The document discusses histamine, an endogenous substance involved in various physiological and pathophysiological processes, and its antagonists. It outlines the synthesis, metabolism, and actions of histamine, including its role in allergic reactions and gastric acid secretion, as well as the types and effects of antihistaminergic drugs. Additionally, it details various substances and conditions that can trigger histamine release and associated clinical symptoms.

1. HISTAMINE AND THEIR
ANTAGONISTS
DR. SHAMSHER SINGH BAJWA
ASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGY
ISF COLLEGE OF PHARMACY
WEBSITE: - WWW.ISFCP.ORG
EMAIL: shamshersinghbajwa@gmail.com
ISF College of Pharmacy, Moga
Ghal Kalan, GT Road, Moga- 142001, Punjab, INDIA
Internal Quality Assurance Cell - (IQAC)

2. INTRODUCTION
Histamine is an endogenous substance that is amine synthesized, stored and released
by the various cells of the body:
(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.
It is an “Autocoid” that is secreted locally and regulate the activity of various near
lying cells and neurons.
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3. 3Actions of Histamine
 HISTAMINE is not a drug but it help to legalize various physiological and
pathophysiological actions. Therefore, drugs that inhibit its release or block
its receptors have therapeutic value.
 Physiological Actions:
A. It stimulant and increased the release of gastric acid and pepsin secretion
(H2) (acid secretion is enhanced by gastrin and vagal stimulation).
B. Act and play a role as a neurotransmitter (H3) (both in the CNS and
peripheral sites).

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Pathophysiological Actions:
 Histamine behave like cellular mediator of immediate hypersensitivity
reaction and acute inflammatory response.
 Anaphylaxis reactions.
 Seasonal allergies and allergic reactions to some drugs.
 Duodenal ulcers (more) and peptic ulcer (less).
 Gastrinoma (Zollinger-Ellison Syndrome).

5. 5Synthesis and metabolism of histamine
It is synthesized from amino acid Histidine in a series of reactions:
Histidine Histamine
It is metabolized by enzyme P450 system in 2 pathways:
1. Methylation to N- histamine (N-methyl transferase), and to N- imidazole acetic acid
(MAO) – (Filtered out in urine).
Oxidative deamination to imidazole acetic acid (DAO), and to imidazole acetic acid
riboside - (Filtered out in urine).
L-histidine
decarboxylase

6. 6Histamine and mediators of Allergy
HA
HA HA
HA
HA
HA
Y YIgE
ANTIGEN
PGs & LTs PROTEASES HISTAMINE OTHER MEDIATORS (PAF,TNF,ILs)
ACUTE INFLAMMATORY RESPONSE
IMMEDIATE HYPERSENSITIVITY REACTION

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 Numbers of food supplement and drugs have been recognized which directly
increase the release of histamine and produce various kind of allergy:
Food: Eggs, peanuts, milk and milk products, grains, strawberries, etc
Drugs: Penicillins, sulfonamides, etc.
Venoms: Fire ants, snake, bee, etc.
Foreign proteins: Nonhuman insulin, serum proteins, etc.
Enzymes: Chymopapain
Inducers to release Histamine

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 Other non-immune releasers:
 Opoid like morphine and other compounds on intravenous administration.
 NSAIDS particularly aspirin and other asthmatics drugs.
 Antibiotics like vancomycin (Red man syndrome), polymixin - B
 Direct exposure to x-ray radiations.
 Succinylcholine, d-tubocurarine.
 Cold stimuli like fog or solar urticaria.

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Mild - Normal urticaria or itching
Moderate - skin reactions, tachycardia, dysrhythmias,
moderate hypotension, mild respiratory distress
Anaphylactic - severe hypotension, ventricular fibrillations,
cardiac arrest, bronchospasm, respiratory arrest
Clinical symptoms associated with release of Histamine

10. 10Histamine receptor and its distribution
 H1 – Smooth muscle, endothelium, CNS. Bronchoconstriction,
vasodilation, separation of endothelial cells, pain and itching, allergic rhinitis,
motion sickness.
 H2 – gastric parietal cell, vascular s.m. cell, basophils. Regulate gastric acid
secretion, vasodilation, inhibition of IgE-dependent degranulation.

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 H3 - CNS cells, and some in peripheral NS. Presynaptic, feedback inhibition
of histamine synthesis and release. They also control release of dopamine,
GABA, acetylcholine, serotonin and norepinephrine.
 H4 - Highly expressed in bone morrow and white blood cells. Mediate mast
cell chemotaxis.

12. 12Response of Histamine
AFTER INTRADERMAL INJECTION HISTAMINE PRODUCES 3-
RESPONSES:
RED SPOT (produce mm) with in seconds: DIRECT
VASODILATATION EFFECT , H1 RECEPTOR MEDIATED.
FLARE (1cm beyond site): AXONAL REFLEXES, INDIRECT
VASODILATATION, AND ITCHING, H1 RECEPTOR MEDIATED.
WHEAL (1-2 min) SAME AREA AS ORIGINAL SPOT, EDEMA DUE
TO INCREASED CAPILLARY PERMEABILITY, H1 RECEPTOR
MEDIATED.

13. 13Antihistaminergic drugs
First Generation:
Antiemetic: Prophylactic for motion sickness (promethazine)
Antivertigo: (meclizine)
Local anesthetic: (diphenhydramine)
Antitussive: (diphenhydramine)
Side Effects: Fatigue, dizziness, lethargy, dryness of mouth, urinary retention
and constipation.

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 Second generation:
 cetirizine or Levocetrizine
Fexofenadine (recent for allergy)
Loratadine (recent for allergy, Fda approved in 2004)
Desloratadine (Fda approved in 2002)
Azelastin (Used as intranasal spray)
Side Effects: Prolong QT interval (particularly terfinabine), sedation, muscle
weakness.

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