Digoxin

Digoxin is a cardiac glycoside derived from the foxglove plant Digitalis lanata. It has been a mainstay in the treatment of heart failure and certain supraventricular arrhythmias for over a century. Its clinical use requires careful monitoring due to a narrow therapeutic index, meaning the difference between an effective and a toxic dose is small. Digoxin exerts its effect through a unique dual mechanism that enhances cardiac contractility and controls heart rate, particularly in atrial fibrillation.

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Pharmacological Classification

• Therapeutic class: Antiarrhythmic agent, Positive inotrope

• Pharmacologic class: Cardiac glycoside

• ATC Code: C01AA05

• Legal status: Prescription-only medicine (Rx) in all countries

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Mechanism of Action

Digoxin primarily acts by inhibiting the sodium-potassium ATPase (Na⁺/K⁺-ATPase) pump on cardiac myocytes. This results in:

1. Increased intracellular sodium concentration

2. Reduced sodium-calcium exchange (Na⁺/Ca²⁺ exchanger activity), leading to accumulation of intracellular calcium

3. Elevated intracellular calcium enhances contractility of the myocardium (positive inotropic effect)

Additionally, digoxin increases vagal tone, leading to:

• Decreased heart rate (negative chronotropic effect)

• Slowed conduction through the atrioventricular (AV) node (negative dromotropic effect)

These effects make it particularly useful in rate control of atrial fibrillation and in heart failure with reduced ejection fraction (HFrEF) when symptoms persist despite optimal treatment.

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Therapeutic Indications

1. Heart Failure

   • Used in chronic systolic heart failure (HFrEF), especially in patients who remain symptomatic despite ACE inhibitors, beta-blockers, and diuretics

   • Improves symptoms and exercise tolerance, reduces hospitalizations, but does not reduce mortality

2. Atrial Fibrillation and Atrial Flutter

   • Used for rate control, particularly in patients with congestive heart failure, where beta-blockers or calcium channel blockers may be contraindicated

   • Not typically effective for rhythm control

3. Other Supraventricular Arrhythmias (e.g., paroxysmal atrial tachycardia)

   • Occasionally used, but less common today due to availability of safer alternatives

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Formulations and Routes of Administration

• Oral tablets: 62.5 mcg, 125 mcg, 250 mcg

• Oral elixir (pediatric use): 50 mcg/mL

• Intravenous injection: 250 mcg/mL ampoules

• Brand names: Lanoxin®, Digitek®, Lanoxicaps®, Digox®, among others

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Dosage and Administration

Oral Dosing (Adults)

Loading dose (rarely used today due to toxicity risk)

• Total digitalizing dose (TDD): 0.75–1.5 mg, administered in divided doses over 24 hours

• Typically reserved for urgent arrhythmia control

Maintenance dose

• Typical daily dose: 125–250 mcg once daily

• Dose adjustment required based on age, renal function, serum digoxin level, and concomitant medications

Pediatrics

• Dose is weight-based (e.g., 10–15 mcg/kg/day in divided doses)

• Close monitoring essential due to narrow safety margin

IV Administration

• Used when rapid onset is required

• Administered over 5–10 minutes under cardiac monitoring

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Monitoring Parameters

• Serum digoxin levels: Therapeutic range for heart failure is 0.5–0.9 ng/mL; higher levels (>2.0 ng/mL) are typically toxic

• Electrolytes: Hypokalemia, hypomagnesemia, and hypercalcemia all increase toxicity risk

• Renal function: Digoxin is primarily renally excreted

• ECG: Watch for arrhythmias or signs of AV block

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Contraindications

• Known hypersensitivity to digoxin or other cardiac glycosides

• Ventricular fibrillation

• Hypertrophic obstructive cardiomyopathy (HOCM)

• Second- or third-degree AV block (without pacemaker)

• Wolff-Parkinson-White syndrome with atrial fibrillation

• Sinus node disease (sick sinus syndrome) unless paced

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Warnings and Precautions

• Narrow therapeutic index: Risk of serious toxicity, especially in elderly or renally impaired patients

