Diphenhydramine (Benadryl)

Diphenhydramine is a first-generation ethanolamine antihistamine. Its primary action is as an inverse agonist / competitive antagonist at histamine H1 receptors, stabilising the receptor in its inactive state and reducing histamine-driven signalling. Peripheral H1 blockade underlies its anti-allergy effects (reduced itching, urticaria and rhinitis). Being small and lipophilic, it readily crosses the blood–brain barrier, so central H1 blockade produces pronounced sedation, the basis of its wide use as an over-the-counter sleep aid, together with the antiemetic and anti-vertigo effects it shares with dimenhydrinate (the 8-chlorotheophylline salt of diphenhydramine). It also has substantial antimuscarinic (anticholinergic) activity, blocking muscarinic acetylcholine receptors. This produces the typical anticholinergic effects, dry mouth, blurred vision, urinary retention, constipation and tachycardia, and, in overdose, an anticholinergic delirium (agitation, hallucinations, mydriasis, flushing, hyperthermia) that makes high-dose diphenhydramine a recreational deliriant with a poor safety margin. At toxic concentrations it also blocks cardiac sodium channels (a quinidine-like, local-anaesthetic effect), which can cause QRS widening, seizures and arrhythmias. It is metabolised chiefly by hepatic CYP2D6 (with CYP1A2/2C9/2C19) and is itself a moderate CYP2D6 inhibitor.