A 45-year-old man with autonomic neuropathy undergoes pharmacogenomic testing that reveals he is an ultrarapid metabolizer of CYP2D6. He is prescribed metoprolol for hypertension. Which consequence is most likely?

• A Subtherapeutic plasma levels with inadequate beta-blockade ✓
• B Drug accumulation leading to bradycardia
• C Increased risk of metoprolol-induced bronchospasm
• D Enhanced conversion to active metabolite with greater efficacy

Explanation

Metoprolol is primarily metabolized by CYP2D6. Ultrarapid metabolizers carry gene duplications (often CYP2D6*1×N or *2×N alleles) that greatly increase enzyme activity, leading to rapid drug clearance, subtherapeutic plasma levels, and inadequate beta-1 blockade. These patients may require dose increases or switching to an alternative beta-blocker such as atenolol or bisoprolol, which have minimal CYP2D6 involvement. Drug accumulation and bradycardia would occur in poor metabolizers with loss-of-function alleles. Metoprolol has no active metabolite relevant to this scenario.

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

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