H1 blocker

**Mechanism:** Reversible competitive antagonists (technically inverse agonists) of the Gq-coupled H1 receptor. They block histamine-mediated vasodilation, increased vascular permeability, bronchial smooth muscle constriction, sensory nerve stimulation (itch), and mucus secretion. They do NOT stop histamine release from mast cells (that is the role of mast cell stabilizers such as cromolyn). They are not a substitute for epinephrine in anaphylaxis.

**First-generation (sedating, lipophilic, cross the BBB):** - Diphenhydramine, dimenhydrinate, chlorpheniramine, brompheniramine, hydroxyzine, promethazine, meclizine, cyproheptadine - Also block muscarinic, α-adrenergic, and serotonin receptors. - Clinical uses: allergic rhinitis, urticaria, pruritus, motion sickness and vertigo (dimenhydrinate, meclizine), insomnia (diphenhydramine), anxiety (hydroxyzine), antiemetic (promethazine), acute dystonia from antipsychotics (diphenhydramine), and appetite stimulation and serotonin syndrome (cyproheptadine). - Adverse effects: sedation, anticholinergic effects ("dry as a bone, red as a beet, hot as a hare, mad as a hatter, blind as a bat"), including dry mouth, urinary retention, constipation, blurred vision, and confusion. Also α-blockade (orthostatic hypotension) and, in overdose, tachycardia, seizures, and QRS widening. - Use caution or avoid in the elderly (Beers criteria), in BPH, narrow-angle glaucoma, and dementia. Promethazine carries a boxed warning for respiratory depression in children under 2 and for tissue injury with IV administration.

**Second-generation (non-sedating, less lipophilic, P-glycoprotein substrates, minimal CNS penetration):** - Loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine - Used for allergic rhinitis and chronic urticaria. - Adverse effects are minimal. Cetirizine can cause mild sedation. Fexofenadine absorption is reduced by fruit juices (grapefruit, orange, apple). - Older agents astemizole and terfenadine were withdrawn because they prolonged the QT interval and caused torsades de pointes, especially when combined with CYP3A4 inhibitors (macrolides, azole antifungals, grapefruit juice).

**Topical and ophthalmic H1 blockers:** azelastine (nasal), olopatadine and ketotifen (eye drops, with mast cell stabilizing activity).

**Contrast with H2 blockers:** Cimetidine, famotidine, and ranitidine (withdrawn in 2020 over NDMA contamination) block H2 receptors on gastric parietal cells and reduce acid secretion. H1 blockers do not affect gastric acid.

**High-yield exam points:** - First-generation agents are used for motion sickness and as sleep aids because they are sedating and cross the BBB. - Anticholinergic toxicity is treated with physostigmine in select cases (avoid if QRS is wide or a tricyclic antidepressant overdose is suspected). - Diphenhydramine is first-line adjunct therapy for acute dystonic reactions. - Anaphylaxis: epinephrine is first-line, and H1 blockers are adjunctive only.