Antihistamines

Histamine is a signaling molecule stored in mast cells and basophils and released during allergic and inflammatory reactions. When it acts on H1 receptors, it produces the familiar allergy picture: it makes blood vessels dilate and leak, causing the swelling of hives, a wheal-and-flare, and nasal congestion; it stimulates sensory nerves, causing itch and sneezing; it drives nasal and bronchial secretions; and it can cause bronchoconstriction. H1 receptors in the brain also help keep us awake.

An antihistamine blocks the H1 receptor to shut this cascade down. Technically these drugs are inverse agonists — they lock the receptor in its inactive shape — but functionally they prevent histamine from firing. That relieves the sneezing, runny nose, itch, and hives of allergic rhinitis and urticaria. Note what they don’t do: an antihistamine is not the treatment for anaphylaxis — that emergency belongs to epinephrine, and an antihistamine is only an adjunct.

A central question for this class: can the drug get into the brain? First-generation antihistamines (diphenhydramine, hydroxyzine, promethazine, chlorpheniramine) are lipophilic and cross the blood-brain barrier. Blocking H1 receptors in the brain makes them sedating, and they aren’t tidy — they also block muscarinic (cholinergic) receptors, adding a load of anticholinergic effects: dry mouth, urinary retention, constipation, blurred vision, and tachycardia.

Second-generation antihistamines (loratadine, cetirizine, fexofenadine, levocetirizine) were designed to be more polar, so they largely stay out of the brain and act peripherally. The payoff is much less sedation and far fewer anticholinergic effects — which is why they are first-line for chronic, daytime allergy. The first-generation drugs still have roles where sedation or drying is the goal (sleep aids, motion sickness, nausea), but for everyday allergy the second generation is preferred and far safer, especially in older adults.

The first-generation side effects are just the two receptor blockades escaping into the wrong places. Central H1 blockade → sedation, drowsiness, and impaired reaction time (dangerous for driving; additive with alcohol and other CNS depressants). Muscarinic blockade → the classic anticholinergic toxidrome, memorized as "red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare, full as a flask" — flushing, dry mouth, blurred vision, confusion, hyperthermia, and urinary retention. This burden is especially hazardous in older adults (the AGS Beers Criteria flag first-generation agents as potentially inappropriate — confusion, falls, retention) and in men with BPH or patients with narrow-angle glaucoma.

One first-generation drug carries specific boxed warnings worth singling out: promethazine (Phenergan). It can cause fatal respiratory depression in children under 2, so it is contraindicated in that age group. And given parenterally it can cause severe tissue injury — including gangrene — from chemical irritation and inadvertent arterial or perivascular injection; IV use is high-risk (deep IM is preferred; intra-arterial and subcutaneous routes, and IV above 1 mg/mL, are contraindicated).