Katzung Chapter 13.pdf

13 C H A P T E R Drugs Used in Heart Failure...

13 C H A P T E R Drugs Used in Heart Failure ∗ Bertram G. Katzung, MD, PhD CASE STUDY A 65-year-old man has developed shortness of breath with jugular venous pressure is elevated. The liver is enlarged, and exertion several weeks after experiencing a viral illness. This there is 3+ edema of the ankles and feet. An echocardiogram is accompanied by swelling of the feet and ankles and shows a dilated, poorly contracting heart with a left ventricu- increasing fatigue. On physical examination he is found to lar ejection fraction of about 20% (normal: 60%). The pre- be mildly short of breath lying down, but feels better sitting sumptive diagnosis is dilated cardiomyopathy secondary to a upright. Pulse is 105 and regular, and blood pressure is viral infection with stage C, class III heart failure. What treat- 90/60 mm Hg. His lungs show crackles at both bases, and his ment is indicated? Heart failure occurs when cardiac output is inadequate to provide Treatment is therefore directed at two somewhat different goals: (1) the oxygen needed by the body. It is a highly lethal condition, with reducing symptoms and slowing progression as much as possible a 5-year mortality rate conventionally said to be about 50%. The during relatively stable periods and (2) managing acute episodes of most common cause of heart failure in the USA is coronary artery decompensated failure. These factors are discussed in Clinical disease, with hypertension also an important factor. Two major Pharmacology of Drugs Used in Heart Failure. types of failure may be distinguished. Approximately 50% of Although it is believed that the primary defect in early systolic younger patients have systolic failure, with reduced mechanical heart failure resides in the excitation-contraction coupling machin- pumping action (contractility) and reduced ejection fraction. The ery of the heart, the clinical condition also involves many other remaining group has diastolic failure, with stiffening and loss of processes and organs, including the baroreceptor reflex, the sym- adequate relaxation playing a major role in reducing filling and pathetic nervous system, the kidneys, angiotensin II and other cardiac output; ejection fraction may be normal even though peptides, aldosterone, and apoptosis of cardiac cells. Recognition stroke volume is significantly reduced. The proportion of patients of these factors has resulted in evolution of a variety of drug treat- with diastolic failure increases with age. Because other cardiovas- ment strategies (Table 13–1). cular conditions (especially myocardial infarction) are now being Large clinical trials have shown that therapy directed at non- treated more effectively, more patients are surviving long enough cardiac targets is more valuable in the long-term treatment of for heart failure to develop, making heart failure one of the cardio- heart failure than traditional positive inotropic agents (cardiac vascular conditions that is actually increasing in prevalence. glycosides [digitalis]). Extensive trials have shown that ACE Heart failure is a progressive disease that is characterized by a inhibitors, angiotensin receptor blockers, certain β blockers, gradual reduction in cardiac performance, punctuated in many cases aldosterone receptor antagonists, and combined hydralazine- by episodes of acute decompensation, often requiring hospitalization. nitrate therapy are the only agents in current use that actually prolong life in patients with chronic heart failure. These strategies are useful in both systolic and diastolic failure. Positive inotropic ∗ The author thanks Dr. William W. Parmley, MD, who was coauthor of drugs, on the other hand, are helpful mainly in acute systolic fail- this chapter in prior editions. ure. Cardiac glycosides also reduce symptoms in chronic systolic 211 212 SECTION III Cardiovascular-Renal Drugs TABLE 13–1 Drug groups used in heart failure. enters the cell through the cell membrane. (Ryanodine is a potent negative inotropic plant alkaloid that interferes with the release of Chronic heart failure Acute heart failure calcium through cardiac SR channels.) Diuretics Diuretics C. Amount of Calcium Stored in the Sarcoplasmic Aldosterone receptor antagonists Vasodilators Reticulum Angiotensin-converting enzyme Beta agonists inhibitors The SR membrane contains a very efficient calcium uptake trans- 2+ Angiotensin receptor blockers Bipyridines porter known as the sarcoplasmic endoplasmic reticulum Ca - ATPase (SERCA). This pump maintains free cytoplasmic calcium Beta blockers Natriuretic peptide at very low levels during diastole by pumping calcium into the SR. Cardiac glycosides SERCA is normally inhibited by phospholamban; phosphoryla- Vasodilators tion of phospholamban by protein kinase A (eg, by β agonists) removes this inhibition. The amount of calcium sequestered in the SR is thus determined, in part, by the amount accessible to this transporter and the activity of the sympathetic nervous system. heart failure. Other positive inotropic drugs have consistently This in turn is dependent on the balance of calcium influx (pri- reduced survival in chronic failure, and their use is discouraged. marily through the voltage-gated membrane L-type calcium chan- nels) and calcium efflux, the amount removed from the cell Control of Normal Cardiac Contractility (primarily via the sodium-calcium exchanger, a transporter in the 2+ The vigor of contraction of heart muscle is determined by several cell membrane). The amount of Ca released from the SR 2+ processes that lead to the movement of actin and myosin filaments depends on the response of the RyR channels to trigger Ca. in the cardiac sarcomere (Figure 13–1). Ultimately, contraction results from the interaction of activator calcium (during systole) D. Amount of Trigger Calcium with the actin-troponin-tropomyosin system, thereby releasing the The amount of trigger calcium that enters the cell depends on the actin-myosin interaction. This activator calcium is released from availability of membrane calcium channels and the duration of the sarcoplasmic reticulum (SR). The amount released depends on their opening. As described in Chapters 6 and 9, sympathomimet- the amount stored in the SR and on the amount of trigger calcium ics cause an increase in calcium influx through an action on these that enters the cell during the plateau of the action potential. channels. Conversely, the calcium channel blockers (see Chapter 12) reduce this influx and depress contractility. A. Sensitivity of the Contractile Proteins to Calcium and Other Contractile Protein Modifications E. Activity of the Sodium-Calcium Exchanger The determinants of calcium sensitivity, ie, the curve relating the This antiporter (NCX) uses the sodium gradient to move calcium shortening of cardiac myofibrils to the cytoplasmic calcium con- against its concentration gradient from the cytoplasm to the extra- centration, are incompletely understood, but several types of drugs cellular space. Extracellular concentrations of these ions are much can be shown to affect calcium sensitivity in vitro. Levosimendan less labile than intracellular concentrations under physiologic con- is the most recent example of a drug that increases calcium sensi- ditions. The sodium-calcium exchanger’s ability to carry out this tivity (it may also inhibit phosphodiesterase) and reduces symp- transport is thus strongly dependent on the intracellular concen- toms in models of heart failure. trations of both ions, especially sodium. A recent report suggests that an experimental drug, omecantiv mecarbil (CK-1827452), alters the rate of transition of myosin F. Intracellular Sodium Concentration and Activity of + + from a low-actin-binding state to a strongly actin-bound force- Na /K -ATPase + + generating state. Preliminary studies in experimental animal mod- Na /K -ATPase, by removing intracellular sodium, is the major els of heart failure indicate that this