 286
nimodipine, thunderclap headache, Octaplex, prothrombin complex
450 concentrates (PCC), 362–63
k
CPPC
k
534 Index
octreotide, pancreatitis, 329 oranges, drug interactions, 195

oestrogen-containing contraception, osteoarthritis
perioperative period, 371 — glucosamine, 192–94
OGTT. See oral glucose tolerance test — transcutaneous electrical nerve
ointment, emollients, 144 stimulation (TENS), 194
omeprazole osteoporosis
— gastro-oesophageal reflux — alendronate, 306
disease (GORD), 292 — calcium, 305
— parenteral administration, — colecalciferol, 482
292–94 — falls, 304
— proton pump inhibitor (PPI), — fragility fractures, 304
292 — raloxifene, 306
— ulcers, 292–93 — risedronate, 306
— Zollinger-Ellison — strontium, 306
syndrome, 292 — teriparatide, 306
oncological emergencies, 281, — vitamin D, 305
296–97 ototoxicity, gentamicin, 185–190
— bisphosphonates, 296 overdose
— hypercalcaemia, 296 — carbamazepine, 173
— metastases, 296 — chloramphenicol (systemic), 78
— metastatic spinal cord — ciclosporin, 85
compression (MSCC), 296 — digoxin, 136
— neutropenic sepsis, 297 — gentamicin, 189
— superior vena cava obstruction — LipidRescue, 248–49
(SVCO), 297 — lithium, 251–52
oncology, neutropenic sepsis, — methotrexate, 270–271
297 — phenytoin, 347–48
k ondansetron — theophylline, 449
— tobramycin, 457
k
— liver disease (chronic), 257
— postoperative nausea and oxcarbazepine
vomiting (PONV), 354 — interactions with other
opioid analgesics antiepileptics, 164
— epidural analgesia in the — therapeutic drug monitoring
postoperative period, 157 (TDM) in adults, 158
— pain management 311–18 oxygen, 308–310
— palliative and end-of-life care, — arterial blood gases and
318–33 acid –base balance, 38–39
— patient-controlled analgesia — chronic obstructive pulmonary
(PCA), 339–41 disease (COPD), 79–86, 308–9
opioid comparative doses — hypoxia, 308–10
— buprenorphine, 298 — long-term oxygen therapy
— diamorphine, 297–98 (LTOT), 309–10
— morphine, 297–98 — oxygen alert card, 308–9
opioid misuse management, — oxygen delivery devices, 308
298–302 oxygen alert card, 308–9
— buprenorphine, 301–2 oxygen delivery devices, 308–9
— lofexidine, 302
— methadone, 299–302 PAH. See pulmonary arterial
— withdrawal, 299–302 hypertension
opioid partial agonists pain management, 311–18, See also
— analgesia, 303 analgesia
— buprenorphine, 303 — antiemetics
— pentazocine, 303 — equivalent, 316–17
oral glucose tolerance test (OGTT), — epidural analgesia in the
diabetes mellitus (DM), 113, 126 postoperative period, 156–58
k
CPPC
k
Index 535
— learning disability patients, 246 — opioid analgesics, 339–41

