eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Digitalis

Author: Donald Schreiber, MD, CM, Associate Professor of Surgery (Emergency Medicine), Stanford University School of Medicine
Contributor Information and Disclosures

Updated: Dec 2, 2009

Introduction

Background

The therapeutic properties of cardiac glycosides (eg, digoxin, a product of the foxglove plant) have been known since the days of the Roman Empire. The ancient Romans used red squill, a cardiac glycoside derived from the sea onion, as a diuretic and heart medicine. Cardiac glycosides are found in certain flowering plants such as oleander and lily-of-the-valley. Certain herbal dietary supplements also contain cardiac glycosides.

Physicians first studied digoxin in the 18th century. 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 had 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, the drug was introduced as treatment of atrial fibrillation. Only subsequently was the value of digitalis for the treatment of congestive heart failure (CHF) established.

The syndrome of digoxin toxicity was originally described in 1785 by Withering.

Pathophysiology

Digoxin's inotropic effect results from the inhibition of the sodium-potassium adenosine triphosphatase (NA⁺/K⁺ ATPase) pump. The subsequent rise in intracellular calcium (Ca⁺⁺) and sodium (NA⁺) coupled with the loss of intracellular potassium (K⁺) increases the force of myocardial muscle contraction (contractility), resulting in a net positive inotropic effect.

Digoxin also increases the automaticity of Purkinje fibers but slows conduction through the atrioventricular (AV) node. Cardiac dysrhythmias associated with an increase in automaticity and a decrease in conduction may result.

The relationship between digoxin toxicity and the serum digoxin level is complex; clinical toxicity results from the interactions between digitalis, various electrolyte abnormalities, and their combined effect on the Na⁺/K⁺ ATPase pump.

Cardiac glycoside toxicity from plants, such as oleander, foxglove, and lily-of-the-valley, is uncommon but potentially lethal. Case reports of toxicity from these sources implicate the preparation of extracts and teas as the usual culprit.

Frequency

United States

Approximately 0.4% of all hospital admissions, 1.1% of outpatients on digoxin, and 10-18% of nursing home patients develop toxicity.

In 2006, the American Association of Poison Control Centers reported an incidence of 2610 toxic digitalis exposures. The overall incidence of digoxin toxicity has decreased because of a number of factors including increased awareness of drug interactions, decreased use of digoxin to treat heart failure and arrhythmias, and the availability of accurate rapid radioimmunoassays to monitor drug levels. Although the number of digitalis exposures is far less than the incidence of calcium channel blocker toxicity (10,031 cases) or beta-blocker toxicity (18,253 cases), the mortality rate from digitalis toxicity is far higher with 22 deaths reported versus 13 deaths from calcium channel antagonists and only 4 deaths attributed to beta-blocker toxicity.¹

Cardiovascular drug poisoning including digitalis toxicity ranks as the third leading cause of death from all poisonings in 2006.

Data from the 2007 Annual Report of the American Association of Poison Control Centers is similar to previous data, with 2565 digitalis exposures reported. However, fatalities were lower, with 10 deaths reported.²

International

Approximately 2.1% of inpatients on digoxin and 0.3% of all admissions develop toxicity.

Mortality/Morbidity

• Morbidity is usually 4.6-10%; however, morbidity is 50% if the digoxin level is greater than 6 ng/mL.
• Mortality due to digoxin exposure varies with the population studied. Adult mortality depends on underlying comorbidity. In general, older people have a worse outcome than adults who, in turn, have a worse outcome than children.

Age

Advanced age (>80 y) is an independent risk factor and is associated with increased morbidity and mortality.

Clinical

History

• Constitutional symptoms (eg, weakness, fatigue)
• Cardiovascular
  • Palpitations
  • Syncope
  • Dyspnea
• Central nervous system
  • Confusion and somnolence
  • Dizziness without vertigo
  • Agitation, delirium, and hallucinations
  • Headache
  • Paresthesias and neuropathic pain
  • Seizures (extremely rare)
• Ocular
  • Disturbances of color vision with a tendency to yellow-green coloring
  • Blurred vision and diplopia
  • Halos and scotomas
  • Photophobia
• Gastrointestinal
  • Nausea, vomiting, anorexia, and diarrhea
  • Abdominal pain (uncommon)

Physical

Hemodynamic instability is related directly to the presence of a dysrhythmia or acute congestive heart failure (CHF).

• Cardiovascular findings on physical examination relate to the severity of CHF, dysrhythmias, or hemodynamic instability.
  • Digoxin toxicity may cause any dysrhythmia. Classically, dysrhythmias that are associated with increased automaticity and decreased AV conduction occur (ie, paroxysmal atrial tachycardia with 2:1 block, accelerated junctional rhythm, or bidirectional ventricular tachycardia [torsade de pointes], depicted in the images below).
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    Bidirectional tachycardia in a patient with digitalis toxicity.

