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

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.
  • 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.

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.
  • 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.”

H2 antihistamines

  • 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).