— non-steroidal anti-inflammatory — pain management, 339–41
drugs (NSAIDs), 313 PCA. See patient-controlled analgesia
— opioid analgesics, 246 PCC. See prothrombin complex
— paracetamol, 313 concentrates
— patient-controlled analgesia PD. See peritoneal dialysis
(PCA), 339–42 PE. See pulmonary embolism
— surgical pharmacy, 434–39 peak expiratory flow rate (PEFR)
palliative and end-of-life care, — asthma, 43–47
318–31 — pulmonary function tests
— constipation, 324–26 (PFTs), 363–65
— nausea and vomiting, 325–26 penicillamine, rheumatoid arthritis,
— opioid analgesics, 318–21 406–7
— symptom control, 319 penicillin, antimicrobial allergy
— syringe pumps, 443–46 management, 28–30
pancreatic enzymes, pancreatitis, pentazocine, opioid partial agonists,
327–31 303
pancreatitis, 327–31 perampanel
— acute pancreatitis, 328 — interactions with other
— alcohol, 327 antiepileptics, 162
— analgesia, 329 — therapeutic drug monitoring
— anti-oxidants, 329–30 (TDM) in adults, 162
— chronic pancreatitis, 327–28 Periactin (cyproheptadine), appetite
— Creon, 329 stimulation, 36–7
— diabetes mellitus (DM), 327 perioperative period
— faecal elastase, 328 — management of long-term
— octreotide, 329 medicines, 284–89
k — pancreatic enzymes, 328–30 — surgical pharmacy, 434–39 k
— somatostatin, 329 peripheral cannulas, parenteral
— steatorrhea, 328, 330 nutrition (PN), 332
— type 3 diabetes, 330 peritoneal dialysis (PD)
paracetamol, pain — automated peritoneal dialysis
management, 313 (APD), 398
parenteral nutrition (PN), 331–33 — continuous ambulatory
— biochemical monitoring, 332 peritoneal dialysis (CAPD), 398
— central venous catheters (CVC), — renal replacement therapy
332 (RRT), 386, 393–95
— peripheral cannulas, 332 PFTs. See pulmonary function tests
— phosphate, 349–51 PH. See pulmonary hypertension
— refeeding syndrome, 332–33 pH paper, enteral feeding systems
Parkinson’s disease and drug administration, 151–6
— apomorphine, 33–36 phaeochromocytoma, 341–42
— clozapine, 88–91 — adrenaline, 341
paroxysmal AF, atrial fibrillation — alpha-blockers, 342
(AF), 52 — beta-blockers, 342
patient consultation, 334–39 — blood pressure, 342
— four E’s structure, 335–37 — catecholamines, 341–42
— health coaching, 335 — noradrenaline, 341–42
— medicines adherence, 336–37 pharmacocultural issues, 343–45
— non-adherence, 337 — gelatin, 344
— patient-centred care, 334 — Jehovah’s Witnesses, 344
patient education, warfarin, 488 — Judaism, 343
patient-centred care, patient — Muslim patients, 344
consultation, 334–39 — porcine products, 343
patient-controlled analgesia (PCA) — Ramadan, 344–45
k
CPPC
k
536 Index
pharmacodynamic profiles of portal hypertension, liver disease

medications, bariatric surgery, (chronic), 253, 255
54–56 postoperative nausea and vomiting
pharmacovigilance (PONV), 352–55
— adverse drug reactions (ADRs), — 5HT3 antagonists, 354
10–19 — cyclizine, 353–54
— Yellow Card scheme, 497–500 — dexamethasone, 355
phenobarbital — dolasetron, 354
— interactions with other — granisetron, 354
antiepileptics, 162–63 — metoclopramide, 354
— therapeutic drug monitoring — ondansetron, 354
(TDM) in adults, 163 — prochlorperazine, 354
phenytoin, 345–48 — tropisetron, 354
— administration, 347–48 postoperative period
— dose, 346 — epidural analgesia, 156
— drug interactions, 348 — fluid balance, 177–83
— monitoring, 346 — surgical pharmacy, 434–39
— overdose, 348 post-renal AKI, 4–7
— pharmacokinetic overview, 346 potassium, 355–59
phosphate, 349–51 — Calcium Resonium, 358–59
— calcium acetate, binding agent, — hyperkalaemia, 358–59
51–53 — hypokalaemia, 356–57
— hyperphosphataemia, 350–351 — Resonium A, 358–59
— hypocalcaemia, 350 — Sando-K, 357
— hypokalaemia, 350 — Slow-K, 357
— hypomagnesaemia, 350 PPI. See proton pump inhibitor
— hypoparathyroidism, 351 prednisolone
k — hypophosphataemia, 349–50 — Addison’s disease, 7–9 k
— magnesium carbonate, binding — corticosteroid oral/intravenous
agent, 351 equivalence, 94
— parenteral nutrition (PN), 349 — eye drops: use and care, 167
— sevelamer, binding agent, 351 pregabalin
— vitamin D, 350–351 — interactions with other
phytomenadione, prothrombin antiepileptics, 163
complex concentrates (PCC), — therapeutic drug monitoring
362–63 (TDM) in adults, 163
pill in the pocket, atrial fibrillation prepayment, prescription charge
(AF), 52 exemptions and prepayment
PIs. See protease inhibitors certificates, 360–61
pituitary, hypopituitarism, 213–15 pre-renal AKI, 4–7
pleurodesis, sclerosants for the prescription charge exemptions and
management of malignant pleural prepayment certificates, 360–62
effusions, 416–18 primidone
PN. See parenteral nutrition — interactions with other
pneumonia, CURB-65 score, 101 antiepileptics, 163
pneumonitis, interstitial lung disease — therapeutic drug monitoring
(ILD), 233–38 (TDM) in adults, 163
polymyalgia rheumatica, erythrocyte prochlorperazine, postoperative
sedimentation rate (ESR), 167 nausea and vomiting (PONV),
pomelos, drug interactions, 195 354–55
PONV. See postoperative nausea and progestogens, appetite stimulation,
vomiting 37
porcine products, pharmacocultural propranolol, liver disease (chronic),
issues, 343–45 255
k
CPPC
k
Index 537
propylthiouracil, thyroid function, — chronic obstructive pulmonary

