Digitalis Toxicity 

Cardiac glycoside toxicity continues to be a problem in the United States because of the wide availability of digoxin (a preparation of digitalis) and a narrow therapeutic window. Digitalis is a plant-derived cardiac glycoside commonly used in the treatment of congestive heart failure (CHF), atrial fibrillation, and reentrant supraventricular tachycardia.^{[1, 2]} Digoxin is the only available preparation of digitalis in the United States. (See Etiology and Epidemiology.)

Cardiac glycosides are found in certain flowering plants, such as oleander and lily-of-the-valley. Certain herbal dietary supplements also contain cardiac glycosides. Indigenous 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. He recognized many of the signs of digitalis toxicity, noting, "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." (See Presentation and Workup.)

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 CHF established. Cardiac glycosides enhance cardiac contractility and slow conduction through the atrioventricular (AV) junction by increasing vagal tone. (See Etiology.)^[3]

Cardiac glycoside toxicity has been known to result from ingestion of some plants, including yellow oleander (Thevetia peruviana) and foxglove, and a similar toxidrome has been associated with the use of herbal dietary supplements.

Digoxin is among the top 50 prescribed drugs in the United States.^[4] Cardiac glycosides account for 2.6% of toxic plant exposures in the United States.^{[5, 6]} Most of these exposures are in children. (See Epidemiology.)^[6]

Digoxin-specific fragment antigen-binding (Fab) antibody fragments have contributed significantly to the improved morbidity and mortality of toxic patients since their approval in 1986 by the US Food and Drug Administration (FDA). (See Prognosis, Treatment, and Medication.)

Mechanism of action

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 ([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 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 pharmacologic 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.

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 (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.^[7]

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.

Electrocardiographic/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.

Dosage and toxicity

The therapeutic daily dose of digoxin ranges from 5-15mcg/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 by 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 6-10L/kg in adults, 10L/kg in neonates, and as much as 16L/kg in infants and toddlers. At therapeutic levels, the elimination half-life is 36 hours with renal excretion. 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 5mg seldom causes severe toxicity, but a dose of more than 10mg is almost always fatal. In the pediatric population, the ingestion of more than 4mg or 0.3mg/kg portends serious toxicity. However, plasma concentration does not always correlate with the risk of toxicity.^[8]

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 a category C drug. 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 an increased resistance to the toxic effects of digitalis.

Patient education

Increase patient awareness about the symptoms of digitalis toxicity. In addition, educate patients about drug interactions and about maintaining adequate hydration. Parents of pediatric patients should be educated about good home childproofing and preventive measures.

For patient education information, see the First Aid and Injuries Center and the Mental Health Center, as well as Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

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 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—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 in 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.

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 digitoxin poisoning. In pediatric patients, hyperkalemia can be a complication of acute toxicity.

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.

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.

Deteriorating renal function, dehydration, electrolyte disturbances, or drug interactions usually precipitate chronic toxicity. Acute overdose or accidental exposure to plants containing cardiac glycosides may cause acute toxicity.

Erroneous dosing, especially in infants receiving parenteral digoxin, is a frequent cause of digoxin toxicity and is usually associated with high mortality.

Toxicity may also occur via increased bioavailability. Bioavailability varies depending on the drug formulation. For example, Lanoxin has 25% less bioavailability than Lanoxicaps. Certain antibiotics that suppress intestinal flora may increase absorption of digoxin.

Acute, nontherapeutic overdose—unintentional, suicidal, or homicidal—can cause toxicity. Other causes of digitalis toxicity include the following:

• Advanced age
• Myocardial infarction or ischemia
• Hypothyroidism
• Hypercalcemia
• Renal insufficiency^[9]
• Hyperthyroidism
• Hypoxemia
• Alkalosis
• Acidosis - Depresses the Na⁺/K⁺ ATPase pump and may cause digoxin toxicity
• Myocardial disease

Myocardial ischemia suppresses the Na⁺/K⁺ ATPase pump and independently alters myocardial automaticity. Digoxin toxicity is more likely in this setting.

Hypothyroid patients are prone to digoxin toxicity secondary to decreased renal excretion and a smaller volume of distribution.

