Toxicology

Digoxin and cardiac glycosides

General overview

Digoxin and digitoxin are cardiac glycoside medications traditionally used in the management of several heart conditions. Their therapeutic actions mainly involve modifying cardiac contraction and electrical conduction.

Pharmaceutical forms

Cardiac glycoside preparations have included deslanoside, digoxin, digitoxin, and powdered digitalis. Digoxin has been marketed in products such as Lanoxin and Lanoxicaps, while digitoxin has appeared under several other brand names.

Animal sources

Certain species of Bufo toads contain naturally occurring substances such as bufogins and bufotoxins that produce effects similar to pharmaceutical cardiac glycosides.

Other sources

Cardiac glycoside–like substances have also been identified in some unregulated topical aphrodisiac products. Numerous plants contain similar compounds and can produce comparable toxicity.

Therapeutic uses

Digoxin and digitoxin have been used to control ventricular rate in atrial fibrillation, atrial flutter, and some forms of supraventricular tachycardia.

Use in heart failure

These medications have also been used to support cardiac output in selected patients with congestive heart failure.

Typical digoxin dosing

Historically, adult digoxin therapy could begin with divided loading doses followed by a lower daily maintenance dose. Exact dosing depends on the patient’s condition, kidney function, age, and other clinical factors.

Toxic dose

Serious and potentially fatal poisoning has occurred after ingestion of more than approximately 10 mg of digoxin in adults or more than 4 mg in children.

Cellular mechanism

Digoxin inhibits the sodium-potassium ATPase pump in cardiac cells. This causes intracellular sodium to rise and indirectly increases intracellular calcium, thereby strengthening myocardial contraction.

Effects on cardiac conduction

Digoxin also increases parasympathetic or vagal activity. This slows the heart rate, reduces conduction through the atrioventricular node, and increases the refractory period of the atrioventricular conduction system.

Frequency of poisoning

Exposure to cardiac glycosides is relatively common. Many cases produce mild effects, but unrecognized toxicity can lead to severe dysrhythmias and death.

Common causes

Significant poisoning may occur after intentional overdose, medication errors, excessive therapeutic dosing, or accumulation during chronic treatment.

Exposure in children

In infants, unexplained exposure may raise concern for inappropriate administration or neglect. In older children and adolescents, intentional ingestion should be considered when supported by the circumstances.

Cardiac risk factors

Patients with underlying structural or electrical heart disease may be more susceptible to dangerous dysrhythmias during cardiac glycoside toxicity.

Risk in older adults

Older patients often require smaller doses because kidney function and drug clearance may decline with age. They are also more likely to have medical conditions that increase susceptibility to toxicity.

Rate-slowing drug interactions

Concurrent use of beta blockers or calcium channel blockers can enhance bradycardia and atrioventricular conduction delay.

Drugs that increase glycoside concentrations

Medications such as quinidine, quinine, verapamil, diltiazem, amiodarone, erythromycin, and tetracycline may increase circulating digitalis concentrations.

Reduced renal clearance

Nifedipine, spironolactone, triamterene, and amiloride may reduce renal clearance of digoxin and therefore increase the potential for accumulation.

Additional medication interaction

Warfarin has historically been reported as a possible contributor to increased digoxin concentrations.

Kidney impairment

Renal failure reduces elimination of digoxin and significantly increases the risk of accumulation and toxicity.

Liver impairment

Digitoxin depends more heavily on hepatic metabolism than digoxin. Reduced liver function can therefore impair digitoxin elimination.

Electrolyte risk factors

Low potassium, elevated calcium, and low magnesium can increase myocardial sensitivity to cardiac glycosides and make dysrhythmias more likely.

Other physiologic risk factors

Increased sympathetic nervous system activity and hypothyroidism may also worsen the clinical effects of digitalis toxicity.

Pregnancy considerations

The historical source classified digoxin as FDA Pregnancy Category C under the former pregnancy classification system. This category indicated possible fetal risk based on animal data or insufficient controlled human studies.

Breast-feeding

Digoxin has not generally been considered an absolute contraindication during breast-feeding.

Diagnosis

Differential diagnosis

Other conditions can resemble cardiac glycoside poisoning, particularly when nausea, hypotension, or bradycardia is present.

Toxic causes with similar features

Possible toxicologic alternatives include poisoning from cardiotoxic plants, beta blockers, calcium channel blockers, and class I antiarrhythmic medications.

Non-toxic causes with similar features

Medical causes such as gastroenteritis, intestinal obstruction, myocardial ischemia, hyperkalemia, and other electrolyte disturbances should also be considered.

Early manifestations

Initial symptoms are often vague and may include general weakness, malaise, or nausea before more obvious cardiovascular abnormalities appear.

Progressive toxicity

As poisoning becomes more severe, disturbances in cardiac impulse formation and conduction become increasingly important.

Vital sign abnormalities

Patients may develop a slow heart rate, rapid heart rate, or low blood pressure depending on the type and severity of toxicity.

Visual disturbances

Visual symptoms may include blurred vision, reduced visual clarity, or abnormal color perception. Some patients describe colored halos around objects.

