Digitalis Toxicity Medication

The goals of pharmacotherapy are to reduce toxic levels of digitalis, prevent complications, and reduce morbidity. Immunotherapy has been an extremely valuable addition to the treatment of digoxin and digitoxin intoxication. In hemodynamically stable or unstable patients, it is a first-line therapy. Introduced in 1976, but not commercially available until a decade later, digoxin-specific Fab fragments are the product of papain digestion of sheep immunoglobulin G (IgG) produced in response to antigenic carrier proteins coupled to digoxin.

The advantages of digoxin-specific Fab compared with whole IgG antibodies include larger volume of distribution and more rapid onset of action. The commercial product (Digibind) is a relatively pure Fab product that is very safe and extremely effective. Onset of action ranges from 20-90 minutes, and digoxin is removed irreversibly from the myocardium and other specific binding sites. A complete response generally occurs within 4 hours.

Immediately following IV administration, digoxin-specific antibodies bind intravascular free digoxin. They then diffuse into the interstitial space, binding free digoxin there. A concentration gradient is established, which facilitates movement of intracellular digoxin and digoxin that is dissociated from its binding sites (external surface of Na⁺/K⁺ -ATPase enzyme) in the heart into interstitial or intravascular spaces. Intravascular concentration of inactive, antibody-bound digoxin rises substantially. The elimination kinetics of Fab antibody–bound digoxin depend on the patient's renal function and capacity for urinary elimination.

Indications for immunotherapy include the following:

• Ingestion of massive quantities of digitalis (children, 4 mg or 0.1 mg/kg; adults 10 mg)
• Hyperkalemia (>5 mEq/L)
• Digoxin-induced ventricular dysrhythmias or high-grade AV block
• Rapidly progressive signs and symptoms of toxicity
• Cardiac arrest or cardiogenic shock in a patient with suspected digoxin toxicity
• Postdistribution serum digoxin levels greater than 5 ng/mL

According to the manufacturer, Digibind should be administered intravenously over 30 minutes via a 0.22-um membrane filter. The 40-mg vial must be reconstituted with 4 mL of sterile water for IV injection, furnishing an iso-osmotic solution. This preparation can be diluted further with sterile isotonic saline (for small infants). Once the product is reconstituted, use it immediately or, if refrigerated, use it within 4 hours. In an unstable clinical situation, Digibind is administered by IV bolus.

Studies have shown that a loading dose of Fab followed by a maintenance infusion is beneficial to the optimization of binding to Fab. The loading dose immediately captures digoxin already in the vascular space, and the maintenance dose provides enough Fab to continue to draw digoxin from the tissue into the serum to be bound. In acute, intentional overdose, administration of 4-6 vials as a loading dose, followed by 0.5 mg/min for 8 hours and then 0.1 mg/min for about 6 hours, appears to be safe and effective.

Possible idiosyncratic allergic reactions are very rare but need to be considered in patients with known sheep protein allergy. One must also be aware of possible volume overload causing exacerbation of CHF with chronic digitalis therapy and hypokalemia due to the movement of potassium into the cell.

Fab fragment interferes with conventional assay, and digoxin measurement is unreliable for 1-2 weeks after the therapy.

Class Summary

This agent improves clinical aspects of digitalis toxicity; it may increase solubilization and removal of immune complexes. In chronic toxicity, plasma drug levels are greater than 6 ng/mL; in acute ingestion, do not base treatment on plasma drug levels alone.

Digoxin immune Fab is used for the treatment of hemodynamic instability, refractory dysrhythmias, and severe or refractory hyperkalemia. This agent has reversed noncardiac digitalis-associated complications (eg, thrombocytopenia).^{[23, 24]}

Initially administering half doses is the best way in patients with chronic toxicity who are dependent on digoxin. This avoids completely reversing the clinical effects of digoxin and precipitating complications. Depending on the patient's status, additional antidote may be administered later. The agent is excreted renally. When it is administered to anephric patients, digitalis toxicity may recur within 7-14 days, as digoxin unbinds (recrudescence toxicity). Plasmapheresis may be performed or Digibind readministered in such situations.

Complications of therapy include allergic reactions (relatively rare and more common in patients with allergic histories), worsening CHF, tachyarrhythmias, and hypokalemia. Overall, the incidence of complications is very low.