agent may provide a new determinant of sodium concentration in the cell. The sodium approach to the treatment of heart failure in humans. Clinical tri- influx through voltage-gated channels, which occurs as a normal als are underway. part of almost all cardiac action potentials, is another determinant, although the amount of sodium that enters with each action B. Amount of Calcium Released from the Sarcoplasmic potential is much less than 1% of the total intracellular sodium. + + Reticulum Na /K -ATPase appears to be the primary target of digoxin and A small rise in free cytoplasmic calcium, brought about by calcium other cardiac glycosides. influx during the action potential, triggers the opening of calcium- gated, ryanodine-sensitive calcium channels (RyR2) in the mem- brane of the cardiac SR and the rapid release of a large amount of Pathophysiology of Heart Failure the ion into the cytoplasm in the vicinity of the actin-troponin- Heart failure is a syndrome with many causes that may involve one tropomyosin complex. The amount released is proportional to the or both ventricles. Cardiac output is usually below the normal amount stored in the SR and the amount of trigger calcium that range (“low-output” failure). Systolic dysfunction, with reduced  CHAPTER 13 Drugs Used in Heart Failure 213 Myofibril syncytium Digoxin – Interstitium Cell membrane Na+/K+-ATPase NCX Cav–L Cytoplasm ATP – Na+ + Ca2+ channel blockers K+ Ca2+ β agonists Trigger Ca2+ SERCA ATP CalS CalS Sarcoplasmic Ca2+ Ca2+ Ca2+ reticulum CalS CalS CalS RyR ATP Ca2+ Ca2+ sensitizers Ca2+ + Actin-tropomyosin- Myosin Z troponin Sarcomere FIGURE 13–1 Schematic diagram of a cardiac muscle sarcomere, with sites of action of several drugs that alter contractility. Na+/K+-ATPase, the sodium pump, is the site of action of cardiac glycosides. NCX is the sodium-calcium exchanger. Cav-L is the voltage-gated, L-type calcium channel. SERCA (sarcoplasmic endoplasmic reticulum Ca2+-ATPase) is a calcium transporter ATPase that pumps calcium into the sarcoplasmic reticulum (SR). CalS is calcium bound to calsequestrin, a high-capacity Ca2+-binding protein. RyR (ryanodine RyR2 receptor) is a calcium-activated calcium channel in the membrane of the SR that is triggered to release stored calcium. Calcium sensitizers act at the actin-troponin-tropomyosin complex where activator calcium brings about the contractile interaction of actin and myosin. Black arrows represent processes that initiate contraction or support basal tone. Green arrows represent processes that promote relaxation. 214 SECTION III Cardiovascular-Renal Drugs cardiac output and significantly reduced ejection fraction (< 45%; normal > 60%), is typical of acute failure, especially that resulting Cardia 1 c perfo from myocardial infarction. Diastolic dysfunction often occurs as rman CO ce a result of hypertrophy and stiffening of the myocardium, and 2 CO although cardiac output is reduced, ejection fraction may be nor- NE, A B mal. Heart failure due to diastolic dysfunction does not usually EF CO ET NE, A respond optimally to positive inotropic drugs. ET EF “High-output” failure is a rare form of heart failure. In this NE, A Afterload EF ET condition, the demands of the body are so great that even increased Afterload cardiac output is insufficient. High-output failure can result from Afterload hyperthyroidism, beriberi, anemia, and arteriovenous shunts. This Time form of failure responds poorly to the drugs discussed in this chap- ter and should be treated by correcting the underlying cause. FIGURE 13–3 Vicious spiral of progression of heart failure. The primary signs and symptoms of all types of heart failure Decreased cardiac output (CO) activates production of neurohor- include tachycardia, decreased exercise tolerance, shortness of mones (NE, norepinephrine; AII, angiotensin II; ET, endothelin), which breath, and cardiomegaly. Peripheral and pulmonary edema (the cause vasoconstriction and increased afterload. This further reduces congestion of congestive heart failure) are often but not always ejection fraction (EF) and CO, and the cycle repeats. The downward present. Decreased exercise tolerance with rapid muscular fatigue spiral is continued until a new steady state is reached in which CO is is the major direct consequence of diminished cardiac output. The lower and afterload is higher than is optimal for normal activity. other manifestations result from the attempts by the body to com- Circled points 1, 2, and B represent points on the ventricular function pensate for the intrinsic cardiac defect. curves depicted in Figure 13–4. Neurohumoral (extrinsic) compensation involves two major mechanisms (previously presented in Figure 6–7)—the sympa- thetic nervous system and the renin-angiotensin-aldosterone hor- monal response—plus several others. Some of the detrimental as heart failure. As a result, baroreceptor sensory input to the vaso- well as beneficial features of these compensatory responses are motor center is reduced even at normal pressures; sympathetic illustrated in Figure 13–2. The baroreceptor reflex appears to be outflow is increased, and parasympathetic outflow is decreased. reset, with a lower sensitivity to arterial pressure, in patients with Increased sympathetic outflow causes tachycardia, increased car- diac contractility, and increased vascular tone. Vascular tone is further increased by angiotensin II and endothelin, a potent vaso- constrictor released by vascular endothelial cells. Vasoconstriction Cardiac output increases afterload, which further reduces ejection fraction and cardiac output. The result is a vicious cycle that is characteristic of heart failure (Figure 13–3). Neurohumoral antagonists and vaso- dilators reduce heart failure mortality by interrupting the cycle Carotid sinus firing Renal blood flow and slowing the downward spiral. After a relatively short exposure to increased sympathetic drive, complex down-regulatory changes in the cardiac β1-adrenoceptor– Sympathetic Renin G protein-effector system take place that result in diminished discharge release stimulatory effects. Beta2 receptors are not down-regulated and may develop increased coupling to the IP3-DAG cascade. It has also been suggested that cardiac β3 receptors (which do not appear Angiotensin II to be down-regulated in failure) may mediate negative inotropic effects. Excessive β activation can lead to leakage of calcium from Force the SR via RyR channels and contributes to stiffening of the ven- Rate tricles and arrhythmias. Prolonged β activation also increases cas- pases, the enzymes responsible for apoptosis. Increased angiotensin Preload Afterload Remodeling II production leads to increased aldosterone secretion (with sodium and water retention), to increased afterload, and to Cardiac output (via compensation) remodeling of both heart and vessels (discussed below). Other hormones are released, including natriuretic peptide, endothelin, FIGURE 13–2 Some compensatory responses that occur during and vasopressin (see Chapter 17). Within the heart, failure- congestive heart failure. In addition to the effects shown, sympathetic induced changes have been documented in calcium handling in discharge facilitates renin release, and angiotensin II increases the SR by SERCA and phospholamban; in transcription factors norepinephrine release by sympathetic nerve endings (dashed that lead to hypertrophy and fibrosis; in mitochondrial function, arrows). which is critical for energy production in the overworked heart;  CHAPTER 13 Drugs Used in Heart Failure 215 and in ion channels, especially potassium channels, which facili- 100 tate arrhythmogenesis, a primary cause of death in heart failure. Phosphorylation of RyR channels in the sarcoplasmic reticulum 2+ enhances and dephosphorylation reduces Ca release; studies in 80 animal models indicate that the enzyme primarily responsible LV stroke work (g-m/m2) for RyR dephosphorylation, protein phosphatase 1 (PP1), is up- Normal range regulated in heart failure. These cellular changes provide many 60 potential targets for future drugs. The most important intrinsic compensatory mechanism is A + Ino myocardial hypertrophy. This increase in muscle mass helps Depressed 40 1 maintain cardiac performance. However, after an initial beneficial 2 effect, hypertrophy can lead to ischemic changes, impairment Vaso B of diastolic filling, and alterations in ventricular geometry. 