OBAT ANTIDIABETES

Hernita Taurustya
A. Overview

∴ glucose
○ Reabsorption sites
 Blood glucose concentrations and Rate of chance of blood glucose

Plasma glucose and insulin concentrations in oral glucose tolerance tests in diabetic and control subjects.
Nondiabetic subjects (A), type1 diabetics (B), type2 diabetics (C), and individuals with impaired glucose
tolerance (D) were tested for 8 hours.
Types of Diabetes Melliutus (DM)
Characteristic Type 1 DM Type 2 DM
Onset (age) Under 30 years Approximately 40 years

Type of onset Abrupt Gradual

Nutritional status of onset Usually thin Usually obese

Clinical symptoms Polydipsia, polyphagia and Often none

polyuria
Ketosis Frequent, unless diet, insulin, Infrequent (except in the
and exercise are properly presence of infection or
coordinated stress)
Endogenous insulin Negligible Present; but relatively
ineffective because of obesity
Related lipid abnormalities Hypercholesterolemia Cholesterol and triglycerides
frequent often elevated; carbohydrate-
induced hypertriglyceridemia
common
Insulin therapy Required Required in only 20-
30percent of patients
Hypoglycemic drugs Should not be used Clinically indicated

Diet Mandatory along with insulin Diet alone frequently

for blood glucose control sufficient to control blood
glucose
 Pathogenesis
Type1 DM
1) Polyuria, Polydipsia, Weight loss, Blurred vision
2) Destruction of insulin producing b-cells
- Autoimmune destruction
- Probably caused by lymphocytic infiltration

- Increased suppressor-inducer T cells or decreased helper-

inducer T cells
- Appearance of anti-islet cell antibodies (ICAs)

Type2 DM
1) Impaired insulin secretion, peripheral insulin resistance,
excessive hepatic glucose production
2) Adipocyte secrete a number of biologic products (leptin,
TNF-a, free fatty acids, resistin, and adiponectin) that
modulate insulin secretion, insulin action, and body weight
and may contribute to the insulin resistance
3) No dramatic decrease of insulin receptor
4) Insulin-mediated stimulation of tyrosine kinase and
autophosphorylation are imparied in type2 DM
 Glucose Homeostasis

Body
cells
Insulin take up more
glucose

Beta cells
of pancreas stimulated
to release insulin into
the blood Liver takes
up glucose Blood glucose level
and stores it as declines to a set point;
High blood glycogen stimulus for insulin
glucose level release diminishes

STIMULUS:
Rising blood glucose
level (e.g., after eating
a carbohydrate-rich
meal) Homeostasis: Normal blood glucose level
(about 90 mg/100 mL) STIMULUS:
Declining blood
glucose level
(e.g., after
skipping a meal)

Blood glucose level

rises to set point; Alpha
stimulus for glucagon cells of
release diminishes pancreas stimulated
to release glucagon
into the blood
Liver
breaks down
glycogen and Glucagon
releases glucose
to the blood
Pancreatic axis
Long Term Complications
OBAT ANTIDIABETES
INSULIN

Hernita Taurustya
 Action of Insulin on Various Tissues
Liver Muscle Adipose
↓ glucose ↑ Glucose ↑ glucose
production transport transport
↑ glycolysis ↑ glycolysis ↑ lipogenesis&
lipoprotein
lipase activity
↑ TG synthesis ↑ glycogen ↓ intracellular
deposition lipolysis
↑ Protein ↑ protein
synthesis synthesis
 Pharmacology of Insulin
A. Structure
B. Insulin Receptor
The receptor are synthesized in the
target cells as single polypeptide
precursors and then they are
cleaved as they are inserted in to
the membrane

ED50 range = 10-11M

Kd (binding) = 10-9M

b-agonist : cAMP ↑, phosphorylation

1) Specific to serine and threonine residues on the beta subunits : lead to inhibition of
insulin binding and f the tyrosine kinase activity
2) May lead to internalization of the receptor
 The Action of Insulin Receptor

