Cardiac Glycosides - The Merck Veterinary Manual

Cardiac Glycosides

The most probable mechanism of action for the inotropic effect of digitalis is inhibition of the membrane-bound Na⁺/K⁺ -ATPase pump; when this occurs, Na⁺ increases in the cell, the exchange of Na⁺ for Ca²⁺ is augmented, and calcium influx is increased. The increased intracellular calcium in turn leads to increased release of Ca²⁺ from the sarcoplasmic reticulum and increased contractility of the cardiac muscle. Changes in the ratio of intracellular and extracellular electrolytes can result in increased automaticity and cardiac arrhythmias.

Digitalis also has a negative chronotropic effect due to decreased conduction velocity in the atrioventricular (AV) node. In addition, digitalis potentiates vagal (cholinergic) activity in the heart. Changes in conduction can ultimately result in AV nodal blockade. At toxic levels, digitalis also can directly slow sinus nodal activity due to increased sensitivity to acetylcholine. Because the atria are sensitive to acetylcholine, atrial conduction is also enhanced in the diseased heart, which can then lead to atrial arrhythmias. Digitalis may also improve vascular baroreceptor responsiveness, thereby minimizing sympathetic activation in heart failure states.

Preparations:

Digoxin and digitoxin are the 2 most widely used preparations. Digoxin is available for administration IV or PO. Administration IV results in pharmacologic effects in 5-30 min with a maximal effect in 2 hr. However, toxic drug concentrations are more difficult to avoid with this route. Digoxin should not be given IM because it causes pain and muscle necrosis. Administration PO results in pharmacologic effects in 1-2 hr.

Disposition:

Absorption of digoxin varies with the preparation. Absorption of the alcohol (elixir) form is best. Variation in bioavailability of tablets results from differences in dissolution between products. Absorption is slowed by food, but the absorption of digitoxin is more complete because it is more lipid soluble. Both drugs are distributed slowly and are concentrated in cardiac tissues. Only 25% of digoxin is bound to plasma proteins, while ~90% of digitoxin is protein bound. Digoxin is primarily eliminated unchanged by the kidneys; its half-life (~1.7 days in dogs) is strongly influenced by renal function. Digitoxin is metabolized by the liver (one of the metabolites is digoxin); its half-life in dogs is 8-12 hr.

Drug Interactions:

The concurrent administration of quinidine increases plasma concentrations of digoxin, probably due to displacement from tissue-binding sites. Verapamil, spironolactone, and captopril also may increase plasma digoxin concentrations. Interactions between digitalis and diuretics (eg, furosemide) stem primarily from the effects on potassium (hypokalemia). Administration of β-adrenergic agonists increases the likelihood of arrhythmias. Amphotericin B and glucocorticoids deplete body K⁺ and thus potentiate digitalis intoxication.

Toxicity:

Toxic effects with digitalis glycosides are frequent and can be lethal. Cats are more sensitive to digoxin than dogs. Probably the most frequent cause of toxicity is overdosing. The potential for toxicity is increased with hypokalemia. The likelihood and severity of toxicity are related to the severity of cardiac disease. Any type of cardiac arrhythmia can be induced by digitalis. Other signs of toxicity include diarrhea, anorexia, and nausea and vomiting due to direct stimulation of the chemoreceptor trigger zone. Frequently, these are the earliest indications of toxicity. Neurologic effects include malaise and drowsiness. Digitalis toxicity can be diagnosed (and avoided) by monitoring plasma drug concentrations. Treatment of intoxication includes discontinuing therapy with digitalis and potassium-depleting diuretics and administering phenytoin (blocks AV nodal effects of digitalis), lidocaine (for ventricular arrhythmias), and if indicated, potassium (preferably PO). Atropine may be useful to treat both sinus bradycardia and second- or third-degree heart block induced by cholinergic augmentation.

Clinical Use:

Digitalis is used for restoring adequate circulation in animals with congestive heart failure (CHF) due to poor systolic (ie, contractile) function or for slowing the ventricular rate during supraventricular tachyarrhythmias, such as atrial fibrillation or flutter. Both syndromes require longterm treatment. Digoxin is the cardiac glycoside more commonly used except in animals with renal disease, in which digitoxin is preferred. The maintenance dosage schedules are 0.0055-0.011 mg/kg, PO, bid, for dogs, and 0.005-0.01 mg/kg, PO, every 24-48 hr for cats. Calculation of digoxin doses should be based on lean body weight, and dosages should be reduced in obese or cachectic animals and in the presence of ascites. The calculated dose should be multiplied by 0.75 for elixir and by 0.85 for tablet formulations of digoxin. Alternatively, dosing of digoxin on the basis of body surface area (0.22 mg/m², bid) is best for large and giant breeds of dogs. See table 9, Table: Table 9. Weight to Body Surface Area Conversion, for weight to body surface area (in m²) conversion. Electrolyte disorders should be corrected before digitalis glycosides are administered.