What is the mechanism of digoxin (digitalis glycoside) on cardiac contractility?

From the Guidelines

Digoxin increases cardiac contractility by inhibiting the sodium-potassium ATPase pump in myocardial cells, producing a transient increase in intracellular calcium that results in an influx of calcium to increase myocardial contractility. This mechanism of action is crucial in understanding the drug's effects on the heart.

Key Points

• The inhibition of the sodium-potassium ATPase pump leads to increased intracellular sodium concentration, which affects the sodium-calcium exchanger, resulting in higher intracellular calcium levels 1.
• The elevated calcium concentration enhances the interaction between actin and myosin filaments, thereby strengthening cardiac muscle contraction.
• Digoxin is typically used in patients with atrial fibrillation and heart failure with reduced ejection fraction, with the goal of improving symptoms and exercise tolerance.
• The drug has a bioavailability of approximately 60% to 80% and an elimination half-life of 36 to 48 hours, with approximately 50% to 70% of the drug excreted unchanged in the urine 1.

Clinical Considerations

• Therapeutic drug monitoring is essential as digoxin has a narrow therapeutic window (0.8-2.0 ng/mL), and toxicity can occur at higher levels.
• Common side effects include nausea, vomiting, visual disturbances, and cardiac arrhythmias.
• Potassium levels should be monitored regularly, as hypokalemia increases the risk of digoxin toxicity.
• The drug's positive inotropic effect improves cardiac output in heart failure, while its vagal effects slow conduction through the AV node, helping control ventricular rate in atrial fibrillation.

Evidence-Based Recommendation

Based on the most recent and highest quality study, digoxin should be used with caution and careful monitoring in patients with heart failure or atrial fibrillation, due to its narrow therapeutic window and potential for toxicity 1.

From the FDA Drug Label

The beneficial effects of digoxin result from direct actions on cardiac muscle, as well as indirect actions on the cardiovascular system mediated by effects on the autonomic nervous system The pharmacologic consequences of these direct and indirect effects are: (1) an increase in the force and velocity of myocardial systolic contraction (positive inotropic action);

The mechanism of digoxin on cardiac contractility is through its positive inotropic action, which increases the force and velocity of myocardial systolic contraction. This is a direct action on cardiac muscle, resulting from the inhibition of sodium-potassium ATPase and the subsequent increase in intracellular calcium concentration 2.

• Key points:
  • Digoxin increases cardiac contractility through a positive inotropic action
  • This action is a direct result of the drug's effect on cardiac muscle
  • The increase in contractility is due to an increase in intracellular calcium concentration 2

From the Research

Digoxin Mechanism on Cardiac Contractility

• Digoxin is a cardiac glycoside that inhibits the membrane Na(+)-K+ ATPase, leading to an increase in intracellular calcium and a decrease in intracellular magnesium 3, 4, 5.
• The inhibition of Na(+)-K+ ATPase activity by digoxin can contribute to an increase in cardiac contractility, as calcium plays a crucial role in modulating cardiac muscle contraction 4, 6.
• The binding of digoxin to the Na(+)-K+ ATPase enzyme has been elucidated, with the C-12 and C-14 hydroxy groups and the C-17 unsaturated lactone unit being important for its cytotoxicity toward human cancer cells 7.
• The molecular docking profiles of digoxin and its derivatives have shown that they bind differentially to Na+/K+-ATPase, with the hydroxy groups of digoxin forming hydrogen bonds with the side-chains of specific amino acids 7.

Key Findings

• Digoxin inhibits the membrane Na(+)-K+ ATPase, leading to an increase in intracellular calcium and a decrease in intracellular magnesium 3, 4, 5.
• The inhibition of Na(+)-K+ ATPase activity by digoxin can contribute to an increase in cardiac contractility 4, 6.
• The binding of digoxin to the Na(+)-K+ ATPase enzyme is specific, with certain hydroxy groups and the lactone unit being important for its activity 7.

Mechanism of Action

• Digoxin binds to the Na(+)-K+ ATPase enzyme, inhibiting its activity and leading to an increase in intracellular calcium 4, 6.
• The increase in intracellular calcium enhances cardiac muscle contraction, leading to an increase in cardiac contractility 4, 6.
• The decrease in intracellular magnesium can also contribute to the increase in cardiac contractility, as magnesium plays a role in regulating cardiac muscle relaxation 3, 5.