From the Guidelines
Digoxin works primarily by inhibiting the sodium-potassium ATPase pump in cardiac myocytes, leading to increased intracellular calcium levels and enhanced cardiac contractility. This mechanism of action is supported by the most recent and highest quality study, which highlights the importance of careful dosing and monitoring to avoid toxicity 1. The inhibition of the sodium-potassium ATPase pump results in a transient increase in intracellular calcium, which in turn increases myocardial contractility, making digoxin useful for treating heart failure and managing certain arrhythmias, such as atrial fibrillation 1.
Key Mechanisms and Effects
- Inhibition of the sodium-potassium ATPase pump in cardiac myocytes
- Increased intracellular sodium and subsequent increase in intracellular calcium levels
- Enhanced cardiac contractility (positive inotropic effect)
- Increased vagal tone, slowing conduction through the AV node, reducing heart rate (negative chronotropic effect), and decreasing conduction velocity (negative dromotropic effect)
Clinical Considerations
- Typical maintenance doses range from 0.125-0.25 mg daily
- Narrow therapeutic window, requiring careful monitoring of serum levels (therapeutic range: 0.8-2.0 ng/mL) to avoid toxicity
- Factors affecting digoxin levels include renal function, electrolyte imbalances (particularly potassium, calcium, and magnesium), and drug interactions, all of which must be monitored during treatment 1.
Recent Guideline Recommendations
The 2022 AHA/ACC/HFSA guideline for the management of heart failure recommends initiating digoxin at a low dose, as higher doses are rarely required and may be potentially detrimental 1. This guideline emphasizes the importance of careful patient selection and monitoring when using digoxin in the management of heart failure.
From the FDA Drug Label
Digoxin inhibits sodium-potassium ATPase, an enzyme that regulates the quantity of sodium and potassium inside cells. Inhibition of the enzyme leads to an increase in the intracellular concentration of sodium and thus (by stimulation of sodium-calcium exchange) an increase in the intracellular concentration of calcium The mechanism of action of digoxin is through the inhibition of sodium-potassium ATPase, leading to an increase in intracellular sodium and calcium concentrations. This results in:
- A positive inotropic action, increasing the force and velocity of myocardial systolic contraction
- A neurohormonal deactivating effect, decreasing the degree of activation of the sympathetic nervous system and renin-angiotensin system
- A vagomimetic effect, slowing the heart rate and decreasing conduction velocity through the AV node 2
From the Research
Mechanism of Action of Digoxin
The mechanism of action of digoxin, a cardiac glycoside, involves the inhibition of the Na+-K+ adenosine triphosphatase (ATPase) enzyme, which is the primary site at which digitalis exerts its effects on the myocardial cell 3. This inhibition leads to an increase in intracellular sodium, which in turn increases calcium influx via Na+-Ca++ exchange, resulting in a positive inotropic effect 4.
Key Effects of Digoxin
- Inhibition of sodium transport, leading to an increase in intracellular sodium 4, 3
- Increase in calcium influx via Na+-Ca++ exchange, resulting in a positive inotropic effect 4
- Enhancement of myocardial contractility and changes in the properties of the cardiac conduction system 4
- Autonomic effects involving alterations in both parasympathetic and sympathetic activity 4
Molecular Receptor for Digitalis Drugs
The sodium pump is considered the principal molecular receptor for the digitalis drugs, with digoxin binding to sites on the NaK-ATPase complex that face the outer surface of nearly all eukaryotic cells 4, 5.
Endogenous Digitalis-Like Compounds
Recent evidence indicates the presence of naturally occurring digitalis-like compounds in mammals, which may be endogenous hormones regulating the biological activity of the sodium pump and its isoforms 5.