20 Remodeling is the term applied to dilation (other than that due to passive stretch) and other slow structural changes that occur in the Shock stressed myocardium. It may include proliferation of connective tissue cells as well as abnormal myocardial cells with some bio- 0 0 10 20 30 40 chemical characteristics of fetal myocytes. Ultimately, myocytes in LV filling pressure (mm Hg) the failing heart die at an accelerated rate through apoptosis, leav- ing the remaining myocytes subject to even greater stress. FIGURE 13–4 Relation of left ventricular (LV) performance to filling pressure in patients with acute myocardial infarction, an important cause of heart failure. The upper line indicates the range Pathophysiology of Cardiac Performance for normal, healthy individuals. At a given level of exercise, the heart Cardiac performance is a function of four primary factors: operates at a stable point, eg, point A. In heart failure, function is shifted down and to the right, through points 1 and 2, finally 1. Preload: When some measure of left ventricular performance reaching point B. A “pure” positive inotropic drug (+ Ino) would move such as stroke volume or stroke work is plotted as a function of the operating point upward by increasing cardiac stroke work. left ventricular filling pressure or end-diastolic fiber length, the A vasodilator (Vaso) would move the point leftward by reducing resulting curve is termed the left ventricular function curve filling pressure. Successful therapy usually results in both effects. (Figure 13–4). The ascending limb (< 15 mm Hg filling pres- (Modified and reproduced with permission, from Swan HJC, Parmley WW: sure) represents the classic Frank-Starling relation described in Congestive heart failure. In: Sodeman WA Jr, Sodeman TM [editors]: Pathologic physiology texts. Beyond approximately 15 mm Hg, there is a Physiology. Saunders, 1979.) plateau of performance. Preloads greater than 20–25 mm Hg result in pulmonary congestion. As noted above, preload is usu- ally increased in heart failure because of increased blood volume and venous tone. Because the function curve of the failing heart 4. Heart rate: The heart rate is a major determinant of cardiac is lower, the plateau is reached at much lower values of stroke output. As the intrinsic function of the heart decreases in fail- work or output. Increased fiber length or filling pressure ure and stroke volume diminishes, an increase in heart rate— increases oxygen demand in the myocardium, as described in through sympathetic activation of β adrenoceptors—is the first Chapter 12. Reduction of high filling pressure is the goal of salt compensatory mechanism that comes into play to maintain restriction and diuretic therapy in heart failure. Venodilator cardiac output. drugs (eg, nitroglycerin) also reduce preload by redistributing blood away from the chest into peripheral veins. 2. Afterload: Afterload is the resistance against which the heart must pump blood and is represented by aortic impedance and BASIC PHARMACOLOGY OF systemic vascular resistance. As noted in Figure 13–2, as cardiac DRUGS USED IN HEART FAILURE output falls in chronic failure, a reflex increase in systemic vas- cular resistance occurs, mediated in part by increased sympa- Although digitalis is not the first drug and never the only drug thetic outflow and circulating catecholamines and in part by activation of the renin-angiotensin system. Endothelin, a potent used in heart failure, we begin our discussion with this group vasoconstrictor peptide, is also involved. This sets the stage for because other drugs are discussed in more detail in other the use of drugs that reduce arteriolar tone in heart failure. chapters. 3. Contractility: Heart muscle obtained by biopsy from patients with chronic low-output failure demonstrates a reduction in DIGITALIS intrinsic contractility. As contractility decreases in the patient, there is a reduction in the velocity of muscle shortening, the rate of intraventricular pressure development (dP/dt), and the Digitalis is the genus name for the family of plants that provide stroke output achieved (Figure 13–4). However, the heart is most of the medically useful cardiac glycosides, eg, digoxin. Such usually still capable of some increase in all of these measures of plants have been known for thousands of years but were used contractility in response to inotropic drugs. erratically and with variable success until 1785, when William 216 SECTION III Cardiovascular-Renal Drugs Withering, an English physician and botanist, published a mono- heart and are discussed below. The fact that a receptor for cardiac graph describing the clinical effects of an extract of the purple glycosides exists on the sodium pump has prompted some investi- foxglove plant (Digitalis purpurea, a major source of these agents). gators to propose that an endogenous digitalis-like steroid, possi- bly ouabain or marinobufagenin, must exist. Furthermore, Chemistry additional functions of Na+/K+-ATPase have been postulated, involving apoptosis, cell growth and differentiation, immunity, All of the cardiac glycosides, or cardenolides—of which digoxin is and carbohydrate metabolism. 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 A. Cardiac Effects pH-dependent. Digoxin is obtained from Digitalis lanata, the white 1. Mechanical effects—Cardiac glycosides increase contrac- foxglove, but many common plants (eg, oleander, lily of the valley, tion of the cardiac sarcomere by increasing the free calcium con- and milkweed) contain cardiac glycosides with similar properties. centration in the vicinity of the contractile proteins during systole. The increase in calcium concentration is the result of a two-step O process: first, an increase of intracellular sodium concentration Aglycone + + (genin) 21 23 C O because of Na /K -ATPase inhibition; and second, a relative HO 20 22 Lactone reduction of calcium expulsion from the cell by the sodium- 18 CH3 H calcium exchanger (NCX in Figure 13–1) caused by the increase 11 12 13 17 16 in intracellular sodium. The increased cytoplasmic calcium is 19 H3 C HH 14 15 sequestered by SERCA in the SR for later release. Other mecha- 1 9 nisms have been proposed but are not well supported. 2 10 8 OH B The net result of the action of therapeutic concentrations of a 3 5 7 Sugar O 4 6 cardiac glycoside is a distinctive increase in cardiac contractility H (Figure 13–5, bottom trace, panels A and B). In isolated myocar- Steroid 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 Pharmacokinetics cardiovascular reflexes and the pathophysiology of heart failure. Digoxin, the only cardiac glycoside used in the USA, is 65–80% absorbed after oral administration. Absorption of other glycosides 2. Electrical effects—The effects of digitalis on the electrical varies from zero to nearly 100%. Once present in the blood, all properties of the heart are a mixture of direct and autonomic cardiac glycosides are widely distributed to tissues, including the actions. Direct actions on the membranes of cardiac cells follow a central nervous system. well-defined progression: an early, brief prolongation of the action Digoxin is not extensively metabolized in humans; almost two potential, followed by shortening (especially the plateau phase). thirds is excreted unchanged by the kidneys. Its renal clearance is The decrease in action potential duration is probably the result of proportional to creatinine clearance, and the half-life is 36–40 increased potassium conductance that is caused by increased intra- hours in patients with normal renal