Loperamide controls diarrhoea effectively but produces little central opioid effect at therapeutic doses. The property responsible for its central safety is:

• A It is a kappa-selective opioid agonist
• B It undergoes rapid first-pass metabolism to an inactive metabolite
• C P-glycoprotein efflux at the blood-brain barrier keeps brain concentrations low ✓
• D It acts only on presynaptic 5-HT receptors in the enteric plexus

Explanation

Loperamide is a mu-opioid receptor agonist that decreases acetylcholine release from the enteric plexus, slowing peristalsis. Although it is a potent mu agonist, it is actively pumped out of the CNS by P-glycoprotein at the blood-brain barrier, so analgesic and euphoric effects are minimal at normal doses. This barrier can be overcome by co-ingestion with P-gp inhibitors such as quinidine, which is why supratherapeutic abuse carries cardiac arrhythmia risk through hERG blockade.

Reference: Katzung's Basic and Clinical Pharmacology, 16th ed.

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