Cetirizine causes less sedation than diphenhydramine despite both being H1 antihistamines because:

• A Cetirizine is a H1 inverse agonist while diphenhydramine is a neutral antagonist
• B Cetirizine is a charged carboxylic acid at physiological pH, limiting blood-brain barrier penetration ✓
• C Cetirizine is metabolized to the active fexofenadine in the liver, which is non-sedating
• D Diphenhydramine has higher affinity for muscarinic receptors causing sedation; cetirizine is purely H1 selective

Explanation

Cetirizine is the carboxylated metabolite of hydroxyzine; the carboxylic acid group is ionized (negatively charged) at physiological pH, markedly reducing lipid solubility and blood-brain barrier penetration compared to the highly lipophilic first-generation antihistamines like diphenhydramine. Reduced CNS H1 receptor occupancy results in much less sedation. Fexofenadine is the active metabolite of terfenadine, not cetirizine.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.