Electrolytes

Hypomagnesemia, hypercalcemia, hypernatremia, and hypokalemia can aggravate toxicity.^[10] Hypokalemia is usually observed with chronic toxicity or in patients taking diuretics; it reduces the rate of Na⁺/K⁺ ATPase pump turnover and exacerbates pump inhibition due to digitalis.

Hyperkalemia can also worsen toxicity. In pediatric patients, hyperkalemia is usually a complication of acute toxicity rather than a cause; however, preexisting hyperkalemia increases the risk of morbidity and mortality.

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.

Medications

Some medications directly increase digoxin plasma levels; other medications alter renal excretion or induce electrolyte abnormalities.^[11] 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 and 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, and 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)

Occurrence in the United States

Approximately 0.4% of all hospital admissions are related to digitalis toxicity, while about 1.1% of outpatients on digoxin and 10-18% of people in nursing homes 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.^[12]

In 2006, the American Association of Poison Control Centers (AAPCC) reported an incidence of 2610 toxic digitalis exposures. The overall incidence of digoxin toxicity has decreased due to 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 was far less than the incidence of calcium channel-blocker toxicities (10,031 cases) or beta-blocker toxicities (18,253 cases), the mortality rate from digitalis toxicity was far higher, with 22 deaths reported versus 13 deaths from calcium channel antagonists and 4 deaths attributed to beta-blocker toxicity.^[13]

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

Data from the 2007 annual AAPCC report was similar to previous data, with 2565 digitalis exposures reported. However, fatalities were lower, with 10 deaths reported.^[14]

International occurrence

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

Sex-related demographics

Pediatric poisonings from any substance are more common in males than in females.^{[5, 6]} However, for digoxin toxicity, a Netherlands study found no difference in incidence between pediatric males and females.^[15] The adult literature suggests that women may be more susceptible to adverse effects than are men.^{[15, 16]}

Age-related demographics

Advanced age (>80 y) is an independent risk factor for digitalis toxicity, being associated with increased morbidity and mortality. Older individuals with multiple comorbid conditions have a lower digitalis tolerance than do younger individuals with few or no comorbid conditions.

Manifestations of digitalis toxicity vary depending on age. For instance, ventricular ectopy is most prevalent in older patients; conduction defects and supraventricular ectopic rhythms are most prevalent in younger patients. Children (≤19 y) account for almost 80% of plant exposures and 20% of drug toxicity/poisonings reported to the AAPCC.^[6] In most of these cases, the child was younger than 6 years. One study suggests that adolescents are more susceptible to digoxin on a mg/kg basis.^[17]

In 1999, the AAPCC reported approximately 3000 pediatric poisonings associated with cardiac glycoside.^[5] Of these, most were plant ingestions (66%) and digoxin exposures (33%, including therapeutic errors and intentional and unintentional ingestions). The number of AAPCC reported cases decreased in 2008 to 1000 plant exposures and 300 digoxin poisonings.^[6] Although the number of reporting poison centers decreased in 2008, this number appears to be a true decline of poisonings related to cardiac glycoside.

Prognosis in digitalis toxicity is poor with increasing age and associated comorbid conditions. Morbidity and mortality rates increase if the patient has a new dysrhythmia, advanced AV block, or other significant ECG abnormality.

Incidence of digitalis toxicity has declined because of a decrease in digitalis usage, improvement in digoxin formulation with more predictable drug bioavailability, better understanding of pharmacokinetics, improved laboratory radioimmunoassay, increased awareness in drug-to-drug interactions,^[11] 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 few years.

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.

Morbidity is usually 4.6-10%; however, morbidity is 50% if the digoxin level is greater than 6ng/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 other adults, who, in turn, have a worse outcome than children.

In 2008, approximately 1 pediatric fatality occurred in 1300 cardiac glycoside exposures reported to poison control centers.^[6] Overall, morbidity varies from study to study. Combined adult and pediatric data reveal that exposures to cardiac glycoside toxic plants cause no morbidity in most cases. The 2008 AAPCC report had follow-up data for 518 patients exposed to digitalislike plants. Of these patients, 509 suffered little to no clinical effect, 17 suffered moderate effects, and only 1 suffered major effects. There were no deaths. Of the data available for 1044 patients with digoxin poisoning, 422 suffered little to no effect, 490 suffered moderate effects, and 115 suffered major effects. There were 17 deaths, only 1 of which was pediatric.