Histamine & Bradykinin Pharmacology  ·  Module 2 of 4

H1 Antihistamines: First and Second Generation

Generation comparison, individual agent profiles, and clinical selection

• H1 antihistamines are inverse agonists, not simple competitive antagonists — they preferentially stabilize the inactive H1 receptor conformation, suppressing constitutive (baseline) receptor activity and producing anti-inflammatory effects beyond simple histamine blockade; the generation difference is entirely pharmacokinetic: first-generation agents are lipophilic and cross the BBB by passive diffusion; second-generation agents are less lipophilic AND are P-glycoprotein substrates (P-gp efflux transporter on brain endothelial cells pumps them back into bloodstream), producing peripheral H1 blockade without meaningful CNS activity.
• First-generation agents carry two off-target burdens that limit daytime use — (1) CNS H1 blockade (tuberomammillary nucleus) → sedation, cognitive impairment, psychomotor slowing; additive with alcohol/opioids/benzodiazepines → dangerous respiratory depression; paradoxical excitation in young children; promethazine contraindicated under age 2 (fatal respiratory depression); (2) muscarinic receptor antagonism → dry mouth, urinary retention, constipation, blurred vision, tachycardia; Beers Criteria (avoid in elderly: falls, cognitive impairment, urinary retention); diphenhydramine overdose = full anticholinergic toxidrome; antidote = physostigmine (AChE inhibitor that crosses BBB).
• Second-generation pharmacokinetic distinctions are high-yield — Loratadine: hepatic metabolism → active metabolite desloratadine; no renal dose adjustment needed; Cetirizine: active metabolite of hydroxyzine; renal elimination unchanged → dose reduction needed in renal impairment; slightly more sedating than loratadine/fexofenadine (modestly greater CNS penetration); levocetirizine is the active enantiomer; Fexofenadine: active metabolite of withdrawn terfenadine; least sedating (strongest P-gp efflux); minimal hepatic metabolism → safe in hepatic impairment; fruit juice (grapefruit, orange, apple) reduces absorption via OATP inhibition → take with water.
• First-generation niches exploit their side effects — motion sickness: combined H1 + muscarinic blockade in vestibular apparatus and vomiting center (diphenhydramine, promethazine); scopolamine preferred for motion sickness prophylaxis; meclizine for vertigo; insomnia: diphenhydramine is the active ingredient in most OTC sleep aids; tolerance to sedation develops within days; nighttime pruritus: hydroxyzine and diphenhydramine acceptable at bedtime when sedation is acceptable.
• Epinephrine is the only correct first-line answer for anaphylaxis — H1 antihistamines (any generation) reduce pruritus and urticaria as adjuncts but do NOT reverse bronchospasm, laryngeal edema, or hemodynamic collapse; H2 blockers are also used as adjuncts alongside H1 blockers in anaphylaxis; for chronic urticaria, second-generation agents are first-line and doses may be increased if standard doses are insufficient; for allergic rhinitis, intranasal corticosteroids are first-line (control nasal congestion better than antihistamines because congestion is partly prostaglandin/leukotriene-mediated).