Digoxin

Mechanism of Action

Digoxin exerts its effects through 2 primary mechanisms of action, selectively utilized based on the clinical indication:

• Positive ionotropic effect: Digoxin increases the force of cardiac contraction by reversibly inhibiting the myocardial sodium-potassium ATP (Na+/K+ ATPase) pump. This enzyme regulates ion movement in the heart. Digoxin increases intracellular sodium levels, which drives an influx of calcium into the heart, enhancing contractility, increasing cardiac output, and subsequently decreasing ventricular filling pressures.[7]

• AV node inhibition: Digoxin exerts vagomimetic effects on the atrioventricular (AV) node by stimulating the parasympathetic nervous system. This action slows electrical conduction through the AV node, reducing heart rate. The increase in intracellular calcium levels prolongs phases 4 and 0 of the cardiac action potential, extending the AV node's refractory period. As a result, conduction through the AV node slows, leading to a decreased ventricular response.[7]

Digoxin was previously used off-label to induce fetal death before second-trimester abortions due to its cytotoxic effects on fetal cells and its potential to compromise fetal tissue integrity. Early studies suggested that digoxin could induce uterine contractions, sparking interest in its use as an abortifacient. However, concerns about its effectiveness and safety have significantly limited its application in this context. These uncertainties led healthcare professionals to approach its use with caution, favoring alternative methods with established efficacy and safety for pregnancy termination.[8]

Pharmacokinetics

Absorption: Digoxin has an oral bioavailability of approximately 75%, though its efficacy may decrease when taken with high-fiber foods. Additionally, certain gut flora in some patients can metabolize digoxin into dihydro-digoxin, further reducing its absorption. 

Distribution: Digoxin undergoes a tissue distribution phase lasting 6 to 8 hours after administration, followed by a gradual decline in serum concentration as it is eliminated. Initial high serum levels do not accurately reflect the drug's activity at its target site, but steady-state concentrations achieved with long-term use better correlate with tissue levels and pharmacological effects. Digoxin is extensively distributed in body tissues, with a large apparent volume of distribution (approximately 475–500 L). It crosses the blood-brain barrier and placenta, resulting in similar serum concentrations in mothers and newborns at delivery. Approximately 25% of plasma digoxin is protein-bound.

Metabolism: In healthy individuals, approximately 13% of a digoxin dose undergoes metabolism. Urinary metabolites include dihydro-digoxin, polar glucuronides, and sulfate conjugates, which are formed through processes such as oxidation, hydrolysis, and conjugation.

Excretion: Digoxin is excreted by the kidneys in direct proportion to the glomerular filtration rate, with its half-life ranging from 36 to 48 hours. This half-life may be prolonged in cases of renal failure.[9] Metoclopramide reduces digoxin absorption, while indomethacin and spironolactone decrease its clearance. The elimination half-life of digoxin can vary based on age and renal function.

In neonates, the half-life of digoxin is longer in premature infants compared to full-term infants. In contrast, infants and children exhibit shorter half-lives, while adults experience moderate-to-extended durations. In adults with renal failure, the half-life is significantly prolonged. A study investigating the impact of body size and weight on the pharmacokinetics of heart failure medications, including digoxin, carvedilol, and enalapril, highlighted variations in drug clearance and distribution. These findings emphasize the importance of personalized treatment approaches to optimize clinical outcomes in heart failure patients.[10]

Administration

Available Dosage Forms and Strengths

Digoxin is available in the following formulations:

• Oral solution: 0.05 mg/mL.
• Injectable solution: 0.1 mg/mL and 0.25 mg/mL.
• Tablets: 0.0625 mg, 0.125 mg, 0.1875 mg, and 0.25 mg.

Intravenous (IV) administration is the preferred method for achieving rapid digitalization with digoxin. Intramuscular injections, although discussed, are less commonly used and should be limited to a maximum of 2 mL per injection site. The infusion should be administered deep into the muscle, and the overlying area should be massaged after injection. IV injections are metabolized more efficiently than intramuscular injections and are preferred, as only about 80% of the drug is absorbed with intramuscular injections compared to IV dosing. The intramuscular route carries a risk of local irritation or myonecrosis.

