HISTAMINE

AND
ANTIHISTAMINES
 Histamine
 Basic amine autacoid stored in
granules of mast cells and basophils.
 IgE-dependent release
 IgE-independent release (C3a and
C5a, or drugs (e.g., d-tubocurarine).
 Acts as neurotransmitter in
histaminergic nerves
Histamine Synthesis

L-

Histamine
 ANTIGEN-INDUCED DEGRANULATION OF MAST CELL
AND THE RELEASE OF ALLERGIC MEDIATORS
allergen

IgE antibody

Mast cell FcєRI

Mediator release
-histamine
Mast Cell
-PAF
-leukotrienes
-PGD2

Degranulating mast cell

 Histamine Receptors

 3 Receptors
• H1, H2, H3 (H4 suggested)
 All receptors G-protein-coupled
 Signaling pathway
• H1 (PLC - IP3 & DAG)
• H2 (AC – cAMP)
• H3 (decrease in Ca2+ flux).
 Physiological Actions of
Histamine/Mediating Receptors
Action Receptor Location

Smooth muscle contraction H1 All sm (except vasc.)

Vasodilatation H1 Endothelial cells (via NO)

Increased Vasc. Permeability H1 (H2?) Endothelial cells

Cardiac stimulation H2 Cardiac muscles

Increased gastric secretion H2 Parietal cells

Pain and itch H1 Sensory nerve endings

Inhibition of transmitter rel. H3 Nerve ending

 Major Pathological Roles
 Allergic diseases
• allergic rhinitis (hay fever)
• Allergic conjunctivitis
• urticaria (Triple response)
• anaphylactic shock
• Allergic angioedema
 Drug reactions
 Insect bites
 Hypersecretion of acid in peptic
ulcers.
 ANTIHISTAMINES

Classification
 1st Generation
 2nd Generation
 1st Generation
 Key Members
• Diphenhydramine
• Chlorpheniramine
• Doxylamine
• Hydroxyzine

 Characteristics
• High lipophilicity, easily enters CNS
• Highly sedative
• Anti-muscarinic, anti-α-adrenergic, anti-5HT
• Some have anti-motion sickness effect
• Some have local anaesthetic effect
• Generally short-acting
 2nd Generation
 Key Members
• Desloratadine (loratadine)
• Fexofenadine (terfenadine)
• Cetirizine
• Azelastine

 Characteristics
• No CNS entry (Low lipophilicity, most ionized;
also protein binding)
• Non-sedating
• No significant autonomic receptor blocking
effect
• Generally long-acting
• Some are cardiotoxic
 Clinical Uses of Antihistamines
 Allergy (eg, any 1st or 2nd generation)
• Allergic rhinitis
• Allergic conjuctivitis
• Urticaria (both acute and chronic)
• Allergic angioedema
• Anaphylactic shock
 Motion sickness (eg, diphenhydramine)
 As hypnotics (eg, Doxylamine)

NB:Not effective in asthma

 Adverse Effects of
Antihistamines
 Sedation (1st gen.)

 Dry mouth, blurred vision (1st gen.)

 Cardiotoxicity: prolongation of QT
intervals (early 2nd gen. terfenadine,
loratadine)

 Drug interaction (many 2nd gen.

metabolized via P450)
 H2 Receptor Antagonists
 Reversible competitive antagonists
 Key Members
• Cimetidine
• Ranitidine
• Famotidine
• nizatidine
 Clinical Uses of H2 antagonists
 Treatment of Ulcers, especially
duodenal ulcer.
 Treatment of Zollinger-Ellison
Syndrome (severe
hypersecretion and ulceration).
 Gastro-esophageal reflux disease
(GERD).

NB: For most of these the more effective proton

pump inhibitors are preferred.
 Adverse Effects of H2
Antagonists
 Drug interaction
(via inhibition of P450; eg with
barbiturates, phenytoin, anticoagulants, etc).

 Antiandrogenic effects (at high doses)

• gynecomastia in men
• galactorrhea in women

 Mental confusion in elderly patients

 Reduction in hepatic blood flow
 H3 Antagonists

 None clinically available

 Specific Learning Objectives

1. Appreciate the physiological and pathological roles

of histamine and the receptors that mediate them.
2. Understand the classification of H1 antagonists into
1st and 2nd generation and describe the characteristics
of the classes, with examples.
3. Understand the clinical uses of H1 and H2
antagonists, with suitable examples.
4. Describe the adverse effects of H1 and H2
antagonists.