A depressed patient who is a CYP2D6 ultrarapid metabolizer is given nortriptyline at standard doses. The expected clinical consequence is:

• A Prolonged QTc interval due to accumulation of the N-demethylated active metabolite
• B Increased risk of serotonin syndrome due to accumulation of the hydroxyl metabolite
• C Anticholinergic toxicity due to impaired phase I metabolism requiring phase II compensation
• D Subtherapeutic plasma levels and treatment failure due to excessively rapid conversion ✓

Explanation

Nortriptyline is a TCA primarily metabolized by CYP2D6 to 10-hydroxynortriptyline. CYP2D6 ultrarapid metabolizers (gene duplication; ~1–2% Europeans, ~20% Ethiopians/Saudi Arabians) have markedly increased enzyme activity, resulting in very rapid first-pass and systemic metabolism. This leads to subtherapeutic plasma concentrations at standard doses and treatment failure. For CYP2D6 poor metabolizers, the same dose would cause toxicity. Pharmacogenomic testing is now recommended before initiating TCAs by some guidelines.

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

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