How does digoxin (inotrope) work?

Mechanism of Action of Digoxin as an Inotrope

Digoxin primarily works as an inotrope by inhibiting sodium-potassium ATPase in cardiac cells, which leads to increased intracellular calcium concentration and enhanced myocardial contractility, while also providing neurohormonal benefits through vagal afferent sensitization and sympathetic inhibition. 1, 2

Primary Cardiac Mechanism

• Digoxin inhibits sodium-potassium (Na-K) adenosine triphosphatase (ATPase) in cardiac cells 1
• This inhibition increases intracellular sodium concentration 2
• Elevated sodium levels stimulate sodium-calcium exchange, resulting in increased intracellular calcium concentration 2
• Higher intracellular calcium enhances the force and velocity of myocardial systolic contraction (positive inotropic effect) 2

Neurohormonal Effects

• Digoxin inhibits Na-K ATPase in vagal afferent fibers, sensitizing cardiac baroreceptors 1
• This sensitization reduces sympathetic outflow from the central nervous system 1
• Baroreceptor sensitization increases afferent inhibitory activity 2
• These effects lead to decreased activation of the sympathetic nervous system and renin-angiotensin system (neurohormonal deactivating effect) 2
• Recent evidence suggests that digoxin's benefits in heart failure may be related more to these neurohormonal effects than to its positive inotropic action 1, 3

Renal Effects

• Digoxin inhibits Na-K ATPase in the kidney, reducing renal tubular reabsorption of sodium 1
• Increased sodium delivery to distal tubules leads to suppression of renin secretion 1
• This contributes to the overall neurohormonal modulation 3

Vagomimetic Actions

• Digoxin has vagomimetic actions that affect the sinoatrial and atrioventricular nodes 2
• These effects result in slowing of heart rate and decreased conduction velocity through the AV node 2
• This mechanism is particularly important in atrial fibrillation rate control 4

Clinical Effects

• Digoxin increases cardiac output both at rest and during exercise 5
• It improves hemodynamics by increasing left ventricular ejection fraction and decreasing end-systolic and end-diastolic dimensions 2
• Digoxin reduces pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance 2
• These effects can improve symptoms, quality of life, and exercise tolerance in patients with heart failure 1
• Therapeutic effects begin within 0.5-2 hours after oral administration, with peak effects at 2-6 hours 2

Important Considerations

• Optimal serum digoxin concentrations for therapeutic benefit are lower than previously recognized (0.8-1.0 ng/mL) 3
• At higher doses, digoxin can increase sympathetic outflow from the central nervous system, which may contribute to toxicity 2
• Women may be more sensitive to digoxin's effects and may require lower doses to achieve therapeutic benefits 1
• Digoxin's effects in heart failure are mediated by both its positive inotropic action and neurohormonal deactivating effects 2

Understanding digoxin's dual mechanism—both as a direct cardiac inotrope and as a neurohormonal modulator—explains its unique position in heart failure management, particularly for patients with persistent symptoms despite standard therapy 1.