CHAPTER 25 Drugs Used in Treating Heart Failure
Heart failure is characterized by a decreased ability of the heart to pump blood in adequate amounts. In addition to changes in the heart, multiple adaptive mechanisms occur, which provide targets for drug therapy. The severity of heart failure is often rated according to the New York Heart Association (NYHA) classification, ranging from class I, in which signs of heart failure occur only at higher exercise levels, to class IV, in which signs of heart failure occur at rest. In addition to drug therapy, other strategies for treating heart failure include auxiliary mechanical pumps (ventricular assist devices)4 and ventricular pacing (resynchronization).
In addition to its role in the action potential, Ca++ is intimately involved in the contractile process. The contraction of cardiac muscle is initiated by extracellular Ca++ entering the cell with the slow inward current. The immediate source of contractile Ca++ in the heart comes largely from intracellular stores, however. Ca++ entering the cell during an action potential must first traverse the plasma membrane through voltage-sensitive Ca++ channels. This influx of Ca++ during the slow inward current triggers the release of much larger amounts of intracellular Ca++ from the sarcoplasmic reticulum (SR). The sudden increase in cytoplasmic Ca++ stimulates contraction.
Tropomyosin and troponin, which are associated with actin, regulate the interaction between actin and myosin. The binding of Ca++ to troponin C initiates a series of conformational changes in troponin and tropomyosin that alter the interaction of tropomyosin and troponin I with actin, favoring the coupling of actin with myosin. Adenosine triphosphate (ATP) is hydrolyzed by myosin-bound adenosine triphosphatase (ATPase) when the actomyosin complex is formed, and chemical energy is converted into mechanical work. The contraction cycle is completed by the active reuptake of Ca++ by the SR (and mitochondria) and extrusion from the cell by Na+-Ca++ exchange.
Drugs such as the β-adrenergic receptor agonists increase cardiac contractility by increasing intracellular cyclic 3′,5′-adenosine monophosphate (cAMP), which enhances Ca++ influx and accelerates uptake of Ca++ by the SR, ultimately making more Ca++ available for contraction.12 The latter effect results from the phosphorylation of phospholamban, a protein associated with the Ca++ pump of the SR. The effect of Ca++ on troponin may also be enhanced by cAMP.
In heart failure, the heart is unable to maintain the requisite cardiac output. The mechanics underlying this failure are incompletely understood. The ability of the SR to participate in the trafficking of Ca++ seems to be hindered.21 The Na+-Ca++ exchange sites seem to be increased in heart failure, leading to a decrease in intracellular Ca++. There are likely to be multiple biochemical defects in heart failure, however.
According to Starling’s law of the heart, cardiac output, or, more precisely, the ventricular stroke volume, increases as ventricular filling pressure increases. Stated simply, the heart pumps whatever is supplied to it by way of venous return, maintaining a near-optimal heart size. As ventricular end-diastolic pressure increases, ventricular stroke work and stroke volume increase. Normal heart function is within well-defined limits and is described by a single curve (Figure 25-1).
FIGURE 25-1 Operation of the Frank-Starling mechanism in the preload compensation for heart failure. The three curves represent ventricular function curves in the normal state, in congestive heart failure (CHF), and in heart failure after treatment with digoxin. Points N through D indicate, in sequence, normal cardiac status (N), depression of contractility with decompensated heart failure (A), Frank-Starling compensation (B), increase in contractility with digoxin (C), and reduction in use of Frank-Starling preload compensation that digoxin allows (D). Points N, D, and B indicate the same cardiac output on the vertical axis, but each point is at a different end-diastolic pressure on the horizontal axis. The excessive end-diastolic pressures causing congestive symptoms and the lowered levels of cardiac performance resulting in low-output symptoms are shown by the hatched areas.
(From Mason DT: Regulation of cardiac performance in clinical heart disease: interactions between contractile state mechanical abnormalities and ventricular compensatory mechanisms, Am J Cardiol 32:437-448, 1973.)
When cardiac contractility is reduced in heart failure, three mechanisms are available by which the heart can compensate for the defect: (1) an increase in ventricular end-diastolic pressure, which enhances cardiac output (Frank-Starling preload mechanism); (2) an increase in number of contractile units (hypertrophy); and (3) use of chronotropic and inotropic reserves of the heart through reflex mechanisms (sympathetic activity). If these mechanisms are sufficient to produce normal cardiac output, the heart failure is said to be compensated. In this condition, a new ventricular function curve is generated (see Figure 25-1). For any given ventricular end-diastolic pressure, however, ventricular stroke work, stroke volume, and cardiac output are lower in the failing heart than in the normal heart. Consequently, the heart enlarges to maintain cardiac output, and heart rate increases to help compensate for poor cardiac function.
