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Pharmacology_Katzung. amount removed from the cell (primarily via the sodium-calcium exchanger, a transporter in the cell membrane). The amount of Ca2+ released from the SR depends on the response of the RyR channels to trigger Ca2+.


Pharmacology_Katzung

Pharmacology_Katzung. D. Amount of Trigger Calcium The amount of trigger calcium that enters the cell depends on the concentration of extracellular calcium, the availability of membrane calcium channels, and the duration of their opening. As described in Chapters 6 and 9, sympathomimetics cause an increase in calcium influx through an action on these channels. Conversely, the calcium channel blockers (see Chapter 12) reduce this influx and depress contractility. E. Activity of the Sodium-Calcium Exchanger This antiporter (NCX) uses the inward movement of three sodium ions to move one calcium ion against its concentration gradient from the cytoplasm to the extracellular space. Extracellular concentrations of these ions are much less labile than intracellular concentrations under physiologic conditions. The sodium-calcium exchanger’s ability to carry out this transport is thus strongly dependent on the intracellular concentrations of both ions, especially sodium.


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Pharmacology_Katzung. F. Intracellular Sodium Concentration and Activity of Na+/K+-ATPase Na+/K+-ATPase, by removing intracellular sodium, is the major determinant of sodium concentration in the cell. The sodium


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 13–1 Schematic diagram of a cardiac muscle sarcomere, with sites of action of several drugs that alter contractility. (Mitochondria, which are critical for the generation of ATP, are omitted for simplicity.) 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. 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. Z is the Z-line, which delimits the sarcomere. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. influx through voltage-gated channels, which occurs as a normal part of almost all cardiac action potentials, is another determinant, although the amount of sodium that enters with each action potential is much less than 1% of the total intracellular sodium. Na+/K+-ATPase appears to be the primary target of digoxin and other cardiac glycosides. Pathophysiology of Heart Failure


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Pharmacology_Katzung. Pathophysiology of Heart Failure Heart failure is a syndrome with many causes that may involve one or both ventricles. Cardiac output is usually below the normal range (“low-output” failure). Systolic dysfunction, with reduced cardiac output and significantly reduced ejection fraction (EF < 45%; normal > 60%), is typical of acute failure, especially that resulting from myocardial infarction. Diastolic dysfunction often occurs as a result of hypertrophy and stiffening of the myocardium, and although cardiac output is reduced, ejection fraction may be normal. Heart failure due to diastolic dysfunction does not usually respond optimally to positive inotropic drugs.


Pharmacology_Katzung

Pharmacology_Katzung. “High-output” failure is a rare form of heart failure. In this condition, the demands of the body are so great that even increased cardiac output is insufficient. High-output failure can result from hyperthyroidism, beriberi, anemia, and arteriovenous shunts. This form of failure responds poorly to the drugs discussed in this chapter and should be treated by correcting the underlying cause. The primary signs and symptoms of all types of heart failure include tachycardia, decreased exercise tolerance, shortness of breath, and cardiomegaly. Peripheral and pulmonary edema (the congestion of congestive heart failure) are often but not always present. Decreased exercise tolerance with rapid muscular fatigue is the major direct consequence of diminished cardiac output. The other manifestations result from the attempts by the body to compensate for the intrinsic cardiac defect.


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Pharmacology_Katzung. Neurohumoral (extrinsic) compensation involves two major mechanisms (previously presented in Figure 6–7)—the sympathetic nervous system and the renin-angiotensin-aldosterone hormonal response—plus several others. Some of the detrimental as well as beneficial features of these compensatory responses are illustrated in Figure 13–2. The baroreceptor reflex appears to be reset, with a lower sensitivity to arterial pressure, in patients with heart failure. As a result, baroreceptor sensory input to the vasomotor center is reduced even at normal pressures; sympathetic outflow is increased, and parasympathetic outflow is decreased. Increased sympathetic outflow causes tachycardia, increased cardiac contractility, and increased vascular tone. Vascular tone is further increased by angiotensin II and endothelin, a potent vasoconstrictor released by vascular endothelial cells. Vasoconstriction increases afterload, which further reduces ejection fraction and cardiac output. The result is a


Pharmacology_Katzung

Pharmacology_Katzung. II and endothelin, a potent vasoconstrictor released by vascular endothelial cells. Vasoconstriction 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 vasodilators reduce heart failure mortality by interrupting the cycle and slowing the downward spiral.


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Pharmacology_Katzung. After a relatively short exposure to increased sympathetic drive, complex down-regulatory changes in the cardiac β1-adrenoceptor–G FIGURE 13–2 Some compensatory responses (orange boxes) that occur during congestive heart failure. In addition to the effects shown, sympathetic discharge facilitates renin release, and angiotensin II increases norepinephrine release by sympathetic nerve endings (dashed arrows). protein-effector system take place that result in diminished stimulatory effects. Beta2 receptors are not down-regulated and may develop increased coupling to the inositol 1,4,5-trisphosphate– diacylglycerol (IP3-DAG) cascade. It has also been suggested that cardiac β3 receptors (which do not appear to be down-regulated in Cardiac performance1 CO NE, A ET NE, A ETAfterload Afterload EF 2 B NE, A ET Afterload EF EF CO CO


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Pharmacology_Katzung. Cardiac performance1 CO NE, A ET NE, A ETAfterload Afterload EF 2 B NE, A ET Afterload EF EF CO CO FIGURE 13–3 Vicious spiral of progression of heart failure. Decreased cardiac output (CO) activates production of neurohormones (NE, norepinephrine; AII, angiotensin II; ET, endothelin), which cause vasoconstriction and increased afterload. This further reduces ejection fraction (EF) and CO, and the cycle repeats. The downward spiral is continued until a new steady state is reached in which CO is lower and afterload is higher than is optimal for normal activity. Circled points 1, 2, and B represent points on the ventricular function curves depicted in Figure 13–4.