function. Equations and cellular calcium (see Chapter 14). All these effects can be observed nomograms are available for adjusting digoxin dosage in patients at therapeutic concentrations in the absence of overt toxicity with renal impairment. (Table 13–2). At higher concentrations, resting membrane potential is reduced (made less negative) as a result of inhibition of the Pharmacodynamics sodium pump and reduced intracellular potassium. As toxicity Digoxin has multiple direct and indirect cardiovascular effects, progresses, oscillatory depolarizing afterpotentials appear follow- with both therapeutic and toxic consequences. In addition, it has ing normally evoked action potentials (Figure 13–5, panel C). undesirable effects on the central nervous system and gut. The afterpotentials (also known as delayed after-depolariza- At the molecular level, all therapeutically useful cardiac glyco- tions, DADs) are associated with overloading of the intracellular sides inhibit Na+/K+-ATPase, the membrane-bound transporter calcium stores and oscillations in the free intracellular calcium often called the sodium pump (Figure 13–1). Although several ion concentration. When afterpotentials reach threshold, they isoforms of this ATPase occur and have varying sensitivity to car- elicit action potentials (premature depolarizations, ectopic diac glycosides, they are highly conserved in evolution. Inhibition “beats”) that are coupled to the preceding normal action poten- of this transporter over most of the dose range has been extensively tials. If afterpotentials in the Purkinje conducting system regu- documented in all tissues studied. It is probable that this inhibi- larly reach threshold in this way, bigeminy will be recorded on tory action is largely responsible for the therapeutic effect (positive the electrocardiogram (Figure 13–6). With further intoxication, inotropy) as well as a major portion of the toxicity of digitalis. each afterpotential-evoked action potential will itself elicit a Other molecular-level effects of digitalis have been studied in the suprathreshold after-potential, and a self-sustaining tachycardia will  CHAPTER 13 Drugs Used in Heart Failure 217 A Control B Ouabain 10–7 mol/L C Ouabain 47 minutes 25 min 0 Membrane mV potential –50 Calcium 10–4 detector L/Lmax light 0 Contraction 3 mg 100 ms FIGURE 13–5 Effects of a cardiac glycoside, ouabain, on isolated cardiac tissue. The top tracing shows action potentials evoked during the control period (panel A), early in the “therapeutic” phase (B), and later, when toxicity is present (C). The middle tracing shows the light (L) emitted by the calcium-detecting protein aequorin (relative to the maximum possible, Lmax) and is roughly proportional to the free intracellular calcium concentration. The bottom tracing records the tension elicited by the action potentials. The early phase of ouabain action (panel B) shows a slight shortening of action potential and a marked increase in free intracellular calcium concentration and contractile tension. The toxic phase (panel C) is associated with depolarization of the resting potential, a marked shortening of the action potential, and the appearance of an oscillatory depolarization, calcium increment, and contraction (arrows). (Unpublished data kindly provided by P Hess and H Gil Wier.) be established. If allowed to progress, such a tachycardia may The most common cardiac manifestations of digitalis toxicity deteriorate into fibrillation; in the case of ventricular fibrillation, include atrioventricular junctional rhythm, premature ventricular the arrhythmia will be rapidly fatal unless corrected. depolarizations, bigeminal rhythm, and second-degree atrioven- Autonomic actions of cardiac glycosides on the heart involve tricular blockade. However, it is claimed that digitalis can cause both the parasympathetic and the sympathetic systems. In the virtually any arrhythmia. lower portion of the dose range, cardioselective parasympathomi- metic effects predominate. In fact, these atropine-blockable effects B. Effects on Other Organs account for a significant portion of the early electrical effects of Cardiac glycosides affect all excitable tissues, including smooth digitalis (Table 13–2). This action involves sensitization of the muscle and the central nervous system. The gastrointestinal tract baroreceptors, central vagal stimulation, and facilitation of musca- is the most common site of digitalis toxicity outside the heart. The rinic transmission at the cardiac muscle cell. Because cholinergic effects include anorexia, nausea, vomiting, and diarrhea. This innervation is much richer in the atria, these actions affect atrial toxicity is caused in part by direct effects on the gastrointestinal and atrioventricular nodal function more than Purkinje or ven- tract and in part by central nervous system actions. tricular function. Some of the cholinomimetic effects are useful in Central nervous system effects include vagal and chemoreceptor the treatment of certain arrhythmias. At toxic levels, sympathetic trigger zone stimulation. Less often, disorientation and hallucinations— outflow is increased by digitalis. This effect is not essential for especially in the elderly—and visual disturbances are noted. The typical digitalis toxicity but sensitizes the myocardium and exag- latter effect may include aberrations of color perception. gerates all the toxic effects of the drug. Gynecomastia is a rare effect reported in men taking digitalis. TABLE 13–2 Effects of digoxin on electrical properties of cardiac tissues. Tissue or Variable Effects at Therapeutic Dosage Effects at Toxic Dosage Sinus node ↓ Rate ↓ Rate Atrial muscle ↓ Refractory period ↓ Refractory period, arrhythmias Atrioventricular node ↓ Conduction velocity, ↑ refractory period ↓ Refractory period, arrhythmias Purkinje system, ventricular muscle Slight ↓ refractory period Extrasystoles, tachycardia, fibrillation Electrocardiogram ↑ PR interval, ↓ QT interval Tachycardia, fibrillation, arrest at extremely high dosage 218 SECTION III Cardiovascular-Renal Drugs NSR PVB NSR PVB (not the USA). A group of β-adrenoceptor stimulants has also been used as digitalis substitutes, but they may increase mortality (see below). V6 BIPYRIDINES ST Inamrinone (previously called amrinone) and milrinone are bipyridine compounds that inhibit phosphodiesterase isozyme 3 FIGURE 13–6 Electrocardiographic record showing digitalis- (PDE-3). They are active orally as well as parenterally but are induced bigeminy. The complexes marked NSR are normal sinus available only in parenteral forms. They have elimination half-lives rhythm beats; an inverted T wave and depressed ST segment are of 3–6 hours, with 10–40% being excreted in the urine. present. The complexes marked PVB are premature ventricular beats and are the electrocardiographic manifestations of depolarizations evoked by delayed oscillatory afterpotentials as shown in Figure Pharmacodynamics 13–5. (Modified and reproduced, with permission, from Goldman MJ: Principles of The bipyridines increase myocardial contractility by increasing Clinical Electrocardiography, 12th ed. Lange, 1986.) inward calcium flux in the heart during the action potential; they may also alter the intracellular movements of calcium by influencing the sarcoplasmic reticulum. They also have an important vasodilat- ing effect. Inhibition of phosphodiesterase results in an increase in C. Interactions with Potassium, Calcium, and Magnesium cAMP and the increase in contractility and vasodilation. Potassium and digitalis interact in two ways. First, they inhibit The toxicity of inamrinone includes nausea and vomiting; each other’s binding to Na+/K+-ATPase; therefore, hyperkalemia arrhythmias, thrombocytopenia, and liver enzyme changes have reduces the enzyme-inhibiting actions of cardiac glycosides, also been reported in a significant number of patients. This drug whereas hypokalemia facilitates these actions. Second, abnormal has been withdrawn in some countries. Milrinone appears less cardiac automaticity is inhibited by hyperkalemia (see Chapter 14). likely to cause bone marrow and liver toxicity than inamrinone, + Moderately increased extracellular K therefore reduces the effects but it does cause arrhythmias. Inamrinone and milrinone are now of digitalis, especially the toxic effects. used only intravenously and only for acute heart failure or severe Calcium ion facilitates the toxic actions of cardiac glycosides by exacerbation of chronic heart failure. 