The incidence of digitalis toxicity has declined in recent years, due to decreased use of this drug along with improved technology for monitoring of drug levels and increased awareness of drug interactions. Nevertheless, cardiac glycoside toxicity continues to be a problem in the United States because of the wide use of digoxin (a preparation of digitalis) and its narrow therapeutic window.

Digoxin and other cardiac glycosides cause direct vasoconstriction in the arterial and venous system in vascular smooth muscle. The positive inotropic effect of digitalis has the following 2 components:

• Direct inhibition of membrane-bound sodium- and potassium-activated adenosine triphosphatase (Na ⁺/K ⁺ -ATPase), which leads to an increase in the intracellular concentration of calcium ([Ca ²⁺]i)
• Associated increase in a slow inward calcium current (iCa) during the action potential (AP); this current is the result of movement of calcium into the cell, and it contributes to the plateau of the AP

Digitalis glycosides bind specifically to Na⁺/K⁺ -ATPase, inhibit its enzymatic activity, and impair active transport of extruding sodium and transport of potassium into the fibers (3:2 ratio). As a result, intracellular sodium ([Na⁺]i) gradually increases, and a gradual, small decrease in intracellular potassium ([K⁺]i) occurs.

Cardiac fiber calcium [Ca²⁺]i is exchanged for extracellular sodium (3:1 ratio) by a transport system that is driven by the concentration gradient for these ions and the transmembrane potential. Increase in [Na⁺]i is related crucially to the positive inotropic effect of digitalis.

In addition, by a mechanism that is not defined clearly, the increase in [Ca²⁺]i increases the peak magnitude of iCa; this change parallels the positive inotropic action. The change in iCa is a consequence of the increase in [Ca²⁺]i and not of the increase in [Na⁺]i. Thus, more calcium is delivered during the plateau of each AP to activate each contraction.

A fall in intracellular pH accompanies the digoxin-induced increase in [Ca²⁺] i, which leads to activation of a sodium/hydrogen exchange pump. This results in extrusion of hydrogen, an increase in [Na⁺]i, and greater inotropy.

The mechanism described assumes that Na⁺/K⁺ -ATPase is the pharmacologic receptor for digitalis and that when digitalis binds to these enzymes, it induces a conformational change that decreases active transport of sodium. Digitalis apparently binds to ATPase in a specific and saturable manner, producing a conformational change of the enzyme such that the binding site for digitalis probably is on the external surface of the membrane. Furthermore, the magnitude of the inotropic effect of digitalis is proportional to degree of inhibition of the enzyme.

Digitalis, in therapeutic concentrations, exerts no effect on the contractile proteins or on the interactions between them.

Electrophysiologic effects

The electrophysiological effects of cardiac glycosides include the following :

• Decreased resting potential (RP) or maximal diastolic potential (MDP), which slows the rate of phase-0 depolarization and conduction velocity
• Decrease in action potential duration (APD), which results in increased responsiveness of fibers to electrical stimuli
• Enhancement of automaticity, which results from an increase in the rate of phase 4 depolarization and from delayed after-depolarization

In general, cardiac glycosides slow conduction and increase the refractory period in specialized cardiac conducting tissue by stimulating vagal tone. Digitalis has parasympathetic properties, which include hypersensitization of carotid sinus baroreceptors and stimulation of central vagal nuclei.

Digoxin also appears to have variable effects on sympathetic tone, depending on the specific cardiac tissue involved.

Dosage and toxicity

The therapeutic daily dose of digoxin ranges from 5-15 mcg/kg. The absorption of digoxin tablets is 70-80%; its bioavailability is 95%. The kidney excretes 60-80% of the digoxin dose unchanged.

The onset of action after oral (PO) administration occurs in 30-120 minutes; the onset of action with intravenous (IV) administration occurs in 5-30 minutes. The peak effect with PO dosing is 2-6 hours, and that with IV dosing is 5-30 minutes. Only 1% of the total amount of digoxin in the body is in the serum; of that amount, approximately 25% is protein bound.