Pharmacology_Katzung

Pharmacology_Katzung. failure) may mediate negative inotropic effects. Excessive β activation can lead to leakage of calcium from the SR via RyR channels and contributes to stiffening of the ventricles and arrhythmias. Reuptake of Ca2+ into the SR by SERCA may also be impaired. Prolonged β activation also increases caspases, the enzymes responsible for apoptosis. Increased angiotensin II production leads to increased aldosterone secretion (with sodium and water retention), to increased afterload, and to remodeling of both heart and vessels. Other hormones are released, including natriuretic peptide, endothelin, and vasopressin (see Chapter 17). Of note, natriuretic peptides released from the heart and possibly other tissues include N-terminal pro-brain natriuretic peptide (NT-proBNP), which has come into use as a surrogate marker for the presence and severity of heart failure. Within the heart, failure-induced changes have been documented in calcium handling in the SR by SERCA and phospholamban; in


Pharmacology_Katzung

Pharmacology_Katzung. use as a surrogate marker for the presence and severity of heart failure. Within the heart, failure-induced changes have been documented in calcium handling in the SR by SERCA and phospholamban; in transcription factors that lead to hypertrophy and fibrosis; in mitochondrial function, which is critical for energy production in the overworked heart; and in ion channels, especially potassium channels, which facilitate arrhythmogenesis, a primary cause of death in heart failure. Phosphorylation of RyR channels in the SR enhances and dephosphorylation reduces Ca2+ release; studies in animal models indicate that the enzyme primarily responsible for RyR dephosphorylation, protein phosphatase 1 (PP1), is up-regulated in heart failure. These cellular changes provide many potential targets for future drugs.


Pharmacology_Katzung

Pharmacology_Katzung. The most obvious intrinsic compensatory mechanism is myocardial hypertrophy. The increase in muscle mass helps maintain cardiac performance. However, after an initial beneficial effect, hypertrophy can lead to ischemic changes, impairment of diastolic filling, and alterations in ventricular geometry. Remodeling is the term applied to dilation (other than that due to passive stretch) and other slow structural changes that occur in the stressed myocardium. It may include proliferation of connective tissue cells as well as abnormal myocardial cells with some biochemical characteristics of fetal myocytes. Ultimately, myocytes in the failing heart die at an accelerated rate through apoptosis, leaving the remaining myocytes subject to even greater stress. Pathophysiology of Cardiac Performance


Pharmacology_Katzung

Pharmacology_Katzung. Cardiac performance is a function of four primary factors: 1. Preload: When some measure of left ventricular performance such as stroke volume or stroke work is plotted as a function of left ventricular filling pressure or end-diastolic fiber length, the resulting curve is termed the left ventricular function curve (Figure 13–4). The ascending limb (< 15 mm Hg filling pressure) represents the classic Frank-Starling relation described in physiology texts. Beyond approximately 15 mm Hg, there is a plateau of performance. Preloads greater than 20–25 mm Hg result in pulmonary congestion. As noted above, preload is usually increased in heart failure because of increased blood volume and venous tone. Because the function curve of the failing heart is lower, the plateau is reached at much lower values of stroke work or output. Increased fiber length or filling pressure increases oxygen demand in the myocardium, as described in Chapter 12. Reduction of high filling pressure is the goal of


Pharmacology_Katzung

Pharmacology_Katzung. 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 for normal, healthy individuals. At a given level of exercise, the heart 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 reaching point B. A “pure” positive inotropic drug (+ Ino) would move the operating point upward by increasing cardiac stroke work. A vasodilator (Vaso) would move the point leftward by reducing filling pressure. Successful therapy usually results in both effects. (Adapted, with permission, from Swan HJC, Parmley WW: Congestive heart failure. In: Sodeman WA Jr, Sodeman TM [editors]: Pathologic Physiology, 7th ed. Saunders, 1985. Copyright Elsevier.) salt restriction and diuretic therapy in heart failure. Venodilator drugs (eg, nitroglycerin) also reduce preload by redistributing blood away


Pharmacology_Katzung

Pharmacology_Katzung. Physiology, 7th ed. Saunders, 1985. Copyright Elsevier.) salt restriction and diuretic therapy in heart failure. Venodilator drugs (eg, nitroglycerin) also reduce preload by redistributing blood away from the chest into peripheral veins.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Afterload: Afterload is the resistance against which the heart must pump blood and is represented by aortic impedance and systemic vascular resistance. As noted in Figure 13–2, as cardiac output falls in chronic failure, a reflex increase in systemic vascular resistance occurs, mediated in part by increased sympathetic outflow and circulating catecholamines and in part by activation of the renin-angiotensin system. Endothelin, a potent vasoconstrictor peptide, is also involved. This sets the stage for the use of drugs that reduce arteriolar tone in heart failure. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Contractility: Heart muscle obtained by biopsy from patients with chronic low-output failure demonstrates a reduction in intrinsic contractility. As contractility decreases in the heart, there is a reduction in the velocity of muscle shortening, the rate of intraventricular pressure development (dP/dt), and the stroke output achieved (Figure 13–4). However, the heart is usually still capable of some increase in all of these measures of contractility in response to inotropic drugs. 4. Heart rate: The heart rate is a major determinant of cardiac output. As the intrinsic function of the heart decreases in failure and stroke volume diminishes, an increase in heart rate—through sympathetic activation of β adrenoceptors— is the first compensatory mechanism that comes into play to maintain cardiac output. However, tachycardia limits diastolic filling time and coronary flow, further stressing the heart. Thus, bradycardic drugs may benefit patients with high heart rates.


