Pathophysiology
Clinical meaning
Digoxin toxicity is a potentially fatal adverse drug reaction resulting from excessive accumulation of digoxin (a cardiac glycoside derived from the foxglove plant Digitalis purpurea) in the body, producing dangerous cardiac arrhythmias, severe gastrointestinal symptoms, and characteristic neurological manifestations. Digoxin remains a commonly prescribed medication for heart failure with reduced ejection fraction and for ventricular rate control in atrial fibrillation, but it has an extremely narrow therapeutic index (therapeutic range 0.5-2.0 ng/mL, with toxicity increasingly likely above 2.0 ng/mL), making toxicity a persistent clinical concern. The fundamental mechanism of digoxin at the cellular level involves inhibition of the Na+/K+-ATPase (sodium-potassium pump), a transmembrane enzyme present in virtually all human cells that actively transports three sodium ions out of the cell and two potassium ions into the cell with each cycle, using ATP hydrolysis as the energy source. Digoxin binds to the extracellular alpha subunit of the Na+/K+-ATPase and locks the pump in a phosphorylated state, preventing the conformational change necessary for potassium binding and transport. This inhibition has profound consequences in cardiomyocytes due to the intimate coupling between sodium, calcium,...