Pathophysiology
Clinical meaning
Digoxin is a cardiac glycoside used therapeutically for heart failure with reduced ejection fraction (HFrEF) and ventricular rate control in atrial fibrillation. Its narrow therapeutic index (therapeutic level 0.5-2.0 ng/mL, with toxicity often occurring above 2.0 ng/mL) makes digoxin toxicity a common and potentially fatal clinical problem. Mechanism of action and toxicity: Digoxin inhibits the sodium-potassium ATPase pump (Na+/K+-ATPase) on cardiac myocyte cell membranes. At therapeutic doses, this produces modest positive inotropic effect โ inhibiting the Na+/K+-ATPase increases intracellular sodium, which reduces the sodium gradient driving the sodium-calcium exchanger (NCX). This causes intracellular calcium accumulation, enhancing cardiac contractility (positive inotropy). Digoxin also increases vagal (parasympathetic) tone, slowing AV nodal conduction and heart rate (negative chronotropy/dromotropy). At TOXIC doses, excessive Na+/K+-ATPase inhibition causes dangerously high intracellular calcium, producing: (1) delayed afterdepolarizations (DADs) โ spontaneous depolarizations during phase 4 of the action potential triggered by calcium overload of the sarcoplasmic reticulum, which can initiate ectopic beats and triggered automaticity (the mechanism of digoxin-induced arrhythmias); (2) enhanced vagal tone causing sinus bradycardia, sinoatrial block, and AV block; (3) enhanced automaticity with suppressed conduction...