eMedicine Specialties > Cardiology > Arrhythmias

Digitalis Toxicity

Author: Vinod Patel, MD, Medical Director, Jefferson Family Medicine Center; Clinical Assistant Professor, Department of Family Medicine, State University of New York at Buffalo
Coauthor(s): Paul Arthur James, MD, IAFP Endowed Chair in Rural Medicine, Associate Professor of Family Medicine, Department of Family Medicine, University of Iowa College of Medicine
Contributor Information and Disclosures

Updated: Dec 22, 2008

Introduction

Background

Native people in various parts of the world have used many plant extracts containing cardiac glycosides as arrow and ordeal poisons. The ancient Egyptians used squill as a medicine. The Romans employed it as a diuretic, heart tonic, emetic, and rat poison. Digitalis, or foxglove, was mentioned in AD 1250 in the writings of Welsh physicians. Fuchsius described it botanically 300 years later and gave it the name Digitalis purpurea.

William Withering published his classic account of foxglove and some of its medical uses in 1785, remarking upon his experience with digitalis. Indians in South America have used cardiac glycosides in their dart poisons. Digitalis toxicity was well known in previous centuries, and some have suggested that the toxic visual symptoms of digitalis may have played a role in Van Gogh's use of swirling greens and yellows.

During the early 20th century, as a result of the work of Cushny, Mackenzie, Lewis, and others, the drug was gradually recognized as specific for treatment of atrial fibrillation. Only subsequently was the value of digitalis for treatment of congestive heart failure (CHF) established. Cardiac glycosides enhances cardiac contractility and slows the conduction through the atrioventricular junction by increasing vagal tone.

In recent years, cardiac glycosides toxicity has been known to result from ingestion of some plants, including yellow oleander (Thevetia peruviana) and foxglove (D purpurea), and a similar toxidrome has been associated with the use of herbal dietary supplements.

Pathophysiology

Mechanism of action

The positive inotropic effect of digitalis has 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 ([Ca²⁺]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, in therapeutic concentrations, exerts no effect on the contractile proteins or on the interactions between them.

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 [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 pharmacological receptor for digitalis and that, when digitalis binds to these enzymes, it induces a conformational change that decreases active transport of sodium. Many studies have provided evidence that digitalis binds to ATPase in a specific and saturable manner and that the binding results in 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.

Electrophysiological effects

The electrophysiological effects of cardiac glycosides include (1) decreased resting potential (RP) or maximal diastolic potential (MDP), which slows the rate of phase-0 depolarization and conduction velocity, (2) decrease in action potential duration (APD), which results in increased responsiveness of fibers to electrical stimuli, and (3) 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.

Vasomotor effects

Digoxin and other cardiac glycosides cause direct vasoconstriction in the arterial and venous system through inhibition of the Na⁺/K⁺ -ATPase pump in vascular smooth muscle.

Alterations in cardiac rate and rhythm occurring in 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 as 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 both myocardial and nodal tissue, resulting in increased PR interval and atrioventricular (AV) block accompanied by decrease in QT interval.

In addition to these effects, the direct effect of digitalis on repolarization often is reflected in the 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—such as nonparoxysmal junctional tachycardia, extrasystole, premature ventricular contractions, ventricular flutter and fibrillation, atrial flutter and fibrillation, and bidirectional ventricular tachycardia—are due to enhanced automaticity, reentry, or both.

Bidirectional ventricular tachycardia is particularly characteristic of severe digitalis toxicity and results from alterations of intraventricular conduction, junctional tachycardia with aberrant intraventricular conduction or, on rare occasions, alternating ventricular pacemakers. Depression of the atrial pacemakers resulting in SA arrest also may be seen. Other features are SA block, AV block, and sinus exit block resulting from depression of normal conduction. Nonparoxysmal atrial tachycardia with block is associated with digitalis toxicity.

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 block of varying degrees, alone or with increased ventricular automaticity, are the most common manifestations of digoxin toxicity, occurring in 30-40% of patients with recognized digoxin toxicity. AV dissociation may occur because of suppression of the dominant pacemaker with escape of a subsidiary pacemaker or inappropriate acceleration of a ventricular pacemaker.