453 disease (COPD), 365–66
prostacyclin, pulmonary — forced expiratory volume
hypertension (PH), 371–72 (FEV1 ), 365
protamine, 361–62 — forced vital capacity (FVC),
— anticoagulants, 362 365–68
— antiplatelet therapy, — peak expiratory flow rate
362 (PEFR), 363–64
— antithrombotics, — spirometry, 365–66
362 pulmonary hypertension (PH),
— bleeding, 362 363–68
— heparins, 361 — bosentan, 370–71
— low-molecular-weight heparins — diuretics, 370
(LMWH), 361 — epoprostenol, 370, 372
— reversal, 361 — prostacyclin, 371
protease inhibitors (PIs), human — pulmonary arterial
immunodeficiency virus (HIV) hypertension (PAH), 368–72
treatment, 231 — sildenafil, 371
protein binding, renal replacement — warfarin, 492
therapy (RRT), 385 pulmonary rehabilitation, chronic
proteinuria, chronic kidney disease obstructive pulmonary disease
(CKD), 390 (COPD), 80
prothrombin complex concentrates
(PCC) quinine, muscle cramps, 373–74
— Beriplex, 362–63
— international normalised ratio
radioactive iodine, thyroid function,
(INR), 362–63
k — Octaplex, 362–63
453 k
raloxifene, osteoporosis, 436
— phytomenadione, 363
Ramadan, pharmacocultural issues,
— vitamin K, 362–63 343–45
prothrombin time (PT), liver function rapid tranquillisation, 375–79
tests (LFTs), 259–62 — agitation, 635–41
prothrombin time, warfarin, 486 — antihistamines, 378
proton pump inhibitor (PPI), — antimuscarinics, 378
omeprazole parenteral — antipsychotics, 376–78
administration, 292–95 — benzodiazepines, 376–78
pruritus, liver disease (chronic), 257 — flumazenil, 378
pseudomonal infection, RBCs. See red blood cells
bronchiectasis (non-cystic RDA. See recommended daily
fibrosis), 67 amounts
Pseudomonas spp., tobramycin, 455 reboxetine, depression, 82
psoriasis receptor sites, nausea and vomiting,
— ciclosporin, 83, 85 278
— emollients, 143–46 recommended daily amounts
— topical corticosteroids (TCs), 96 (RDA), vitamins and
PT. See prothrombin time minerals, 474–84
pulmonary embolism (PE) rectal administration, 359
— antiphospholipid syndrome red blood cells (RBCs), anaemias, 21
(APS), 30–31 refeeding syndrome, parenteral
— D-dimer, 107 nutrition (PN), 332–33
— tinzaparin, 454–55 regimen or regime, xi
— Wells score, 495–96 Refer-to-Pharmacy, xii
pulmonary function tests (PFTs) renal bone disease, chronic kidney
— asthma, 363–64 disease (CKD), 388
k
CPPC
k
538 Index
renal calculi (kidney stones), — disease-modifying