Bradycardia

A reduction in heart rate can result from increased vagal activity and slowed atrioventricular conduction.

Atrioventricular block

Different degrees of atrioventricular block may occur as toxicity interferes with conduction through the atrioventricular node.

Atrial tachycardia

Paroxysmal atrial tachycardia accompanied by conduction block is a classic rhythm disturbance associated with digoxin toxicity.

Ventricular conduction abnormalities

Intraventricular conduction delays and ventricular dysrhythmias may develop in more serious poisoning.

Heart failure

Cardiac glycoside toxicity can worsen cardiac function and may contribute to congestive heart failure in susceptible individuals.

Gastrointestinal symptoms

Nausea, vomiting, loss of appetite, and abdominal discomfort are common and may appear before significant cardiac manifestations.

Potassium elevation

Hyperkalemia frequently occurs in acute, severe digoxin overdose and may indicate significant sodium-potassium ATPase inhibition.

Potassium depletion

Low potassium is more commonly associated with chronic toxicity or concurrent diuretic treatment and can make the myocardium more sensitive to digoxin.

Neurologic symptoms

Severe toxicity may cause headache, weakness, drowsiness, hallucinations, or confusion.

Investigations

Serum digoxin concentration

Measurement of serum digoxin concentration is an important part of evaluating suspected toxicity. The historical therapeutic range cited in the source is approximately 0.5–2 ng/mL.

Serum digitoxin concentration

The historical therapeutic range given for digitoxin is approximately 18–22 ng/mL.

Interpretation of drug levels

A concentration within the usual therapeutic range does not completely exclude toxicity. Electrolyte abnormalities, especially hypokalemia, can increase sensitivity to cardiac glycosides.

Electrocardiogram

An electrocardiogram is essential because nearly every type of cardiac rhythm abnormality has been reported during cardiac glycoside poisoning.

Common ECG changes

Frequently described findings include prolongation of the PR interval and shortening of the corrected QT interval.

Characteristic rhythm abnormalities

Sinus bradycardia, atrioventricular block, and atrial or junctional tachydysrhythmias are strongly associated with clinically important toxicity.

Highly suggestive rhythms

Bidirectional ventricular tachycardia, paroxysmal atrial tachycardia with 2:1 block, and junctional tachycardia are particularly suggestive of digoxin poisoning.

Electrolyte testing

Serum potassium, calcium, and magnesium should be assessed because abnormalities in these electrolytes can significantly alter the severity of cardiac toxicity.

Kidney function testing

Blood urea nitrogen and creatinine should be measured because impaired kidney function can reduce digoxin clearance.

Significance of hyperkalemia

In acute overdose, significant hyperkalemia indicates severe poisoning and may support the need for digoxin-specific antibody therapy.

Significance of hypokalemia

Low potassium increases myocardial sensitivity to digoxin and can promote dangerous rhythm disturbances even when the serum drug concentration is not markedly elevated.

Calcium and magnesium abnormalities

High calcium and low magnesium may further predispose the patient to cardiac dysrhythmias.

Liver function testing

Liver function tests may be useful when digitoxin exposure is suspected because impaired hepatic function can slow its metabolism and increase serum concentrations.

Screening for coingestants

In intentional overdose, acetaminophen and salicylate levels may be measured to identify additional substances that were not initially reported.

Effect of digoxin immune Fab on testing

After digoxin immune Fab is administered, measured serum digoxin concentrations may appear markedly elevated because many laboratory assays detect both antibody-bound and free digoxin.

Digoxin-like immunoreactive substances

Naturally occurring digoxin-like substances can occasionally interfere with laboratory testing and produce an apparent digoxin concentration even without therapeutic digoxin exposure.

Situations associated with assay interference

These substances have been described particularly in newborns and, less commonly, in pregnancy or in patients with significant kidney or liver disease.

Treatment

General approach

Management focuses on stabilizing the patient, identifying dangerous cardiac abnormalities, correcting relevant electrolyte disturbances, and administering digoxin immune Fab when indicated.

Exposure assessment

The amount ingested, timing of exposure, product involved, and presence of any additional substances should be determined whenever possible.

Poison control consultation

Specialist toxicology advice should be obtained when dangerous cardiac dysrhythmias, altered mental status, or other serious manifestations are present.

Atypical clinical findings

Poison-control consultation is also appropriate when the patient’s symptoms do not match the expected pattern of cardiac glycoside poisoning or when another illness, medication interaction, or coingestant complicates management.

Referral for medical assessment

Evaluation in a health-care facility is appropriate when ingestion of more than approximately 2–3 mg of digoxin is suspected, when intentional poisoning is possible, or when clinical toxicity develops.

Reliability concerns

Medical evaluation is also warranted when the patient or caregiver cannot reliably provide observation or an accurate history.

Admission considerations

Patients with symptoms or newly developed ECG abnormalities generally require inpatient treatment, often with intensive cardiac monitoring.

Historical out-of-hospital decontamination

The historical source described induced vomiting with ipecac within 1 hour of an acute ingestion in selected alert patients when medical evaluation would be delayed.

Historical in-hospital decontamination

The source also described gastric emptying procedures for selected patients presenting soon after a large ingestion or with serious manifestations.