Insulin signal transduction pathway in skelectal muscle. The insulin receptor has
intrinsic tyrosine kinase activity and interacts with insulin receptor substrate (IRS and
Shc) proteins.
Glucose transporters
Transporter Tissues Glucose Km Function
(mmol/L)
GLUT1 All tissue, 1-2 Basal uptake of
especially red cells glucose; transport
brain across the blood-
brain barrier
GLUT2 b cells of pancreas, 15-20 Regulation of
liver, kidney, gut insulin release,
other aspects
homeostasis
GLUT3 Brain, kidney, <1 Uptake into
placenta, other neurons, other
tissues tissues
GLUT4 Muscle, adipose =5 Insulin mediated
uptake of glucose

GLUT5 Gut, kidney 1-2 Intestinal

absorption of
fructose
C. Secretion of Insulin
• ATP sensitive K+ channel determines the resting potential of b-cells
• Glucose metabolism : ↑ATP → block K+ channel → depolarization → open
voltage gated Ca2+ channel

Glucose

fructose Sorbitol
: cataract in the lens
(Retinopathy)
Neuropathy

↑Insulin secretion
1) Glucagon
2) ACTH
3) Growth hormone
4) Secretin
5) Gastrin
6) CCK ↓Insulin secretion
7) Pancreozymin 1) Somatostatin
8) Cholinergic agonist 2) a-adrenergic agonist
D. Treatment

Typical profile of insulin and glucose concentrations in a normal individual

E. Insulin Formulation
Insulin Type Onset (hr) Duration Peak (hr) Other Characteristics
(hr)

Rapid action Subcutaneous injection dose

0.5-1.0 3-6 2-3 not produce sharp
regular, crystalline
physiologic peak; because
zinc insulin [CZI] onset is delayed, must be
Lispro, insulin aspart <0.25 3-4 0.5-1.5 given 30-60 min before
meals

Intermediate
Should not be mixed with
(Lente, neutral 2-4 10-20 4-10
CZI more than 10 min before
protamine injection
Hagaforn[NPH]
insulin)

Because of very long-half life,

Long acting 8-14 24-36 Minimal new steady state is not
(Ultralente) reached for 4-5 days after
change in dose

∴ Human insulin → humulin R, Novolin R

Common multidose insulin
regimens

A. A typical ‘split-mixed
regimen consisting of twice-
daily injections of a mixture
of regular and intermediate-
action insulin.
B. A variation in which the
evening dose of
intermediate-acting insulin is
delayed until bedtime to
increase the amount of
insulin available the next
morning.
C. A regimen that incorporates
ultralente insulin.
D. Pattern of insulin
administration with a
regimen of continuous
subcutaneous insulin
infusion
F. Overview of Insulin Action

Fatty acids glucose amino acids

Triglyceride Glycogen Protein

(Adipose tissue) (Liver) (muscle)

Fatty acids

Inhibited by insulin
Stimulated by insulin
increased by fasting and
increased by feeding
in diabetes
G. Side effects
1) Severe hypoglycemia
2) Insulin allergy
3) Insulin lipodystropy
4) Obesity

H. Hypoglycemic vs. Diabetic Coma

Hypoglycemic Coma Diabetic Coma

Onset Rapid Gradual – over days

Acidosis, dehydration No ++++

Preceding infection No Common, often with

vomiting or diarrhea
Skin Pale, sweating Hot, dry

Respiration Normal or shallow Deep- ‘air hunger’

CNS Tremor, occasionally General depression

convulsions; may have
+babinski sign
Preparation Species Concentration
Source
Rapid-acting insulins

Insulin lispro, Humalog (Lilly) Human U100

analog
Insulin Aspart, Novolog (Novo Human U100
Nordisk) analog
Short-acting insulins

Regular (Novo Nordisk)3 Human U100

Regular Humulin (Lilly) Human U100, U500

Velosulin BR (Novo Nordisk)4 Human U100

Preparation Species Concentration
Source

Intermediate-acting insulins
Lente Humulin (Lilly) Human U100
Lente (Novo Nordisk) Human U100
NPH Humulin (Lilly) Human U100
NPH (Novo Nordisk) Human U100
Long-acting insulins
Ultralente Humulin U (Lilly) Human U100
Insulin glargine-lantus Human U100
(Aventis/Hoechst Marion
Roussel)
Preparation Species Concentration
Source
Premixed insulins (% NPH, % regular)

Novolin 70/30 (Novo Nordisk) Human U100

Humulin 70/30 and 50/50 (Lilly) Human U100
Premixed (% NP-analog, % Human U100
rapid acting analog) analog
50/50 NPL, Lispro (Lilly) Human U100
analog
75/25 NPL, Lispro (Lilly) Human U100
analog
70/30 NPA, Aspart Human U100
(NovoNordisk) analog
Cara Pemberian Insulin
 Penyimpanan Insulin

