How does digoxin increase intracellular calcium levels?

From the Guidelines

Digoxin increases intracellular calcium levels by inhibiting the sodium-potassium ATPase pump in myocardial cells, producing a transient increase in intracellular calcium that in turn results in an influx of calcium to increase myocardial contractility. This mechanism is crucial for its use as an inotrope in patients with heart failure with reduced ejection fraction, as explained in the study published in Circulation in 2016 1. The inhibition of the sodium-potassium ATPase pump leads to an increase in intracellular sodium concentration, which affects the sodium-calcium exchanger, resulting in decreased calcium efflux or even calcium influx.

The resulting elevation in intracellular calcium enhances cardiac contractility by increasing the interaction between actin and myosin filaments. This positive inotropic effect makes digoxin useful in treating heart failure. Additionally, digoxin's effects on calcium handling contribute to its ability to slow conduction through the atrioventricular node, beneficial in managing certain arrhythmias like atrial fibrillation. It's essential to monitor calcium levels, as hypercalcemia can enhance digoxin toxicity, and the therapeutic dose range for digoxin is narrow (0.5-2.0 ng/mL).

Key points to consider when using digoxin include:

• Monitoring serum electrolytes and renal function is mandatory due to the risk of arrhythmias, particularly in the context of hypokalemia 1.
• The concomitant use of certain drugs can increase serum digoxin concentrations and may increase the likelihood of digoxin toxicity 1.
• Digoxin has a bioavailability of ≈60% to 80%, with an onset of effect observed within 1 to 3 hours after oral absorption, and an elimination half-life of 36 to 48 hours 1.

Overall, the use of digoxin must be carefully managed to maximize its benefits while minimizing its risks, particularly in terms of morbidity, mortality, and quality of life.

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

• Mechanism of Action: Digoxin increases intracellular calcium levels by inhibiting sodium-potassium ATPase, leading to an increase in intracellular sodium concentration, which in turn stimulates sodium-calcium exchange and increases intracellular calcium concentration.
• Key Effect: The increase in intracellular calcium concentration results in a positive inotropic action, increasing the force and velocity of myocardial systolic contraction. 2

From the Research

Mechanism of Digoxin-Induced Increase in Intracellular Calcium

• Digoxin inhibits the membrane Na+-K+ ATPase, leading to an increase in intracellular sodium and a subsequent increase in intracellular calcium 3, 4, 5, 6.
• The inhibition of Na+-K+ ATPase activity by digoxin can cause intracellular magnesium depletion and an increase in intracellular calcium load 3.
• The increased intracellular calcium can contribute to various cellular processes, including defective neurotransmitter transport mechanism, neuronal degeneration and apoptosis, mitochondrial dysfunction, defective golgi body function and protein processing dysfunction, immune dysfunction and oncogenesis 5.
• The positive inotropic effect of digoxin is correlated with an increased intracellular Na+, which is responsible for the increased myocardial contractility caused by digoxin 6.

Key Findings

• Studies have shown that digoxin levels are increased in patients with various disorders, including mucoid angiopathy, endomyocardial fibrosis, syndrome X, and familial basal ganglia calcification 3, 4, 5.
• The inhibition of Na+-K+ ATPase activity by digoxin is a common pathway in central nervous system disorders, including CNS glioma, multiple sclerosis, systemic lupus erythematosis, and Parkinson's disease 5.
• Digoxin has exhibited potential antitumor activity, by targeting directly HIF-1α, NKA, and NF-κB, and has been used for the treatment of congestive heart failure 7.