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- BETA-ADRENOCEPTOR AGONISTS duced arrhythmia. The effects of magnesium ion are opposite to those of calcium. These interactions mandate careful evaluation of The general pharmacology of these agents is discussed in Chapter 9. serum electrolytes in patients with digitalis-induced arrhythmias. The selective β1 agonist that has been most widely used in patients with heart failure is dobutamine. This parenteral drug produces an increase in cardiac output together with a decrease in ventricu- lar filling pressure. Some tachycardia and an increase in myocar- OTHER POSITIVE INOTROPIC dial oxygen consumption have been reported. Therefore, the DRUGS USED IN HEART FAILURE potential for producing angina or arrhythmias in patients with coronary artery disease is significant, as is the tachyphylaxis that Istaroxime is an investigational steroid derivative that increases + + accompanies the use of any β stimulant. Intermittent dobutamine contractility by inhibiting Na /K -ATPase (like cardiac glycosides) 2+ infusion may benefit some patients with chronic heart failure. but in addition facilitates sequestration of Ca by the SR. The Dopamine has also been used in acute heart failure and may be latter action may render the drug less arrhythmogenic than particularly helpful if there is a need to raise blood pressure. digoxin. Istaroxime is in phase 2 clinical trials. Drugs that inhibit phosphodiesterases, the family of enzymes that inactivate cAMP and cGMP, have long been used in therapy of heart failure. Although they have positive inotropic effects, DRUGS WITHOUT POSITIVE most of their benefits appear to derive from vasodilation, as dis- INOTROPIC EFFECTS USED IN cussed below. The bipyridines inamrinone and milrinone are the most successful of these agents found to date, but their usefulness HEART FAILURE is limited. Levosimendan, a drug that sensitizes the troponin These agents—not positive inotropic drugs—are the first-line system to calcium, also appears to inhibit phosphodiesterase and therapies for chronic heart failure. The drugs most commonly to cause some vasodilation in addition to its inotropic effects. used are diuretics, ACE inhibitors, angiotensin receptor antago- Some clinical trials suggest that this drug may be useful in patients nists, aldosterone antagonists, and β blockers (Table 13–1). In with heart failure, and the drug has been approved in some countries acute failure, diuretics and vasodilators play important roles.  CHAPTER 13 Drugs Used in Heart Failure 219 DIURETICS intravenous dose followed by continuous infusion. Excessive hypotension is the most common adverse effect. Reports of sig- Diuretics, especially furosemide, are drugs of choice in heart failure nificant renal damage and deaths have resulted in extra warnings and are discussed in detail in Chapter 15. They have no direct regarding this agent, and it should be used with great caution. effect on cardiac contractility; their major mechanism of action in Plasma concentrations of endogenous BNP rise in most patients heart failure is to reduce venous pressure and ventricular preload. with heart failure and are correlated with severity. Measurement of This results in reduction of salt and water retention and edema and plasma BNP has become a useful diagnostic or prognostic test in its symptoms. The reduction of cardiac size, which leads to some centers. improved pump efficiency, is of major importance in systolic fail- Related peptides include atrial natriuretic peptide (ANP) and ure. Spironolactone and eplerenone, the aldosterone antagonist urodilatin, a similar peptide produced in the kidney. Carperitide and diuretics (see Chapter 15), have the additional benefit of decreasing ularitide, respectively, are investigational synthetic analogs of these morbidity and mortality in patients with severe heart failure who endogenous peptides and are in clinical trials (see Chapter 15). are also receiving ACE inhibitors and other standard therapy. One Bosentan and tezosentan, orally active competitive inhibitors possible mechanism for this benefit lies in accumulating evidence of endothelin (see Chapter 17), have been shown to have some that aldosterone may also cause myocardial and vascular fibrosis benefits in experimental animal models with heart failure, but and baroreceptor dysfunction in addition to its renal effects. results in human trials have been disappointing. Bosentan is approved for use in pulmonary hypertension (see Chapter 11). It has significant teratogenic and hepatotoxic effects. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, ANGIOTENSIN RECEPTOR BETA-ADRENOCEPTOR BLOCKERS BLOCKERS, & RELATED AGENTS Most patients with chronic heart failure respond favorably to cer- ACE inhibitors such as captopril are introduced in Chapter 11 tain β blockers in spite of the fact that these drugs can precipitate and discussed again in Chapter 17. These versatile drugs reduce acute decompensation of cardiac function (see Chapter 10). peripheral resistance and thereby reduce afterload; they also reduce Studies with bisoprolol, carvedilol, metoprolol, and nebivolol salt and water retention (by reducing aldosterone secretion) and in showed a reduction in mortality in patients with stable severe that way reduce preload. The reduction in tissue angiotensin levels heart failure, but this effect was not observed with another β also reduces sympathetic activity through diminution of angio- blocker, bucindolol. A full understanding of the beneficial action tensin’s presynaptic effects on norepinephrine release. Finally, these of β blockade is lacking, but suggested mechanisms include drugs reduce the long-term remodeling of the heart and vessels, an attenuation of the adverse effects of high concentrations of cate- effect that may be responsible for the observed reduction in mortal- cholamines (including apoptosis), up-regulation of β receptors, ity and morbidity (see Clinical Pharmacology). decreased heart rate, and reduced remodeling through inhibition Angiotensin AT1 receptor blockers such as losartan (see of the mitogenic activity of catecholamines. Chapters 11 and 17) appear to have similar but more limited beneficial effects. Angiotensin receptor blockers should be consid- ered in patients intolerant of ACE inhibitors because of incessant CLINICAL PHARMACOLOGY OF cough. In some trials, candesartan was beneficial when added to an ACE inhibitor. DRUGS USED IN HEART FAILURE Aliskiren, a renin inhibitor recently approved for hyperten- The American College of Cardiology/American Heart Association sion, is in clinical trials for heart failure. Preliminary results sug- (ACC/AHA) guidelines for management of chronic heart failure gest an efficacy similar to that of ACE inhibitors. specify four stages in the development of heart failure (Table 13–3). Patients in stage A are at high risk because of other disease but VASODILATORS have no signs or symptoms of heart failure. Stage B patients have evidence of structural heart disease but no symptoms of heart Vasodilators are effective in acute heart failure because they pro- failure. Stage C patients have structural heart disease and symp- vide a reduction in preload (through venodilation), or reduction toms of failure, and symptoms are responsive to ordinary therapy. in afterload (through arteriolar dilation), or both. Some evidence Stage D patients have heart failure refractory to ordinary therapy, suggests that long-term use of hydralazine and isosorbide