If the ventricular end-diastolic pressure becomes too elevated (i.e., the heart is working to the far right along the Frank-Starling curve), venous pressures upstream also increase excessively, leading to symptoms of “backward” heart failure. Signs and symptoms include pulmonary congestion and dyspnea (left-sided failure) and systemic venous distention and edema (right-sided failure). If compensatory mechanisms are unable to maintain cardiac output sufficient for the needs of the peripheral tissues, “forward” heart failure ensues. Adverse effects from impaired tissue perfusion include weakness, lassitude, and acute renal failure. In chronic heart failure, aspects of backward and forward failure interact to produce clinical manifestations. Salt and water retention caused by forward failure contributes to the venous hypertension and edema associated with backward failure. Conversely, impaired gas exchange in the congested lungs augments muscle weakness and fatigue associated with reduced cardiac output and delivery of oxygen to skeletal muscle.
Heart failure occurs whenever the workload placed on the heart exceeds the ability of the heart to perform. Heart failure often arises from myocardial infarction or hypertension. Myocardial infarction can lead to heart failure as a result of a reduction in the heart’s ability to perform work (pump failure).
An increase in total peripheral vascular resistance, as seen in hypertension or as a reflex reaction in congestive heart failure, can contribute to heart failure because of increased outflow resistance on cardiac contraction. The first reaction of the heart to an increase in outflow resistance is often enlargement, resulting in temporary higher efficiency in cardiac function. This initial reaction is followed, however, by progressive signs of cardiac failure characterized by decreased stroke volume and stroke work, as indicated earlier. Reducing preload and afterload by reducing peripheral resistance is an important strategy in treating heart failure.
Figure 25-2 shows some important adaptive mechanisms that result from heart failure. These changes, including an increase in sympathetic discharge, can compensate for the heart failure. If these and other responses are insufficient, however, the heart failure becomes uncompensated. Adaptive mechanisms also include an increase in production of angiotensin II, leading to remodeling of the heart over time.10 Remodeling results in cardiac hypertrophy, and several cellular changes, which, although they tend to compensate for heart failure, may hasten the course of the disease. This cardiac remodeling in heart failure has a parallel in hypertension, in which vascular smooth muscle slowly undergoes hypertrophy and hyperplasia.
FIGURE 25-2 Adaptive mechanisms in heart failure. A decrease in cardiac output leads to a cascade of events that result in a compensatory increase in cardiac output (box). In addition, activation of the renin-angiotensin system leads to changes that put further burden on the failing heart and promote detrimental and long-term remodeling of the cardiovascular system.
As a result of the complexity of changes in heart failure, there are numerous processes that can be targeted by drugs: neurohumoral events, vascular dynamics, fluid volume, the sympathetic nervous system, and contractility of the heart.10 The pharmacologic features of angiotensin-converting enzyme (ACE) inhibitors and other vasodilators, diuretics, β blockers, and catecholamines are discussed elsewhere in this book. They are also discussed in this chapter in relation to the treatment of heart failure. The cardiac glycosides are not extensively discussed elsewhere in the book and so are discussed more fully in this chapter than other drugs used for heart failure.
Table 25-1 lists the drugs used to treat heart failure and their mechanisms of action. The drugs are often used in combination. Heart failure can be classified as diastolic or systolic failure. In diastolic failure, the heart has inadequate distention and inadequate filling capabilities. Contraction as measured by the ejection function may be normal. This type of heart failure is often seen in patients with hypertension. Systolic heart failure is a deficiency in contractility with a low ejection fraction.
|DRUG OR DRUG CLASS||MECHANISM(S)|
|Thiazide and loop diuretics||Reduce fluid volume (reduce preload and afterload)|
|ACE inhibitors||Reduce effect of angiotensin II, prevent remodeling|
|Angiotensin II receptor blockers||Reduce effect of angiotensin II, prevent remodeling|
|β Blockers*||Reduce sympathetic effect, prevent remodeling, prevent arrhythmias|
|Aldosterone antagonists||Inhibit effect of aldosterone|
|Digoxin||Direct cardiotonic effect|
|Isosorbide dinitrate-hydralazine||Reduce afterload and preload|
|Dobutamine||Direct cardiotonic effect|
|Dopamine||Direct cardiotonic effect|
|Nesiritide||Reduces preload and afterload|
|Phosphodiesterase III inhibitors||Reduce preload and afterload; direct cardiotonic effect|
|Nitroglycerin||Reduces preload and afterload|
|Nitroprusside||Reduces preload and afterload|
ACE, Angiotensin-converting enzyme.