241–42 antirheumatic drugs
renal disease-dosing in renal (DMARDs), 400–10
impairment and renal replacement — erythrocyte sedimentation rate
therapy, 382–85, See also chronic (ESR), 400
kidney disease (CKD) — etanercept, 409
— absorption, 382 — gold, 402
— distribution, 382 — hydroxychloroquine, 403
— excretion, 383 — infliximab, 410
— loading doses, 383–84 — leflunomide, 403–4
— metabolism, 383 — methotrexate, 405–6, 408
— pharmacodynamics, 383 — penicillamine, 406–7
— pharmacokinetics, 382–83 — sodium aurothiomalate, 402
— protein binding, 385 — sulfasalazine, 407
— therapeutic index, 380 rickettsial diseases, chloramphenicol
— volume of distribution, 382, 385 (systemic), 77
renal function rifampicin
— assessment, 379–81 — endocarditis, 149
— Cockcroft and Gault equation, — liver disease (chronic), 257
379–81 rifaximin, liver disease (chronic), 256
— creatinine clearance (CrCl), risedronate, osteoporosis, 306
379–80 rivaroxaban, atrial fibrillation (AF),
— estimated glomerular filtration 50–51
rate (eGFR), 379–81 Rockall score, gastrointestinal
— lithium, 384 bleeding risk management, 185,
renal replacement therapy (RRT). See 411
also renal disease-dosing in renal RRT. See renal replacement therapy
k impairment and renal replacement rufinamide k
therapy — interactions with other
— drug removal, 384 antiepileptics, 164
— haemodialysis (HD), 395 — therapeutic drug monitoring
— haemofiltration (HF), 396–97 (TDM) in adults, 164
— peritoneal dialysis (PD), 385,
398–99
— protein binding, 385 SABA. See short-acting beta-2 agonist
Resonium A, potassium, 358–59 SAMA. See short-acting muscarinic
respiratory acidosis, arterial blood antagonists
gases and acid –base balance, 38 Sando-K, potassium, 357
respiratory alkalosis, arterial blood sarcoidosis
gases and acid –base balance, 39 — azathioprine, 401
resuscitation, fluid balance, 177–82 — corticosteroids, 413
retigabine — granulomas, 413
— interactions with other — hydroxychloroquine, 403
antiepileptics, 163–64 — interstitial lung disease (ILD),
— therapeutic drug monitoring 233–38
(TDM) in adults, 164 — methotrexate, 414
reversal, protamine, 361 SBP. See spontaneous bacterial
rheumatoid arthritis, 400–10 peritonitis
— adalimumab, 408–9 schizophrenia, clozapine, 88–90
— anti-TNFs, 400, 407, 408 sclerosants for the management of
— azathioprine, 401 malignant pleural effusions
— biologics, 400 — pleurodesis, 415
— ciclosporin, 83–6, 401–2 — talc, 416
— C-reactive protein (CRP), 100 sclerotherapy, liver disease (chronic),
— cytokine inhibitors, 407–10 255
k
CPPC
k
Index 539
sedation Slow-K, potassium, 357

— agitation, 109 smoking/smoking cessation
— antipsychotics, 111 — cigarette smoking-calculation of
— delirium, 111 pack-years, 86–87
selective serotonin reuptake — cigarette smoking-drug
inhibitors (SSRIs), 417 interactions, 87
— depression, 113 — nicotine replacement therapy
— serotonin syndrome, 416–18 (NRT), 282–83
— syndrome of inappropriate — withdrawal, 282–83
secretion of antidiuretic soap substitutes, emollients, 144
hormone (SIADH), 442–44 sodium, 420–22
sepsis, systemic inflammatory — diabetes insipidus (cranial), 116
response syndrome (SIRS), — hypernatraemia, 420
418–419 — hyponatraemia, 420–21
septicaemia, chloramphenicol — Slow Sodium, 421
(systemic), 77 — syndrome of inappropriate
serotonin syndrome secretion of antidiuretic
— drug interactions, 417 hormone (SIADH), 421
— monoamine oxidase inhibitors sodium aurothiomalate, rheumatoid
(MAOIs), 417 arthritis, 402
— selective serotonin reuptake sodium bicarbonate
inhibitors (SSRIs), 417 — acidosis, 60
— tramadol, 417–18
— alkalosis, 60
serum osmolality, hyperosmolar
— arterial blood gases and
hyperglycaemia state (HHS),
acid –base balance, 38–39
208–11
— buffer, 59
sevelamer, phosphate binding agent,
— diabetic ketoacidosis (DKA), 60
k 351
— in cardiac arrest, 60 k
short-acting muscarinic antagonists
— intravenous, 60
(SAMA), chronic obstructive
— oral, 59–60
pulmonary disease (COPD), 81
sodium chloride, fluid balance, 233
short-acting beta-2 agonist (SABA)
— asthma, 41–7 sodium valproate
— chronic obstructive pulmonary — interactions with other
disease (COPD), 79–83 antiepileptics, 159
SIADH. See syndrome of — therapeutic drug monitoring
inappropriate secretion of (TDM) in adults, 159
antidiuretic hormone Solvazinc, zinc preparation, 505
sicca syndrome, artificial saliva, somatostatin, pancreatitis, 329
39–41 spasticity, multiple sclerosis, 275
sick-day rules, diabetes mellitus spill/spillage, cytotoxic
(DM)-acute illness, 122–23 chemotherapy waste, 103–6
sickle cell disease, 24 spirometry
— anaemias, 20, 24 — interstitial lung disease (ILD),
— folic acid, 24 233–38
sildenafil, pulmonary hypertension — pulmonary function tests
(PH), 370–371 (PFTs), 365–68
Sjögren’s syndrome spontaneous bacterial peritonitis
— artificial saliva, 39–41 (SBP), liver disease (chronic),
— eye ointments: use and care, 253–58
170–172 squint, eye drops: use and care, 170
sliding scale insulin, variable rate SSRIs. See selective serotonin
intravenous insulin infusion reuptake inhibitors
(VRIII), 231–33 St John’s Wort, adverse drug
Slow Sodium, 421–23 reactions (ADRs), 12
k
CPPC
k
540 Index
statins surgical pharmacy, 434–39

