Cardiac Glycosides and Toxicity

Digoxin is a cardiac glycoside with two clinically useful effects: it can increase myocardial contractility and slow conduction through the atrioventricular (AV) node. Its safety margin is narrow, so a modest change in renal function, electrolytes, dose, or interacting medications can shift a therapeutic regimen toward toxicity. Digoxin inhibits myocardial sodium–potassium adenosine triphosphatase (Na⁺/K⁺-ATPase). Intracellular sodium rises, and the sodium–calcium exchanger (NCX1) has less ability to extrude calcium from the cell. More cytosolic calcium remains available for contraction, producing positive inotropy. A 2025 study refined this traditional explanation: the contractility response depends on sodium-dependent allosteric inactivation of NCX1, not merely on dissipation of the sodium gradient. Digoxin also increases vagal tone. At the SA and AV nodes, this prolongs AV nodal refractoriness and slows conduction. That is why digoxin can reduce the ventricular rate in atrial fibrillation. The same nodal effect becomes dangerous when toxicity produces marked bradycardia, junctional rhythms, or AV block. In Canada, digoxin is authorized for heart failure and atrial fibrillation with rapid ventricular response. It is not one of the four foundational medication classes for HFrEF....