Pharmacology_Katzung

Pharmacology_Katzung. Although digitalis is not the first drug and never the only drug used in heart failure, we begin our discussion with this group because other drugs used in this condition are discussed in more detail in other chapters. Digitalis is the name of the genus 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 monograph describing the clinical effects of an extract of the purple foxglove plant (Digitalis purpurea, a major source of these agents).


Pharmacology_Katzung

Pharmacology_Katzung. 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, milkweed, and others) contain cardiac glycosides with similar properties. Digoxin, the only cardiac glycoside used in the USA, is 65–80% absorbed after oral administration. Absorption of other glycosides varies from zero to nearly 100%. Once present in the blood, all cardiac glycosides are widely distributed to tissues, including the central nervous system (CNS).


Pharmacology_Katzung

Pharmacology_Katzung. Digoxin is not extensively metabolized in humans; almost two thirds is excreted unchanged by the kidneys. Its renal clearance is proportional to creatinine clearance, and the half-life is 36–40 hours in patients with normal renal function. Equations and nomograms are available for adjusting digoxin dosage in patients with renal impairment. Digoxin has multiple direct and indirect cardiovascular effects, with both therapeutic and toxic consequences. In addition, it has undesirable effects on the CNS and gut.


Pharmacology_Katzung

Pharmacology_Katzung. At the molecular level, all therapeutically useful cardiac glycosides inhibit Na+/K+-ATPase, the membrane-bound transporter often called the sodium pump (Figure 13–1). Although several isoforms of this ATPase occur and have varying sensitivity to cardiac glycosides, they are highly conserved in evolution. Inhibition of this transporter over most of the dose range has been extensively documented in all tissues studied. It is probable that this inhibitory action is largely responsible for the therapeutic effect (positive inotropy) as well as a major portion of the toxicity of digitalis. Other molecular-level effects of digitalis have been studied in the heart and are discussed below. The fact that a receptor for cardiac glycosides exists on the sodium pump has prompted some investigators to propose that an endogenous digitalis-like steroid, possibly ouabain or marinobufagenin, must exist. Furthermore, additional functions of Na+/K+-ATPase have been postulated, involving apoptosis, cell


Pharmacology_Katzung

Pharmacology_Katzung. propose that an endogenous digitalis-like steroid, possibly ouabain or marinobufagenin, must exist. Furthermore, additional functions of Na+/K+-ATPase have been postulated, involving apoptosis, cell growth and differentiation, immunity, and carbohydrate metabolism. Indirect evidence for such endogenous digitalis-like activity has been inferred from clinical studies showing some protective effect of digoxin antibodies in preeclampsia.


Pharmacology_Katzung

Pharmacology_Katzung. A. Cardiac Effects 1. Mechanical effects—Cardiac glycosides increase contraction of the cardiac sarcomere by increasing the free calcium concentration in the vicinity of the contractile proteins during systole. The increase in calcium concentration is the result of a two-step process: first, an increase of intracellular sodium concentration because of Na+/K+-ATPase inhibition; and second, a relative reduction of calcium expulsion from the cell by the sodium-calcium exchanger (NCX in Figure 13–1) caused by the increase in intracellular sodium. The increased cytoplasmic calcium is sequestered by SERCA in the SR for later release. Other mechanisms have been proposed but are not well supported.


Pharmacology_Katzung

Pharmacology_Katzung. The net result of the action of therapeutic concentrations of a cardiac glycoside is a distinctive increase in cardiac contractility (Figure 13–5, bottom trace, panels A and B). In isolated myocardial preparations, the rate of development of tension and of relaxation are both increased, with little or no change in time to peak tension. This effect occurs in both normal and failing myocardium, but in the intact patient, the responses are modified by cardiovascular reflexes and the pathophysiology of heart failure. 2. Electrical effects—The effects of digitalis on the electrical properties of the heart are a mixture of direct and autonomic actions. Direct actions on the membranes of cardiac cells follow a well-defined progression: an early, brief prolongation of the action potential, followed by shortening (especially the plateau phase).


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 13–5 Effects of a cardiac glycoside, ouabain, on isolated cardiac tissue. The top tracing shows action potentials evoked during the control period (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 (B) shows a slight shortening of action potential and a marked increase in free intracellular calcium concentration and contractile tension. The toxic phase (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.)


Pharmacology_Katzung

Pharmacology_Katzung. The decrease in action potential duration is probably the result of increased potassium conductance that is caused by increased intracellular calcium (see Chapter 14). All these effects can be observed at therapeutic concentrations in the absence of overt toxicity (Table 13–2).