Key considerations for digoxin administration include the following:

• An electrocardiogram (ECG) should be obtained before administering digoxin.
• Electrolyte levels, particularly potassium, should be assessed and normalized before administration.
• If bradycardia is detected, treatment should be reevaluated, and digoxin should be withheld if necessary.[11]
• Plasma digoxin levels should be monitored by clinical staff 6 to 12 hours after the last loading dose to confirm steady-state levels.
• Digoxin injections may be administered either undiluted or diluted. If dilution is required, the volume of sterile diluent should be at least 4 times the injection volume. Suitable diluents include sterile water for injection, normal saline, or dextrose. Diluting with less than a 4-fold volume increases the risk of digoxin precipitation.

Adult Dosage

Heart failure: The ACC/AHA guidelines recommend a digoxin dosage of 0.125 to 0.25 mg/d for patients with symptomatic stage C heart failure with reduced ejection fraction. The dosage should be tailored to the individual patient, guided by a dosing nomogram, to achieve a target serum digoxin concentration of 0.5 to less than 0.9 ng/mL.[12]

Atrial fibrillation: The 2023 ACC, AHA, ACCP, and HRS guidelines for managing atrial fibrillation recommend an initial loading dosage of digoxin 0.25 to 0.5 mg, administered over several minutes. Additional dosages of 0.25 mg may be given every 6 hours, not exceeding 1.5 mg in 24 hours. The maintenance dosage typically ranges from 0.0625 to 0.25 mg/d. As digoxin is primarily eliminated through the kidneys, plasma concentrations exceeding 1.2 ng/mL are linked to an increased mortality risk.[13]

Specific Patient Populations

Hepatic impairment: Dosage adjustments for digoxin are typically not required in patients with hepatic impairment.

Renal impairment: As digoxin clearance is closely related to renal function, as measured by creatinine clearance, patients with impaired renal function require reduced maintenance doses. The extended elimination half-life in these individuals delays the attainment of a new steady-state serum concentration, increasing the risk of toxicity if dosing adjustments are not made appropriately.

Pregnancy considerations: Digoxin crosses the placenta, making it important to monitor neonates for signs of toxicity following in-utero exposure. Pregnancy increases susceptibility to arrhythmias and can exacerbate preexisting cardiac conditions, posing potential risks to both mother and fetus. Physiological changes during pregnancy may necessitate dosage adjustments. Digoxin is recommended as a first-line treatment for symptomatic supraventricular tachycardia during pregnancy. Digoxin may also be used to manage maternal atrial tachycardia or atrial fibrillation when other therapies prove ineffective.[14][5]

Breastfeeding considerations: Digoxin concentrations in breast milk are low, resulting in minimal infant exposure and a low likelihood of adverse effects. To further reduce exposure, it is recommended to delay breastfeeding for at least 2 hours after IV administration of digoxin.[15]

Pediatric patients: The safety and efficacy of digoxin for ventricular rate control in children with atrial fibrillation remain insufficiently established. Although some studies indicate potential benefits in improving hemodynamics and symptoms in pediatric heart failure, dosing must be carefully individualized, particularly for newborns and premature infants.

Older patients: According to the ACC/AHA guidelines, for patients aged 70 or older, those with impaired renal function, or individuals with low lean body mass, a low starting dosage of digoxin (0.125 mg/d or every other day) should be considered for initial treatment.[3]

Adverse Effects

Digoxin toxicity is clinically significant, as it can lead to fatal cardiac arrhythmias. The estimated incidence is around 0.8% to 4% of patients on steady digoxin therapy. The risk of toxicity increases when serum digoxin concentrations exceed 2.0 ng/mL. However, toxicity can also occur at lower levels, particularly in the presence of other risk factors such as low body weight, advanced age, impaired renal function, and hypokalemia.

Adverse reactions to digoxin are dose-dependent and occur more frequently at higher doses. Mild symptoms may include nausea, vomiting, and anorexia. Visual disturbances, such as color changes (xanthopsia), are also common. However, yellow or green-tinted vision is typically associated with digoxin toxicity, as discussed below. Patients may also report blurry vision or photopsia. At toxic levels, digoxin becomes proarrhythmic, with an impaired ventricle being more susceptible to ventricular tachyarrhythmias and ectopy. Elevated digoxin levels can stimulate atrial activation, making atrial tachycardias in a patient on digoxin highly suggestive of toxicity. These atrial tachycardias tend to persist and resolve with a reduction in serum digoxin levels. Other common adverse effects include rash, headache, and gynecomastia.[16]

Drug-Drug Interactions

• Azole antifungals: Azole antifungals can inhibit P-glycoprotein, potentially increasing digoxin levels.

