A patient on digoxin develops toxicity. The toxic manifestations include ventricular extrasystoles (DADs — delayed afterdepolarisations) arising from which mechanism?

• A Digoxin activates L-type calcium channels directly causing calcium overload
• B Digoxin prolongs QT interval by inhibiting IKr (hERG) channels
• C Digoxin inhibits Na/K-ATPase, raising intracellular Na+ which reverses the Na/Ca exchanger, overloading the sarcoplasmic reticulum with Ca2+ causing oscillatory calcium release and DADs ✓
• D Digoxin blocks cardiac gap junctions impairing electrical coupling between cardiomyocytes

Explanation

Digoxin inhibits Na/K-ATPase, raising intracellular [Na+]. The Na/Ca exchanger (NCX), driven by the Na+ gradient, normally exports Ca2+ from cells; with elevated [Na+], NCX reversal increases intracellular [Ca2+], overloading the sarcoplasmic reticulum. Oscillatory spontaneous Ca2+ release from the SR generates inward depolarising currents (transient inward current, Iti) — these are delayed afterdepolarisations (DADs) that can trigger ventricular ectopics. This is distinct from the therapeutic positive inotropic mechanism (desired moderate Ca2+ increase improving contractility). hERG inhibition causing QT prolongation is the mechanism of drug-induced TdP.

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

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