A patient on methadone maintenance therapy for opioid use disorder (OUD) develops QT prolongation on ECG. The pharmacological mechanism is:

• A Methadone activates L-type calcium channels, increasing depolarization duration
• B Methadone inhibits Na+/K+-ATPase, increasing intracellular Ca2+ and prolonging action potential
• C Methadone blocks hERG (IKr) potassium channels, prolonging cardiac repolarization ✓
• D Methadone competes with potassium for cardiac K+ channels, reducing repolarizing current

Explanation

Methadone is unique among opioids in causing dose-dependent QT prolongation and risk of Torsades de Pointes. The mechanism is blockade of the cardiac hERG (human ether-a-go-go related gene) K+ channel, which conducts the rapid delayed rectifier K+ current (IKr) essential for cardiac repolarization. By reducing IKr, methadone prolongs the QT interval. This risk is exacerbated by concurrent use of other QT-prolonging drugs, hypokalemia, hypomagnesemia, and CYP3A4 inhibitors that increase methadone plasma levels. Baseline ECG and monitoring are recommended before initiating methadone for OUD.

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

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Written and medically reviewed by the StethoPrep medical team.