The primary drugs used to treat chronic heart failure are ACE inhibitors, angiotensin II receptor blockers, thiazide and loop diuretics, β-adrenergic receptor blockers, aldosterone antagonists, digoxin, and directly acting vasodilators. For short-term acute treatment, certain catecholamines, nesiritide, other vasodilators, and the phosphodiesterase III inhibitors have special application. Figure 25-3 shows the drugs used in each type of heart failure.4,7
FIGURE 25-3 Heart failure and choice of drug. The choice of digoxin depends on the presence of systolic failure, especially if it occurs with atrial fibrillation. Dobutamine, dopamine, nesiritide, nitroglycerin, nitroprusside, inamrinone, and milrinone are reserved for short-term therapy in refractory cases. ACE, Angiotensin-converting enzyme.
Therapy of mild congestive heart failure has often involved salt restriction and the use of diuretic drugs to reduce tissue edema and blood volume. The resulting reduction in the preload, or diastolic filling pressure, helps decrease wall tension in the heart and lessen myocardial oxygen demand. The vasodilation caused by the thiazide diuretics also aids in reducing the afterload, or the arterial pressure against which the heart has to pump in moving blood. Diuretics also indirectly reduce sympathetic nervous system activity.
The action of spironolactone as a diuretic is caused by its antagonism of aldosterone at the convoluted tubule of the kidney. Antagonism of aldosterone leads to several other effects that are beneficial in patients with heart failure. These are shown in Figure 25-4. K+-sparing actions help in preventing hypokalemia. Reducing Mg++ loss seems to reduce ventricular arrhythmias in patients with heart failure. Because aldosterone can inhibit norepinephrine uptake (uptake 2), spironolactone prevents the enhanced sympathetic activation from aldosterone.18 Spironolactone also blocks the inhibition of the baroreceptor reflex seen with aldosterone. A consequence of inhibiting the baroreceptor reflex is the lack of parasympathetic nerve response.13 The latter response is important in counteracting the adverse effects of sympathetic stimulation, such as arrhythmias and cardiac ischemia. Myocardial fibrosis is also inhibited by spironolactone.
Spironolactone has many salutary effects in heart failure. These beneficial effects also occur when it is used with other drugs such as ACE inhibitors. Because the reduction of aldosterone release by ACE inhibitors is only partial, an added benefit is gained from the use of an aldosterone antagonist.
Eplerenone is another aldosterone receptor antagonist for the treatment of heart failure. Compared with spironolactone, it has a lower affinity for the androgen receptor and is reported to have a lower incidence of related side effects including gynecomastia.
A major effect of ACE inhibitors is to reduce afterload and preload. These drugs improve symptoms in patients with heart failure. In addition, the progressive deterioration of the heart is slowed with ACE inhibitors. ACE inhibitors control remodeling that occurs with chronic heart failure. Remodeling results from growth of the myocardial cell and myocardial fibrosis. This probable cardioprotective effect provides added support for the use of ACE inhibitors in heart failure. Inhibiting the production of angiotensin II or blocking its receptor reduces aldosterone secretion, which reduces Na+ and water retention. Reduction of aldosterone release by ACE inhibitors also reduces sympathetic discharge, as described in Chapter 28 (see Figure 25-4).
Evidence also suggests that ACE inhibitors stimulate the proliferation of capillaries in the coronary circulation, increasing blood flow. It is unknown whether this action of ACE inhibitors occurs as a result of the decrease in angiotensin II, an increase in bradykinin, or both. Most likely, the ability of ACE inhibitors to reduce blood pressure in hypertensive patients also contributes to a cardioprotective effect. Early treatment of congestive heart disease with an ACE inhibitor could be a major factor in slowing the progress of the disease and in relieving symptoms. Enalapril is one of the first drugs whose administration was associated with an increased survival time in patients with heart failure.15 These drugs also are useful in combination with other drugs, including digoxin and diuretics, in treating heart failure.