Pharmacology_Katzung

Pharmacology_Katzung. 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 following normally evoked action potentials (Figure 13–5, panel C). The afterpotentials (also known as delayed after-depolarizations, DADs) are associated with overloading of the intracellular calcium 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 potentials. If afterpotentials in the Purkinje conducting system regularly 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 afterpotential, and a self-sustaining


Pharmacology_Katzung

Pharmacology_Katzung. be recorded on the electrocardiogram (Figure 13–6). With further intoxication, each afterpotential-evoked action potential will itself elicit a suprathreshold afterpotential, 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.


Pharmacology_Katzung

Pharmacology_Katzung. Autonomic actions of cardiac glycosides on the heart involve both the parasympathetic and the sympathetic systems. At low therapeutic doses, cardioselective parasympathomimetic 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 muscarinic transmission at the nerve ending–myocyte synapse. Because cholinergic innervation is much richer in the atria, these actions affect atrial and atrioventricular nodal function more than Purkinje or ventricular 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 exaggerates all the toxic effects of the drug.


Pharmacology_Katzung

Pharmacology_Katzung. The most common cardiac manifestations of digitalis toxicity include atrioventricular junctional rhythm, premature ventricular depolarizations, bigeminal rhythm, ventricular tachycardia, and TABLE 13–2 Effects of digoxin on electrical properties of cardiac tissues. FIGURE 13–6 Electrocardiographic record showing digitalis-induced bigeminy. The complexes marked NSR are normal sinus rhythm beats; an inverted T wave and depressed ST segment are 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 13–5. (Adapted, with permission, from Goldman MJ: Principles of Clinical Electrocardiogra phy, 12th ed. Lange, 1986. Copyright © The McGraw-Hill Companies, Inc.) second-degree atrioventricular blockade. However, it is claimed that digitalis can cause virtually any arrhythmia. B. Effects on Other Organs


Pharmacology_Katzung

Pharmacology_Katzung. B. Effects on Other Organs Cardiac glycosides affect all excitable tissues, including smooth muscle and the CNS. 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 CNS actions. CNS 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 digitalis. C. Interactions with Potassium, Calcium, and Magnesium


Pharmacology_Katzung

Pharmacology_Katzung. 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, increased cardiac automaticity is inhibited by hyperkalemia (see Chapter 14). Moderately increased extracellular K+ therefore reduces the toxic effects of digitalis. 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 automaticity. Hypercalcemia therefore increases the risk of a digitalis-induced 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.


Pharmacology_Katzung

Pharmacology_Katzung. Major efforts are being made to find safer positive inotropic agents because cardiac glycosides have an extremely narrow therapeutic window and may not decrease mortality in chronic heart failure. Milrinone is a bipyridine compound that inhibits phosphodiesterase isozyme 3 (PDE-3). It is active orally as well as parenterally but is available only in parenteral form. It has an elimination half-life of 3–6 hours, with 10–40% being excreted in the urine. An older congener, inamrinone, has been withdrawn in the USA. The bipyridines increase myocardial contractility by increasing inward calcium flux in the heart during the action potential; they may also alter the intracellular movements of calcium by influencing the SR. In addition, they have an important vasodilating effect. Inhibition of phosphodiesterase results in an increase in cAMP and the increase in contractility and vasodilation.


Pharmacology_Katzung

Pharmacology_Katzung. The toxicity of inamrinone includes nausea and vomiting; arrhythmias, thrombocytopenia, and liver enzyme changes have also been reported in a significant number of patients. As noted, this drug has been withdrawn. Milrinone appears less likely to cause bone marrow and liver toxicity, but it does cause arrhythmias. Milrinone is now used only intravenously and only for acute heart failure or severe exacerbation of chronic heart failure.


Pharmacology_Katzung

Pharmacology_Katzung. The general pharmacology of these agents is discussed in Chapter 9. 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 ventricular filling pressure. Some tachycardia and an increase in myocardial oxygen consumption have been reported. Therefore, the potential for producing angina or arrhythmias in patients with coronary artery disease is significant, as is the tachyphylaxis that accompanies the use of any β stimulant. Intermittent dobutamine infusion may benefit some patients with chronic heart failure. Dopamine has also been used in acute heart failure and may be particularly helpful if there is a need to raise blood pressure.


Pharmacology_Katzung

Pharmacology_Katzung. Dopamine has also been used in acute heart failure and may be particularly helpful if there is a need to raise blood pressure. Istaroxime is an investigational steroid derivative that increases contractility by inhibiting Na+/K+-ATPase (like cardiac glycosides) but in addition appears to facilitate sequestration of Ca2+ by the SR. The latter action may render the drug less arrhythmogenic than digitalis. Levosimendan, a drug that sensitizes the troponin system to calcium, also appears to inhibit phosphodiesterase and to cause some vasodilation in addition to its inotropic effects. Some clinical trials suggest that this drug may be useful in patients with heart failure, and the drug has been approved in some countries (not the USA).


Pharmacology_Katzung

Pharmacology_Katzung. Omecamtiv mecarbil is an investigational parenteral agent that activates cardiac myosin and prolongs systole without increasing oxygen consumption of the heart. It has been shown to reduce signs of heart failure in animal models, and a small initial phase 2 clinical trial in patients with heart failure showed increased systolic time and stroke volume and reduced heart rate and end-systolic and diastolic volumes. A larger trial in patients with acute heart failure was disappointing, but another trial in those with chronic failure is under way. These agents—not positive inotropic drugs—are the first-line therapies for chronic heart failure. The drugs most commonly used are diuretics, ACE inhibitors, angiotensin receptor antagonists, aldosterone antagonists, and β blockers (Table 13–1). In acute failure, diuretics and vasodilators play important roles.


