Digoxin: Action as a cardiac glycoside

Digoxin (brand names Lanicor, Digacin and generics) is the most frequently used cardiac glycoside internationally. Compared to digitoxin, it has a shorter half-life and is eliminated predominantly renally. These properties make digoxin easy to manage, but require careful dose adjustment in renal insufficiency. In Germany, digoxin retains a fixed, albeit reduced role in the treatment of chronic heart failure and rate control in atrial fibrillation despite newer therapies.

Digoxin is an active substance with a narrow therapeutic window that requires close monitoring. The DIG study from the 1990s demonstrated that digoxin can reduce hospitalization rates in heart failure without significantly affecting mortality. In modern quadruple therapy for heart failure with reduced ejection fraction (RAS inhibition, beta blockers, aldosterone antagonists, SGLT 2 inhibitors), digoxin is a reserve or add-on option for persistent symptoms. In rate control for atrial fibrillation, it is a reasonable option in patients with impaired ejection fraction or beta blocker intolerance.

Mechanism of action

Like all cardiac glycosides, digoxin inhibits sodium-potassium ATPase in the cardiac muscle cell. This reduces the sodium gradient, less sodium is transported out of the cell via the sodium-calcium exchanger, and intracellular calcium increases. The contractile force of the heart increases (positive inotropic effect). Clinically, this effect manifests as symptom improvement in heart failure with reduced ejection fraction.

Additionally, digoxin activates vagal tone and slows conduction through the AV node. In atrial fibrillation, this lowers ventricular rate, especially at rest. With physical exertion, the heart rate-reducing effect is less reliable, which is why digoxin is often combined with a beta blocker. Digoxin does not have an antiarrhythmic effect in the strict sense; the therapeutic concept is rate control, not rhythm control.

Oral bioavailability ranges from 60 to 80 percent, depending on formulation and comedication. The half-life is approximately 36 to 48 hours with normal renal function. Steady state is reached after five to seven days. Plasma protein binding is low (approximately 25 percent). Digoxin is eliminated predominantly renally in unchanged form; it accumulates significantly in renal insufficiency.

Indications

• Chronic heart failure with reduced left ventricular ejection fraction, supplementary to standard therapy with ACE inhibitors or ARNI, beta blockers, aldosterone antagonists, and SGLT 2 inhibitors
• Atrial fibrillation and atrial flutter for rate control, especially in patients with heart failure and insufficient response to beta blockers
• Symptomatic patients despite optimal standard therapy, in whom positive inotropy and heart rate reduction are desired

Digoxin is not first-line therapy for acute tachycardias without heart failure because other substances are more manageable. In atrial fibrillation with preexcited conduction as part of Wolff-Parkinson-White syndrome, digoxin is contraindicated.

Dosage and administration

Maintenance dose adults: 0.125 to 0.25 mg per day orally, individualized according to serum level and tolerability. In elderly patients and renal insufficiency, often 0.0625 to 0.125 mg per day.

Loading: rarely practiced today because it increases toxicity risk. Rapid loading may be necessary for acute rate control and is performed under clinical monitoring.

Serum level measurement: target range today usually 0.5 to 0.9 ng per ml, lower than previously recommended. Values above 1.2 ng per ml are associated with increased mortality in some analyses. Levels are determined 8 to 12 hours after the last dose, at earliest five days after therapy initiation or dose change.

Renal insufficiency: dose adjustment according to eGFR is essential. With eGFR 30 to 50 ml per minute, halved standard dose; with eGFR below 30, even lower doses with close serum level monitoring.

Hepatic insufficiency: usually no dose adjustment required.

Administration: once daily, preferably at the same time of day. With or without food, adequate water. If a dose is missed, the next regular dose is taken at the usual time; do not double up on doses.

Side effects

At therapeutic serum levels: nausea, loss of appetite, fatigue, headaches, visual disturbances with color vision changes (yellowish or greenish hue).

In toxicity: vomiting, diarrhea, marked visual disturbances, confusion, hallucinations, dizziness.

Cardiac toxicity: bradycardia, AV block of all degrees, supraventricular tachycardias with AV block, ventricular ectopic beats, ventricular tachycardias including bidirectional tachycardia and ventricular fibrillation. Severe hyperkalemia is an accompaniment of acute toxicity.

Antidote: for life-threatening digoxin intoxication, the administration of specific Fab fragments (DigiFab) is established. They bind digoxin and lead to rapid inactivation. Dose calculation based on plasma level and estimated amount absorbed.

Rebound hypoglycemia and other metabolic effects are not typical under digoxin; however, mild weight loss or anorexia may occur with chronic therapy.

Drug interactions

• Diuretics (loop diuretics, thiazides): hypokalemia and hypomagnesemia increase toxicity risk, electrolyte monitoring and supplementation important.
• Calcium antagonists (verapamil, diltiazem): serum level increase of 50 to 75 percent, dose adjustment required.
• Amiodarone, propafenone, flecainide: serum level increase and additive electrophysiological effects.
• Spironolactone, eplerenone: serum level changes and potassium retention, monitor levels and electrolytes.
• Antibiotics such as erythromycin, clarithromycin, and tetracyclines: changes in intestinal flora and thus absorption, possible serum level fluctuations.
• Cholestyramine and colestipol: reduced absorption, possible loss of efficacy.
• Itraconazole, cyclosporine, tacrolimus: P-glycoprotein inhibition, serum level increase.
• NSAIDs and ACE inhibitors combined with diuretics: deterioration of renal function with serum level increase.
• Beta blockers: additional heart rate reduction and AV conduction delay, combination possible but careful monitoring required.

Special notes

Pregnancy: Digoxin is among the longest-used cardiac agents in pregnancy and is even used transplacentally in specific indications such as fetal tachycardia. Serum level measurement and close monitoring are essential. Breastfeeding: transfer into breast milk in small amounts, breastfeeding usually possible, clinically observe the infant.

Children: use in pediatric cardiology for congenital heart defects, individualized dosing adapted to body weight.

Elderly patients: increased toxicity risk due to renal insufficiency, comorbidity, and polypharmacy. Low starting doses and close serum level monitoring are essential.

Before starting therapy: ECG, electrolytes (potassium, magnesium, calcium), renal and liver values. If hypokalemia below 3.5 mmol per l, correct potassium first.

Monitoring: serum level at onset five to seven days after therapy start, then individually. ECG to observe heart rate, conduction behavior, and arrhythmogenic patterns. At clinical signs such as nausea, loss of appetite, or visual disturbances, immediate serum level check.

Lifestyle: patients benefit from salt reduction, regular physical activity, weight management, and treatment adherence. Sudden discontinuation should be avoided because rebound phenomena are possible.

Fitness to drive: usually maintained with stable therapy, individually assess if dizziness or visual disturbances occur.

You may also be interested in

• Digitoxin, longer-acting glycoside with predominantly hepatic elimination
• Eplerenon, selective aldosterone antagonist in heart failure
• Enalapril, ACE inhibitor as basis of heart failure therapy
• Amiodarone, Class III antiarrhythmic
• Heparin, anticoagulant for cardiac indications

Frequently asked questions

Sources

• Gelbe Liste, Digoxin active ingredient profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines for heart failure and atrial fibrillation
• European Society of Cardiology, cardiological guidelines