Pada suhu 2-8°C

 Insulin vial Eli Lily yang sudah dipakai dapat
disimpan selama 6 bulan atau sampai 200
suntikan bila dimasukkan dalam lemari es.
 Vial Novo Nordisk insulin

yang sudah dibuka, dapat disimpan selama 90

hari bila dimasukkan lemari es.
 Insulin dapat disimpan pada suhu kamar dengan
penyejuk 15-20°C bila seluruh isi vial akan
digunakan dalam satu bulan.
 Penfill dan pen yang disposable berbeda masa

simpannya. Penfill regular dapat disimpan pada

temperatur kamar selama 30 hari sesudah
tutupnya ditusuk. Penfill 30/70 dan NPH dapat
disimpan pada temperatur kamar selama 7 hari
sesudah tutupnya ditusuk.
OBAT ANTIDIABETES
ORAL

HERNITA TAURUSTYA
 Meglitinide Analogs
1
Sulphonylureas Alpha Glucosidase
Inhibitors 3

Metformin (Biguanides)
2

Thiazolindinediones
4
Non-Insulin Hypoglycemic Agents
Oral Parenteral

Biguanides  Amylin analogs

Sulfonylureas  Incretin mimetics
Meglitinides
Thiazolidinediones
Alpha Glucosidase
inhibitors
Incretin Enhancers

(DPP-IV inhibitors)
Resin binder
1. Sulfonylurea
Class Sulfonylureas (2nd generation) Sulfonylureas

Compound • Glibenclamide/Glyburide
• Glipizide
• Gliclazide
• Glimepiride

Mechanism Closes KATP channels on β-cell plasma membranes

Action(s)  Insulin secretion

Advantages • Generally well tolerated

• Reduction in cardiovascular events and mortality
(UKPDS f/u)
Disadvantages • Relatively glucose-independent stimulation of insulin
secretion: Hypoglycemia, including episodes
necessitating hospital admission and causing death
• Weight gain
• Primary and secondary failure

Cost Low
C. Side Effects
1) Hypoglycemic crisis
2) Allergic skin reaction
3) Bone marrow depression : leukopenia,
thrombocytopenia, agranulocysis
4) Potentiate effects of barbiturates and other sedative-
hypnotics
5) Potentiate action of circulating ADH : ex)chlorpromide
causes water retention
6) GI upsets

• Contraindication : renal impairment, hepatic

disease
 Pharmacological comparison of sulfonylureas

Repa- Tolbu- Gliben- Glime-

glinide tamide Gliclazide Glipizide clamide piride

Relative + 400 1 30 50 - 100 150 - 400 400-1000

potency

mg/tab 0.5-2 500 80 5-10 1.25-5 1- 4

Plasma peak <1 3 4 1 3 2.4

(h)
Duration of action <6 6 - 10 24 16 - 24 24 24
(h)
 Meglitinide
<Repaglinide, Nateglinide>
• Pharmacological Action
- Similar to sulfonylurea
- Given orally or parenterally lower blood sugar level
- Effective ONLY in the presence of functional pancreas
• Mechanisms of Action
- Closing ATP-dependent potassium channel in pancreatic b-
cells
• Pharmacokinetics :
- Administered orally
- Half-life is about one hour
- Small proportion (about 10~15%) of repaglinide is metabolized
by kidney
- Nateglinide is metabolized primarily by the liver and 16% of
drug is excreted by the kidney as unchanged form

• Contraindication : renal impairment, hepatic disease

 Meglitinides
Class Meglitinides

Compound • Repaglinide (Prandin®)

• Nateglinide (Starlix®)

Mechanism Closes KATP channels on β-cell plasma

membranes
Action(s) Insulin secretion 

Advantages Accentuated effects around meal ingestion

Disadvantages • Hypoglycemia, weight gain

• Dosing frequency

Cost Medium
 2. Biguanide
• Pharmacological Action
- Decrease hepatic glucose output
- Inhibit absorption of glucose from the gut
- Increase glucose uptake by muscle and fat cells
• Mechanisms of Action
- Involve activation of cAMP dependent protein kinase
- Increased glucose transport by promoting translocation of GLUT4 to the cell
surface
• Pharmacokinetics :
- Administered orally
- Half-life is 2 to 4 hours
- Excreted unchanged in the urine
• Side effects :
1) Transient GI disturbance
2) Rate lactic acidosis
3) No hypoglycemia and No weight gain

