Naloxegol is used for opioid-induced constipation (OIC) in patients on long-term opioids without compromising analgesia. This selectivity is achieved because:

• A Naloxegol is a peripherally restricted mu-opioid antagonist — its PEGylation reduces lipophilicity and CNS penetration, restricting its antagonism to peripheral gut mu receptors ✓
• B Naloxegol is a selective kappa-opioid antagonist that reverses opioid action only on colonic smooth muscle
• C Naloxegol is a prodrug activated only by intestinal bacterial enzymes, limiting systemic opioid antagonism
• D Naloxegol is a partial agonist at mu receptors in the CNS, maintaining analgesia while blocking gut receptors fully

Explanation

Naloxegol is naloxol — the PEGylated (polyethylene glycol-modified) derivative of naloxone. The PEG chain renders the molecule more hydrophilic and makes it a substrate for P-glycoprotein (P-gp) at the blood-brain barrier. This combination of reduced lipophilicity and active efflux by P-gp at the BBB results in very low CNS penetration, so naloxegol antagonises mu receptors in the gut (reversing opioid-induced decrease in gut motility and secretion) without reversing central mu-receptor-mediated analgesia. It is not a kappa antagonist, is not bacterially activated, and is not a partial agonist.

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

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Written and medically reviewed by the StethoPrep medical team.