dinitrate and special interventions (resynchronization therapy, transplant) can also reduce damaging remodeling of the heart. are required. A synthetic form of the endogenous peptide brain natriuretic Once stage C is reached, the severity of heart failure is usually peptide (BNP) is approved for use in acute (not chronic) cardiac described according to a scale devised by the New York Heart failure as nesiritide. This recombinant product increases cGMP Association. Class I failure is associated with no limitations on in smooth muscle cells and reduces venous and arteriolar tone in ordinary activities, and symptoms that occur only with greater experimental preparations. It also causes diuresis. The peptide has than ordinary exercise. Class II is characterized by slight limitation a short half-life of about 18 minutes and is administered as a bolus of activities, and results in fatigue and palpitations with ordinary 220 SECTION III Cardiovascular-Renal Drugs TABLE 13–3 Classification and treatment of chronic heart failure. ACC/AHA Stage1 NYHA Class2 Description Management 3 A Prefailure No symptoms but risk factors present Treat obesity, hypertension, diabetes, hyperlipidemia, etc B I Symptoms with severe exercise ACEI/ARB, β blocker, diuretic C II/III Symptoms with marked (class II) or mild Add aldosterone antagonist, digoxin; CRT, hydralazine/ (class III) exercise nitrate4 D IV Severe symptoms at rest Transplant, LVAD 1 American College of Cardiology/American Heart Association classification. 2 New York Heart Association classification. 3 Risk factors include hypertension, myocardial infarct, diabetes. 4 For selected populations, eg, African American. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CRT, cardiac resynchronization therapy; LVAD, left ventricular assist device. physical activity. Class III failure results in no symptoms at rest, diuretics, as first-line therapy for chronic heart failure. However, but fatigue, shortness of breath, and tachycardia occur with less ACE inhibitors cannot replace digoxin in patients already receiv- than ordinary physical activity. Class IV is associated with symp- ing the glycoside because patients withdrawn from digoxin dete- toms even when the patient is at rest. riorate while on ACE inhibitor therapy. By reducing preload and afterload in asymptomatic patients, ACE inhibitors (eg, enalapril) slow the progress of ventricular MANAGEMENT OF CHRONIC dilation and thus slow the downward spiral of heart failure. HEART FAILURE Consequently, ACE inhibitors are beneficial in all subsets of patients—from those who are asymptomatic to those in severe The major steps in the management of patients with chronic heart chronic failure. This benefit appears to be a class effect; that is, all failure are outlined in Table 13–3. The 2009 update to the ACC/ ACE inhibitors appear to be effective. AHA 2005 guidelines suggests that treatment of patients at high The angiotensin II AT1 receptor blockers (ARBs, eg, losartan) risk (stages A and B) should be focused on control of hyperten- produce beneficial hemodynamic effects similar to those of ACE sion, hyperlipidemia, and diabetes, if present. Once symptoms inhibitors. However, large clinical trials suggest that angiotensin and signs of failure are present, stage C has been entered, and receptor blockers are best reserved for patients who cannot tolerate active treatment of failure must be initiated. ACE inhibitors (usually because of cough). SODIUM REMOVAL VASODILATORS Sodium removal—by dietary salt restriction and a diuretic—is the mainstay in management of symptomatic heart failure, especially Vasodilator drugs can be divided into selective arteriolar dilators, if edema is present. In very mild failure a thiazide diuretic may be venous dilators, and drugs with nonselective vasodilating effects. tried, but a loop agent such as furosemide is usually required. The choice of agent should be based on the patient’s signs and Sodium loss causes secondary loss of potassium, which is particu- symptoms and hemodynamic measurements. Thus, in patients larly hazardous if the patient is to be given digitalis. Hypokalemia with high filling pressures in whom the principal symptom is can be treated with potassium supplementation or through the dyspnea, venous dilators such as long-acting nitrates will be most addition of an ACE inhibitor or a potassium-sparing diuretic such helpful in reducing filling pressures and the symptoms of pulmo- as spironolactone. Spironolactone or eplerenone should probably nary congestion. In patients in whom fatigue due to low left ven- be considered in all patients with moderate or severe heart failure, tricular output is a primary symptom, an arteriolar dilator such as since both appear to reduce both morbidity and mortality. hydralazine may be helpful in increasing forward cardiac output. In most patients with severe chronic failure that responds poorly to other therapy, the problem usually involves both elevated filling ACE INHIBITORS & ANGIOTENSIN pressures and reduced cardiac output. In these circumstances, dila- RECEPTOR BLOCKERS tion of both arterioles and veins is required. In a trial in African- American patients already receiving ACE inhibitors, addition of In patients with left ventricular dysfunction but no edema, an hydralazine and isosorbide dinitrate reduced mortality. As a result, ACE inhibitor should be the first drug used. Several large studies a fixed combination of these two agents has been made available have showed clearly that ACE inhibitors are superior to both pla- as isosorbide dinitrate/hydralazine (BiDil), and this is currently cebo and to vasodilators and must be considered, along with approved for use only in African Americans.  CHAPTER 13 Drugs Used in Heart Failure 221 BETA BLOCKERS & ION CHANNEL atrioventricular nodal tachycardia. At present, calcium channel blockers and adenosine are preferred for this application. Digoxin BLOCKERS is explicitly contraindicated in patients with Wolff-Parkinson- Trials of β-blocker therapy in patients with heart failure are based White syndrome and atrial fibrillation (see Chapter 14). on the hypothesis that excessive tachycardia and adverse effects of high catecholamine levels on the heart contribute to the down- Toxicity ward course of heart failure. The results clearly indicate that such In spite of its limited benefits and recognized hazards, digitalis is therapy is beneficial if initiated cautiously at low doses, even still heavily used and toxicity is common. Therapy for toxicity though acutely blocking the supportive effects of catecholamines manifested as visual changes or gastrointestinal disturbances gen- can worsen heart failure. Several months of therapy may be erally requires no more than reducing the dose of the drug. If required before improvement is noted; this usually consists of a cardiac arrhythmia is present and can be ascribed to digitalis, more slight rise in ejection fraction, slower heart rate, and reduction in vigorous therapy may be necessary. Serum digitalis and potassium symptoms. As noted above, not all β blockers have proved useful, levels and the electrocardiogram should always be monitored dur- but bisoprolol, carvedilol, metoprolol, and nebivolol have been ing therapy of significant digitalis toxicity. Electrolyte status shown to reduce mortality. should be corrected if abnormal (see above). Monitoring of potas- In contrast, the calcium-blocking drugs appear to have no role sium levels is particularly important in patients on renal dialysis. in the treatment of patients with heart failure. Their depressant In severe digitalis intoxication, serum potassium will already be effects on the heart may worsen heart failure. On the other hand, elevated at the time of diagnosis (because of potassium loss from slowing of heart rate with ivabradine (an If blocker, see Chapter 12) the intracellular compartment of skeletal muscle and other tis- appears to be of benefit. sues). Furthermore, automaticity is usually