Cardiac Glycosides

Diverse plants (A) are sources of sugar-containing compounds (glycosides) that also contain a steroid ring (structural formulas, p. 133) and augment the contractile force of heart muscle (B): cardiotonic glycosides. cardiosteroids, or "digitalis."

If the inotropic, "therapeutic" dose is exceeded by a small increment, signs of poisoning appear: arrhythmia and contracture (B). The narrow therapeutic margin can be explained by the mechanism of action.

Cardiac glycosides (CG) bind to the extracellular side of Na+/K+-ATPases of cardiomyocytes and inhibit enzyme activity. The Na+/K+-ATPases operate to pump out Na+ leaked into the cell and to retrieve K+ leaked from the cell. In this manner, they maintain the transmembrane gradients for K+ and Na+, the negative resting membrane potential, and the normal electrical excitability of the cell membrane. When part of the enzyme is occupied and inhibited by CG, the unoccupied remainder can increase its level of activity and maintain Na+ and K+ transport. The effective stimulus is a small elevation of intracellular Na+ concentration (normally approx. 7 mM). Concomitantly, the amount of Ca2+ mobilized during systole and, thus, contractile force, increases. It is generally thought that the underlying cause is the decrease in the Na+ transmembrane gradient, i.e., the driving force for the Na+/Ca2+ exchange (p. 128), allowing the intracellular Ca2+ level to rise. When too many ATPases are blocked, K+ and Na+ homeostasis is deranged; the membrane potential falls, arrhythmias occur. Flooding with Ca2+ prevents relaxation during diastole, resulting in contracture.

The CNS effects of CG (C) are also due to binding to Na+/K+-ATPases. Enhanced vagal nerve activity causes a decrease in sinoatrial beating rate and velocity of atrioventricular conduction. In patients with heart failure, improved circulation also contributes to the reduction in heart rate. Stimulation of the area postrema leads to nausea and vomiting. Disturbances in color vision are evident.

Indications for CG are: (1) chronic congestive heart failure; and (2) atrial fibrillation or flutter, where inhibition of AV conduction protects the ventricles from excessive atrial impulse activity and thereby improves cardiac performance (D). Occasionally, sinus rhythm is restored.

Signs of intoxication are: (1) cardiac arrhythmias, which under certain circumstances are life-threatening, e.g., sinus bradycardia, AV-block, ventricular extrasystoles, ventricular fibrillation (ECG); (2) CNS disturbances — altered color vision (xanthopsia), agitation, confusion, nightmares, hallucinations; (3) gastrointestinal — anorexia, nausea, vomiting, diarrhea; (4) renal — loss of electrolytes and water, which must be differentiated from mobilization of accumulated edema fluid that occurs with therapeutic dosage.

Therapy of intoxication: administration of K+, which inter alia reduces binding of CG, but may impair AV-con-duction; administration of antiarrhyth-mics, such as phenytoin or lidocaine (p. 136); oral administration of colestyra-mine (p. 154, 156) for binding and preventing absorption of digitoxin present in the intestines (enterohepatic cycle); injection of antibody (Fab) fragments that bind and inactivate digitoxin and digoxin. Compared with full antibodies, fragments have superior tissue penetrability, more rapid renal elimination, and lower antigenicity.

Digitalis purpurea Red foxglove

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Digitalis purpurea Red foxglove

A. Plants containing cardiac glycosides

A. Plants containing cardiac glycosides

'toxic' Dose of cardiac glycoside (CG)

Na+ Na/K-ATPase

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