• Contraindication : renal impairment, hepatic disease

• Phenformin : Lactic acidosis (Withdrawn from US market)
can be used only on approval by the FDA
Class Biguanides Biguanides
Compound Metformin
Mechanism Activates AMP-kinase
Action(s) • Hepatic glucose production 
• Intestinal glucose absorption 
• Insulin action 
Glucose • Fasting
Lowering Effect • Post Prandial
Advantages • No weight gain
• No hypoglycemia
• Reduction in cardiovascular events and mortality
(UKPDS f/u)
Disadvantages • Gastrointestinal side effects (diarrhea, abdominal
cramping)
• Lactic acidosis (rare)
• Vitamin B12 deficiency
• Contraindications: reduced kidney function
Cost Low
 Biguanide
1) Do not require functioning b-cells
2) Mainly reduce gluconeogenesis in liver
3) Can be combined with sulphonylurea drugs
Biguanide Daily Dose Duration of
Action (hours)

Phenformin (DBI, 0.025-0.15g as 4-6

Meltrol-50) single dose or in 8-14
divided doses

Buformin -NH-(CH2)3-CH3 0.05g-0.3g in 10-12

divided doses

Metformin -N-(CH3)2 1-3g in divided 10-12

doses
 3. a-glicosidase inhibitor

<Acarbose, miglitol>
• Pharmacological Action
- Preventing generation of monosaccharides
- Blunt the rise in blood glucose concentration
• Mechanisms of Action
- a-glucosidase inhibition
• Pharmacokinetics :
- The amount of acarbose absorbed systemically is
negligible
- Half-life of miglitol is 2 hours
- Excreted unchanged in the urine
• Side effects :
1) Carbohydrate malabsorption
2) Abdominal pain, diarrhea, flatulence (contraindication to
irritable bowel syndrome)
Alpha-Glucosidase Inhibitors
Class α-Glucosidase inhibitors
Compound • Acarbose
• Miglitol
Mechanism Inhibits intestinal α-glucosidase
Action(s) Intestinal carbohydrate digestion and
absorption slowed
Advantages • Nonsystemic medication
• Postprandial glucose 
Disadvantages • Gastrointestinal side effects (gas, flatulence,
diarrhea)
• Dosing frequency
Cost Medium

.
 4. Thiazolinediones
<Rosiglitazone, Pioglitazone>
• Pharmacological Action
- Increasing insulin sensitivity
- b-cell protection
• Mechanisms of Action
- Activation transcription factor PPAR-g through the thiazolinedione
receptor
- Expression of mRNAs encoding enzymes and proteins required for
optimal insulin sensitivity
• Pharmacokinetics :
- Administered orally
- Half-life of rosiglitazone is 3 to 4 hours
- Metabolized to inactive products in the liver
- Excreted in the bile
• Side effects :
1) Fluid retention
2) Weight gain
3) hepatotoxicity except troglitazone

• Contraindication : liver disease, congestive heart failure

Insulin Sensitizers
Thiazolidinediones (Glitazones)
 Thiazolidinediones (TZD)
Class Thiazolidinediones (Glitazones)

Compound Pioglitazone (Actos®)

Mechanism Activates the nuclear transcription factor PPAR-

Action(s) Peripheral insulin sensitivity 

Advantages • No hypoglycemia
• HDL cholesterol 
• Triglycerides 

Disadvantages • Weight gain

• Edema
• Heart failure (CI with stage III and IV)
• Bone fractures

Cost High
TZDs and The FDA
 Rosiglitazone
 Restricted by FDA – can only be used by patients
currently benefiting from therapy or do not get
adequate DM treatment from other agents and
not willing to use pioglitazone
 1-800-AVANDIA

 Pioglitazone
 FDA alert – ongoing analysis of risk of bladder

cancer (with prolonged use >12 months)