Activated charcoal

A single dose of activated charcoal was described following substantial recent ingestion when clinically appropriate and when airway protection could be ensured.

Antidote treatment

Digoxin immune Fab

Digoxin immune Fab consists of antibody fragments that bind circulating digoxin and related cardiac glycosides, reducing the amount of active drug available to interact with cardiac tissue.

Cardiovascular instability

Use of digoxin immune Fab is indicated when poisoning causes serious cardiovascular instability, including clinically significant hypotension, symptomatic bradycardia, or potentially unstable dysrhythmias.

Rapidly worsening toxicity

Antibody treatment should also be considered when gastrointestinal or cardiovascular manifestations are progressing rapidly.

Severe hyperkalemia

A serum potassium concentration greater than approximately 5.5 mEq/L in acute digoxin poisoning is a major indicator of severe toxicity and has historically been considered an indication for digoxin immune Fab.

Cardiac arrest

Digoxin immune Fab may still provide benefit during cardiac arrest caused by cardiac glycoside poisoning when treatment can be administered promptly.

Empirical dosing

The historical source describes empirical administration of multiple vials in critically ill patients with strongly suspected digoxin poisoning when a serum concentration is not yet available.

Dose calculation

The precise dose of digoxin immune Fab depends on factors such as the estimated amount ingested, measured serum digoxin concentration, body weight, and severity of clinical toxicity.

Adjunctive treatment

Potassium replacement

Low potassium should be corrected cautiously because hypokalemia increases the myocardium’s sensitivity to cardiac glycosides.

Treatment of dysrhythmias

Digoxin immune Fab is the preferred treatment when dangerous rhythm disturbances are directly related to cardiac glycoside poisoning.

Ventricular dysrhythmias

Lidocaine and phenytoin have historically been used to manage ventricular rhythm disturbances associated with digitalis toxicity.

Supraventricular dysrhythmias

Magnesium or phenytoin may be considered for selected supraventricular tachydysrhythmias when clinically appropriate.

Bradycardia management

Atropine may be used for clinically significant bradycardia while definitive treatment is being arranged.

Circulatory support

Vasopressors may be necessary during initial stabilization of patients with severe hypotension or shock, particularly before digoxin immune Fab becomes available or takes effect.

Therapies to avoid

The historical source cautions that procainamide, quinidine, disopyramide, and propranolol may aggravate atrioventricular conduction block in digitalis poisoning.

Historical calcium warning

The original source advises against calcium administration in severe digoxin toxicity because of concern for worsening cardiac excitability. Management of calcium abnormalities in suspected digoxin poisoning should follow current toxicology guidance.

Follow-up

Cardiac monitoring

Symptomatic patients should undergo continuous cardiac rhythm monitoring because potentially serious dysrhythmias may appear or change rapidly.

Hemodynamic monitoring

Blood pressure and overall circulatory status should be followed closely, particularly in patients with significant bradycardia, tachydysrhythmia, or shock.

Potassium monitoring

Serum potassium should be checked repeatedly during significant poisoning because potassium abnormalities can change as treatment progresses.

Expected recovery

Complete recovery is common when toxicity is recognized and treated promptly, although the patient’s underlying cardiac or systemic disease can complicate the clinical course.

Complications of severe poisoning

Prolonged hypotension or inadequate oxygen delivery may result in secondary organ injury even after the direct effects of digoxin have been reversed.

Response to digoxin immune Fab

Clinical improvement can occur relatively rapidly after appropriate digoxin immune Fab treatment, particularly when severe shock, hypoxia, or another toxic exposure has not already produced complications.

Emergency department discharge

Patients who remain asymptomatic, have a non-toxic digoxin concentration, normal electrolytes, and a normal ECG may be considered for discharge after an appropriate observation period and any necessary decontamination.

Observation period

The historical source describes approximately 6 hours of observation before discharge in otherwise stable patients following acute exposure.

Hospital discharge

Hospitalized patients may be discharged after cardiac abnormalities and other toxic manifestations have resolved or stabilized sufficiently for safe outpatient care.

Psychiatric assessment

Mental health evaluation should be considered when the exposure was deliberate or when self-harm is suspected.

Clinical pitfalls

Nonspecific presentation

Digitalis toxicity may initially resemble many other illnesses because early manifestations such as nausea, weakness, or confusion are nonspecific.

Therapeutic levels do not exclude toxicity

Patients can experience clinically significant digitalis toxicity despite serum digoxin concentrations that fall within the usual therapeutic range, particularly when electrolyte abnormalities or interacting medications are present.

Delayed treatment

Significant cardiac glycoside poisoning can deteriorate rapidly, making prompt recognition and treatment important.

Availability of antidote

Facilities treating severe digoxin poisoning need timely access to adequate quantities of digoxin immune Fab because insufficient availability may delay definitive therapy.

Recurrent toxicity

Clinical toxicity may recur after digoxin immune Fab treatment, particularly in patients with impaired kidney function or when the administered antibody dose is insufficient.

Classification

ICD-9-CM 972 refers to poisoning by substances that primarily affect the cardiovascular system.