• Macrolide: Macrolide antibiotics inhibit P-glycoprotein, which can lead to increased intestinal absorption of digoxin.

• Class III antiarrhythmic drugs: Concomitant use of dofetilide with digoxin has been associated with an increased risk of torsades de pointes. In patients taking sotalol and digoxin together, proarrhythmic events occurred more frequently than with either drug alone. However, it is unclear whether this is due to a drug interaction or the presence of congestive heart failure, which is a known arrhythmia risk factor. Additionally, combining digoxin with dronedarone has been linked to a higher incidence of sudden death compared to either drug alone. It remains uncertain whether this is a direct drug interaction or related to advanced heart disease, which also increases the risk of sudden death in patients on digoxin.

• Ibarbadine: Ivabradine can increase the risk of bradycardia when used concurrently with digoxin.

• Quinidine: Concomitant use of quinidine with digoxin may significantly increase serum digoxin levels. Measuring serum levels before starting quinidine and reducing the digoxin dose by 30% to 50% or adjusting the dosing frequency is recommended. Ongoing monitoring of serum levels is essential.

• IV calcium products: When administered rapidly via the IV route, calcium can induce severe arrhythmias in patients who are digitalized.

• Beta-blockers and calcium channel blockers: Beta-blockers and calcium channel blockers can potentiate digoxin’s effects on AV node conduction, increasing the risk of bradycardia and advanced or complete heart block.[17]

Contraindications

According to the product labeling, digoxin is contraindicated in the following conditions:

• Acute myocardial infarction
• Ventricular fibrillation
• Hypersensitivity to the drug

Warning and Precautions

• Acute myocardial infarction (increases myocardial oxygen demand and worsens ischemia)
• Myocarditis
• Hypomagnesemia
• Hypokalemia
• Wolf-Parkinson-White syndrome [18] 
• Hypercalcemia or hypocalcemia
• Renal impairment
• Diseased SA node
• Bradycardia
• AV block
• Restrictive cardiomyopathy
• Hypothyroidism (delays digoxin clearance, increasing the risk of toxicity)

Monitoring

Digoxin has a narrow therapeutic index, with recommended serum levels ranging from 0.8 to 2 ng/mL.[19] Blood should be drawn at least 6 to 8 hours after the last dose to accurately measure serum digoxin levels. Toxicity risk increases as serum levels exceed 2.0 ng/mL. The prescriber should monitor levels, especially if there have been recent changes in medication. Approximately 70% of digoxin is excreted by the kidneys, which is directly proportional to the patient's glomerular filtration rate. The physician should request regular ECGs and bloodwork to assess renal function, with close monitoring of electrolyte levels.[20] Digoxin levels should be checked 1 week after starting the medication and regularly afterward. 

The 2013 ACC Foundation guidelines and the AHA recommend digoxin plasma levels between 0.5 and 0.9 ng/mL for heart failure. The 2022 guidelines from the AHA, ACC, and Heart Failure Society of America suggest an upper limit of 1.0 ng/mL, noting increased mortality risks at 1.2 ng/mL or higher and advocating for low doses. While these guidelines apply to heart failure, there is no consensus on the therapeutic range for digoxin in atrial fibrillation, with recommendations ranging from less than 0.9 to 1.2 ng/mL. Some discussions suggest a target range of 0.5 to 1.0 ng/mL, emphasizing the importance of monitoring to avoid supratherapeutic levels.[21]

ECG changes associated with digoxin include downsloping ST-segment depression, often referred to as the "reverse check" sign. The ST segments may appear "scooped" without abnormal Q- or T-wave inversions.[22] Regular digoxin use results in a decreased QT interval, prolonged PR interval, and T wave inversion or flattening. In the case of an overdose, digoxin immune fab should be administered. This molecule binds to digoxin, preventing it from binding to its active sites.

