Digoxin

Cardiac Glycosides / Positive Inotropics

Common trade names: Lanoxin, Digoxin Apo, Lanicor.

Mechanism

Pharmacological Class and Group

Cardiotonic, positive inotropic and antiarrhythmic belonging to the class of Cardiac Glycosides (derived from the digitalis lanata plant).

Mechanism of Action

Digoxin exerts direct mechanical hemodynamic effects on the myocyte and potently modulates cardiac sympathetic and parasympathetic autonomic tone.

Myocardial and Autonomic Control Molecular Mechanism

1. Inhibition of the Na+/K+ ATPase Pump (Positive Inotropic Effect): It binds reversibly and competitively to the extracellular subunit of the active sodium-potassium ATPase pump of the ventricular myocyte sarcolemma. This blocks the active transport of sodium efflux, discretely raising the intracellular sodium concentration:

Digoxin Pump Na⁺/K⁺ ATPase ↑ [Na⁺] intracellular ↓ Sodium electrochemical gradient

2. Inversion or Retardation of the Sodium-Calcium Exchanger (NCX): By decreasing the electrochemical sodium gradient that drives the NCX transporter, the flow of cellular calcium expulsion is stopped or reversed, increasing cytoplasmic levels of free calcium. This excess calcium is captured by the SERCA2 pump into the sarcoplasmic reticulum, being released massively in the following systole:

↑ [Ca²⁺] in Sarcoplasmic Reticulum ↑ Actin-Myosin coupling strength (Positive Inotropism)

3. Vagomimetic Effect (Negative Chronotropic and Dromotropic Effect): Directly increases efferent parasympathetic (vagal) tone and decreases sympathetic tone. This results in a slowing of the firing rate of the sinus node and a prolongation of the refractory period of the AV node, effectively decreasing the ventricular response in atrial tachyarrhythmias.

Pharmacokinetics

High Resolution Pharmacokinetics

Absorption and Bioavailability: Variable oral bioavailability from 60% to 80% (depending on the formulation and intestinal bacterial flora, since the bacteria Eubacterium lentum degrades digoxin in the intestine of some patients, attenuating its effectiveness).
Distribution: Large apparent volume of distribution (V_d ≈ 500 to 700 L), massively accumulating in the striated and cardiac skeletal tissue linked to the ATPase pump. It freely crosses the blood-brain barrier. Low binding to plasma proteins (25%).
Metabolism: Marginal hepatic metabolism (barely 16%), independent of the cytochrome CYP450 enzyme systems.
Excretion: Exclusive renal excretion by glomerular filtration and active tubular secretion mediated directly by P-glycoprotein (P-gp).

Half-life (t_1/2): It has a prolonged terminal elimination half-life of 36 to 48 hours in patients with normal kidney function, which is critically doubled or tripled in patients with underlying advanced kidney disease, favoring digitalis poisoning.

Indicators and dose
Clinical Indications and Uses

Chronic Atrial Fibrillation with Rapid Ventricular Response: Rate control is especially indicated in sedentary patients or patients with heart failure with a depressed baseline LVEF.

Heart Failure with Reduced Ejection Fraction (HFrEF): Indicated to reduce the rate of hospitalizations and relieve congestive symptoms in patients with persistent NYHA II-IV despite optimal first-line medical treatment (demonstrated in the DIG clinical trial). It does not offer overall survival benefits.

Dosage and Clinical Adjustment

Usual Maintenance Dose: 0.125 mg to 0.25 mg once daily orally, administered in the morning, or every other day.

Mandatory Adjustment in Renal Failure: The dose should be reduced proportionally according to the glomerular filtration rate:

eGFR (mL/min/1.73 m²) Digoxin Maintenance Dose Adjustment

> 60 Standard dose: 0.125 mg to 0.25 mg per day by mouth

30 - 59 Reduce dose: 0.125 mg per day or 0.0625 mg per day

15 - 29 0.0625 mg per day or 0.125 mg every other day (Monday, Wednesday, Friday)

< 15 or Dialysis Avoid its use as much as possible. If essential, dose 0.0625 mg 2 to 3 times a week under strict control of blood levels (Narrow safety range)

Security
Absolute and Relative Contraindications

Absolute Contraindications

Second or third degree atrioventricular block without pacemaker.