depressed, and antiar- rhythmic agents administered in this setting may lead to cardiac Digitalis arrest. Such patients are best treated with prompt insertion of a temporary cardiac pacemaker catheter and administration of digi- Digoxin is indicated in patients with heart failure and atrial fibril- talis antibodies (digoxin immune fab). These antibodies recog- lation. It is usually given only when diuretics and ACE inhibitors nize digitoxin and cardiac glycosides from many other plants in have failed to control symptoms. Only about 50% of patients with addition to digoxin. They are extremely useful in reversing severe normal sinus rhythm (usually those with documented systolic intoxication with most glycosides. dysfunction) will have relief of heart failure from digitalis. Better Digitalis-induced arrhythmias are frequently made worse by results are obtained in patients with atrial fibrillation. If the deci- cardioversion; this therapy should be reserved for ventricular sion is made to use a cardiac glycoside, digoxin is the one chosen fibrillation if the arrhythmia is glycoside-induced. in most cases (and the only one available in the USA). When symptoms are mild, slow loading (digitalization) with 0.125–0.25 mg per day is safer and just as effective as the rapid method CARDIAC RESYNCHRONIZATION (0.5–0.75 mg every 8 hours for three doses, followed by 0.125– 0.25 mg per day). THERAPY Determining the optimal level of digitalis effect may be diffi- Patients with normal sinus rhythm and a wide QRS interval, eg, cult. Unfortunately, toxic effects may occur before the therapeutic greater than 120 ms, have impaired synchronization of right and end point is detected. Measurement of plasma digoxin levels is left ventricular contraction. Poor synchronization of ventricular useful in patients who appear unusually resistant or sensitive; a contraction results in diminished cardiac output. Resynchronization, level of 1 ng/mL or less is appropriate. with left ventricular or biventricular pacing, has been shown to Because it has a moderate but persistent positive inotropic reduce mortality in patients with chronic heart failure who were effect, digitalis can, in theory, reverse all the signs and symptoms already receiving optimal medical therapy. of heart failure. Although the net effect of the drug on mortality is mixed, it reduces hospitalization and deaths from progressive heart failure at the expense of an increase in sudden death. It is important to note that the mortality rate is reduced in patients MANAGEMENT OF DIASTOLIC with serum digoxin concentrations of less than 0.9 ng/mL but HEART FAILURE increased in those with digoxin levels greater than 1.5 ng/mL. Most clinical trials have been carried out in patients with systolic dysfunction, so the evidence regarding the superiority or inferior- Other Clinical Uses of Digitalis ity of drugs in heart failure with preserved ejection fraction is Digitalis is useful in the management of atrial arrhythmias because meager. Most authorities support the use of the drug groups of its cardioselective parasympathomimetic effects. In atrial flutter described above, and the SENIORS 2009 study suggests that and fibrillation, the depressant effect of the drug on atrioventricu- nebivolol is effective in both systolic and diastolic failure. Control lar conduction helps control an excessively high ventricular rate. of hypertension is particularly important, and revascularization Digitalis has also been used in the control of paroxysmal atrial and should be considered if coronary artery disease is present. 222 SECTION III Cardiovascular-Renal Drugs Tachycardia limits filling time; therefore, bradycardic drugs may failure. Such patients can be usefully characterized on the basis of be particularly useful, at least in theory. three hemodynamic measurements: arterial pressure, left ventricu- lar filling pressure, and cardiac index. When filling pressure is 2 greater than 15 mm Hg and stroke work index is less than 20 g-m/m , MANAGEMENT OF ACUTE the mortality rate is high. Intermediate levels of these two variables imply a much better prognosis. HEART FAILURE Intravenous treatment is the rule in acute heart failure. Among Acute heart failure occurs frequently in patients with chronic fail- diuretics, furosemide is the most commonly used. Dopamine or ure. Such episodes are usually associated with increased exertion, dobutamine are positive inotropic drugs with prompt onset and emotion, excess salt intake, nonadherence to medical therapy, or short durations of action; they are most useful in patients with increased metabolic demand occasioned by fever, anemia, etc. A severe hypotension. Levosimendan has been approved for use in particularly common and important cause of acute failure—with acute failure in Europe, and noninferiority has been demonstrated or without chronic failure—is acute myocardial infarction. against dobutamine. Vasodilators in use in patients with acute Patients with acute myocardial infarction are best treated with decompensation include nitroprusside, nitroglycerine, and emergency revascularization using either coronary angioplasty and nesiritide. Reduction in afterload often improves ejection fraction, a stent, or a thrombolytic agent. Even with revascularization, acute but improved survival has not been documented. A small subset failure may develop in such patients. Many of the signs and symp- of patients in acute heart failure will have hyponatremia, presum- toms of acute and chronic failure are identical, but their therapies ably due to increased vasopressin activity. A V1a and V2 receptor diverge because of the need for more rapid response and the rela- antagonist, conivaptan, is approved for parenteral treatment of tively greater frequency and severity of pulmonary vascular con- euvolemic hyponatremia. Several clinical trials have indicated that gestion in the acute form. this drug and related V2 antagonists (tolvaptan) may have a ben- Measurements of arterial pressure, cardiac output, stroke work eficial effect in some patients with acute heart failure and hypona- index, and pulmonary capillary wedge pressure are particularly tremia. Thus far, vasopressin antagonists do not seem to reduce useful in patients with acute myocardial infarction and acute heart mortality. SUMMARY Drugs Used in Heart Failure Pharmacokinetics, Toxicities, Subclass Mechanism of Action Effects Clinical Applications Interactions DIURETICS Furosemide Loop diuretic: Decreases NaCl Increased excretion of salt Acute and chronic heart Oral and IV duration 2–4 h Toxicity: and KCl reabsorption in thick and water reduces failure severe hyperten- Hypovolemia, hypokalemia, ascending limb of the loop of cardiac preload and sion edematous orthostatic hypotension, ototoxicity, Henle in the nephron (see afterload reduces conditions sulfonamide allergy Chapter 15) pulmonary and peripheral edema Hydrochlorothiazide Decreases NaCl reabsorption Same as furosemide, but Mild chronic failure mild- Oral only duration 10–12 h Toxicity: in the distal convoluted tubule less efficacious moderate hypertension Hyponatremia, hypokalemia, hypercalciuria has not hyperglycemia, hyperuricemia, been shown to reduce hyperlipidemia, sulfonamide allergy mortality Three other loop diuretics: Bumetanide and torsemide similar to furosemide; ethacrynic acid not a sulfonamide Many other thiazides: All basically similar to hydrochlorothiazide, differing only in pharmacokinetics ALDOSTERONE ANTAGONISTS Spironolactone Blocks cytoplasmic aldoster- Increased salt and water Chronic heart failure Oral duration 24–72 h (slow onset one receptors in collecting excretion reduces remod- aldosteronism (cirrhosis, and offset) Toxicity: Hyperkalemia, tubules of nephron possible eling reduces mortality adrenal tumor) hyperten- antiandrogen actions membrane effect sion has been shown to reduce mortality Eplerenone: Similar to spironolactone; more selective antialdosterone effect; no significant antiandrogen action; has been shown to reduce