— stroke, 424–32 — antibiotic prophylaxis, 437–39
— transient ischaemic attack — medicines reconciliation,
(TIA), 424–32 434–35
steatorrhea, pancreatitis, 328, 330 — nausea and vomiting, 434
sterile larvae — pain management, 438–39
— debridement, 422 — perioperative period, 434–35
— wounds, 422–23 — postoperative period, 439
steroids, 26, See also corticosteroid — thromboprophylaxis, 435–36
oral/intravenous equivalence; Synacthen (tetracosactide) tests,
inhaled corticosteroid (ICS); 440–41
topical corticosteroids (TCs), — Addison’s disease, 440–41
appetite stimulation — adrenocorticotrophic hormone
stroke, 424–32 (ACTH), 440
— ABCD2 scoring system, 1 — Cushing’s syndrome, 441
— alteplase, 425 — hypopituitarism, 440
— antiphospholipid syndrome syndrome of inappropriate secretion
(APS), 30–31 of antidiuretic hormone (SIADH),
— aspirin, 425–28 442–43
— atrial fibrillation (AF), 47–52, — demeclocycline, 442–43
430–32 — fluid restriction, 442–43
— CHA2 DS2 -VASc score, 430–32, — hyponatraemia, 442–43
487 — selective serotonin reuptake
— cholesterol, 455 inhibitors (SSRIs), 442
— clopidogrel, 427 — sodium, 421
— dipyridamole, 427 — tolvaptan, 442–43
— Driver Vehicle Licensing — tricyclic antidepressants
k Authority (DVLA), 140 (TCAs), 442 k
— dysphagia, 429 syringe pumps, 443–46
— haemorrhagic stroke, 424, 426 — continuous subcutaneous
— hypertension, 428, 431 infusion, 443, 445
— ischaemic stroke, 424, 425, 427, — palliative and end-of-life care,
428 319
— novel oral anticoagulants — syringe drivers, 444
(NOACs), 425 systemic inflammatory response
— statins, 426, 428 syndrome (SIRS), 418–19
— transient ischaemic attack — infection, 418–19
(TIA), 424–32 — sepsis, 418–19
— warfarin, 427–28, 431 — venous thromboembolism
strontium, osteoporosis, 306–7 (VTE), 419
subarachnoid headache, thunderclap
headache, 450
subcutaneous (SC) injection, T3 thyroid function test, 451
insulins, 224 T4 thyroid function test, 451
sulfasalazine, rheumatoid arthritis, tangerines, drug (non)interactions,
407 195
superior vena cava obstruction TCAs. See tricyclic antidepressants
(SVCO), oncological emergencies, TCs. See topical corticosteroids
297 TDM. See therapeutic drug
suppositories, 433 monitoring
surgery. See also perioperative temporal arteritis, erythrocyte
period; postoperative period sedimentation rate (ESR), 167
— bariatric surgery, 54–56 TENS. See transcutaneous electrical
— management of long-term nerve stimulation
medicines, 284–89 teriparatide, osteoporosis, 306
k
CPPC
k
Index 541
tetracosactide, Synacthen tiagabine

