Mechanism of Action of Digoxin
Digoxin works by inhibiting the sodium-potassium ATPase pump in cardiac myocytes, which increases intracellular calcium to enhance contractility, while simultaneously exerting neurohormonal effects through vagal stimulation and sympathetic suppression. 1, 2
Primary Cardiac Mechanism
Direct Myocardial Effects:
- Digoxin inhibits the Na-K ATPase enzyme in cardiac cell membranes, leading to increased intracellular sodium concentration 2
- This sodium accumulation stimulates the sodium-calcium exchange mechanism, resulting in elevated intracellular calcium 2
- The increased calcium availability enhances the force and velocity of myocardial systolic contraction (positive inotropic effect) 2
Neurohormonal Modulation
Autonomic Nervous System Effects:
- Digoxin sensitizes cardiac baroreceptors through inhibition of Na-K ATPase in vagal afferent fibers, increasing afferent inhibitory activity 3, 2
- This leads to decreased sympathetic nervous system activation and reduced renin-angiotensin system activity (neurohormonal deactivating effect) 3, 2
- Recent evidence suggests these neurohormonal benefits may be as important as—or more important than—the direct inotropic effects in heart failure management 3
Vagomimetic Actions:
- Digoxin produces vagal stimulation that slows heart rate and decreases conduction velocity through the atrioventricular node 1, 2
- In atrial fibrillation, digoxin suppresses AV node conduction to increase the effective refractory period 1
Renal Effects
- Digoxin inhibits Na-K ATPase in renal tubules, reducing sodium reabsorption 3
- Increased sodium delivery to distal tubules suppresses renin secretion, contributing to neurohormonal modulation 3
Clinical Implications
Dual Mechanism Understanding:
- The benefits in heart failure result from both increased cardiac output (inotropic effect) and reduced neurohormonal activation 1, 2
- In atrial arrhythmias, the therapeutic effects are primarily related to vagomimetic actions on AV nodal conduction 2
Important Caveat:
- At high doses, digoxin paradoxically increases sympathetic outflow from the central nervous system, which may contribute to digitalis toxicity 2