Cardiac glycosides and related cardenolides are found in several plants, including digitalis, oleander, foxglove, Cerbera spp (pong pong), lily of the valley, red squill, and dogbane, and in toad venom (bufadienolides, Bufo species), which may be found in some Chinese herbal medications and herbal aphrodisiacs. Cardiac glycosides are used therapeutically in tablet form as digoxin and digitoxin. Digoxin is also available in liquid-filled capsules with greater bioavailability.

1. Cardiac glycosides inhibit the function of the sodium-potassium-ATPase pump. After acute overdose, this results in hyperkalemia (with chronic intoxication, the serum potassium level is usually normal or low owing to concurrent diuretic therapy).
2. Direct effects and potentiation of vagal tone result in slowing of the sinus rate and decreased sinus and atrioventricular (AV) node conduction velocity.
3. Increased atrial and ventricular automaticity occurs because of accumulation of intracellular calcium, enhanced diastolic depolarization, and development of afterdepolarizations. These effects are augmented by hypokalemia and hypomagnesemia.
4. Pharmacokinetics. The bioavailability of digoxin ranges from 60% to 80%; for digitoxin, more than 90% is absorbed. The volume of distribution (Vd) of digoxin is very large (5-10 L/kg), whereas for digitoxin the Vd is small (~0.5 L/kg). Peak effects occur after a delay of 6-12 hours due to slow myocardial uptake. The elimination half-life of digoxin is 30-50 hours, and is dependent on renal function. The elimination of digitoxin is via the liver; its half-life is 5-8 days (owing to enterohepatic recirculation).
5. Drug interactions. A number of drugs that are often co-administered with digitalis inhibit its metabolism and/or its cellular transport (via P-glycoprotein), increasing serum levels, and may induce toxicity. These include amiodarone, verapamil, diltiazem, quinidine, macrolide antibiotics, and others.

Acute ingestion of as little as 1 mg of digoxin in a child or 3 mg of digoxin in an adult can result in serum concentrations well above the therapeutic range. More than these amounts of digoxin and other cardiac glycosides may be found in just a few leaves of oleander or foxglove. Generally, children appear to be more resistant than adults to the cardiotoxic effects of cardiac glycosides.

Intoxication may occur after acute accidental or suicidal ingestion or with chronic therapy. Signs and symptoms depend on the chronicity of the intoxication.

1. With acute overdose, nausea, vomiting, hyperkalemia, and cardiac arrhythmias are often seen. Bradyarrhythmias include sinus bradycardia, sinoatrial arrest, second- or third-degree AV block, and asystole. Tachyarrhythmias include paroxysmal atrial tachycardia with AV block, accelerated junctional tachycardia, ventricular bigeminy, ventricular tachycardia, bidirectional ventricular tachycardia, and ventricular fibrillation.
2. With chronic intoxication, nausea, anorexia, abdominal pain, visual disturbances (flashing lights, halos, green-yellow perceptual impairment), weakness, fatigue, sinus bradycardia, atrial fibrillation with slow ventricular response rate or junctional escape rhythm, and ventricular arrhythmias (ventricular bigeminy or trigeminy, ventricular tachycardia, bidirectional tachycardia, and ventricular fibrillation) are common. Accelerated junctional tachycardia and paroxysmal atrial tachycardia with block are seen frequently. Hypokalemia and hypomagnesemia from chronic diuretic use may be evident and appear to worsen the tachyarrhythmias. Mental status changes are common in the elderly and include confusion, depression, and hallucinations.

Is based on a history of recent overdose or characteristic arrhythmias (eg, bidirectional tachycardia and accelerated junctional rhythm) in a patient receiving chronic therapy. Hyperkalemia suggests acute ingestion but also may be seen with very severe chronic poisoning. Serum potassium levels higher than 5.5 mEq/L are associated with severe poisoning, with the extent of hyperkalemia a predictor of mortality.

