PHARMACOLOGY

ANTIHISTAMINE

dr. Ratih Dewi Yudhani., M.Sc

Pharmacology Department
2019
Outline
• Definition Histamine
• Histamine Receptor
• Histamine and Allergy
• Definition Antihistamine
• Classification of Antihistamine and Clinical Aplications
Histamine:

is an endogenous substance synthesized,

stored and released in
(a) mast cells, which are abundant in the
skin, GI, and the respiratory tract,
(b) basophils in the blood, and
(c) some neurons in the CNS and peripheral NS
HISTAMINE
• Biogenic amine, autacoid
• In plants and animals as well human – 3 functions :
1. allergy mediator
2. HCl production
3. neurotransmitter

• Stored in mast cells and basophil

• impulses for histamin release:

1.antigen + IgE
2.physical influence
3.drugs
HISTAMINE
• Low molecular weight amine,
• A natural body constituent, synthesized from L-histidine by histidine
decarboxylase
• Histamine plays an important role in human health, exerting its
diverse biological effects through four types of receptors.
 HISTAMIN- metabolisms
L-histidine

Pyridoxyl phosphat histidindecarboxylase

imidazol-N-
methyltransferase
Histamine
diaminooxydase
methylhistamine

MAO
imidazole acetaldehyde
methylhimidazole acetaldehyde

Aldehyd dehydrogenase

methylimidazolacetic acid imidazolacetic acid

 Histamine exerts its effects on many tissues and organs:

It is not a drug but is important due to its physiological

and pathophysiological actions. Therefore, drugs that
inhibit its release or block its receptors have therapeutic
value.

Physiological Actions of Histamine

• Primary stimulant for gastric acid and pepsin secretion (H2)
(acid secretion is enhanced by gastrin and vagal stimulation)
• Has a role as a neurotransmitter (H3) (both in the CNS and
peripheral sites)
Pathophysiological Actions of Histamine

• Cellular mediator of immediate hypersensitivity reaction and

acute inflammatory response
• Anaphylaxis
• Seasonal allergies
• Duodenal ulcers
• Gastrinoma (Zollinger-Ellison Syndrome)
Why is this important?
• Allergies are very common in America, 50 million
people suffer from them (about 1 in 4 people)
• Allergies are the 6th leading cause of chronic
disease and they cause the health care system $18
billion annually
• Over 60% of people with allergies develop asthma
as well
• Keeping them under control is very important!!
Why it is important ?
• The prevalence of allergic diseases (asthma, allergic rhinitis, atopic
dermatitis etc.) has been rapidly growing
• The goal of treatment of these conditions  blocking effect of
histamine release (considered to be the key cause of all the symptoms
associated with allergic inflammatory response) from basophils and
mast cells  Anti Histamine
HISTAMINE AND ALLERGY
HISTAMINE RECEPTOR
H1 Receptor  G-Protein coupled receptor  Cellular Switches :
- On State
- Off State

Histamine  Interact with Histamine receptor 1 in transmembrane

domain III & V  Receptor in active state

Antihistamine  Interact with Histamine receptor 1 in

transmembrane domain IV & VI  Receptor in inactive state

Theory 1
Antihistamine  antagonist receptor

Theory 2
Antihistamine I  is not antagonist receptor  but agonist inverse
 produce opposite effect on the histamine receptor

Is Called : H1 antihistamine not histamine antagonist

 The different Histamine receptors
Location Type of Effect Treatment
receptor
Throughout the body, specifically G-protein coupled, Mediate an increase Allergies, nausea,
H1 in smooth muscles, on vascular linked to in vascular sleep disorders
endothelial cells, in the heart and intercellular Gq, permeability at sites
the CNS which activates of inflammation
phospholipase C induced by histamine

