Cardiac Glycoside Drugs

Myocardial cell membrane ATPase, the enzyme present in heart muscle, is the site of action of the cardiac steroid glycosides, which have a specific action on the heart muscle. These drugs increase the force of contraction of the muscle (positive inotropic effect) as well as its conductivity and automaticity. They are also valuable in treating congestive heart failure, in which the circulatory needs of organs are no longer satisfied, and heart arrhythmias, in which the rhythm of the cardiac contractions is upset. The effect of the drug is that the force of contraction increases and the heart rate is slowed (chronotropic effect). Consequently, the cardiac output is elevated while the size of the heart decreases. 

The weakening or even loss of potency in such derivatives of C[D-trans steroids has led to the tacit opinion that CfD-trans steroids as such cannot elicit inotropic activity and serve as potential cardiac drug candidates. Most remarkably, however, certain steroid representatives with trans junction of the rings C and D have recently been demonstrated to evolve similar or even higher interaction energies with human NaVK -ATPase compared with their CfD-cis counterparts [88]. This discovery has prompted studies on the impact of glycosidation on the biological activity of CfD-trans steroids in view of their possible suitability to serve as a novel type of pharmacophoric lead structure [22,183,184]. This is evaluated below. 

From the vast number of steroid alkaloids we have chosen solanine as a representative. As the formula shows, it also is a glycoside. It occurs in potato shoots. The steroid alkaloids cannot all be derived from one common structure, as is possible with the cardiac drugs. For other representatives, see special reference works. 

Cardiac Glycosides Potent Drugs from Ancient Times... 

If 50% of Europeans with essential hypertension are affected by this disease because of an elevated secretion of endogenous ouabain, then there might be a chance to block its interaction at the cardiac glycoside binding site of Na+/K+-ATPase and thus lower blood pressure. This therapeutic approach seems to be successfiil. Recent studies provide evidence that the cardenolide analogue Rostafuroxin (PST 2238 Fig. 4) at very low concentrations can overcome the ouabain-induced tise of hypertension in experimental animals [6]. This compound has recently entered the phase I of clinical trials and is certainly a prototype of a new class of antihypertensive drugs. 

Figure 9.14 A steroid glycoside. Digitoxenin is a cardiac-stimulating drug. It is a steroid glucoside in which a compound with a steroid structure is linked to a-D-glu-copyranose by condensation of the anomeric hydroxyl group on the carbohydrate and the alcohol group at position 5 on the steroid nucleus.

Digoxin (cardiac glycoside) and trihexyphenidyl (antimuscarinic drug) must be used with caution in elderly patients. Low doses are recommended in elderly patients to avoid toxicity. Lactulose may be safely administered to elderly patients with constipation. 

Atrial flutter or fibrillation. An excessive ventricular rate can be decreased by verapamil (p. 122) or cardiac glycosides (p. 130). These drugs inhibit impulse propagation through the AV node, so that fewer impulses reach the ventricles. 

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