Which drug class exploits the fact that the blood-brain barrier expresses high levels of P-glycoprotein (P-gp) efflux pump to PREVENT CNS penetration and thus limit CNS side effects?

• A Loperamide (opioid antidiarrheal) is a P-gp substrate effluxed from the CNS, limiting central opioid effects
• B Morphine undergoes P-gp–mediated biliary excretion reducing systemic availability
• C Second-generation antihistamines are P-gp substrates excluded from the CNS, avoiding sedation
• D Both A and C are correct examples of P-gp–mediated CNS exclusion ✓

Explanation

P-glycoprotein at the blood-brain barrier acts as an efflux pump preventing lipophilic molecules from accumulating in the CNS. Loperamide is an opioid that is a substrate for P-gp — it is actively pumped out of the CNS, confining its action to intestinal opioid receptors and avoiding respiratory depression or analgesia. Second-generation antihistamines (e.g., cetirizine, fexofenadine) are also P-gp substrates and/or poorly lipophilic, preventing CNS penetration and avoiding the sedation caused by first-generation antihistamines. Both options A and C are correct, making D the best answer.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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