Number 35, 2007
Cardiac toxicity

Mechanisms, manifestations, and management of digoxin toxicity

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Lionel G. Lelièvre¹, Philippe Lechat^2
1Pharmacochimie et Systèmes membranaires, Université Paris 7, Paris ²Service de Pharmacologie, Hôpital Pitié Salpêtrière, Université Pierre et Marie Curie, Paris, France
Correspondence: Prof. Lionel G. Lelièvre, Pharmacologie Transports Ioniques, Case 7124.EA.23 81, Tour 54/64, 5th floor, Université Paris 7, 2 Place Jussieu, 75251 Paris cedex 05 France. Tel: +33 1 44 27 57 03; fax: +33 1 44 27 69 66; e-mail: lelièvre@univ-paris-diderot.fr

Introduction
The mechanisms of action of digitalis (digoxin) in the human heart have been studied extensively, including the clinical and molecular basis of both its therapeutic and its toxic effects.

Molecular mechanisms of action of digoxin
Digoxin is a cardiac glycoside that binds to and inhibits sarcolemma-bound (Na⁺/K⁺-) Mg²⁺-ATPase^*. This ATPase catalyses both an active influx of 2 K⁺ ions and an efflux of 3 Na⁺ ions against their respective concentration gradients, the energy being provided by the hydrolysis of ATP. The inhibition induced by digoxin leads to an efflux of potassium from the cell and, in proportion to the extent of inhibition of the ATPase, an increase in internal sodium ion concentration ([Na⁺]) at the inner face of the cardiac membranes. This local accumulation of sodium causes an increase in free calcium concentrations via the Na⁺–Ca²⁺ exchanger. This free cellular calcium concentration ([Ca²⁺]) is responsible for the inotropic action of digoxin, secondary to the release of Ca²⁺ from the sarcoplasmic reticulum Figure 1 [1].

Manifestations of digoxin toxicity
Therapeutic effects of cardiac glycosides are observed in the presence of plasma concentrations between 1 and 2 ng/ml (about 2 nmol/L). Toxicity occurs at doses exceeding 3.1 ng/ml; its origin can be either a therapeutic overdose (5% of reported cases) or ingestion of a large quantity.
There are extracardiac and cardiac manifestations of digoxin toxicity. In 80% of the toxic episodes observed, anorexia is an early symptom of toxicity that can be hidden by vomiting that is directly related to the plasma concentration of digoxin. High concentrations of digoxin also affect color vision, and between 25 and 67% of patients have neurological problems, mainly headache and dizziness (vertigo).
Several other symptoms of digoxin toxicity have been described: significant arterial vasoconstriction, muscular and cutaneous pathologies (caused by hypersensitivity to cardiac glycosides), severe thrombocytopenia that disappears over a period of 7 days after withdrawal of digoxin, and interference with estrogen as a result of structural similarities that it shared with digoxin metabolites.
The cardiac manifestations of toxicity caused by digoxin are characterized by ‘abnormal’ rhythms and alterations in conduction. Atrial systolic tachycardia with atrioventricular blockade immediately evoke the typical digitalis-induced arrhythmias. Ectopic rhythms as a result of re-entry and increases in automatism lead to atrial flutter, atrial fibrillation, ventricular premature beats and ventricular tachycardia. These phenomena are the results of increased excitability of fibers and diminished conduction velocity at the level of the Tawara node.
Non paroxysmal junctional tachycardias are frequently observed. Redundant 3- or 4-multiform ventricular extra-systoles also represent a frequent manifestation, but this is a less specific criterion in the presence of previous cardiac impairment. Digoxin toxicity is clearly characterized when ventricular extra-systoles and atrioventricular block are associated symptoms. It is worthy of note that these manifestations are enhanced by pre-existing factors such as age, cardiomyopathies, plasma concentration of digitalis, and hyperkalemia (>6.5 mmol/L)

Management of digoxin toxicity
When the toxic effects of digoxin are associated with hypokalemia, the hydroelectrolytic imbalance can be corrected by intravenous perfusion of potassium chloride 40 mmol/L per hour, with electrocardiographic monitoring. Hyperkalemia can be corrected only by using digoxin-specific immunoglobulin fragments (Fab)^* that remove the drug from the Na⁺/K⁺ pumps and restore the potassium fluxes into the cells. Such antidigoxin Fab fragments represent a rapid and efficient treatment of this drug-induced toxicity. Prescribed in humans since 1976, this approach is used even in the presence of plasma concentrations of digoxin as high as 100 ng/ml (200 nmol/L). Typically, potassium concentrations are normalized in 1 h, by which time normal behavior is also partially restored; complete neutralization of toxicity occurs in 4 h.
For the treatment of arrhythmias, classical antiarrhythmic compounds – β-blockers, converting enzyme inhibitors, and vagolytic agents such as atropine – can be used (reviewed in [10]). Intracavitary ventricular stimulation can also be prescribed.
^* See glossary for definition of these terms.

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