Digoxin levels drawn after administration may be exponentially higher because many assays for measuring digoxin measure total digoxin (including digoxin bound to Digibind). This may be misinterpreted as a therapeutic failure and worsening toxicity. Assays that measure only free digoxin are accurate and should reflect true posttreatment levels. Knowledge of your laboratory's digoxin assay is critically important in evaluating therapeutic effect.

Activated charcoal is useful in limiting the absorption of ingested digoxin. It is most beneficial if administered within 4 hours of ingestion.

Resin is used in the management of hypercholesterolemia and can bind drugs that are enterohepatically recycled. Upwards of 30% of a digoxin dose (higher in some individuals) and the majority of a digitoxin dose are enterohepatically recycled.

Digoxin immune Fab (Digibind)

Digoxin immune Fab is an immunoglobulin fragment with specific and high affinity for digoxin and digitoxin molecules. It removes digoxin or digitoxin molecules from tissue-binding sites. Each vial contains 40 mg of purified digoxin-specific antibody fragments, which will bind approximately 0.6 mg of digoxin or digitoxin.

A 50,000-Da molecule, Fab is derived from the IgG fragment of sheep antidigoxin antibodies. This relatively pure Fab product is safe and extremely effective. Indications for use include life-threatening arrhythmias (eg, severe bradyarrhythmia, second- or third-degree heart block, ventricular tachycardia or fibrillation), an initial potassium level of more than 5 mmol/L, digoxin serum levels of more than 10 ng/mL at 6-8 hours after ingestion, digoxin serum levels of over 15 ng/mL in acute ingestion, and ingestion of more than 10 mg in healthy adults or more than 4 mg in children.

Fab binds free digoxin in vascular and interstitial space and decreases free plasma digoxin levels by binding intracellular digoxin from its binding sites in the heart and in interstitial and intravascular spaces. Fab raises intravascular levels of inactive antibody-bound digoxin to very high levels, which decrease over several days as it is excreted renally. A response is typically observed within 20-30 minutes; the elimination half-life of the drug-antibody complex is about 16 hours.

Affinity for digitoxin is 10 times less than for digoxin. In a case series that included pediatric patients, there was a 90-93% response rate within minutes or hours, with complete resolution within 180 minutes in as many as 79% of patients. The mean time to the initial response was 19 minutes; complete resolution of symptoms occurred in 88 minutes.

Activated charcoal (Kerr Insta-Char, Actidose-Aqua, EZ-Char)

Activated charcoal prevents absorption by adsorbing drug in intestine. A network of pores present in activated charcoal absorbs 100-1000mg of drug per gram of charcoal. Multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption.

Theoretically, by constantly bathing the GI tract with charcoal, the intestinal lumen serves as a dialysis membrane for the reverse absorption of drug from the intestinal villous capillary blood into the intestine. The charcoal is supplied as an aqueous mixture or in combination with a cathartic (usually sorbitol 70%). It does not dissolve in water. For maximum effect, administer the charcoal within 30 minutes of poison ingestion.

Cholestyramine (Questran, Prevalite)

Cholestyramine forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts. It has been shown to decrease digoxin levels following therapeutic dosing and acute or chronic digitalis toxicity. However, this agent may not change the ultimate outcome, because a prolonged administration time is necessary.

Class Summary

These agents may improve sinus and AV node conduction by inhibiting vagal activity. They are used as an alternative to digoxin immune Fab.

Atropine sulfate

Atropine sulfate increases the heart rate through vagolytic effects, causing an increase in cardiac output.

Class Summary

Anticonvulsants that shorten the action potential in the heart may be effective.

Phenytoin (Dilantin, Phenytek)

Phenytoin prolongs effective refractory period and depresses spontaneous depolarization in ventricular tissues.

Class Summary

Antidysrhythmics 1b increase electrical stimulation threshold of ventricle by suppressing automaticity of conduction.

Lidocaine hydrochloride (Xylocaine)

Lidocaine hydrochloride is a class IB antiarrhythmic that increases the electrical stimulation threshold of the ventricle, suppressing the automaticity of conduction through the tissue.

Class Summary

Magnesium is useful as a temporizing antiarrhythmic agent until digoxin Fab fragments are available.

Magnesium sulfate

Magnesium sulfate possesses antiarrhythmic properties that are beneficial with treatment of digoxin toxicity. It may be a lifesaving adjunct in the treatment of digoxin-induced ventricular tachycardia or ventricular fibrillation.