(tetracosactide) tests, 440–41 — interactions with other
thalassaemia, 20 antiepileptics, 164
theophylline, 447–49 — therapeutic drug monitoring
— aminophylline, 448–49 (TDM) in adults, 165
— bronchodilators, 447 tinzaparin
— cigarette smoking-drug — deep-vein thrombosis (DVT),
interactions, 87 454–55
— dose, 447–49 — dosing, 454–55
— drug interactions, 447 — enoxaparin dosing in unstable
— narrow therapeutic range, 447 angina, 150–151
— overdose, 449 — low-molecular-weight heparins
— xanthines, 447 (LMWH), 262–63
therapeutic drug monitoring (TDM). — pulmonary embolism (PE),
See epilepsy-therapeutic drug 454–55
monitoring (TDM) of antiepileptics tobacco. See cigarette
in adults smoking-calculation of pack-years;
therapeutic index, renal impairment, cigarette smoking-drug
382–85 interactions; smoking/smoking
thiopurines, inflammatory bowel cessation
disease (IBD), 221 tobramycin, 455–58
thromboembolism — administration, 457
— atrial fibrillation (AF), 47–52 — dose, 456
— low-molecular-weight heparins — drug interactions, 458
(LMWH), 262–63 — gentamicin, 455–56
thromboprophylaxis, 435–37 — monitoring, 455–58
thunderclap headache, 450 — overdose, 457
k — nimodipine, 450 — pharmacokinetic overview, 455 k
— subarachnoid headache, 450 — Pseudomonas spp., 455
thyroid TOE. See transoesophageal
— hyperparathyroidism, 68 echocardiogram
— hypopituitarism, 213–14 tolvaptan, syndrome of inappropriate
— hypothyroidism, 251 secretion of antidiuretic hormone
thyroid function, 450–53 (SIADH), 442–43
— amiodarone, 452 tonics and bitters, appetite
— carbimazole, 452–53 stimulation, 36–37
— Graves’ disease, 452 topical corticosteroids (TCs), 96–98
— hyperthyroidism, 452–53 — choice of preparation, 96
— hypothyroidism, 451–52 — course length, 97–98
— levothyroxine, 451–52 — dose and application, 97
— liothyronine, 452 — eczema, 96
— lithium, 250 — emollients, 96–98
— propylthiouracil, 453 — fingertip unit (FTU), 97
— radioactive iodine, 453 — pharmaceutical care and
— T3 thyroid function test, 453 counselling points, 98
— T4 thyroid function test, — psoriasis, 96, 98
451–52 topiramate
— thyroid-stimulating hormone — interactions with other
(TSH), 451 antiepileptics, 164–65
— thyrotoxicosis, 453 — therapeutic drug monitoring
thyroid-stimulating hormone (TSH), (TDM) in adults, 165
451 trace elements, 503
— hypopituitarism, 213–14 tramadol, serotonin syndrome, 314
thyrotoxicosis, 453 tranexamic acid, von Willebrand
TIA. See transient ischaemic attack disease, 418
k
CPPC
k
542 Index
transcutaneous electrical nerve — interferon-gamma release assay