Caution is required when using digoxin immune fab, as reversing digoxin's effects may reduce serum potassium levels. A systematic review highlights the correlation between elevated serum digoxin concentrations and increased mortality and morbidity in patients with atrial fibrillation and heart failure with reduced ejection fraction. These findings underscore the importance of careful monitoring and personalized treatment strategies to improve patient outcomes.[23]

Toxicity

Signs and Symptoms of Overdose

The most common signs of digoxin toxicity include nausea, vomiting, anorexia, and fatigue. Overdose can lead to life-threatening arrhythmias or malignant hyperkalemia.[22] Concerns regarding digoxin's association with increased mortality have been raised, as evidence suggests it may elevate mortality risks. Given its narrow therapeutic index, digoxin's administration is highly influenced by drug-drug interactions and comorbid conditions.

Bradycardia is commonly observed in digoxin toxicity. Neurological symptoms, such as confusion and weakness, may occur as the drug redistributes to the central nervous system. In cases of chronic toxicity, neurological manifestations can include lethargy, delirium, and generalized weakness. Visual disturbances may include xanthopsia (yellow vision), diplopia, and photophobia.[24] Hyperkalemia is a significant marker of toxicity, while hypomagnesemia, hypokalemia, and hypercalcemia can increase susceptibility to digoxin's effects. Loop diuretics often contribute to hypokalemia, further amplifying the risk of toxicity.

Evaluation of renal function is crucial and should include measurements of blood urea nitrogen (BUN), creatinine, and urine output. An ECG should be obtained, as typical findings include premature ventricular contractions, bradycardia, atrial tachyarrhythmias with AV block, ventricular bigeminy, ventricular tachycardia, and ventricular fibrillation. Bidirectional ventricular tachycardia, though rare, is highly suggestive of digoxin toxicity and is characterized by beat-to-beat alternation in the QRS axis.[25][26]

Management of Overdose

For life-threatening hyperkalemia, treatment should be initiated with glucose and insulin. Activated charcoal may be administered in cases of acute overdose to reduce the elimination half-life of digoxin.[27] Ventricular arrhythmias can be treated with lidocaine or phenytoin. In the event of an overdose, digoxin immune fab is the recommended reversal agent.

The following conditions indicate the use of digoxin immune fab:

• Any life-threatening digoxin-related dysrhythmia
• Refractory hyperkalemia
• Serum digoxin concentration greater than 15 ng/mL at any time or above 10 ng/mL 6 hours post-ingestion
• Acute ingestion of 10 mg in adults
• Acute ingestion of 4 mg in children
• Chronic elevation of serum digoxin concentration with altered mental status, dysrhythmias, or severe gastrointestinal symptoms

Enhancing Healthcare Team Outcomes

An overdose of digoxin can lead to severe arrhythmias and malignant hyperkalemia. The association between digoxin use and increased mortality has raised significant concerns among researchers, as it appears to elevate the risk of death. Due to these risks, digoxin therapy requires oversight from an interprofessional healthcare team, including clinicians, specialists, advanced-practice providers, nurses, and pharmacists. This healthcare team must collaborate, share information, and coordinate care to optimize therapy and prevent adverse effects. 

Digoxin has a narrow therapeutic index, and its administration is influenced by drug-drug interactions and comorbidities. The management of digoxin toxicity primarily involves supportive therapy, including IV hydration and electrolyte repletion.[28] Timely and specific intervention from the medical team is essential, as patients may face a significant mortality risk without it. If digoxin toxicity is confirmed, following the assessment of serum digoxin levels and the ECG, the clinician should promptly request a digoxin immune fab from the pharmacy and review the patient's medication profile for potential drug interactions. This approach requires the collaboration of the entire medical team.

Additionally, consultation with a nephrologist should be considered if emergent hemodialysis is indicated. Supportive care, including IV hydration and electrolyte repletion, is essential. Involving a toxicologist for specialized guidance may also be beneficial, and for international overdose cases, a psychiatry consultation should be considered to address any underlying psychological issues. The patient may require admission to the medical intensive care unit (MICU) or cardiac care unit (CCU) under the supervision of a critical care physician. An interprofessional team approach, with communication among clinicians, specialists, pharmacists, and nurses, is crucial to minimizing toxicity and improving patient outcomes related to digoxin therapy.