Loperamide is a mu-opioid receptor agonist yet, unlike other opioids, does not produce analgesia, euphoria, or respiratory depression even at supratherapeutic doses. The principal reason is:

• A It is a full antagonist at central mu receptors but a peripheral agonist
• B P-glycoprotein actively pumps it back out of the blood-brain barrier ✓
• C It is rapidly inactivated by plasma esterases before reaching the brain
• D Its affinity for mu receptors is far lower than that of morphine

Explanation

Loperamide is a genuine mu agonist acting on enteric neurons to reduce peristalsis and secretion, but it is a substrate for P-glycoprotein efflux at the blood-brain barrier, which keeps central concentrations negligible. Combined with extensive first-pass metabolism, this preserves its antidiarrhoeal action without central opioid effects. Its mu affinity is comparable to other agonists, so weak binding does not explain the selectivity.

Reference: Katzung Basic and Clinical Pharmacology, 15th ed.

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Written and medically reviewed by the StethoPrep medical team.