Cardiac Drugs

Cardiac Glycosides

Diverse plants are sources of sugar-contain- ing compounds (glycosides) that also contain a steroid ring system (structural formulas, A) and augment the contractile force of heart muscle: cardiotonic glycosides, cardiosteroids, “digitalis.”

The cardiosteroids possess a small therapeutic margin, signs of intoxication are arrhythmia and contracture (B). This therapeutic drawback can be explained by the mechanism of action.

Cardiac glycosides (CG) bind to the extracellular domain of Na+/K+-ATPases and exclude this enzyme molecule for a time from further ion transport activity. The high-af nity binding of CG is restricted to a particular conformation that the enzyme adopts during its transport cycle. In the resting state, Na+/K+-ATPase molecules are not binding partners. Under normal conditions only a fraction of the Na+/K+-ATPase transport activity is required to maintain the high gradients of Na+ and K+ across the plasmalemma. Low therapeutic concentrations of CG occupy onlya fraction of Na+/K+-ATPases; the decrease of the resulting pump activity can easily be compensated for by recruitment of resting ATPase molecules via a small increase of the intracellular Na+ concentration.

Attached to the ATPases there are Na+ channels which, upon binding of CG to the enzyme, lose their specificity for Na+ and are converted to nonselective, promiscuous channels: during systole, Ca2+ will easily pass through this channel owing to its huge gradient (almost 4 orders of magnitude!). This results in an increased Ca2+-influx and augmented contractile force. It should, however, be noted that the mode of action of cardiosteroids is still a matter of debate.

Mobilization of edema (weight loss) and lowering of heart rate are simple but decisive criteria for achieving optimal dosing. If ATPase activity is inhibited too much, K+ and Na+ homeostasisisdisturbed:the membrane

potential declines, arrhythmias occur. Intracellular flooding with Ca2+ prevents relaxation during diastole: contracture.

The CNS effects of CGs (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.

Indications for CGs are:

1 chronic congestive heart failure,

2 atrial fibrillation or flutter, where inhibition of AV conduction protects the ventricles from excessive atrial impulse activity and thereby improves cardiac performance (D).

Signs of intoxication are:

1Cardiac arrhythmias, which under certain circumstancesarelife-threatening,e.g.,si- nus bradycardia, AV-block, ventricular ex-

trasystoles, ventricular fibrillation (ECG); 2 CNS disturbances: characteristically, altered color vision (xanthopsia), and also fatigue, disorientation, hallucinations;

3 anorexia, nausea, vomiting, diarrhea;

4renal: loss of electrolytes and water; this must be differentiated from mobilization of edema fluid accumulated in front of the heart during congestive failure, an effect expected with therapeutic dosage.

Therapy of intoxication: administration of K+, which inter alia reduces binding of CG, but may impair AV-conduction; administration of antiarrhythmics, such as phenytoin or lidocaine (p.136); oral administration of colestyramine (p.160) for binding and preventing absorption of digitoxin present in the intestines (enterohepatic cycle), and most importantly injection of antibody (Fab) fragments that bind and inactivate digitoxin and digoxin. Compared with fullantibodies, fragments have superior tissue penetrability, more rapid renal elimination, and lower antigenicity.

Contracture

Dose of cardiac glycoside (CG)

CG