Frequency

United States

Approximately 0.4% of all hospital admissions are related to digitalis toxicity. Of people in nursing homes, 10-18% develop this toxicity. According to a large study published in 1990, definite digoxin toxicity occurred in 0.8% of patients with heart failure treated with digoxin.¹

International

Approximately 2.1% of inpatients are taking digoxin. Of all admissions, 0.3% of patients develop toxicity.

Mortality/Morbidity

• Incidence of digitalis toxicity has declined in recent years because of a decrease in digitalis usage, improvement in digoxin formulation with more predictable drug bioavailability, better understanding of pharmacokinetics, improved laboratory radioimmunoassay, increasing awareness in drug-to-drug interactions, increased appreciation for factors that can increase the risk of toxicity, and availability of other drugs to treat heart failure and techniques like catheter ablation therapy for supraventricular tachycardias. The morbidity and mortality rates associated with digitalis toxicity have remained constant over the past 5 years.
• According to the American Association of Poison Control Centers, of the patients reported in 1997 who developed cardiac glycoside toxicity, 34% demonstrated moderate or major morbidity, and 1% died.
• The lethal dose of most glycosides is approximately 5-10 times the minimal effective dose and only about twice the dose that leads to minor toxic manifestations.

Age

Older individuals with multiple comorbid conditions have lower tolerance of digitalis than younger individuals with few or no comorbid conditions, and they are prone to digitalis toxicity.

Clinical

History

• Withering recognized many of the signs of digitalis toxicity: "The foxglove, when given in very large and quickly repeated doses, occasions sickness, vomiting, purging, giddiness, confused vision, objects appearing green or yellow; increased secretion of urine, slow pulses, even as low as 35 in a minute, cold sweats, convulsions, syncope, death."
• Extracardiac symptoms
  • Central nervous system: Drowsiness, lethargy, fatigue, neuralgia, headache, dizziness, and confusion may occur.
  • Ophthalmic: Visual aberration often is an early indication of digitalis toxicity. Yellow-green distortion is most common, but red, brown, blue, and white also occur. Drug intoxication also may cause snowy vision, photophobia, photopsia, and decreased visual acuity.
  • GI: In acute and chronic toxicity, anorexia, nausea, vomiting, abdominal pain, and diarrhea may occur. Mesenteric ischemia is a rare complication of rapid intravenous infusion.
  • Many extracardiac toxic manifestations of cardiac glycosides are mediated neurally by chemoreceptors in the area postrema of the medulla.
  • History of dementia, medication noncompliance
• Cardiac symptoms
  • Palpitations
  • Shortness of breath
  • Syncope
  • Swelling of lower extremities
  • Bradycardia
  • Hypotension
• Pharmacy - Recent addition of new drugs, such as verapamil, diltiazem, erythromycin or tetracycline, that can elevate digoxin level

Physical

• General: Patient's mentation may change according to severity of digoxin toxicity, as well as associated comorbid conditions.
• Vital signs: Pulse may be irregular depending on arrhythmias secondary to atrial fibrillation or arising from the digoxin toxicity itself. Hypotension may be observed if patient has CHF or dehydration secondary to decreased oral intake.
• Neck: Findings include increased jugular venous pressure.
• Cardiovascular: Findings may relate to severity of CHF. Associated cardiomegaly may be identified.
• Respiratory: Sometimes, respiratory rate is increased. Basal crepitations are associated with CHF.
• GI: Enlarged liver is secondary to CHF (ie, hepatic congestion). Hepatojugular reflux is present.
• Neurological: Signs include changes in mental status.
• Extremities: Pedal edema is noted if patient has renal failure or decompensated CHF.

Causes

The most common precipitating cause of digitalis intoxication is depletion of potassium stores, which occurs often in patients with heart failure as a result of diuretic therapy and secondary hyperaldosteronism.

• Other causes include the following:
  • Advanced age
  • Myocardial infarction or ischemia
  • Hypothyroidism
  • Hypercalcemia
  • Renal insufficiency
• Also consider drug interactions. Drugs that have been reported to potentiate digoxin toxicity include the following:
  • Quinidine
  • Erythromycin
  • Verapamil, diltiazem, nifedipine
  • Captopril
  • Anticholinergic drugs
  • Ibuprofen
  • Amiodarone

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