stimulation (TENS), osteoarthritis, (IGRA), 466
194 — latent tuberculosis, 466–67
transfer of care, medicines — Mantoux test, 466–67
reconciliation, 268 — monitoring, 461–63
transient ischaemic attack (TIA), — multidrug-resistant tuberculosis
424–32 (MDR-TB), 463–66
— ABCD2 scoring system, 1 — treatment, 459–62
— alteplase, 425 type 3 diabetes, pancreatitis, 330
— antiphospholipid syndrome Type A reactions/Type B reactions,
(APS), 30–31 adverse drug reactions (ADRs),
— aspirin, 425–28 10–11, 13
— cholesterol, 455 tyramine, food-drug interactions,
— clopidogrel, 427 183
— dipyridamole, 427
— hypertension, 428, 431 ulcerative colitis (UC), 83–84, 219,
— novel oral anticoagulants See also inflammatory bowel
(NOACs), 425 disease (IBD), ciclosporin
— statins, 426, 428 ulcers
— stroke, 424–32 — gastro-oesophageal reflux
— warfarin, 427–28, 431 disease (GORD), 292
transoesophageal echocardiogram — omeprazole, 292–95
(TOE), endocarditis, 148 ultrafiltration
transplant, ciclosporin, 83–85 — haemodialysis (HD), 393–95
transthoracic echocardiogram (TTE), — haemofiltration (HF), 396
endocarditis, 148 unconsciousness, Glasgow Coma
travel recommendations, 458–59 Scale (GCS), 190–191
k — holiday, 458 uraemia, chronic kidney disease
(CKD), 388, 390
k
— malaria, 459
— vaccination, 459 urine glucose monitoring, diabetes
trazodone, depression, 114 mellitus (DM), 125
tricyclic antidepressants (TCAs) urine ketone monitoring, diabetes
— depression, 113 mellitus (DM), 125
— syndrome of inappropriate urticaria
secretion of antidiuretic — ACEI-related angioedema, 26
hormone (SIADH), 442–43 — immediate hypersensitivity
trigeminal neuralgia, angioedema, 25
carbamazepine, 71–73 — NSAID/aspirin-induced
tropisetron, postoperative nausea angioedema, 25–26
and vomiting (PONV), 354
TSH. See thyroid-stimulating vaccination, travel recomm,
hormone 458–59
TTE. See transthoracic
echocardiogram withdrawal
tuberculosis, 459–68 — benzodiazepines, 57
— active tuberculosis, 460–61 — methadone, 299
— adherence, 463 — nicotine, 282
— diagnosing, 466
— drug interactions, 463 zeaxanthin, 291

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CPPC ffirs.tex V3 - 11/19/2015 11:52 A.M. Page ii

Alistair Howard Gray

Published by Pharmaceutical Press

66–68 East Smithﬁeld, London E1W 1AW, UK

© The Royal Pharmaceutical Society 2016

is a trade mark of Pharmaceutical Press

Pharmaceutical Press is the publishing division of the Royal Pharmaceutical Society

First edition published 2006

Typeset by SPi Global, Chennai, India

Printed in Great Britain by TJ International, Padstow, Cornwall

ISBN 978 0 85711 157 9 (print)

We would like to thank everyone at the Pharmaceutical Press who has

Jenny would like to thank Simon for his support.

About the authors xvii

ABCD2 scoring system 1

ACE inhibitor-induced cough 2

Acetylcysteine for nebulisation 3

Acute kidney injury 4

Adverse drug reactions 10

Angioedema: drug causes and treatment 25

Antimicrobial allergy management 28

Antipsychotics: equivalent doses 32

Arterial blood gases and acid–base balance 38

Benzodiazepines and ‘z’ hypnotics 57

Body surface area calculation 61

Bronchiectasis (non-cystic ﬁbrosis) 65

Chemotherapy-induced nausea and vomiting 74

Chronic obstructive pulmonary disease 79

Ciclosporin: management and monitoring 83

Cognitive assessment tools 90

Corticosteroid oral/intravenous equivalence 94

C-reactive protein 100

Cushing’s syndrome 102

Cytotoxic chemotherapy waste 104

Diabetes insipidus (cranial) 116

Diabetes mellitus 117

Diabetes mellitus: management of hypoglycaemia

Diabetes mellitus: management of acute illness

Diabetes mellitus: monitoring and tests 123

Diabetic ketoacidosis 127

DVLA: advice concerning medication and medical conditions 140

Early warning score 142

Enoxaparin dosing in unstable angina 150

Enteral feeding systems and drug administration 151

Epidural analgesia in the postoperative period 156

Epilepsy: therapeutic drug monitoring of antiepileptics in

Erythrocyte sedimentation rate 167

Eye drops: use and care 168

Eye ointments: use and care 170

Falls: pharmaceutical care 173

Glasgow Coma Scale 190

Grapefruit juice –drug interactions 194

Ideal body weight 216

Immunoglobulin (normal) for intravenous administration 216

Inhaler devices in respiratory disease 223

Insulin: variable-rate intravenous insulin infusion 231

k Interstitial lung disease 233 k

Iron: guidance on parenteral dosing and administration 238

Kidney stones (renal calculi) 241