What are the pharmacokinetics and pharmacodynamics of Digoxin (digitalis glycoside)?

From the Guidelines

Digoxin should be used with caution in patients with heart failure, with a target serum concentration of 0.5 to 1.0 ng per mL, as this range has been associated with the prevention of worsening heart failure without increased risk of mortality 1. The pharmacokinetics of digoxin involve a half-life of 36-48 hours in patients with normal renal function, but this can extend to 3-5 days in those with kidney impairment. After oral administration, digoxin is absorbed at 60-80% bioavailability, with peak serum concentrations occurring 2-6 hours post-dose.

Key Points to Consider

• The drug distributes widely throughout the body with a large volume of distribution (5-7 L/kg), concentrating particularly in heart, skeletal muscle, and kidney tissues.
• Digoxin is primarily eliminated unchanged through renal excretion (60-80%), making dose adjustments necessary in patients with reduced kidney function.
• Pharmacodynamically, digoxin inhibits the sodium-potassium ATPase pump, leading to increased intracellular sodium and calcium concentrations in cardiac myocytes, which enhances cardiac contractility (positive inotropic effect) while simultaneously decreasing conduction through the AV node (negative chronotropic effect).
• The therapeutic serum concentration range is narrow (0.5-1.0 ng/mL), with toxicity often occurring above 1.0 ng/mL, as suggested by the retrospective analysis of the Digitalis Investigation Group trial 1.

Practical Use of Digoxin

• Therapy with digoxin is commonly initiated and maintained at a dose of 0.125 to 0.25 mg daily, with low doses (0.125 mg daily or every other day) recommended for patients over 70 years old, those with impaired renal function, or those with a low lean body mass.
• There is no reason to use loading doses of digoxin to initiate therapy in patients with heart failure, and higher doses (e.g., digoxin 0.375 to 0.50 mg daily) are rarely used or needed in the management of patients with heart failure.
• Concomitant use of certain drugs, such as clarithromycin, erythromycin, amiodarone, itraconazole, cyclosporine, verapamil, or quinidine, can increase serum digoxin concentrations and may increase the likelihood of digitalis toxicity, necessitating dose reduction 1.

Risks of Treatment

• The principal adverse reactions occur primarily when digoxin is administered in large doses, but large doses may not be needed to produce clinical benefits.
• The major side effects include cardiac arrhythmias (e.g., ectopic and re-entrant cardiac rhythms and heart block), gastrointestinal symptoms (e.g., anorexia, nausea, and vomiting), and neurological complaints (e.g., visual disturbances, disorientation, and confusion).
• Overt digitalis toxicity is commonly associated with serum digoxin levels greater than 2 ng per mL, but toxicity may occur with lower digoxin levels, especially if hypokalemia, hypomagnesemia, or hypothyroidism coexists 1.

From the FDA Drug Label

Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its site of action, but that with chronic use, the steady-state post-distribution serum concentrations are in equilibrium with tissue concentrations and correlate with pharmacologic effects In individual patients, these post-distribution serum concentrations may be useful in evaluating therapeutic and toxic effects

The pharmacologic consequences of these direct and indirect effects are: (1) an increase in the force and velocity of myocardial systolic contraction (positive inotropic action); (2) a decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system (neurohormonal deactivating effect); and (3) slowing of the heart rate and decreased conduction velocity through the AV node (vagomimetic effect).

Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution. Digoxin crosses both the blood-brain barrier and the placenta At delivery, the serum digoxin concentration in the newborn is similar to the serum concentration in the mother. Approximately 25% of digoxin in the plasma is bound to protein.

The pharmacokinetics of digoxin involve:

• Absorption: 60% to 80% complete compared to an identical intravenous dose of digoxin
• Distribution: large apparent volume of distribution, concentrated in tissues, crosses blood-brain barrier and placenta
• Metabolism: only a small percentage (16%) of a dose of digoxin is metabolized
• Excretion: follows first-order kinetics, 50% to 70% of a digoxin dose is excreted unchanged in the urine

The pharmacodynamics of digoxin involve:

• Positive inotropic action: increase in the force and velocity of myocardial systolic contraction
• Neurohormonal deactivating effect: decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system
• Vagomimetic effect: slowing of the heart rate and decreased conduction velocity through the AV node
• Therapeutic effects: increase in cardiac output, decrease in pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance 2
• Toxic effects: may produce clinical benefits even at serum concentrations below the therapeutic range, but may also cause toxicity at high serum concentrations 2

From the Research

Pharmacokinetics of Digoxin

• Digoxin has a complex pharmacokinetic profile 3
• Its pharmacokinetics is summarized in a review article, including its absorption, distribution, metabolism, and excretion 4
• The drug's narrow therapeutic index makes its use challenging, and dosing based on patient-specific factors such as age, lean body weight, and renal function is crucial to minimize toxicity while maintaining efficacy 3

Pharmacodynamics of Digoxin

• Digoxin's hemodynamic, neurohormonal, and electrophysiologic actions make it a suitable adjunctive therapy for heart failure and atrial fibrillation 5
• The drug has a cardiotoxic effect, and its toxicology is well-documented 4
• The pharmacodynamics of digoxin is influenced by its narrow therapeutic window, and understanding its unique properties is essential for safe and effective use in practice 3

Factors Affecting Digoxin Toxicity

• Digoxin toxicity can be caused by inappropriately high dosages, often prescribed in the setting of renal dysfunction 6
• Other cases of toxicity can be attributed to system errors such as multiple prescriptions, poor patient counseling, or errors in transcribing 6
• The incidence of digoxin toxicity has been declining due to the development of more effective drug therapies, more accurate dosing methods, and the use of antidigoxin Fab fragments 6

Management of Digoxin Toxicity

• Digoxin immune Fab fragments can be used to quickly and effectively treat digoxin toxicity 6, 7
• A systematic review of published literature on digoxin toxicity was performed to develop consensus statements on diagnostic and therapeutic approaches 7
• The use of digoxin immune Fab for life-threatening exposure can decrease the risk of death, and its administration should be guided by the time of ingestion and nature of the exposure 7