Pharmacology_Katzung

Pharmacology_Katzung. Diuretics, especially furosemide, are drugs of choice in heart failure and are discussed in detail in Chapter 15. They reduce salt and water retention, edema, and symptoms. They have no direct effect on cardiac contractility; their major mechanism of action in heart failure is to reduce venous pressure and ventricular preload. The reduction of cardiac size, which leads to improved pump efficiency, is of major importance in systolic failure. In heart failure associated with hypertension, the reduction in blood pressure also reduces afterload. Spironolactone and eplerenone, the aldosterone (mineralocorticoid) antagonist diuretics (see Chapter 15), have the additional benefit of decreasing morbidity and mortality in patients with severe heart failure who are also receiving ACE inhibitors and other standard therapy. One possible mechanism for this benefit lies in accumulating evidence that aldosterone may also cause myocardial and vascular fibrosis and baroreceptor dysfunction in addition


Pharmacology_Katzung

Pharmacology_Katzung. other standard therapy. One possible mechanism for this benefit lies in accumulating evidence that aldosterone may also cause myocardial and vascular fibrosis and baroreceptor dysfunction in addition to its renal effects. Finerenone is an investigational mineralocorticoid antagonist that may be less likely to induce hyperkalemia.


Pharmacology_Katzung

Pharmacology_Katzung. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, ANGIOTENSIN RECEPTOR BLOCKERS, & RELATED AGENTS ACE inhibitors such as captopril were introduced in Chapter 11 and are discussed again in Chapter 17. These versatile drugs reduce peripheral resistance and thereby reduce afterload; they also reduce salt and water retention (by reducing aldosterone secretion) and in that way reduce preload. The reduction in tissue angiotensin levels also reduces sympathetic activity through diminution of angiotensin’s presynaptic effects on norepinephrine release. Finally, these drugs reduce the long-term remodeling of the heart and vessels, an effect that may be responsible for the observed reduction in mortality and morbidity (see Clinical Pharmacology).


Pharmacology_Katzung

Pharmacology_Katzung. Angiotensin AT1 receptor blockers such as losartan (see Chapters 11 and 17) appear to have similar beneficial effects. In combination with sacubitril, valsartan is now approved for HFrEF. Angiotensin receptor blockers should be considered in patients intolerant of ACE inhibitors because of incessant cough. Aliskiren, a renin inhibitor approved for hypertension, was found to have no definitive benefit in clinical trials for heart failure. Vasodilators are effective in acute heart failure because they provide a reduction in preload (through venodilation), or reduction in afterload (through arteriolar dilation), or both. Some evidence suggests that long-term vasodilation by hydralazine and isosorbide dinitrate can also reduce damaging remodeling of the heart.


Pharmacology_Katzung

Pharmacology_Katzung. A synthetic form of the endogenous peptide brain natriuretic peptide (BNP) is approved for use in acute (not chronic) cardiac failure as nesiritide. This recombinant product increases cGMP in smooth muscle cells and reduces venous and arteriolar tone in experimental preparations. It also causes diuresis. However, large trials with this drug have failed to show an improvement in mortality or rehospitalizations. The peptide has a short half-life of about 18 minutes and is administered as a bolus intravenous dose followed by continuous infusion. Excessive hypotension is the most common adverse effect. Reports of significant renal damage and deaths have resulted in extra warnings regarding this agent, and it should be used with great caution. A newer approach to modulation of the natriuretic peptide system is inhibition of the neutral endopeptidase enzyme, neprilysin, which is responsible for the degradation of BNP and atrial natriuretic peptide (ANP), as well as angiotensin II,


Pharmacology_Katzung

Pharmacology_Katzung. peptide system is inhibition of the neutral endopeptidase enzyme, neprilysin, which is responsible for the degradation of BNP and atrial natriuretic peptide (ANP), as well as angiotensin II, bradykinin, and other peptides. Sacubitril is a prodrug that is metabolized to an active neprilysin inhibitor plus an ARB. A combination of valsartan plus sacubitril has recently been approved for use in HFrEF.


Pharmacology_Katzung

Pharmacology_Katzung. Plasma concentrations of endogenous BNP rise in most patients with heart failure and are correlated with severity. Measurement of the plasma precursor NT-proBNP is a useful diagnostic or prognostic test and has been used as a surrogate marker in clinical trials. Related peptides include ANP and urodilatin, a similar peptide produced in the kidney. Carperitide and ularitide, respectively, are investigational synthetic analogs of these endogenous peptides and are in clinical trials (see Chapter 15). Bosentan and tezosentan, orally active competitive inhibitors of endothelin (see Chapter 17), have been shown to have some benefits in experimental animal models with heart failure, but results in human trials have been disappointing. Bosentan is approved for use in pulmonary hypertension. It has significant teratogenic and hepatotoxic effects.


Pharmacology_Katzung

Pharmacology_Katzung. Several newer agents are thought to stabilize the RyR channel and may reduce Ca2+ leak from the SR. They are currently denoted only by code numbers (eg, TRV027, JTV519, S44121). This action, if confirmed to reduce diastolic stiffness, would be especially useful in diastolic failure with preserved ejection fraction.


