A patient with opioid-induced constipation on long-term morphine therapy is given methylnaltrexone. This drug relieves constipation without reversing central analgesia. This selective peripheral effect is explained by:

• A Methylnaltrexone is a quaternary ammonium compound that does not cross the blood-brain barrier ✓
• B Methylnaltrexone specifically binds only peripheral kappa-opioid receptors
• C Methylnaltrexone is metabolised to an inactive compound upon CNS penetration
• D Methylnaltrexone selectively inhibits enteric mu-opioid receptors by an allosteric mechanism

Explanation

Methylnaltrexone is a quaternary ammonium derivative of naltrexone; the positively charged quaternary nitrogen prevents its passage through the lipophilic blood-brain barrier by making the molecule too polar. Therefore, it selectively blocks peripheral mu-opioid receptors in the enteric nervous system (responsible for delayed gastric emptying and reduced colonic motility) without antagonising central mu receptors mediating analgesia. This peripherally restricted mechanism of action is the pharmacological basis for its clinical utility in opioid-induced constipation.

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

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