Al-Rafidain University College

Dentistry Department

Branch of pharmacology dentistry

Student Name: ‫يُسرُدمحمُباسل‬

Grade: third stage
Group: b2

Evaluation score: -----

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INTRODUCTION
Histamine is an organic nitrogenous compound involved in local
immune responses, as well as regulating physiological function in the
gut and acting as a neurotransmitter for the brain, spinal cord, and
uterus.[1][2] Histamine is involved in the inflammatory response and
has a central role as a mediator of itching. Histamine increases the
permeability of the capillaries to white blood cells and some proteins,
to allow them to engage pathogens in the infected tissues.[3] It
consists of an imidazole ring attached to an ethylamine chain; under
physiological conditions, the amino group of the side-chain is
protonated.

Mechanism of action of histamine

In humans, histamine exerts its effects primarily by binding to G
protein-coupled histamine receptors, designated H1 through H4. [4]
As of 2015, histamine is believed to activate ligand-gated chloride
channels in the brain and intestinal epithelium.[5] Histamine N-
methyltransferase metabolizes the majority of histamine (50 to 80%)
to N-methyl histamine, which is further metabolized to the primary
urinary metabolite. M-methylimidazole acetic acid by monoamine
oxidase. Diamine oxidase metabolizes the histamine (15 to 30%) to
imidazole acetic acid [6].

Synthesis and metabolisms

Histamine is derived from the decarboxylation of the amino acid
histidine,a reaction catalyzed by the enzyme L-histidine
decarboxylase. It is a hydrophilic vasoactive amine.

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Conversion of histidine to histamine by histidine decarboxylase

Once formed, histamine is either stored or rapidly inactivated by its

primary degradative enzymes, histamine-N-methyltransferase or
diamine oxidase. In the central nervous system, histamine released
into the synapses is primarily broken down by histamine-N-
methyltransferase, while in other tissues both enzymes may play a
role. Several other enzymes, including MAO-B and ALDH2, further
process the immediate metabolites of histamine for excretion or
recycling. A non-infectious form of foodborne disease, scombroid
poisoning, is due to histamine production by bacteria in spoiled food,
particularly fish. Fermented foods and beverages naturally contain
small quantities of histamine due to a similar conversion performed
by fermenting bacteria or yeasts. Sake contains histamine in the 20–
40 mg/L range; wines contain it in the 2–10 mg/L range.[7]

Storage and release

Most histamine in the body is generated in granules in mast cells and
in white blood cells (leukocytes) called basophils. Mast cells are
especially numerous at sites of potential injury the nose, mouth, and
feet, internal body surfaces, and blood vessels. The most important
pathophysiologic mechanism of mast cell and basophil histamine
release is immunologic. These cells, if sensitized by IgE antibodies
attached to their membranes, degranulate when exposed to the
appropriate antigen. Histamine release occurs when allergens bind to

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mast-cell-bound IgE antibodies. Reduction of IgE overproduction
may lower the likelihood of allergens finding sufficient free IgE to
trigger a mast-cell-release of histamine.

Role in allergy and anaphylaxis

The symptoms resulting from intravenous injection of histamine are
similar to those associated with anaphylactic shock and allergic
reactions. These include contraction of airway smooth muscle,
stimulation of secretions, dilation and increased permeability of the
capillaries, and stimulation of sensory nerve endings. Symptoms
associated with allergy and anaphylactic shock result from the
release of certain mediators fromtheir storage sites. Such mediators
include: histamine,ُserotoninُ,ُleukotrienes,ُandُtheُeosinophil
chemotacticُfactorُofُanaphylaxis. Under other conditions, these
mediators may cause a full-blown anaphylactic response. It is
thought that the difference between these two situations. Results
from differences in the sites from which mediators are released and
in their rates of release. However, if histamine release is too fast for
efficientُinactivation, a full-blown anaphylactic reaction occurs. [8]
It is highly significant in field of immunomodulation that endogenous
levels of histamine influence the repertoire ofُautoantibodies.
Histamine has been observed to influence several aspects of the
immune response, including antibody production .[9, 10, 11]

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ُ

Histamine antagonists(antihistamine)
 A drug that reduces or eliminates the effects mediated by the
chemical histamine.
 The term antihistamine only refers to H1, receptor antagonists.