Class Thiazolidinediones (Glitazones)
Compound Rosiglitazone (Avandia®)
Mechanism Activates the nuclear transcription factor
PPAR-
Action(s) Peripheral insulin sensitivity 
Advantages No hypoglycemia
Disadvantages • LDL cholesterol 
• Weight gain
• Edema
• Heart failure (CI with stages III and IV)
• Bone fractures
• Increased cardiovascular events (mixed
evidence)
• FDA warnings on cardiovascular safety
Cost High
5. Incretin Therapy
 Incretin Enhancers
Class DPP-4 inhibitors (incretin enhancers)

Compound • Sitagliptin (Januvia®)

• Vildagliptin (available in Europe)
• Saxagliptin (Onglza®)
• Linagliptin (Tradjenta®)

Mechanism Inhibits DPP-4 activity, prolongs survival of

endogenously released incretin hormones
Action(s) • Active GLP-1 concentration 
• Insulin secretion 
• Glucagon secretion 
Advantages • No hypoglycemia
• Weight “neutrality”
Disadvantages • Occasional reports of urticaria/angioedema
• Cases of pancreatitis observed
• Long-term safety unknown (cancer ?)
Cost High
Incretin Mimetics
Class GLP-1 receptor agonists (incretin mimetics)
Compound • Exenatide (Byetta®)
• Liraglutide (Victoza®)
Mechanism Activates GLP-1 receptors (β-cells/endocrine pancreas;
brain/autonomous nervous system
Action(s) • Insulin secretion  (glucose-dependent)
• Glucagon secretion  (glucose-dependent)
• Slows gastric emptying
• Satiety 
Advantages • Weight reduction
• Potential for improved β-cell mass/function
Disadvantages • Gastrointestinal side effects (nausea, vomiting, diarrhea)
• Cases of acute pancreatitis observed
• C-cell hyperplasia/medullary thyroid tumors in animals
(liraglutide)
• Injectable
• Long-term safety unknown
Cost High
 Amylin Analog
Class Antihyperglycemic Synthetic Analog

Compound • Pramlintide (Symilin®)

Mechanism • Amylinomimetic

Action(s) • Glucagon secretion  (glucose-dependent)

• Slows gastric emptying
• Satiety 

Advantages • Potential weight loss

Disadvantages • Meal time injections

• Nausea
• Hypoglycemia in combination with insulin

Cost High
 Bile Acid Sequestrants
Class Bile acid sequestrants

Compound Colesevelam (Welchol®)

Mechanism Binds bile acids/cholesterol

Action(s) Bile acids stimulate receptor on liver to
produce glucose
Results • Lowers fasting and post prandial glucose
Advantages • No hypoglycemia
• LDL cholesterol 
Disadvantage • Constipation
s • Triglycerides 
• May interfere with absorption of other
medications
Cost High
Medication PRO CON

Metformin Low cost, A1c lowering, + CV Renal or hepatic

effects, weight loss, PCOS impairment
Sulfonylurea Low cost, A1c lowering Hypoglycemia, treatment
failure
Meglitinides Erratic meals, renal insufficiency Hypoglycemia, treatment
failure
Pioglitazone Insulin resistance, decrease in Edema, wt gain, CI with
adipose tissue, TG reduction HF class III and IV
α-glucosidase Patients with constipation Long duration of T2DM,
inhibitors patients with GI problems
DPP-4 Well tolerated ? long term safety

GLP-1 agonists Obese patients GI side effects

Amylin analogs Poor PPG control despite GI side effects

insulin therapy
Insulin Flexible treatment (basal, basal Hypoglycemia, weight
bolus, etc) gain
Conceptual Model
 In obese patients:
 Try metformin first
 Shown to reduce diabetic events and
mortality (UKPDS)
 Side effect :
- lactic acidosis (rare but fatal)
- anorexia, vomiting, abdominal pain,
cramps, malaise, weight loss
 Contra-indicated: renal and hepatic
impairment, heart failure, specially in
old age.
 In non-obese NIDDM patients:

 Of the sulfonylureas: glibenclamide has

the best data to significantly reduce the
incidence of diabetes-related events

 Gliclacide and glipizide lacks long term

data

 Chlorpropamide :not recommended

 Repaglinide is short acting and should

be given before each meal. Fit for
patients with erratic eating times
 Strategy of diabetic management
 Strict blood glucose control, but …...
no hypoglycaemic bouts allowed!

 Through diet first,…. then exercise

 Understand OAD profile you are using,

such as kinetics and dosing

 No meal, no drug!