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    Bidirectional tachycardia in a patient with digitalis toxicity.

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    Torsades de pointes.

    [ CLOSE WINDOW ]

    

    Torsades de pointes.

    
    {{mediacaption:1525555_2}}  
  • Premature ventricular contractions (PVCs) are the most common dysrhythmia. Bigeminy or trigeminy occurs frequently.
  • Sinus bradycardia and other bradyarrhythmias are very common. Slow atrial fibrillation with very little variation in the ventricular rate (regularization of the R-R interval) may occur.
  • First-degree heart block, second-degree AV block, complete AV dissociation, and third-degree heart block are also very common.
  • Rapid atrial fibrillation or atrial flutter is rare.
  • Ventricular tachycardia is an especially serious finding.
  • Cardiac arrest from asystole or ventricular fibrillation is usually fatal.
• Gastrointestinal symptoms are common, but the abdominal examination is usually nonspecific.
• Neurological findings are related to changes in sensorium or mental status. Lateralizing findings usually indicate another disease process.
• Visual changes occur, but the pupils are spared, and objective findings are few.
• Drug-induced fever does not occur.

Causes

• Deteriorating renal function, dehydration, electrolyte disturbances, or drug interactions usually precipitates chronic toxicity.
• Acute overdose or accidental exposure to plants containing cardiac glycosides may cause acute toxicity.
• Hypokalemia, hypernatremia, or hypomagnesemia increases the toxic cardiovascular effects of digoxin because of their depressive effects on the NA⁺/K⁺ ATPase pump.
  • Digoxin toxicity does not cause hypokalemia, but hypokalemia can worsen digoxin toxicity.
  • Hyperkalemia is the usual electrolyte abnormality precipitated by digoxin toxicity, primarily in the acute setting. Hyperkalemia may be associated with acute renal failure that subsequently precipitates digoxin toxicity. Chronic digoxin toxicity does not usually cause hyperkalemia.
• Acidosis depresses the Na⁺/K⁺ ATPase pump and may cause digoxin toxicity.
• Myocardial ischemia suppresses the Na⁺/K⁺ ATPase pump and independently alters myocardial automaticity. Digoxin toxicity is more likely in this setting.
• Erroneous dosing, especially in infants receiving parenteral digoxin, unfortunately, is a frequent cause of digoxin toxicity and is usually associated with high mortality.
• Hypothyroid patients are prone to digoxin toxicity secondary to decreased renal excretion and a smaller volume of distribution.
• Bioavailability varies depending on the drug formulation.
  • Lanoxin has 25% less bioavailability than Lanoxicaps.
  • Toxicity may occur by increasing bioavailability.
  • Certain antibiotics that suppress intestinal flora may increase absorption of digoxin.
• Drug interactions are one of the most common causes of digoxin toxicity.
  • Some medications directly increase digoxin plasma levels; other medications alter renal excretion or induce electrolyte abnormalities.
  • Drugs that have been reported to cause digoxin toxicity include the following:
    • Amiloride - May reduce the inotropic response to digoxin
    • Amiodarone - Reduces renal and nonrenal clearance of digoxin and may have additive effects on the heart rate
    • Benzodiazepines (alprazolam, diazepam) - Have been associated with isolated reports of digoxin toxicity
    • Beta-blockers (propranolol, metoprolol, atenolol) - May have additive effects on the heart rate; carvedilol may increase digoxin blood levels in addition to potentiating its effects on the heart rate
    • Calcium channel blockers - Diltiazem and verapamil increase serum digoxin levels; not all calcium channel blockers share this effect.
    • Cyclosporine - May increase digoxin levels, possibly due to reduced renal excretion
    • Erythromycin, clarithromycin, and tetracyclines - May increase digoxin levels
    • Propafenone - Increases digoxin level; effects are variable.
    • Quinidine - Increases digoxin level substantially but clinical effect is variable; related drugs such as hydroxychloroquine or quinine may also affect levels.
    • Propylthiouracil - May increase digoxin levels by reducing thyroid hormone levels
    • Indomethacin
    • Spironolactone - May interfere with digoxin assays; may directly increase digoxin levels; may alter renal excretion.
    • Hydrochlorothiazide
    • Furosemide and other loop diuretics
    • Triamterene
    • Amphotericin B - May precipitate hypokalemia and subsequent digoxin toxicity
    • Succinylcholine - Increased risk of dysrhythmias has been reported.
  • Herb/nutraceutical - Avoid ephedra (risk of cardiac stimulation); avoid natural licorice (causes sodium and water retention and increases potassium loss).
• Clinical digoxin toxicity represents a complex interaction between digoxin and various electrolyte and renal abnormalities. A patient with normal digoxin levels (0.5-2 ng/mL) but renal insufficiency or severe hypokalemia may have more serious cardiotoxicity than a patient with high digoxin levels and no renal or electrolyte disturbances.

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