H1 receptor antagonists (Antihistamine)

H1 antagonists, also called H1 blockers, are a class of medications
that block the action of histamine at the H1 receptor, helping to
relieve allergic reactions. Virtually all H1-antihistamines function as
inverse agonists at the histamine H1-receptor, as opposed to neutral
antagonists, as was previously believed. [12][13][14] Mostly used to
treat allergies or cold and flu symptoms , although some first-
generation antihistamines may also be used for other conditions such
as motion sickness, nausea, vomiting, cough, sleep problems
and Parkinson‟s disease.

Classification

They are classified into first & second

generation drugs:

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First generation, These are the oldest H1-antihistaminergic drugs
and are relatively inexpensive and widely available. They are
effective in the relief of allergic symptoms, but are typically
moderately to highly potent muscarinic acetylcholine receptor
(anticholinergic) antagonists as well. These agents also commonly
have action at α-adrenergic receptors and/or 5-HT receptors. This
lack of receptor selectivity is the basis of the poor tolerability profile
of some of these agents, especially when compared with the second-
generation H1-antihistamines. Some commonly used first generation
antihistamines are: Carbinoxamine, Arbinox

Second generation, are newer drugs that are much more selective
for peripheral H1 receptors as opposed to the central nervous system
H1 receptors and cholinergic receptors. This selectivity significantly
reduces the occurrence of adverse drug reactions, such as sedation,
while still providing effective relief of allergic conditions. As such,
they are very polar , meaning that they are less likely to cross the
blood–brain barrier and act mainly outside the central nervous
system. However, some second-generation antihistamines, notably
cetirizine, can interact with CNS psychoactive drugs such as [15]
some commonly used second bupropion and benzodiazepines.
Generation antihistamines are: Quzttir, Zyrtec.

Mechanism of action
H1 antagonists act by competitively inhabiting the effects of
histamine at H1 receptor.

H1 receptor blockade results in decreased vascular permeability,

reduction of pruritus, relaxation of smooth muscle in respiratory.

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ُ

Figure:Effects of H1 antihistamines at histamine,

adrenergic, cholinergic, and serotonin-binding receptors.

Clinical uses of Antihistamines:

1.ُAllergic rhinitis (common cold).

2. Allergic conjunctivitis (pink eye).

3.ُAllergic dermatological conditions.

4. Urticaria (hives)

5. Angioedema (swelling of skin).

6. Pruritus (atopic dermatitis, insect bites).

7. Anaphylactic reactions (severe allergies).

8.ُNausea and vomiting ( first generation H1- antihistamines).

9. Sedation (first generation H1antihistamines).

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Side effect
First generation antihistamines are used less often to treat
allergies because they cause significant sedation. First generation
antihistamines also should be used cautiously in older adults as they
are more susceptible to their anticholinergic side effects including:
drowsiness, dry mouth, urinary retention, blurred vision.

Second generation antihistamines are less sedating than their

first generation counterparts. Cetirizine can be sedating for some
patients at normal recommended doses while sedation seems to only
be a concern with loratadine at higher than normally recommended
doses. Fexofenadine is the least sedating .Side effects common to all
antihistamines include: Dizziness, Dry mouth , Dry eyes,
Blurred vision, Problems urinating.

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Precaution
 Diabetes.
 Orthostatic hypotension.
 Epilepsy (seizure disorder).
 Pyloroduodenal obstruction.

Contraindications
 Benign prostatic hypertrophy.
 Pyloric stenosis.
 Childhood and pregnancy.
 Chronic idiopathic constipation.
 Inability to completely empty the bladder.
 Breast feeding.
 Glaucoma.

