Digitoxin: Effect as a Cardiac Glycoside

Digitoxin (brand names Digimerck and generics) is a cardiac glycoside from the leaves of the red foxglove (Digitalis purpurea). It has been known for centuries and shares the cardiac principles of action with digoxin. Unlike digoxin, digitoxin is metabolized predominantly hepatically and excreted renally only to a small extent. This results in the most important practical difference: digitoxin can be used even with impaired renal function without profound dose adjustment, whereas digoxin requires careful renal dose adjustment.

In clinical practice, digitoxin has been largely displaced by the more modern digoxin in recent decades. In Germany, it remains available and is used particularly in elderly patients with atrial fibrillation and concurrent renal insufficiency. In chronic heart failure with reduced pump function and persistent symptoms despite optimal standard therapy, digitoxin may also be suitable as add-on therapy. Because of the narrow therapeutic window and long half-life, careful therapy management with level measurements is required.

Mechanism of Action

Digitoxin inhibits the sodium potassium ATPase at the cardiac muscle cell. This decreases the sodium gradient, less sodium is transported out of the cell via the sodium calcium exchanger, and intracellular calcium increases. The result is improved contractile force (positive inotropic effect), which can relieve symptoms in patients with reduced pump function.

Additionally, digitoxin acts on the autonomic nervous system with increased vagal tone. This leads to slowing of AV node conduction and can reduce ventricular rate in atrial fibrillation. The antiarrhythmic component is clinically relevant, especially in patients with heart failure and persistent tachyarrhythmia.

Pharmacokinetically, digitoxin is distinguished by high plasma protein binding (approximately 95 percent), a very long half-life of around seven days, and predominantly hepatic elimination with enterohepatic circulation. Oral bioavailability is high (approximately 90 to 100 percent). Steady-state levels are reached only after three to four weeks. This lag is simultaneously an advantage (consistent effect) and a risk (delayed response to dose changes and toxicity).

Areas of Use

• Chronic heart failure with reduced left ventricular ejection fraction, supplementary to standard therapy consisting of ACE inhibitor or ARNI, beta blocker, aldosterone antagonist, and SGLT 2 inhibitor
• Atrial fibrillation and atrial flutter for rate control, especially in patients with heart failure and renal insufficiency
• Symptomatic patients despite optimal standard therapy, in whom rate reduction and positive inotropy are desired

Digitoxin is not first choice in acute tachycardias without heart failure because other substances are better controllable. In atrial fibrillation with pre-excited conduction in the setting of Wolff Parkinson White syndrome, digitoxin is contraindicated.

Dosage and Administration

Maintenance dose: 0.07 to 0.1 mg per day orally, individualized according to level and effect. Loading is rarely practiced today because it increases toxicity risk. Slow titration is safer.

Level measurement: Target range 10 to 25 ng per ml. Values above 30 ng per ml are toxic. Levels are determined 12 to 24 hours after last dose, at earliest three weeks after therapy initiation or dose change, because steady state is only then established.

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, no double catch-up.

Renal insufficiency: usually no dose adjustment required because hepatic elimination is dominant. This is the most important advantage over digoxin. Liver insufficiency: caution with severe impairment, dose reduction after level check.

Elderly patients: halve initial dose, slow titration, level check earlier and more frequently, because comorbidities and concomitant medications are common.

Side Effects

At therapeutic levels: nausea, loss of appetite, fatigue, headache, visual disturbances, especially color vision with yellowish or greenish cast.

With toxicity (levels above 30 ng per ml): vomiting, diarrhea, marked visual disturbances, confusion, hallucinations, dizziness.

Cardiac toxicity: bradycardia, AV block of all degrees, supraventricular tachycardias with AV block, ventricular extrasystoles, ventricular tachycardias including bidirectional tachycardia and ventricular fibrillation. Severe hyperkalemia accompanies acute toxicity.

Antidote: for life-threatening digitoxin or digoxin intoxication, administration of specific Fab fragments (digitalis antitoxin) is established. They bind the glycoside and lead to rapid inactivation. Dose calculation based on plasma level and approximate amount ingested.

Long half-life: digitoxin toxicity resolves slowly, sometimes over weeks. Intensive care monitoring is mandatory.

Drug Interactions

• Diuretics (loop diuretics, thiazides): hypokalemia and hypomagnesemia increase toxicity risk, electrolyte monitoring and supplementation important.
• Calcium antagonists (verapamil, diltiazem): level increase and additive bradycardia.
• Beta blockers: additional rate reduction and AV conduction delay, combination possible but careful monitoring required.
• Antiarrhythmics such as amiodarone, propafenone, and flecainide: level increase and additive electrophysiologic effects.
• Cholestyramine and colestipol: inhibit enterohepatic circulation, levels decrease, possible weakening of effect.
• Antibiotics such as erythromycin, clarithromycin, and tetracyclines: through alteration of intestinal flora, enterohepatic circulation may be disturbed, level fluctuations possible.
• NSAIDs and ACE inhibitors in combination with diuretics: worsening of renal function, indirectly risk for level changes.
• Intravenous calcium for hyperkalemia under glycoside toxicity: with caution, because too rapid calcium administration can worsen arrhythmias.

Special Notes

Pregnancy: digitoxin is among the longest-used cardiac agents in pregnancy. Use is possible, especially in maternal heart failure, with close monitoring and level measurement. Breastfeeding: transfer into breast milk in small amount, breastfeeding usually possible after consultation.

Children: use in pediatric cardiology, individual dosing weight-adapted with level measurement.

Elderly patients: increased toxicity risk through comorbidity and polypharmacy. Low starting doses and frequent level checks are essential.

Before therapy initiation: EKG, electrolytes (potassium, magnesium, calcium), renal and liver values. With hypokalemia below 3.5 mmol per liter, first correct potassium, because potassium deficiency can provoke toxicity.

Monitoring: level at initiation three to four weeks after therapy start, then individually. EKG to monitor rate, conduction behavior, and arrhythmogenic patterns. With clinical signs such as nausea, loss of appetite, or visual disturbances, immediately check level.

Lifestyle: patients benefit from salt reduction, regular exercise within exercise tolerance, weight management, and therapy adherence. Sudden discontinuation should be avoided because rebound phenomena are possible.

Driving ability: usually preserved with stable therapy, individualize if dizziness or visual disturbances occur.

You May Also Be Interested In

• Digoxin, shorter-acting glycoside with predominantly renal 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, Digitoxin active ingredient profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines for Heart Failure and Atrial Fibrillation
• European Society of Cardiology, cardiologic guidelines