Digoxin

Digoxin is a cardiac glycoside used primarily to treat heart failure and atrial fibrillation. It
has positive inotropic, negative chronotropic, and negative dromotropic effects, making it
useful for managing certain cardiovascular conditions.
1. Mechanism of Action
Digoxin exerts its primary effects by inhibiting the Na⁺/K⁺-ATPase pump on cardiac cell
membranes. This inhibition leads to:
 Increased Intracellular Sodium ([Na⁺]ᵢ): By blocking the Na⁺/K⁺-ATPase, digoxin
prevents the extrusion of Na⁺ from the cell, resulting in elevated [Na⁺]ᵢ.
 Reduced Na⁺/Ca²⁺ Exchange: The increased [Na⁺]ᵢ diminishes the activity of the
Na⁺/Ca²⁺ exchanger, which normally expels Ca²⁺ from the cell in exchange for Na⁺.
 Increased Intracellular Calcium ([Ca²⁺]ᵢ): The reduction in Na⁺/Ca²⁺ exchange leads to an
accumulation of Ca²⁺ within the cell, enhancing calcium-induced calcium release from
the sarcoplasmic reticulum. This results in augmented myocardial contractility (positive
inotropic effect).
 Enhanced Vagal Tone: Digoxin increases parasympathetic (vagal) activity, which slows
sinoatrial (SA) node firing and prolongs atrioventricular (AV) node conduction,
contributing to its negative chronotropic (heart rate-reducing) and negative dromotropic
(conduction velocity-reducing) effects.
2. Pharmacokinetics
 Absorption: Digoxin has an oral bioavailability of approximately 60-80%. Factors such
as gastrointestinal motility and the presence of food can influence its absorption.
 Distribution: It has a large volume of distribution (Vd) of about 6-8 L/kg, indicating
extensive tissue binding, particularly in the heart, skeletal muscle, and kidneys.
Approximately 25% of digoxin is bound to plasma proteins.
 Metabolism: A small fraction of digoxin undergoes hepatic metabolism to inactive
metabolites.
 Excretion: The majority of digoxin is excreted unchanged by the kidneys. Its renal
clearance is proportional to creatinine clearance, necessitating dose adjustments in
patients with renal impairment.
 Half-life: In individuals with normal renal function, the elimination half-life is about 36-
40 hours. This can be prolonged in cases of renal dysfunction.
3. Therapeutic Uses
 Heart Failure: Digoxin is used in the management of chronic heart failure with reduced
ejection fraction (HFrEF). By increasing myocardial contractility, it enhances cardiac
output and reduces symptoms. However, it does not confer a mortality benefit and is
primarily used for symptomatic relief.
 Atrial Fibrillation and Atrial Flutter: Its ability to slow AV nodal conduction makes
digoxin effective in controlling ventricular rate in supraventricular tachyarrhythmias.
4. Adverse Effects
 Cardiac Toxicity: Digoxin can induce various arrhythmias, including ventricular
premature beats, ventricular tachycardia, and AV block. These effects are due to
increased automaticity and altered conduction properties.
 Gastrointestinal Symptoms: Nausea, vomiting, anorexia, and diarrhea are common and
may precede more severe toxicity.
  Central Nervous System Effects: Patients may experience fatigue, confusion, dizziness,
and visual disturbances, such as blurred vision and seeing yellow or green halos around
lights.
 Electrolyte Imbalances: Hypokalemia, hypercalcemia, and hypomagnesemia can
predispose patients to digoxin toxicity by further enhancing its effects on the
myocardium.
5. Drug Interactions
 Potentiation of Toxicity:
o Diuretics: Loop and thiazide diuretics can cause hypokalemia, increasing the risk
of digoxin toxicity.
o Amiodarone, Quinidine, Verapamil: These drugs can increase digoxin plasma
levels by reducing its renal clearance or displacing it from tissue binding sites.
 Reduced Efficacy:
o Antacids and Cholestyramine: These agents can decrease digoxin absorption
from the gastrointestinal tract.
o Rifampin and St. John's Wort: They may enhance digoxin metabolism, leading
to reduced plasma concentrations.
6. Toxicity and Management
 Clinical Presentation of Toxicity: Symptoms include cardiac arrhythmias,
gastrointestinal distress, and neurological manifestations.
 Management Strategies:
o Discontinuation: Stop digoxin administration.
o Electrolyte Correction: Address hypokalemia, hypomagnesemia, and
hypercalcemia.
o Antiarrhythmic Therapy: Use agents like lidocaine or phenytoin for ventricular
arrhythmias.
o Digoxin-Specific Antibodies: In severe cases, administer digoxin-specific Fab
fragments to neutralize circulating digoxin.
7. Monitoring Parameters
 Serum Digoxin Levels: Maintain therapeutic concentrations between 0.5-2 ng/mL, with
levels on the lower end preferred for heart failure management to minimize toxicity risk.
 Electrolytes: Regularly monitor potassium, calcium, and magnesium levels, especially
when patients are on concomitant diuretic therapy.
 Renal Function: Assess creatinine clearance to guide dosing adjustments.
 Electrocardiogram (ECG): Monitor for changes indicative of digoxin effect or toxicity,
such as scooped ST segments, AV block, or arrhythmias.