Smooth muscles (especially bronchial and nasopharyngeal lining)
Vascular endothelial cell surfaces
Central nervous system
Histamine effects on H1 receptors
↑ Capillary dilation and permeability → hypotension and edema
↑ Bronchiolar smooth muscle contraction (via IP3 and DAG release) → bronchoconstriction
↑ Nasal and bronchial mucus production
Target: histamine H2 receptors
Location of H2 receptors
Gastric parietal cells (oxyntic cells)
Histamine effects on H2 receptors
Increased gastric acid secretion
H1 antihistamines
First-generation antihistamines
Mechanism of Action: Reversible inhibitors of H1 histamine receptors. They are lipophilic and readily cross the BBB. They also block muscarinic, alpha-adrenergic, and serotonergic receptors.
Motion Sickness/Vertigo: Due to anti-muscarinic effects (e.g., Meclizine, Dimenhydrinate).
Insomnia: Due to sedative properties (e.g., Diphenhydramine, Doxylamine).
Nausea/Vomiting: Especially in pregnancy (Doxylamine).
Key Associations/Complications (Side Effects):
Sedation/Drowsiness: Due to central H1 receptor blockade. This is a defining and frequently tested side effect.
Anticholinergic (Antimuscarinic) Effects: Dry mouth, blurry vision, urinary retention, constipation, confusion. This is especially problematic in the elderly (on Beers list).
Anti-alpha-1 Adrenergic Effects: Can lead to orthostatic hypotension and dizziness.
Buzzwords: “Lipophilic,” “crosses BBB,” “sedating,” “anticholinergic side effects.” Avoid in the elderly due to increased risk of delirium and falls.
Second-generation antihistamines
Mechanism of Action: Reversible inhibitors of peripheral H1 histamine receptors. They are less lipophilic and do not readily cross the BBB, resulting in fewer CNS side effects.
Note: While also called “antihistamines,” H2 blockers are distinct and primarily used for GI conditions.
Mechanism: Competitively block H2 receptors on gastric parietal cells, leading to decreased gastric acid secretion.
Examples:Cimetidine, Famotidine, Nizatidine.
Uses:Peptic ulcer disease, GERD, gastritis.
High-Yield Side Effect: Cimetidine is a potent inhibitor of CYP450 and can cause antiandrogenic effects (gynecomastia, impotence) and cross the BBB to cause confusion.
Special Use Case: Cyproheptadine
A first-generation antihistamine with potent anti-serotonergic (5-HT2A antagonist) properties.
Primary Use: Used as an antidote for Serotonin Syndrome. Serotonin syndrome presents with a triad of autonomic instability, altered mental status, and neuromuscular hyperactivity (e.g., clonus, hyperreflexia).