Digoxin has a large volume of distribution, being 6-10 L/kg in adults, 10 L/kg in neonates, and as much as 16L/kg in infants and toddlers. At therapeutic levels, the elimination half-life is 36 hours. In acute digoxin intoxication in toddlers and children, the average plasma half-life is 11 hours. With acute intoxication, plasma concentrations extrapolated to time zero are lower in toddlers than in infants and older children because of their increased volume of distribution and clearance.

The lethal dose of digoxin is considered to be 20-50 times the maintenance dose taken at once. In healthy adults, a dose of less than 5 mg seldom causes severe toxicity, but a dose of more than 10 mg is almost always fatal. In the pediatric population, the ingestion of more than 4 mg or 0.3 mg/kg portends serious toxicity. However, plasma concentration does not always correlate with the risk of toxicity.

Digoxin in pregnancy

Digoxin is used widely in the acute management and prophylaxis of fetal paroxysmal supraventricular tachycardia, as well as in rate control of atrial fibrillation. It is an FDA pregnancy category C drug. An increased digoxin dosage may be necessary during pregnancy because of enhanced renal clearance and expanded blood volume.

No series has been published regarding toxicity in the pregnant woman. Digoxin-specific Fab fragments can be used in pregnancy with the caveat that careful monitoring of the fetus must be maintained. Fetal myocardium has a higher resistance to the toxic effects of digitalis.

Dysrhythmias

Alterations in cardiac rate and rhythm from digitalis toxicity may simulate almost every known type of dysrhythmia. Although no dysrhythmia is pathognomonic for digoxin toxicity, toxicity should be suspected when evidence of increased automaticity and depressed conduction is noted. Underlying these dysrhythmias is a complex influence of digitalis on the electrophysiologic properties of the heart through the means already discussed, as well as via the cumulative results of the direct, vagotonic, and antiadrenergic actions of digitalis.

The effects of digoxin vary with the dose and differ depending on the type of cardiac tissue involved. The atria and ventricles exhibit increased automaticity and excitability, resulting in extrasystoles and tachydysrhythmias. Conduction velocity is reduced in myocardial and nodal tissue, resulting in increased PR interval and AV block accompanied by a decrease in the QT interval.

In addition to these effects, the direct effect of digitalis on repolarization often is reflected in the electrocardiogram (ECG) by ST segment and T-wave forces opposite in direction to the major QRS forces. The initial electrophysiologic manifestation of digitalis effects and toxicity usually is mediated by increased vagal tone.

Early in acute intoxication, depression of sinoatrial (SA) or AV nodal function may be reversed by atropine. Subsequent manifestations are the result of direct and vagomimetic actions of the drug on the heart and are not reversed by atropine.

Ectopic rhythms are due to enhanced automaticity, reentry, or both, and may include the following:

• Nonparoxysmal junctional tachycardia
• Extrasystole
• Premature ventricular contractions
• Ventricular flutter and fibrillation
• Atrial flutter and fibrillation
• Bidirectional ventricular tachycardia

Bidirectional ventricular tachycardia is particularly characteristic of severe digitalis toxicity and results from alterations in intraventricular conduction, junctional tachycardia with aberrant intraventricular conduction, or, on rare occasions, alternating ventricular pacemakers.

The following features may also be seen:

• Depression of the atrial pacemakers, resulting in SA arrest
• SA block
• AV block
• Sinus exit block resulting from depression of normal conduction
• Nonparoxysmal atrial tachycardia with block

When conduction and the normal pacemaker are both depressed, ectopic pacemakers may take over, producing atrial tachycardia with AV block and nonparoxysmal automatic AV junctional tachycardia. Indeed, AV junctional blocks of varying degrees, alone or with increased ventricular automaticity, are the most common manifestations of digoxin toxicity, occurring in 30-40% of cases. AV dissociation may result from suppression of the dominant pacemaker with escape of a subsidiary pacemaker or inappropriate acceleration of a ventricular pacemaker.

Arrhythmias can cause inadequate tissue perfusion, with resultant central nervous system (CNS) and renal complications, such as the following:

• Hypoxic seizures
• Encephalopathies
• Loss of vasoregulation
• Acute tubular necrosis

Hyperkalemia is the major electrolytic complication in acute, massive digoxin poisoning. In pediatric patients, hyperkalemia can be a complication of acute toxicity.

Etiology