A pharmacogenomics study reveals that a patient carries the CYP2D6*4/*4 genotype (poor metabolizer). This patient is started on metoprolol. The expected pharmacodynamic consequence is:
- A Excessive β1 blockade with bradycardia and hypotension due to markedly elevated metoprolol plasma levels ✓
- B Reduced efficacy due to failure to convert metoprolol to its active hydroxyl metabolite
- C Paradoxical hypertension due to increased α1 agonism in absence of β1 blockade
- D Tachyphylaxis due to upregulation of β1 receptors in the absence of normal drug metabolism
Correct answer: A. Excessive β1 blockade with bradycardia and hypotension due to markedly elevated metoprolol plasma levels
Explanation
Metoprolol is a CYP2D6 substrate. CYP2D6 poor metabolizers (homozygous for loss-of-function alleles such as *4/*4) cannot efficiently hydroxylate metoprolol, leading to 3–10× higher plasma concentrations compared to extensive metabolizers. This results in exaggerated β1 blockade — profound bradycardia, heart block, and hypotension. Metoprolol has no significant active metabolite; its parent compound is the pharmacologically active entity. Clinical significance: dose reduction is required in CYP2D6 poor metabolizers.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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