A 60-year-old man on phenelzine for depression is prescribed pethidine for postoperative pain. Within 30 minutes he develops agitation, hyperthermia, rigidity, and clonus. The underlying pharmacodynamic interaction is due to which property of pethidine?

• A Pethidine's metabolite norpethidine accumulates causing direct neurotoxicity
• B Pethidine displaces phenelzine from plasma proteins increasing free MAOI levels
• C Pethidine directly blocks GABA-A receptors lowering the seizure threshold
• D Pethidine inhibits serotonin reuptake, and combined with MAOI causes excessive serotonergic stimulation ✓

Explanation

Pethidine inhibits serotonin reuptake. When combined with an MAOI, serotonin breakdown is also impaired, leading to serotonin syndrome with hyperthermia, rigidity, and clonus. This is a well-documented lethal interaction. Option A describes norpethidine toxicity, which causes seizures, not serotonin syndrome. Option C is incorrect. Option B describes a protein-binding displacement interaction, which does not explain this syndrome.

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

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