Lecture 22 - Histamine & Anti-histamine

HISTAMINE AND ANTIHISTAMINES

Histamine 

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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

Mediator release -histamine -PAF -leukotrienes -PGD2 Degranulating mast cell

FcєRI

Mast Cell

Histamine Receptors 

3 Receptors • H1, H2, H3 (H4 suggested)

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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 • • • • •

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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 • • • •

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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

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Motion sickness (eg, diphenhydramine) As hypnotics (eg, Doxylamine)

NB:Not effective in asthma

Adverse Effects of Antihistamines 

Sedation (1st gen.)

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Dry mouth, blurred vision (1st gen.)

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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 

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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.