Pharmacology_Katzung

Pharmacology_Katzung. Most patients with chronic heart failure respond favorably to certain β blockers despite the fact that these drugs can precipitate acute decompensation of cardiac function (see Chapter 10). Studies with bisoprolol, carvedilol, metoprolol, and nebivolol showed a reduction in mortality in patients with stable severe heart failure, but this effect was not observed with another β blocker, bucindolol. A full understanding of the beneficial action of β blockade is lacking, but suggested mechanisms include attenuation of the adverse effects of high concentrations of catecholamines (including apoptosis), up-regulation of β receptors, decreased heart rate, and reduced remodeling through inhibition of the mitogenic activity of catecholamines.


Pharmacology_Katzung

Pharmacology_Katzung. Neuroregulatory proteins appear to have cardiac and neural effects. The neuregulin GGF2 protein (cimaglermin) has been shown to benefit cardiac function in several animal models of heart failure. Drugs used in type 2 diabetes have been of concern because of the association of this condition with cardiac events. Therefore, it is of interest that some of these agents appear to benefit patients with both heart failure and type 2 diabetes. Liraglutide, a GLP-1 agonist (see Chapter 41), has been shown in some studies to nonsignificantly reduce deaths from cardiovascular causes as well as the rates of myocardial infarction, nonfatal stroke, and hospitalization for heart failure. Empagliflozin, an SGLT2 inhibitor, has also been shown to reduce hospitalizations for heart failure.


Pharmacology_Katzung

Pharmacology_Katzung. Detailed guidelines are issued by US and European expert groups (see References). The American College of Cardiology/American Heart Association (ACC/AHA) guidelines for management of chronic heart failure 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 have no signs or symptoms of heart failure. Stage B patients have evidence of structural heart disease but no symptoms of heart failure. Stage C patients have structural heart disease and symptoms of failure, and symptoms are responsive to ordinary therapy. Patients in stage C must often be hospitalized for acute decompensation, and after discharge, they often decompensate again, requiring rehospitalization. Stage D patients have heart failure refractory to ordinary therapy, and special interventions (eg, resynchronization therapy, transplant) are required.


Pharmacology_Katzung

Pharmacology_Katzung. Once stage C is reached, the severity of heart failure is usually described according to a scale devised by the New York Heart Association. Class I failure is associated with no limitations on ordinary activities and symptoms that occur only with greater than ordinary exercise. Class II failure is characterized by slight limitation of activities and results in fatigue and palpitations with ordinary physical activity. Class III failure results in fatigue, shortness of breath, and tachycardia with less than ordinary physical activity, but no symptoms at rest. Class IV failure is associated with symptoms even when the patient is at rest.


Pharmacology_Katzung

Pharmacology_Katzung. The major steps in the management of patients with chronic heart failure are outlined in Tables 13–3 and 13–4. Updates to the ACC/AHA guidelines suggest that treatment of patients at high risk (stages A and B) should be focused on control of hypertension, arrhythmias, hyperlipidemia, and diabetes, if present. Once symptoms and signs of failure are present, stage C has been entered, and active treatment of failure must be initiated. Sodium removal—by dietary salt restriction and a diuretic—is the mainstay in management of symptomatic heart failure, especially if edema is present. The use of diuretics is discussed in greater detail in Chapter 15. In very mild failure, a thiazide diuretic may be tried, but a loop agent such as furosemide is usually required. Sodium loss causes secondary loss of potassium, which is TABLE 13–3 Classification and treatment of chronic heart failure.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 13–3 Classification and treatment of chronic heart failure. 1American College of Cardiology/American Heart Association classification. 2New York Heart Association classification. 3Risk factors include hypertension, myocardial infarct, diabetes. 4For selected populations, eg, African Americans. ACC, American College of Cardiology; ACEI, angiotensin-converting enzyme inhibitor; AHA, American Heart Association; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor inhibitor plus neprilysin inhibitor; CRT, cardiac resynchronization therapy; LVAD, left ventricular assist device; NYHA, New York Heart Association. TABLE 13–4 Differences between systolic and diastolic heart failure. 1Avoid excessive reduction of filling pressures. 2Limited to certain β blockers (see text). 3Benefit, if any, may be due to BP reduction. 4Useful combined with hydralazine in selected patients, especially African Americans.


Pharmacology_Katzung

Pharmacology_Katzung. 2Limited to certain β blockers (see text). 3Benefit, if any, may be due to BP reduction. 4Useful combined with hydralazine in selected patients, especially African Americans. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor inhibitor plus neprilysin inhibitor; BP, blood pressure; HF, heart failure; HR, heart rate; LVH, left ventricular hypertrophy; NT-proBNP, N-terminal pro-brain natriuretic peptide; PDE, phosphodiesterase. particularly hazardous if the patient is to be given digitalis. Hypokalemia can be treated with potassium supplementation or through the addition of an ACE inhibitor or a potassium-sparing diuretic such as spironolactone. Spironolactone or eplerenone should probably be considered in all patients with moderate or severe heart failure, since both appear to reduce both morbidity and mortality.


Pharmacology_Katzung

Pharmacology_Katzung. In patients with left ventricular dysfunction but no edema, an ACE inhibitor should be the first drug used. Several large studies have shown clearly that ACE inhibitors are superior to both placebo and to vasodilators and must be considered, along with diuretics, as first-line therapy for chronic heart failure. However, ACE inhibitors cannot replace digoxin in patients already receiving the glycoside because patients withdrawn from digoxin deteriorate while on ACE inhibitor therapy. By reducing preload and afterload in asymptomatic patients, ACE inhibitors (eg, enalapril) slow the progress of ventricular dilation and thus slow the downward spiral of heart failure. Consequently, ACE inhibitors are beneficial in all subsets of patients—from those who are asymptomatic to those in severe chronic failure. This benefit appears to be a class effect; that is, all ACE inhibitors appear to be effective.