Drug interactions
Interaction of H1-receptor blockers with other drugs can cause
serious consequences, such as potentiation of effects of other CNS
depressants, including alcohol. Patients taking monoamine oxidase
inhibitors(MAOIs), should not take antihistamines because the
MAOIs can exacerbate the sedative and anticholinergic effects of
antihistamines. In addition, the first-generation antihistamines
(diphenhydramine and others) with anticholinergic (antimuscarinic)
actions may decrease the effectiveness of cholinesterase inhibitors in

the treatment of Alzheimer disease.

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H2 receptor antagonists
H2 blockers are a group of medicines that reduce the amount of acid
produced by the cells in the lining of the stomach. They are also
called „histamine H2-receptor antagonists‟ but are commonly called
H2 blockers. They include: cimetidine, famotidine, nizatidine
and ranitidine, and have various different brand names.

References:
1. Marieb, E. (2001). Human anatomy & physiology. San Francisco:
Benjamin Cummings. pp. 414. ISBN 0-8053-4989-8.

2. Nieto-Alamilla, G; Márquez-Gómez, R; García-Gálvez, AM;

Morales-Figueroa, GE; Arias-Montaño, JA (November 2016). "The
Histamine H3 Receptor: Structure, Pharmacology, and Function".
Molecular Pharmacology. 90 (5): 649–673.
doi:10.1124/mol.116.104752. PMID 27563055.

3. Di Giuseppe, M.; et al. (2003). Nelson Biology 12. Toronto:

Thomson Canada. p. 473. ISBN 0-17-625987-2.

4. Panula P, Chazot PL, Cowart M, et al. (2015). “International

Union of Basic and Clinical Pharmacology. XCVIII. Histamine
Receptors”. Pharmacol. Rev. 67 (3): 601–55.
Doi:10.1124/pr.114.010249. PMC 4485016. PMID 26084539

5. Wouters MM, Vicario M, Santos J (2015). “The role of mast cells

in functional GI disorders”. Gut. 65 (1): 155–168. Doi:10.1136/gutjnl-
2015-309151. PMID 26194403.

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6. Akdis CA, Blaser K. Histamine in the immune regulation of
allergic inflammation. J Allergy Clin Immunol 2003; 112: 15-22.

7. ”Archived copy” (PDF). Archived (PDF) from the original on

2011-07-19. Retrieved 2010-02-20.

8. ippi whalen et al , ippincott Illustrated reviews, sixth edition,

USA ,2015 ,394.

9. Jutel M, Watanabe T, Akdis M, Blaser K, Akdis CA. Immune

regulation by histamine. Curr Opin Immunol 2002; 14: 735-40.

10. Schneider E, Rolli-Derkinderen M, Arock M, Dy M. Trends in

histamine research: new functions during immune responses and
hematopoiesis. Trends Immunol 2002; 23: 255-63.

11. Jutel M, Watanabe T, Klunker S, et al. Histamine regulates T-

cell and antibody responses by differential expression of H1 and H2
receptors. Nature 2001; 413: 420-25.

12. Leurs R, Church MK, Taglialatela M (April 2002). “H1-

antihistamines: inverse agonism, anti-inflammatory actions and
cardiac effects”. Clinical and Experimental Allergy. 32 (4): 489–98.
Doi:10.1046/j.0954-7894.2002.01314.x. PMID 11972592.

13. Simons FE (November 2004). “Advances in H1-antihistamines”.

The New England Journal of Medicine. 351 (21): 2203–17.
Doi:10.1056/NEJMra033121. PMID 15548781.

14. Khilnani G, Khilnani AK (September 2011). “Inverse agonism

and its therapeutic significance”. Indian Journal of Pharmacology.
43 (5): 492–501. Doi:10.4103/0253-7613.84947. PMC 3195115. PMID
22021988.

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15. “Drug Interaction Report”. Drugs.com. Retrieved 28 January
2017.

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