H1 antihistamine

MECHANISM: H1 receptors are Gq-coupled (↑PLC → ↑IP3/DAG → ↑Ca2+). Histamine at H1 causes bronchoconstriction, ↑vascular permeability and vasodilation (wheal and flare, edema), pruritus (sensory nerve stimulation), and ↑nasal mucus secretion. H1 blockers act as inverse agonists/competitive antagonists. They block the effects of histamine but do not prevent its release from mast cells and basophils. They do not stop mast cell degranulation (cromolyn does). They are more effective for prevention than for reversing established symptoms.

FIRST-GENERATION (lipophilic, cross the BBB): diphenhydramine, dimenhydrinate, chlorpheniramine, brompheniramine, hydroxyzine, promethazine, meclizine, cyproheptadine, doxylamine. - Adverse effects: sedation, anticholinergic effects (dry mouth, urinary retention, constipation, blurred vision, tachycardia, confusion, "hot as a hare, dry as a bone"), and α-blockade (orthostasis). Some also block serotonin receptors. - Uses: allergic reactions, motion sickness and vertigo (meclizine, dimenhydrinate), nausea/vomiting (promethazine), insomnia (diphenhydramine, doxylamine), pruritus (hydroxyzine), anxiety (hydroxyzine), appetite stimulation and serotonin syndrome (cyproheptadine), and acute dystonia from antipsychotics (diphenhydramine, which also has anticholinergic activity). - Cautions: avoid in elderly patients (Beers criteria), BPH, narrow-angle glaucoma, and with other CNS depressants. Overdose causes an anticholinergic toxidrome (seizures, QRS/QT prolongation). Promethazine can cause tissue injury with IV administration and respiratory depression in young children.

SECOND-GENERATION (less lipophilic, P-glycoprotein substrates, minimal CNS penetration): loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine. - Less sedating and no significant anticholinergic effects. Cetirizine can still cause mild sedation. - Uses: allergic rhinitis, chronic urticaria. First-line for chronic urticaria is a second-generation H1 blocker. - Older agents terfenadine and astemizole were withdrawn because of QT prolongation and torsades de pointes when metabolized slowly (CYP3A4 inhibitors such as macrolides and azole antifungals). Fexofenadine is the active metabolite of terfenadine and lacks this risk.

CLINICAL PEARLS: - Epinephrine, not antihistamines, is first-line for anaphylaxis. H1 blockers are adjunctive and treat only cutaneous symptoms. - H1 blockers do not block gastric acid secretion. That is mediated by H2 receptors (cimetidine, famotidine). H2 blockers may be added to H1 blockers for urticaria or anaphylaxis. - Intranasal antihistamines (azelastine, olopatadine) and ophthalmic antihistamines (ketotifen) are used for local symptoms. - Intranasal corticosteroids are more effective than antihistamines for allergic rhinitis overall. - Key Step 1 distinction: first-generation agents are lipophilic and sedating with anticholinergic effects. Second-generation agents are the opposite.