Pharmacology_Katzung

Pharmacology_Katzung. The angiotensin II AT1 receptor blockers (ARBs, eg, losartan) produce beneficial hemodynamic effects similar to those of ACE inhibitors. However, large clinical trials suggest that when used alone, ARBs are best reserved for patients who cannot tolerate ACE inhibitors (usually because of cough). In contrast, the ARB valsartan combined with the neprilysin inhibitor sacubitril (Entresto) has additional benefit in HFrEF and is recommended in 2016 guidelines.


Pharmacology_Katzung

Pharmacology_Katzung. Vasodilator drugs can be divided into selective arteriolar dilators, venous dilators, and drugs with nonselective vasodilating effects. The choice of agent should be based on the patient’s signs and symptoms and hemodynamic measurements. Thus, in patients with high filling pressures in whom the principal symptom is dyspnea, venous dilators such as long-acting nitrates will be most helpful in reducing filling pressures and the symptoms of pulmonary congestion. In patients in whom fatigue due to low left ventricular output is a primary symptom, an arteriolar dilator such as 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 pressures and reduced cardiac output. In these circumstances, dilation of both arterioles and veins is required. A fixed combination of hydralazine and isosorbide dinitrate is available as isosorbide


Pharmacology_Katzung

Pharmacology_Katzung. pressures and reduced cardiac output. In these circumstances, dilation of both arterioles and veins is required. A fixed combination of hydralazine and isosorbide dinitrate is available as isosorbide dinitrate/hydralazine (BiDil), and this is currently recommended for use in African Americans.


Pharmacology_Katzung

Pharmacology_Katzung. Beta blocker therapy in patients with heart failure is based on the hypothesis that excessive tachycardia and adverse effects of high catecholamine levels on the heart contribute to the downward course of heart failure. The results of clinical trials clearly indicate that such therapy is beneficial if initiated cautiously at low doses, even though acutely blocking the supportive effects of catecholamines can worsen heart failure. Several months of therapy may be required before improvement is noted; this usually consists of a slight rise in ejection fraction, slower heart rate, and reduction in symptoms. As noted above, not all β blockers have proved useful, but bisoprolol, carvedilol, metoprolol, and nebivolol have been shown to reduce mortality.


Pharmacology_Katzung

Pharmacology_Katzung. In contrast, the calcium-blocking drugs appear to have no role in the treatment of patients with heart failure. Their depressant effects on the heart may worsen heart failure. On the other hand, slowing of heart rate with ivabradine (an If blocker, see Chapter 12) may be of benefit. Digoxin is indicated in patients with heart failure and atrial fibrillation. It is usually given only when diuretics and ACE inhibitors have failed to control symptoms. Only about 50% of patients with normal sinus rhythm (usually those with documented systolic dysfunction) will have relief of heart failure from digitalis. If the decision is made to use a cardiac glycoside, digoxin is the one chosen in most cases (and the only one available in the USA). When symptoms are mild, slow loading (digitalization) with 0.125–0.25 mg/d is safer and just as effective as the rapid method (0.5–0.75 mg every 8 hours for three doses, followed by 0.125–0.25 mg/d).


Pharmacology_Katzung

Pharmacology_Katzung. Determining the optimal level of digitalis effect may be difficult. Unfortunately, toxic effects may occur before therapeutic effects are detected. Measurement of plasma digoxin levels is useful in patients who appear unusually resistant or sensitive; a level of 1 ng/mL or less is appropriate; higher levels may be required in patients with atrial fibrillation. Because it has a moderate but persistent positive inotropic effect, digitalis can, in theory, reverse all the signs and symptoms 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 with serum digoxin concentrations of less than 0.9 ng/mL but increased in those with digoxin levels greater than 1.5 ng/mL. Other Clinical Uses of Digitalis


Pharmacology_Katzung

Pharmacology_Katzung. Other Clinical Uses of Digitalis Digitalis is useful in the management of atrial arrhythmias because of its cardioselective parasympathomimetic effects. In atrial flutter and fibrillation, the depressant effect of the drug on atrioventricular conduction helps control an excessively high ventricular rate. Digitalis has also been used in the control of paroxysmal atrial and atrioventricular nodal tachycardia. At present, calcium channel blockers and adenosine are preferred for this application. Digoxin is explicitly contraindicated in patients with both Wolff-Parkinson-White syndrome and atrial fibrillation (see Chapter 14).


Pharmacology_Katzung

Pharmacology_Katzung. Despite its limited benefits and recognized hazards, digitalis is still often used inappropriately, and toxicity is common. Therapy for toxicity manifested as visual changes or gastrointestinal disturbances generally requires no more than reducing the dose of the drug. If cardiac arrhythmia is present, more vigorous therapy may be necessary. Serum digitalis level, potassium level, and the electrocardiogram should always be monitored during therapy of significant digitalis toxicity. Electrolytes should be monitored and corrected if abnormal. Digitalis-induced arrhythmias are frequently made worse by cardioversion; this therapy should be reserved for ventricular fibrillation if the arrhythmia is digitalis-induced.


