Basic Pharmacology of Drugs Used in Heart Failure

BASIC PHARMACOLOGY OF DRUGS USED IN HEART FAILURE

Although digitalis is not the first drug and never the only drug used in heart failure.

DIGITALIS

Digitalis is the genus name for the family of plants that provide most of the medically useful cardiac glycosides, eg, digoxin. Such plants have been known for thousands of years but were used erratically and with variable success until 1785, when William Withering, an English physician and botanist, published a mono-graph describing the clinical effects of an extract of the purple foxglove plant (Digitalis purpurea, a major source of these agents).

Chemistry

All of the cardiac glycosides, or cardenolides—of which digoxin is the prototype—combine a steroid nucleus linked to a lactone ring at the 17 position and a series of sugars at carbon 3 of the nucleus. Because they lack an easily ionizable group, their solubility is not pH-dependent. Digoxin is obtained from Digitalis lanata, the white foxglove, but many common plants (eg, oleander, lily of the valley, and milkweed) contain cardiac glycosides with similar properties.

Pharmacokinetics

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.

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.

Pharmacodynamics

Digoxin has multiple direct and indirect cardiovascular effects, with both therapeutic and toxic consequences. In addition, it has undesirable effects on the central nervous system and gut.At the molecular level, all therapeutically useful cardiac glyco-sides 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 car-diac 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 inhibi-tory 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 theheart and are discussed below. The fact that a receptor for cardiac glycosides exists on the sodium pump has prompted some investi-gators to propose that an endogenous digitalis-like steroid, possi-bly 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.

A. Cardiac Effects

1. Mechanical effects— Cardiac glycosides increase contrac-tion of the cardiac sarcomere by increasing the free calcium con-centration 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 mecha-nisms 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 myocar-dial preparations, the rate of development of tension and of relax-ation are both increased, with little or no change in time to peak tension. This effect occurs in both normal and failing myocar-dium, 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 electricalproperties 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). The decrease in action potential duration is probably the result of increased potassium conductance that is caused by increased intra-cellular calcium . All these effects can be observed at therapeutic concentrations in the absence of overt toxicity (Table 13–2).

At higher concentrations, resting membrane potential is reduced (made less negative) as a result of inhibition of the sodium pump and reduced intracellular potassium. As toxicity progresses, oscillatory depolarizing afterpotentials appear follow-ing normally evoked action potentials (Figure 13–5, panel C). The afterpotentials (also known as delayed after-depolariza-tions, DADs) are associated with overloading of the intracellularcalcium stores and oscillations in the free intracellular calcium ion concentration. When afterpotentials reach threshold, they elicit action potentials (premature depolarizations, ectopic “beats”) that are coupled to the preceding normal action poten-tials. If afterpotentials in the Purkinje conducting system regu-larly reach threshold in this way, bigeminy will be recorded on the electrocardiogram (Figure 13–6 ). With further intoxication, each afterpotential-evoked action potential will itself elicit a suprathreshold after-potential, and a self-sustaining tachycardia will be established. If allowed to progress, such a tachycardia may deteriorate into fibrillation; in the case of ventricular fibrillation, the arrhythmia will be rapidly fatal unless corrected. Autonomic actions of cardiac glycosides on the heart involve both the parasympathetic and the sympathetic systems. In the lower portion of the dose range, cardioselective parasympathomi-metic effects predominate. In fact, these atropine-blockable effects account for a significant portion of the early electrical effects of digitalis (Table 13–2). This action involves sensitization of the baroreceptors, central vagal stimulation, and facilitation of musca-rinic transmission at the cardiac muscle cell. Because cholinergic innervation is much richer in the atria, these actions affect atrial and atrioventricular nodal function more than Purkinje or ven-tricular function. Some of the cholinomimetic effects are useful in the treatment of certain arrhythmias. At toxic levels, sympathetic outflow is increased by digitalis. This effect is not essential for typical digitalis toxicity but sensitizes the myocardium and exag-gerates all the toxic effects of the drug.

The most common cardiac manifestations of digitalis toxicity include atrioventricular junctional rhythm, premature ventricular depolarizations, bigeminal rhythm, and second-degree atrioven-tricular blockade. However, it is claimed that digitalis can cause virtually any arrhythmia.

B. Effects on Other Organs

Cardiac glycosides affect all excitable tissues, including smooth muscle and the central nervous system. The gastrointestinal tract is the most common site of digitalis toxicity outside the heart. The effects include anorexia, nausea, vomiting, and diarrhea. This toxicity is caused in part by direct effects on the gastrointestinal tract and in part by central nervous system

Central nervous system effects include vagal and chemoreceptor trigger zone stimulation. Less often, disorientation and hallucinations— especially in the elderly—and visual disturbances are noted. The latter effect may include aberrations of color perception. Gynecomastia is a rare effect reported in men taking digitals.

C. Interactions with Potassium, Calcium, and Magnesium

Potassium and digitalis interact in two ways. First, they inhibit each other’s binding to Na⁺/K⁺-ATPase; therefore, hyperkalemia reduces the enzyme-inhibiting actions of cardiac glycosides, whereas hypokalemia facilitates these actions. Second, abnormal cardiac automaticity is inhibited by hyperkalemia . Moderately increased extracellular K⁺ therefore reduces the effects of digitalis, especially the toxic effects.

Calcium ion facilitates the toxic actions of cardiac glycosides by accelerating the overloading of intracellular calcium stores that appears to be responsible for digitalis-induced abnormal automa-ticity. Hypercalcemia therefore increases the risk of a digitalis-in-duced arrhythmia. The effects of magnesium ion are opposite to those of calcium. These interactions mandate careful evaluation of serum electrolytes in patients with digitalis-induced arrhythmias.