• Electrolyte imbalances: Hypokalemia, hypomagnesemia, and hypercalcemia increase sensitivity

• Bradyarrhythmias: Risk of AV block and junctional rhythms

• Thyroid disease: Hypothyroidism increases sensitivity to digoxin; hyperthyroidism decreases efficacy

• Renal impairment: Requires significant dose reduction and frequent monitoring

• Elderly patients: Require lower doses and more frequent monitoring

• Amiodarone, verapamil, and quinidine: Increase serum digoxin levels significantly

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Adverse Effects

Common (1–10%)

• Nausea

• Vomiting

• Anorexia

• Diarrhea

• Fatigue

• Confusion, especially in elderly

• Blurred or yellow vision (xanthopsia)

Less Common / Serious

• Arrhythmias (e.g., ventricular ectopy, bigeminy, tachycardia, fibrillation)

• Bradycardia

• Heart block

• Visual disturbances (e.g., halos, photophobia)

• Delirium and psychosis (especially in older adults)

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Toxicity and Overdose

Causes

• Overdose, renal impairment, drug interactions, or electrolyte disturbances

Symptoms

• Nausea, vomiting, dizziness

• Visual changes: halos, blurred vision, yellow-tinted vision

• Bradyarrhythmias or tachyarrhythmias

• Confusion or delirium

Management

• Stop digoxin and correct electrolyte imbalances

• Monitor ECG and serum digoxin level

• Administer digoxin-specific antibody fragments (Digibind® or DigiFab®) in life-threatening toxicity

• Activated charcoal if ingestion was recent

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Drug Interactions

Pharmacokinetic Interactions

• Amiodarone, verapamil, quinidine, diltiazem: Reduce renal clearance → ↑ digoxin levels

• Macrolide antibiotics (erythromycin, clarithromycin): Increase absorption

• P-gp inhibitors (e.g., spironolactone, dronedarone): Increase serum digoxin concentration

• St. John's Wort, rifampin: ↓ digoxin levels via enzyme induction

Pharmacodynamic Interactions

• Loop and thiazide diuretics: Cause hypokalemia → ↑ toxicity

• Corticosteroids: May reduce serum potassium

• Beta-blockers and non-dihydropyridine calcium channel blockers: Additive bradycardia and AV block risk

• Sympathomimetics: May cause arrhythmias when combined

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Use in Pregnancy and Lactation

Pregnancy

• Category C (US FDA)

• Crosses placenta, but used safely when necessary (e.g., fetal SVT)

• No evidence of teratogenicity in humans

Lactation

• Small amounts excreted in breast milk

• Generally considered safe while breastfeeding, though caution advised with high maternal doses

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Comparison with Other Agents (No Tables)

Digoxin vs. Beta-blockers (e.g., metoprolol)

• Both reduce AV nodal conduction and control heart rate in atrial fibrillation

• Beta-blockers reduce mortality in heart failure, digoxin does not

• Digoxin is preferred in low blood pressure or asthma/COPD patients where beta-blockers are contraindicated

• Beta-blockers better for exertional tachycardia control

Digoxin vs. Calcium Channel Blockers (e.g., verapamil, diltiazem)

• Verapamil/diltiazem also control heart rate in AF

• More potent negative inotropes than digoxin

• Digoxin safer in heart failure with reduced ejection fraction (EF)

• CCBs contraindicated in decompensated heart failure

Digoxin vs. Amiodarone

• Amiodarone used for rhythm control; digoxin for rate control

• Amiodarone increases digoxin levels → requires dose adjustment

• Digoxin has fewer systemic toxicities but higher arrhythmia risk in toxicity

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Patient Counseling Points

• Take at the same time every day, preferably after meals

• Do not stop without consulting your doctor

• Avoid over-the-counter medications or herbal supplements without advice

• Inform all healthcare providers about digoxin use

• Report symptoms of toxicity: visual disturbances, confusion, palpitations, fainting

• Maintain regular monitoring of kidney function, electrolytes, and serum digoxin levels

• Avoid becoming dehydrated; drink adequate fluids

• Limit use of antacids or bulk-forming laxatives around digoxin administration time (they can interfere with absorption)