Which antihistamine has the least sedating profile among the H1 antagonists and why?
- A Cetirizine; it is a zwitterion at physiological pH, reducing CNS penetration compared to first-generation antihistamines
- B Loratadine; it is highly protein-bound in plasma, preventing CNS penetration
- C Fexofenadine; it is a P-glycoprotein substrate that is actively pumped back out of the CNS at the blood-brain barrier, minimising brain penetration ✓
- D Diphenhydramine; its large molecular size prevents crossing the blood-brain barrier
Correct answer: C. Fexofenadine; it is a P-glycoprotein substrate that is actively pumped back out of the CNS at the blood-brain barrier, minimising brain penetration
Explanation
Fexofenadine is the least sedating second-generation antihistamine. Unlike cetirizine and loratadine which have minimal CNS penetration due to polarity and limited lipid solubility, fexofenadine is additionally a substrate for P-glycoprotein efflux transporters at the blood-brain barrier, which actively expel the drug back into systemic circulation. This ATP-dependent efflux mechanism makes fexofenadine CNS impenetration near-complete, giving it the most favourable non-sedating profile.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.