Digoxin: Toxicity

Digoxin belongs to a class of drugs known as cardiac glycosides that (1) improves contractility and (2) decreases conduction velocity at the AV node. Clinically, given the above therapeutic benefits, digoxin is used to treat heart failure with reduced ejection fraction (especially in patients with corresponding atrial fibrillation or have symptoms non-responsive to ACE inhibitors, beta blockers, and diuretics) and arrhythmias (such as atrial fibrillation, atrial flutter, and PSVT). Unfortunately, the therapeutic window for digoxin is low, resulting in the possibility of digoxin toxicity.

Mechanism of Action of Digoxin:

• Reversible inhibition of sarcolemmal sodium-potassium-ATPase pump (resulting in increase in intracellular sodium and decrease in intracellular potassium)
• This indirectly causes calcium concentrations inside the sarcolemmal reticulum to increase, as intracellular sodium increases causing the sodium-calcium-exchanger drive less sodium out of the cell
• Increases vagal tone, decreasing conduction through SA and AV node

Clinical manifestations

• Cardiac manifestations, particularly arrhythmias due to increases in vagal tone (most commonly PVCs)
• Both acute and chronic toxicity may also result in GI symptoms (nausea, vomiting, abdominal pain, anoxeria), neurologic symptoms (confusion, weakness), and visual disturbances (classically xanthopsia, where objects appear yellow, however may also manifest as diplopia, blindness, decreased visual acuity, or photophobia)
• Acute intoxication may lead to hyperkalemia (from inhibition of sodium-potassium-ATPase pump)

Factors Contributing to Digoxin Toxicity:

• Hypokalemia (further inhibition of sodium-potassium-ATPase pump, may be exacerbated by diuretic administration)
• Other drugs (may lead to alteration of p-glycoprotein, an efflux pump that excretes digoxin into the intestine or proximal renal tubule)
• Renal dysfunction

Management and Treatment:

• Airway, breathing, circulation
• Obtain serum digoxin concentration, serum potassium concentration, creatinine and BUN, and serial EKGs
• Potassium replacement (if hypokalemia present)
• Atropine (0.5 mg IV in adults, 0.02 mg/kg IV in children, minimum dose of 0.1 mg) or temporary pacemaker for bradyarrhythmias
• Crystalloids for hypotension
• Digoxin-specific antibodies (Fab fragments)

Of note, there is the “digitalis effect” on EKGs, typically seen with chronic use rather than acute toxicity. These include downward sloping, scooped ST segments, T wave flattening or inversions, shortened QT interval, and U waves.

Updated definition 2020:

Digoxin is a cardiac glycoside that is used both as an inotrope in patients with heart failure, as well as an AV nodal blocking agent in managing atrial tachydysrhythmias. Its utility is limited by its narrow therapeutic index. Toxicity can present acutely (intentional or accidental overdose), or chronically (i.e. a patient on digoxin develops AKI). Its mechanism of action of both its therapeutic and toxic effects is inhibiting the sodium-potassium ATPase leading to an increase in intracellular calcium causing an increase in inotropy and automaticity. Digoxin also increases vagal tone by decreasing dromotropy at the AV node. Approximately 1% of CHF patients treated with digoxin develop toxicity, and 1% of all adverse drug effects in patients greater than 40 can be attributed to digoxin toxicity. Digoxin excretion is primarily renal, and hence why elderly and patients with CKD are more likely to develop toxicity.

The most common presenting symptom of digoxin toxicity is gastrointestinal upset. Some patients also report visual symptoms which are classically described (especially on board exams) as yellow-green discoloration. Cardiovascular symptoms may include palpitations, dyspnea and syncope. Elderly patients may present with more vague symptoms such as dizziness and fatigue.

Evaluation and Treatment

In evaluating patients for acute digoxin toxicity, one should obtain an ECG, BMP and digoxin level on arrival, and repeat 6 hours post-ingestion. The most common ECG abnormality is frequent PVCs, although the “pathognomonic” sign is bidirectional ventricular tachycardia.

Digoxin-specific antibody antigen-binding fragments (DSFab) is an effective antidote that directly binds digoxin. It is indicated for life-threatening toxicity. If DSFab is not available, then treatments such multidose-activated charcoal, atropine, and antidysrhythmics such as phenytoin or lidocaine may be employed. Cardioversion and pacing may induce dysrhythmias and are typically not used, but they may be needed in patients without other therapeutic options.

Dialysis also may be indicated in the patient with acute renal failure or refractory hyperkalemia; however, it is not useful as a treatment for digoxin toxicity itself.