Angiotensin II antagonists, such as losartan and valsartan, are additional candidates for treating heart failure.7,10 They share the benefits of ACE inhibitors, while avoiding such side effects as angioedema and persistent coughing. The pharmacologic features of angiotensin II antagonists and ACE inhibitors are discussed in detail in Chapter 28.
The use of β-adrenoceptor blockers to reduce the adverse cardiac effects of heightened sympathetic discharge that occur as heart failure progresses is a strategy used in the long-term treatment of heart failure.20 β Blockers reduce the work of the heart, reduce renin secretion, prevent remodeling of the heart, act as antiarrhythmic drugs, and reduce the downregulation of β1-adrenergic receptors in heart failure. All of these effects are beneficial in heart failure. Their use is consistent with a neurohumoral component of heart failure. Bisoprolol, betaxolol, and metoprolol are selective β1-adrenergic receptor blockers that are used in treating heart failure.
Carvedilol is a nonselective β-adrenoceptor blocker and selective α1-adrenoceptor blocker used in patients with heart failure. β-adrenergic blockade reduces remodeling, whereas α1-adrenergic blockade reduces preload and afterload. It also has antioxidant properties that result in cell protection against free radicals, in addition to the other effects of β blockers. The relative importance of each mechanism in achieving favorable results in heart failure is unknown.
Vasodilators such as nitrates and hydralazine reduce the load on the heart, improve tissue perfusion in heart failure, and increase survival rates in these patients. Vasodilators are usually administered in combination with other drugs, such as inotropic agents or ACE inhibitors. Disadvantages of nitrates and hydralazine include the indirect enhancement of sympathetic discharge and activation of the renin-angiotensin pathway. Added interest in vasodilator therapy resulted from evidence supporting the clinical efficacy of two vasodilators in combination: isosorbide dinitrate and hydralazine. The fixed-dose therapy was found to be effective in patients of African descent with class III and class IV heart failure.3,17 This drug combination may be particularly effective in this group of patients, who may be less responsive to drugs such as ACE inhibitors. The isosorbide dinitrate–hydralazine combination may also be useful as added therapy in resistant cases or in patients who cannot tolerate other heart failure medications. The pharmacologic characteristics of nitrates and hydralazine are discussed in Chapters 26 and 28, respectively.
Digoxin is a cardiac glycoside that is often called digitalis, referring to the plant from which it is derived. Digoxin is currently indicated for the treatment of congestive heart failure and the management of atrial flutter and fibrillation.
The first detailed scientific study of digitalis on record was made by Sir William Withering19 of Shropshire, England, in 1785. In his treatise, “An Account of the Foxglove, and Some of Its Medical Uses; With Practical Remarks on Dropsy, and Other Diseases,” Withering detailed clinical uses for the leaf of the Digitalis purpurea (purple foxglove) plant and described its effects on the heart. His recognition of the potential usefulness of digitalis plant derivatives was occasioned by their extensive use in local folk medicines. Withering ascribed the beneficial effects of digitalis in treating dropsy to a direct diuretic effect, although he was aware of beneficial effects on the heart as well. He also detailed many toxic effects of the plant.
The history of the use of digitalis since Withering’s time has been characterized by a realization of its potential therapeutic benefits on the one hand and its low margin of safety on the other. Advances in digitalis research and clinical use up to the present have contributed greatly to our knowledge of this drug class.
The term digitalis is often used interchangeably with the term cardiac glycoside. Both terms refer to many compounds, naturally occurring or semisynthetic, that have similar cardiotonic effects. Only one such compound, digoxin, is commonly used clinically in the United States today. Another agent, digitoxin, is available in Canada and elsewhere. The structure of digoxin is shown in Figure 25-5. The molecule is composed of a steroid ring structure. Other distinguishing molecular characteristics include an α,β-unsaturated lactone ring, and a carbohydrate moiety in glycosidic linkage at C3. The presence of a sugar in glycosidic linkage accounts for the name glycoside. A steroid plus lactone lacking the sugar group is generically called a genin or aglycone. The genin of digoxin is digoxigenin.
Digoxin has a direct inotropic effect on the heart; it directly increases the force of contraction. The inotropic action of digoxin does not depend on release of endogenous catecholamines. Rather, digoxin has a direct action on heart cells. Digoxin is known to be a specific inhibitor of the Na+-K+ pump, by inhibiting Na+,K+-activated ATPase (Na+,K+-ATPase), which is the enzymatic equivalent of the Na+-K+ pump. The α subunit of Na+,K