General physiology

Target: histamine H1 receptors

Location of H1 receptors
- 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

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.
Examples: Diphenhydramine, Dimenhydrinate, Chlorpheniramine, Hydroxyzine, Meclizine, Doxylamine, Promethazine.
Clinical Presentation/Uses:
- Allergic Conditions: Allergic rhinitis, urticaria (hives).
- 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.

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.
Examples: Loratadine (rat), Fexofenadine (fox), Cetirizine (satan), Desloratadine.
Clinical Presentation/Uses:
- Allergic Conditions: Preferred for long-term management of allergic rhinitis and chronic urticaria due to a better side-effect profile.
Key Associations/Complications (Side Effects):
- Minimal to no sedation: Fexofenadine is the least sedating, while Cetirizine can be mildly sedating in some individuals.
- Far fewer anticholinergic and anti-alpha-adrenergic effects compared to the first generation.
Buzzwords: “Lipophobic,” “non-sedating,” “peripheral H1 blockade.”

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.

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).