In more specific locations in the G-protein coupled, Increases the release Stomach ulcers
H2 body mainly in gastric parietal linked to of gastric acid
cells, a low level can be found in intercellular Gs
vascular smooth muscle,
neutrophils, CNS, heart, uterus
Found mostly in the CNS, with a G-protein coupled, Neural presynaptic Unknown
H3 high level in the thalamus, possibly linked to receptor, may
caudate nucleus and cortex, also intercellular Gi function to release
a low level detected in small histamine
intestine, testis and prostate.
They were recently discovered in Unknown, most Unknown In addition to
H4 2000. They are widely expressed likely also G- benefiting allergic
conditions, research in
in components of the immune protein coupled
the h4 receptor may
system such as the spleen, lead to the treatment of
thymus and leukocytes. autoimmune diseases.
(rheumatoid arthritis
and IBS)
Receptors: Distribution and Function
• H1 – Smooth muscle, endothelium, CNS. Bronchoconstriction,
vasodilation, separation of endothelial cells, pain and itching,
allergic rhinitis, motion sickness.

• H2 – gastric parietal cell, vascular smooth muscle cell, basophils.

Regulate gastric acid secretion, vasodilation, inhibition of IgE-
dependent degranulation.

• H3 - CNS cells, and some in peripheral NS. Presynaptic, feedback

inhibition of histamine synthesis and release. They also control
release of GABA, ACh, 5-HT & NE

• H4 - Highly expressed in bone morrow and white blood cells.

Mediate mast cell chemotaxis.
 IgE - Antibody ANTIGEN
Induced Release IgE Y Y
(food, penicillin, Non-immune
venoms, etc) Releasers
HA HA
(opioids,
tubocurarine,
vancomycin etc)
Inhibitors of HA
Release HA
HA
(Cromolyn,
Albuterol) HA

HA

PGs & LTs PROTEASES HISTAMINE OTHER MEDIATORS (PAF,TNF,ILs)

ACUTE INFLAMMATORY RESPONSE

IMMEDIATE HYPERSENSITIVITY REACTION
IgE - Mediated Releasers

• Food: eggs, peanuts, milk products, grains, strawberries, etc

• Drugs: penicillins, sulfonamides, etc
• Venoms: fire ants, snake, bee, etc
• Foreign proteins: nonhuman insulin, serum proteins, etc
• Enzymes: chymopapain
Non-immune Releasers

• Morphine and other opioids, i.v.

• Aspirin and other NSAIDs in some asthmatics
• Vancomycin i.v. , polymixin B
• Some x-ray contrast media
• Succinylcholine, d-tubocurarine, 48/80
• Anaphylotoxins: c3a, c5a
• Cold or solar urticaria
Clinical Symptoms Associated With Histamine Release

• mild/cutaneous • erythema, urticaria, and/or itching

• skin reactions, tachycardia, dysrhythmias,

• mild to moderate moderate hypotension, mild respiratory
distress

• severe/anaphylactic • severe hypotension, ventricular

fibrillations, cardiac arrest, bronchospasm,
respiratory arrest
Histamine and Cadiovascular System
Inj.Histamine

Endothelin Derivat Stimulasi Kerja

Relaxing Factor Jantung

Vasodilatasi Denyut Jantung

Vaskular & Arteriole Meningkat

Sistole &
Diastole

Reflek
Takikardi
HISTAMINE AND GIT
• Histamine has an essential role in the gastrointestinal system for gastric
acid secretion.

• Gastrin and vagal stimulation  induce enterochromaffine cells

 release histamine  act on the H+K+ATPases,  secretion of H+,
a key element for synthesis of HCl in the stomach.

Gastrointestinal System
 H2 - acid, fluid and pepsin secretion
 H1 - increased intestinal motility
and secretions
ANTIHISTAMINES H1
ANTIHISTAMINE H1
Mechanism action of Antihistamine
 First Generation AH1 Agents
Uses:
• Adjunctive in anaphylaxis and other cases where histamine release can occur (H2
antagonist, and epinephrine must also be used in anaphylaxis)
• Antiallergy (allergic rhinitis, allergic dermatoses, contact dermatitis)
• Sedative/sleep aid
• To prevent motion sickness (meclizine, cyclizine)

• Antiemetic: prophylactic for motion sickness (promethazine)

