Digoxin, the only cardiac glycoside used in the USA, is 65–80% absorbed after oral administration. Absorption of other glycosides varies from zero to nearly 100%. Once present in the blood, all cardiac glycosides are widely distributed to tissues, including the central nervous system (CNS).
Digoxin is not extensively metabolized in humans; almost two thirds is excreted unchanged by the kidneys. Its renal clearance is proportional to creatinine clearance, and the half-life is 36–40 hours in patients with normal renal function. Equations and nomograms are available for adjusting digoxin dosage in patients with renal impairment.
Digoxin has multiple direct and indirect cardiovascular effects, with both therapeutic and toxic consequences. In addition, it has undesirable effects on the CNS and gut.
At the molecular level, all therapeutically useful cardiac glycosides inhibit Na+/K+-ATPase, the membrane-bound transporter often called the sodium pump (Figure 13–1). Although several isoforms of this ATPase occur and have varying sensitivity to cardiac glycosides, they are highly conserved in evolution. Inhibition of this transporter over most of the dose range has been extensively documented in all tissues studied. It is probable that this inhibitory action is largely responsible for the therapeutic effect (positive inotropy) as well as a major portion of the toxicity of digitalis. Other molecular-level effects of digitalis have been studied in the heart and are discussed below. The fact that a receptor for cardiac glycosides exists on the sodium pump has prompted some investigators to propose that an endogenous digitalis-like steroid, possibly ouabain or marinobufagenin, must exist. Furthermore, additional functions of Na+/K+-ATPase have been postulated, involving apoptosis, cell growth and differentiation, immunity, and carbohydrate metabolism. Indirect evidence for such endogenous digitalis-like activity has been inferred from clinical studies showing some protective effect of digoxin antibodies in preeclampsia.
A. Cardiac Effects 1.
Mechanical effects—Cardiac glycosides increase contraction of the cardiac sarcomere by increasing the free calcium concentration in the vicinity of the contractile proteins during systole. The increase in calcium concentration is the result of a two-step process: first, an increase of intracellular sodium concentration because of Na+/K+-ATPase inhibition; and second, a relative reduction of calcium expulsion from the cell by the sodium-calcium exchanger (NCX in Figure 13–1) caused by the increase in intracellular sodium. The increased cytoplasmic calcium is sequestered by SERCA in the SR for later release. Other mechanisms have been proposed but are not well supported.
The net result of the action of therapeutic concentrations of a cardiac glycoside is a distinctive increase in cardiac contractility (Figure 13–5, bottom trace, panels A and B). In isolated myocardial preparations, the rate of development of tension and of relaxation are both increased, with little or no change in time to peak tension. This effect occurs in both normal and failing myocardium, but in the intact patient, the responses are modified by cardiovascular reflexes and the pathophysiology of heart failure.
2.
Electrical effects—The effects of digitalis on the electrical properties of the heart are a mixture of direct and autonomic actions. Direct actions on the membranes of cardiac cells follow a well-defined progression: an early, brief prolongation of the action potential, followed by shortening (especially the plateau phase).