Cardiac Glycosides
Pharmacology of digoxin and related cardiac glycosides, including mechanism of action, therapeutic monitoring, toxicity, and the role of digoxin-specific antibodies.
## Overview
Cardiac glycosides, primarily digoxin, have been used in cardiovascular medicine for over 200 years. Originally derived from Digitalis purpurea (foxglove), digoxin remains relevant for heart failure symptom control and atrial fibrillation rate management, though its role has narrowed as newer therapies have emerged.
## Mechanism of Action
Digoxin inhibits the Na+/K+-ATPase pump on cardiomyocyte membranes. Increased intracellular sodium reduces sodium-calcium exchanger (NCX) activity, raising intracellular calcium and enhancing contractile force (positive inotropy). Digoxin also increases vagal tone at the AV node, slowing heart rate (negative chronotropy) and AV conduction (negative dromotropy).
## Pharmacokinetics
Digoxin is renally eliminated with a half-life of 36-48 hours. Its large volume of distribution (~500 L) reflects extensive tissue binding. Steady state takes approximately 7 days. Amiodarone, verapamil, and quinidine all increase digoxin levels by reducing renal clearance or displacing tissue binding.
## Therapeutic Drug Monitoring
The therapeutic range is 0.5-0.9 ng/mL for heart failure (lower than historically used). Levels above 2.0 ng/mL are associated with increased toxicity risk but toxicity can occur at lower levels, especially with hypokalemia. Hypokalemia potentiates digoxin toxicity because both digoxin and potassium compete for binding on the Na+/K+-ATPase. Hypomagnesemia and hypercalcemia also increase toxicity risk.
## Toxicity
Digoxin has one of the narrowest therapeutic windows of any commonly used drug. Toxicity manifests as GI symptoms (nausea, anorexia), neurological effects (yellow-green visual halos, confusion), and cardiac arrhythmias (classically bidirectional VT, accelerated junctional rhythm, and atrial tachycardia with AV block).
## Management of Toxicity
Digoxin-specific antibody fragments (DigiFab) bind free digoxin and are the definitive treatment for life-threatening toxicity, indicated for hemodynamically significant arrhythmias or potassium >5.0 mEq/L in acute ingestion. Supportive measures include potassium correction, magnesium supplementation, and atropine for bradycardia.
## Current Clinical Role
Digoxin reduces heart failure hospitalizations but does not reduce mortality (DIG trial). It is a second- or third-line agent for rate control in atrial fibrillation when beta-blockers and calcium channel blockers are insufficient. Serum levels should be maintained at the lower end of the therapeutic range.
## Key Takeaways
- Digoxin inhibits Na+/K+-ATPase, increasing contractility and vagal tone
- Therapeutic range is narrow (0.5-0.9 ng/mL for HF); monitor potassium closely
- Hypokalemia, hypomagnesemia, and several drug interactions potentiate toxicity
- Digoxin-specific antibody fragments are the definitive antidote for severe toxicity