1. Specific levels. Therapeutic levels of digoxin are 0.5-1 ng/mL, and those of digitoxin are 10-30 ng/mL. (1 ng digoxin = 1.28 nmol)
   1. Stat serum digoxin and/or digitoxin levels are recommended, although they may not correlate accurately with the severity of intoxication. This is especially true after acute ingestion, when the serum level is high for 6-12 hours before tissue distribution is complete. Serum levels taken more than 6 hours after ingestion are better correlated with digoxin effects.
   2. After use of digitalis-specific antibodies, the immunoassay digoxin level is falsely markedly elevated.
   3. The presence of human anti-mouse antibodies may falsely elevate digoxin levels in some patients if older immunoassays are used. Levels as high as 45.9 ng/mL have been reported.
   4. Even in the absence of digoxin use, false-positive digoxin can also occur for some immunoassays for selected patient populations (uremia, hypertension, liver disease, and preeclampsia) owing to the presence of digoxin-like immunoreactive factor (DLIF).
2. Other useful laboratory studies include electrolytes, BUN, creatinine, serum magnesium, cardiac troponin, and ECG and ECG monitoring.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary.
   2. Monitor the patient closely for at least 12-24 hours after significant ingestion because of delayed tissue distribution.
   3. Treat hyperkalemia with digoxin-specific antibodies (see below); calcium (calcium gluconate 10%, 10-20 mL or 0.2-0.3 mL/kg, or calcium chloride 10%, 5-10 mL or 0.1-0.2 mL/kg, slowly IV); sodium bicarbonate, 1 mEq/kg; glucose, 0.5 g/kg IV, with insulin, 0.1 U/kg IV; and/or sodium polystyrene sulfonate, 0.5 g/kg orally.
      1. Note: Although it has been widely recommended that calcium be avoided in patients with cardiac glycoside toxicity because of concern that it will worsen ventricular arrhythmias, this warning is based on old and weak case reports and is not substantiated by animal studies. Calcium is the drug of first choice for life-threatening cardiac toxicity due to hyperkalemia.
      2. Mild hyperkalemia may actually protect against tachyarrhythmias.
   4. Hypokalemia and hypomagnesemia should be corrected, as these may contribute to cardiac toxicity.
   5. Treat bradycardia or heart block with atropine, 0.5-2 mg IV and consider digoxin-specific antibodies (see below) if available. Temporary transvenous cardiac pacemaker (or isoproterenol infusion) may be needed for persistent symptomatic bradycardia, but can trigger serious arrhythmias in patients with digitalis toxicity, and are only recommended after failure or unavailability of digoxin-specific antibodies.
   6. Ventricular tachyarrhythmias may respond to correction of low potassium or magnesium. Lidocaine and phenytoin have been used, but digoxin-specific antibody is the preferred treatment for life-threatening arrhythmias. Avoid quinidine, procainamide, and other type Ia or type Ic antiarrhythmic drugs.
2. Specific drugs and antidotes. Fab fragments of digoxin-specific antibodies are highly effective in reversing digoxin toxicity and are indicated for significant poisoning. This includes hyperkalemia (>5 mEq/L), symptomatic arrhythmias, high-degree AV block, ventricular arrhythmias, and hemodynamic instability. Digoxin antibodies should also be considered in digoxin-toxic patients with renal failure and for prophylactic treatment in a patient with massive oral overdose and high serum levels. Digoxin antibodies rapidly bind to digoxin and, to a lesser extent, digitoxin and other cardiac glycosides. The inactive complex that is formed is excreted rapidly in the urine. Details of dose calculation and infusion rate are given on p 519.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
4. Enhanced elimination
   1. Because of its large volume of distribution, digoxin is not effectively removed by dialysis or hemoperfusion. Repeat-dose activated charcoal may be useful in patients with severe renal insufficiency, in whom clearance of digoxin is markedly diminished.
   2. Digitoxin has a small volume of distribution and also undergoes extensive enterohepatic recirculation, and its elimination can be markedly enhanced by repeat-dose charcoal or cholestyramine.