Digoxin - Drug Monograph

Introduction

Digoxin is a cardiac glycoside derived from the leaves of Digitalis lanata that has been used in clinical practice for centuries. It remains an important medication in the management of heart failure and atrial fibrillation, though its use has declined with the advent of newer agents. Digoxin's narrow therapeutic index requires careful dosing and monitoring to balance efficacy with toxicity risk.

Mechanism of Action

Digoxin exerts its therapeutic effects through two primary mechanisms:

• Positive inotropic effect: Inhibition of myocardial sodium-potassium ATPase pump, increasing intracellular sodium and calcium concentrations via sodium-calcium exchange, resulting in enhanced myocardial contractility
• Negative chronotropic effect: Vagomimetic actions that slow conduction through the atrioventricular (AV) node and decrease sympathetic nervous system activity

These combined effects make digoxin particularly useful for controlling ventricular rate in atrial fibrillation while providing inotropic support in heart failure.

Indications

• Mild to moderate heart failure (as adjunctive therapy)
• Control of ventricular rate in patients with chronic atrial fibrillation

• Paroxysmal atrial tachycardia
• Supraventricular tachyarrhythmias

Dosage and Administration

• Loading dose: 0.5-1 mg IV or PO in divided doses over 24 hours
• Maintenance dose: 0.125-0.5 mg daily (typically 0.25 mg/day)

• Renal impairment: Dose reduction required (CrCl <50 mL/min)
• Elderly patients: Lower doses typically needed
• Pediatric patients: Dosing based on age and weight (consult pediatric references)

Pharmacokinetics

• Absorption: Oral bioavailability 60-80% (tablets); food may delay but not reduce absorption
• Distribution: Large volume of distribution (4-7 L/kg); extensively tissue-bound
• Metabolism: Hepatic metabolism minimal (≈16%); primarily excreted unchanged
• Elimination: Renal excretion (50-70% unchanged); elimination half-life 36-48 hours (prolonged in renal impairment)

Contraindications

• Ventricular fibrillation
• Hypersensitivity to digoxin or other digitalis preparations
• Second- or third-degree AV block (without permanent pacemaker)
• Wolff-Parkinson-White syndrome with atrial fibrillation
• Constrictive pericarditis
• Idiopathic hypertrophic subaortic stenosis

Warnings and Precautions

• Narrow therapeutic index: Small margin between therapeutic and toxic doses
• Electrolyte imbalances: Hypokalemia, hypomagnesemia, and hypercalcemia increase toxicity risk
• Renal impairment: Requires dose adjustment and careful monitoring
• Thyroid disorders: Altered sensitivity to digoxin
• Acute myocardial infarction: Increased risk of arrhythmias
• Elderly patients: Increased susceptibility to adverse effects

Drug Interactions

• Diuretics: Thiazides and loop diuretics (hypokalemia increases toxicity risk)
• Amiodarone, verapamil, diltiazem: Reduce renal clearance of digoxin
• Quinidine: Displaces digoxin from tissue binding sites
• Macrolide antibiotics: May increase digoxin absorption
• Thyroid medications: Altered digoxin requirements

Adverse Effects

• Various arrhythmias (PVCs, PAT with block, ventricular tachycardia)
• AV block (first-, second-, or third-degree)
• Atrial tachycardia with block

• Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain
• Neurological: Fatigue, weakness, dizziness, visual disturbances (yellow-green halos)
• Psychiatric: Confusion, depression

Monitoring Parameters

• Serum digoxin levels (draw ≥6-8 hours post-dose)
• Renal function (serum creatinine, BUN, calculated CrCl)
• Electrolytes (potassium, magnesium, calcium)
• ECG (for signs of toxicity or conduction abnormalities)
• Clinical signs/symptoms of efficacy and toxicity

Patient Education

• Take at same time each day
• Do not miss or double doses
• Report signs of toxicity: nausea, vomiting, diarrhea, visual changes, dizziness
• Maintain consistent dietary potassium intake
• Inform all healthcare providers of digoxin use
• Use same brand consistently (variations in bioavailability)
• Regular follow-up and blood tests are essential

References

1. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336(8):525-533. 2. Gheorghiade M, Adams KF Jr, Colucci WS. Digoxin in the management of cardiovascular disorders. Circulation. 2004;109(23):2959-2964. 3. Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA. 2003;289(7):871-878. 4. American College of Cardiology/American Heart Association Heart Failure Guidelines. J Am Coll Cardiol. 2017;70(6):776-803. 5. Product Information: Lanoxin® (digoxin). GlaxoSmithKline, 2021. 6. Bauman JL, DiDomenico RJ, Galanter WL. Mechanisms, manifestations, and management of digoxin toxicity in the modern era. Am J Cardiovasc Drugs. 2006;6(2):77-86.