mortality (continued )  CHAPTER 13 Drugs Used in Heart Failure 223 Pharmacokinetics, Toxicities, Subclass Mechanism of Action Effects Clinical Applications Interactions ANGIOTENSIN ANTAGONISTS Angiotensin-converting Inhibits ACE reduces AII Arteriolar and venous Chronic heart failure Oral half-life 2–4 h but given in large enzyme (ACE) inhibitors: formation by inhibiting con- dilation reduces aldoster- hypertension diabetic doses so duration 12–24 h Toxicity: Captopril version of AI to All one secretion reduces renal disease has been Cough, hyperkalemia, angioneurotic cardiac remodeling shown to reduce mortality edema Interactions: Additive with other angiotensin antagonists Angiotensin receptor Antagonize AII effects at AT1 Like ACE inhibitors Like ACE inhibitors used Oral duration 6–8 h Toxicity: blockers (ARBs): receptors in patients intolerant to Hyperkalemia; angioneurotic edema Losartan ACE inhibitors has been Interactions: Additive with other shown to reduce mortality angiotensin antagonists Enalapril, many other ACE inhibitors: Like captopril Candesartan, many other ARBs: Like losartan BETA BLOCKERS Carvedilol Competitively blocks β1 Slows heart rate reduces Chronic heart failure: To Oral duration 10–12 h Toxicity: receptors (see Chapter 10) blood pressure poorly slow progression reduce Bronchospasm, bradycardia, understood effects mortality in moderate and atrioventricular block, acute cardiac reduces heart failure severe heart failure many decompensation see Chapter 10 for mortality other indications in other toxicities and interactions Chapter 10 Metoprolol, bisoprolol, nebivolol: Select group of b blockers that have been shown to reduce heart failure mortality CARDIAC GLYCOSIDE Digoxin Na+/K+-ATPase inhibition Increases cardiac Chronic symptomatic heart Oral, parenteral duration 36–40 h 2+ results in reduced Ca expul- contractility cardiac failure rapid ventricular Toxicity: Nausea, vomiting, diarrhea sion and increased Ca2+ stored parasympathomimetic rate in atrial fibrillation cardiac arrhythmias in sarcoplasmic reticulum effect (slowed sinus has not been definitively heart rate, slowed shown to reduce mortality atrioventricular conduction) VASODILATORS Venodilators: Releases nitric oxide (NO) Venodilation reduces Acute and chronic heart Oral 4–6 h duration Toxicity: Isosorbide dinitrate activates guanylyl cyclase (see preload and ventricular failure angina Postural hypotension, tachycardia, Chapter 12) stretch headache Interactions: Additive with other vasodilators and synergistic with phosphodiesterase type 5 inhibitors Arteriolar dilators: Probably increases NO Reduces blood pressure Hydralazine plus nitrates Oral 8–12 h duration Toxicity: Hydralazine synthesis in endothelium (see and afterload results in have reduced mortality Tachycardia, fluid retention, lupus-like Chapter 11) increased cardiac output syndrome Combined arteriolar and Releases NO spontaneously Marked vasodilation Acute cardiac decompen- IV only duration 1–2 min Toxicity: venodilator: activates guanylyl cyclase reduces preload and sation hypertensive emer- Excessive hypotension, thiocyanate Nitroprusside afterload gencies (malignant and cyanide toxicity Interactions: hypertension) Additive with other vasodilators BETA-ADRENOCEPTOR AGONISTS Dobutamine Beta1-selective agonist Increases cardiac Acute decompensated IV only duration a few minutes increases cAMP synthesis contractility, output heart failure intermittent Toxicity: Arrhythmias Interactions: therapy in chronic failure Additive with other sympathomimetics reduces symptoms Dopamine Dopamine receptor agonist Increases renal blood flow Acute decompensated IV only duration a few minutes higher doses activate β and α higher doses increase heart failure shock Toxicity: Arrhythmias Interactions: adrenoceptors cardiac force and blood Additive with sympathomimetics pressure (continued ) 224 SECTION III Cardiovascular-Renal Drugs Pharmacokinetics, Toxicities, Subclass Mechanism of Action Effects Clinical Applications Interactions BIPYRIDINES Inamrinone, Phosphodiesterase type 3 Vasodilators; lower periph- Acute decompensated IV only duration 3–6 h Toxicity: milrinone inhibitors decrease cAMP eral vascular resistance heart failure increase Arrhythmias Interactions: Additive breakdown also increase cardiac mortality in chronic failure with other arrhythmogenic agents contractility NATRIURETIC PEPTIDE Nesiritide Activates BNP receptors, Vasodilation diuresis Acute decompensated IV only duration 18 minutes increases cGMP failure has not been Toxicity: Renal damage, hypotension, shown to reduce mortality may increase mortality P R E P A R A T I O N S A V A I L A B L E DIURETICS Fosinopril (generic, Monopril) Oral: 10, 20, 40 mg tablets See Chapter 15. Lisinopril (generic, Prinivil, Zestril) Oral: 2.5, 5, 10, 20, 30, 40 mg tablets DIGITALIS Moexipril (generic, Univasc) Oral: 7.5, 15 mg tablets Digoxin (generic, Lanoxicaps, Lanoxin) ∗ Perindopril (Aceon) Oral: 0.125, 0.25 mg tablets; 0.05, 0.1, 0.2 mg capsules ; 0.05 mg/mL Oral: 2, 4, 8 mg tablets elixir Parenteral: 0.1, 0.25 mg/mL for injection Quinapril (generic, Accupril) Oral: 5, 10, 20, 40 mg tablets Ramipril (Altace) DIGITALIS ANTIBODY Oral: 1.25, 2.5, 5, 10 mg capsules Digoxin immune fab (ovine) (Digibind, DigiFab) Trandolapril (Mavik) Parenteral: 38 or 40 mg per vial with 75 mg sorbitol lyophilized Oral: 1, 2, 4 mg tablets powder to reconstitute for IV injection. Each vial will bind approximately 0.5 mg digoxin or digitoxin. ANGIOTENSIN RECEPTOR BLOCKERS Candesartan (Atacand) SYMPATHOMIMETICS MOST COMMONLY Oral: 4, 8, 16, 32 mg tablets USED IN CONGESTIVE HEART FAILURE Eprosartan (Teveten) Oral: 600 mg tablets Dobutamine (generic) Parenteral: 12.5 mg/mL for IV infusion Irbesartan (Avapro) Oral: 75, 150, 300 mg tablets Dopamine (generic, Intropin) Parenteral: 40, 80, 160 mg/mL for IV injection; 80, 160, 320 mg/dL Losartan (Cozaar) in 5% dextrose for IV infusion Oral: 25, 50, 100 mg tablets Olmesartan (Benicar) Oral: 5, 20, 40 mg tablets ANGIOTENSIN-CONVERTING ENZYME Telmisartan (Micardis) INHIBITORS Oral: 20, 40, 80 mg tablets Benazepril (generic, Lotensin) Valsartan (Diovan) Oral: 5, 10, 20, 40 mg tablets Oral: 40, 80, 160, 320 mg tablets Captopril (generic, Capoten) Oral: 12.5, 25, 50, 100 mg tablets BETA BLOCKERS THAT HAVE REDUCED Enalapril (generic, Vasotec, Vasotec I.V.) Oral: 2.5, 5, 10, 20 mg tablets MORTALITY IN HEART FAILURE Parenteral: 1.25 mg enalaprilat/mL Bisoprolol (generic, Zebeta, off-label use) Oral: 5, 10 mg tablets  CHAPTER 13 Drugs Used in Heart Failure 225 Carvedilol (Coreg) OTHER DRUGS Oral: 3.125, 6.25, 12.5, 25 mg tablets; 10, 20, 40, 80 mg extended-re- lease capsules Hydralazine (generic) (see Chapter 11) Metoprolol (Lopressor, Toprol XL) Isosorbide dinitrate (see Chapter 12) Oral: 50, 100 mg tablets; 25, 50, 100, 200 mg extended-release Nitroglycerine (see Chapter 12) tablets Hydralazine plus isosorbide dinitrate fixed dose (BiDil) Parenteral: 1 mg/mL for IV injection Oral: 37.5 mg hydralazine + 20 mg isosorbide dinitrate tablets Nebivolol (Bystolic) Inamrinone (generic) Oral: 2.5, 5, 10 mg tablets Parenteral: 5 mg/mL for IV injection Milrinone (generic, Primacor) Parenteral: 1 mg/mL for IV injection ALDOSTERONE ANTAGONISTS Nesiritide (Natrecor) Spironolactone (generic, Aldactone) Parenteral: 1.58 mg powder to reconstitute for IV injection Oral: 25, 50 mg tablets Bosentan (Tracleer) Eplerenone (Inspra) Oral: 62.5, 125 mg tablets Oral: 25, 50 mg tablets ∗ Digoxin capsules (Lanoxicaps) have greater bioavailability than digoxin tablets. REFERENCES Lingrel JB: The physiological significance of the cardiotonic steroid/ouabain- binding site of the Na,K-ATPase. Annu Rev Physiol 2010;72:395. Abraham WT, Greenberg BH, Yancy CW: Pharmacologic therapies across the Malik FI et al: Cardiac myosin activation: A potential therapeutic approach for continuum of left ventricular dysfunction. Am J Cardiol 2008;102 systolic heart failure. Science 2011;331:1439. (Suppl):21G. Post SR, Hammond HK, Insel PA: β-Adren