• Antivertigo (meclizine)
• Local anesthetic (diphenhydramine)
• Antitussive (diphenhydramine)
H 1 RECEPTOR ANTAGONIST
First Generation H1-AntiHistamine
• Cross the blood brain barrier
• Poor receptor selectivity and often interact with receptors of other biologically active amines 
antimuscarinic, anti 𝛼-adrenergic, and antiserotonin effects
• Histamine  important neuromediator in the human brain (64,000 histamine-producing
neurones)  stimulate H1-receptors in all of the major parts of the cerebrum, cerebellum,
posterior pituitary, and spinal cord  increase arousal in the circadian sleep/wake cycle, reinforce
learning and memory, fluid balance, suppression of feeding, control of body temperature, control
of the cardiovascular system, and mediation of stress- triggered release of adrenocorticotrophic
hormone and 𝛽- endorphin from the pituitary gland
• When taken during the day, first-generation H1-antihistamines  daytime somnolence, sedation,
drowsiness, fatigue, and impaired concentration and memory
First Generation of Antihistamine
1. Propylamines
Chlorpheniramine Maleat, Pheniramine Maleat, Brompheniramine Maleat
2. Ethanolamines --> long duration of action
a. Diphenhydramine HCl  motion sickness, hyperemesis gravidarum
b. Dimenhidrinate
c. Doxylamine  night hipnotic
3. Ethylenediamines
Phenbenzamine
4. Piperazines (Potential Teratogenic)
a. Hydroxyzine HCl
b. Cyclizine HCL,
c. Meclizine HCL  vertigo, motion sickness
d. Chlorcyclizine HCL
5. Phenothiazines
Promethazine HCl
6. Dibenzocycloheptenes/heptanes/piperadines --> antihistamine and antiserotonin activity
Azatadines, Cyproheptadine
Second Generation H1-AntiHistamine
• Minimally sedating or nonsedating
because of their limited penetration
of the blood- brain barrier.
• Highly selective
for the histamine H1-receptor
and have no anticholinergic effects.
 Second Generation Agents
Adverse effects:
• in general, these agents have a much lower incidence of
adverse effects than the first generation agents.

• terfenadine (seldane) and astemizole (hismanal) were

removed from the market due to effects on cardiac K+
channels - prolong QT interval (potentially fatal arrhythmia
“torsades de pointes”)

• fexofenadine is active metabolite of terfenadine

Second Generation Agents
Adverse effects:
• Cetirizine appears to have more CNS actions (sedative)
than fexofenadine or loratadine  recommended that
cetirizine not be used by pilots.

• Erythromycin and ketoconazole inhibit the metabolism

of fexofenadine and loratadine in healthy subjects
ANTIHISTAMINE H2
Available Antihistamine H2

1. Cimetidine
2. Ranitidine
3. Famotidine
4. Nizatidine
H2 Antagonist Therapeutic Uses
1. Duodenal Ulcer
2. Gastric Ulcer
3. Zollinger-Ellison syndrome (a pathological hypersecretory state
resulting in excessive gastric pepsin & HCl)
4. Gastroesophageal reflux disease
5. Used prior to surgery in patients with GI obstruction to elevate
gastric pH
6. Reflux Esophagitis
ANTIHISTAMINE H3
Antihistamine In Children
Indications :
• Acute allergic reactions in food allergy
• Allergic rhinitis (AR)
• Chronic spontaneous urticaria (CSU)

Second-generation H(1)- antihistamines are preferable to first-generation H(1)-antihistamines due

to their better safety profile :
• minimal cognitive and antimuscarinic side effects
• a longer duration of action
Referensi
Fitzsimons R, van der Poel LA, Thornhill W, du Toit G, Shah N, Brough HA. Antihistamine use in children. Arch Dis Child Educ Pract Ed
2015;100:122–131
Church DS and Church MK. Pharmacology of Antihistamines WAO Journal, 2011, Supplement

Stojković N, Cekić S, Ristov M, Ristić M, Đukić D, Binić M, Virijević D. Histamine and Antihistamines. Scientific Journal of the Faculty of Medicine
in Niš 2015;32(1):7-22

,
Jack DeRuiter Histamine H1-receptor Antagonists: Antihistaminic Agents. Principles of Drug Action 2, Fall 2001
Katzung
Goodman and Ghilman. 11th edition. Chapter 24