Hypertrophic obstructive cardiomyopathy (positive inotropism worsens outflow tract obstruction).

Wolff-Parkinson-White syndrome associated with atrial fibrillation (critical risk of triggering VF).

Acute myocarditis or active suspicion of previous digitalis poisoning.

Relative Contraindications

Moderate to advanced renal failure (requires proportional dose reduction and periodic determinations of digoxin in the blood).

Hypokalemia, hypomagnesemia or hypercalcemia (predispose to severe digitalis toxicity).

Adverse Effects and Specific Toxicity

Digoxin has a narrow therapeutic range (optimal recommended range in blood of 0.5 to 0.9 ng/mL). Concentrations greater than 1.2-2.0 ng/mL invariably induce the appearance of Acute or Chronic Digital Intoxication:

Clinical Manifestations of Intoxication:

Gastrointestinal Symptoms (Early): Persistent anorexia, nausea, central vomiting, crampy abdominal pain and diarrhea.

Neurological and Visual Symptoms: Extreme generalized fatigue, confusion, headache, delirium in the elderly, and chromatic visual alteration with vision of yellow-green halos (Xanthopsia due to ATPase blockade in retinal photoreceptors).

Arrhythmic Manifestations (Life Risk): Frequent bigeminy-type ventricular extrasystoles (very common), progressive atrioventricular block, non-paroxysmal atrial tachycardia with AV block, and the most specific arrhythmia: bidirectional ventricular tachycardia.

Critical Toxicity: Pathophysiology of Hypokalemia in Digital Intoxication

Extracellular potassium and digoxin compete directly for the same binding site on the outer subunit of the sarcolemma Na+/K+ ATPase pump. Faced with a decrease in serum potassium concentration (hypokalemia), free molecular competition decreases, allowing minimal amounts of digoxin to bind massively and irreversibly to the pump, triggering the toxicity of the compound in the presence of normal levels of serum digoxin:

↓ [K⁺] serum ↑ Digoxin affinity for ATPase Digitalis intoxication at therapeutic levels

Management of severe digital poisoning involves immediate correction of intravenous potassium (if it is less than 5.0 mEq/L) and the use of specific antibodies of choice (antidigoxin Fab antibody fragments - DigiFab) in cases of lethal ventricular arrhythmias or acute refractory hyperkalemia.

Relevant Drug Interactions

P-Glycoprotein Inhibitors (Amiodarone, Verapamil, Quinidine, Spironolactone): They drastically reduce the renal clearance of digoxin by inhibiting its active tubular secretion mediated by P-gp, doubling its blood levels. They require a 50% reduction in the digoxin dose when starting any of these drugs.

Drugs that induce Hypokalemia (Furosemide, Thiazides): They indirectly increase the risk of lethal arrhythmias due to digoxin.

Epistemis is educational review material. It is not a medical device, does not diagnose or prescribe treatment, and does not replace formal medical training, current clinical guidelines, or professional clinical judgment.

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System
Cardiovascular

Cluster
Cardiac Glycosides / Positive Inotropics

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eGFR (mL/min/1.73 m²)	Digoxin Maintenance Dose Adjustment
> 60	Standard dose: 0.125 mg to 0.25 mg per day by mouth
30 - 59	Reduce dose: 0.125 mg per day or 0.0625 mg per day
15 - 29	0.0625 mg per day or 0.125 mg every other day (Monday, Wednesday, Friday)
< 15 or Dialysis	Avoid its use as much as possible. If essential, dose 0.0625 mg 2 to 3 times a week under strict control of blood levels (Narrow safety range)