Pharmacology_Katzung

Pharmacology_Katzung. In severe digitalis intoxication, serum potassium will already be elevated at the time of diagnosis (because of potassium loss from the intracellular compartment of skeletal muscle and other tissues). Automaticity is usually depressed, and antiarrhythmic agents may cause cardiac arrest. Treatment should include prompt insertion of a temporary cardiac pacemaker and administration of digitalis antibodies (digoxin immune fab). These antibodies recognize cardiac glycosides from many plants in addition to digoxin. They are extremely useful in reversing severe intoxication with most glycosides. As noted previously, they may also be useful in eclampsia and preeclampsia.


Pharmacology_Katzung

Pharmacology_Katzung. Patients with normal sinus rhythm and a wide QRS interval, eg, greater than 120 ms, have impaired synchronization of right and left ventricular contraction. Poor synchronization of ventricular contraction results in diminished cardiac output. Resynchronization, with left ventricular or biventricular pacing, has been shown to reduce mortality in patients with chronic heart failure who were already receiving optimal medical therapy. Because the immediate cause of death in severe heart failure is often an arrhythmia, a combined biventricular pacemaker/cardioverter-defibrillator is usually implanted. Repeated application of a brief electric current through the myocardium during the QRS deflection of the electrocardiogram results in increased contractility, presumably by increasing Ca2+ release, in the intact heart. Preliminary clinical studies of this cardiac contractility modulation therapy are under way.


Pharmacology_Katzung

Pharmacology_Katzung. Most clinical trials have been carried out in patients with systolic dysfunction, so the evidence regarding the superiority or inferiority of drugs in HFpEF is less extensive. Most authorities support the use of the drug groups described above (Table 13–4), and the SENIORS 2009 study suggests that the β blocker nebivolol is effective in both systolic and diastolic failure. Control of hypertension is particularly important, hyperlipidemia should be treated, and revascularization should be considered if coronary artery disease is present. ACE inhibitors and ARBs are useful. Atrial fibrillation is common in HFpEF, and rhythm control is desirable. Even in sinus rhythm, tachycardia limits filling time. Therefore, bradycardic drugs, eg, ivabradine, may be particularly useful, at least in theory.


Pharmacology_Katzung

Pharmacology_Katzung. Acute heart failure occurs frequently in patients with chronic failure. Such episodes are usually associated with increased exertion, emotion, excess salt intake, nonadherence to medical therapy, or increased metabolic demand occasioned by fever, anemia, etc. A particularly common and important cause of acute failure—with or without chronic failure—is acute myocardial infarction. Measurements of arterial pressure, cardiac output, stroke work index, and pulmonary capillary wedge pressure are particularly useful in patients with acute myocardial infarction and acute heart failure. Patients with acute myocardial infarction are often treated with emergency revascularization using either coronary angioplasty and a stent, or a thrombolytic agent. Even with revascularization, acute failure may develop in such patients.


Pharmacology_Katzung

Pharmacology_Katzung. Intravenous treatment is the rule in drug therapy of acute heart failure. Among diuretics, furosemide is the most commonly used. Dopamine or dobutamine are positive inotropic drugs with prompt onset and short durations of action; they are most useful in patients with failure complicated by severe hypotension. Levosimendan has been approved for use in acute failure in Europe, and noninferiority has been demonstrated against dobutamine.


Pharmacology_Katzung

Pharmacology_Katzung. Vasodilators in use in patients with acute decompensation include nitroprusside, nitroglycerine, and nesiritide. Reduction in after-load often improves ejection fraction, but improved survival has not been documented. A small subset of patients in acute heart failure will have dilutional hyponatremia, presumably due to increased vasopressin activity. A V1a and V2 receptor antagonist, conivaptan, is approved for parenteral treatment of euvolemic hyponatremia. Some clinical trials have indicated that this drug and related V2 antagonists (tolvaptan) may have a beneficial effect in some patients with acute heart failure and hyponatremia. However, vasopressin antagonists do not seem to reduce mortality. Clinical trials are under way with the myosin activator, omecamtiv mecarbil. Three other loop diuretics: Bumetanide and torsemide similar to furosemide; ethacrynic acid not a sulfonamide


Pharmacology_Katzung

Pharmacology_Katzung. 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 •SpironolactoneBlocks cytoplasmic aldosterone receptors in collecting tubules ofnephron•possiblemembrane effect Increased salt and water excretion•reducesremodeling Chronic heart failure •aldosteronism(cirrhosis,adrenal tumor) •hypertension•hasbeenshown to reduce mortality Oral•duration24–72h(slowonsetandoffset)•Toxicity: Hyperkalemia, antiandrogen actions •Eplerenone: Similar to spironolactone; more selective antimineralocorticoid effect; no significant antiandrogen action; has been shown to reduce mortality Angiotensin-converting enzyme (ACE) inhibitors: Angiotensin receptor blockers (ARBs): formation by inhibiting conversion of AI to AII Enalapril, many other ACE inhibitors: Like captopril


Pharmacology_Katzung

Pharmacology_Katzung. Angiotensin-converting enzyme (ACE) inhibitors: Angiotensin receptor blockers (ARBs): formation by inhibiting conversion of AI to AII Enalapril, many other ACE inhibitors: Like captopril Candesartan, valsartan, many other ARBs: Like losartan Chronic heart failure: To slow failure • many other indications in Chapter 10 Oral • duration 10–12 h • Toxicity:


Pharmacology_Katzung

Pharmacology_Katzung. Candesartan, valsartan, many other ARBs: Like losartan Chronic heart failure: To slow failure • many other indications in Chapter 10 Oral • duration 10–12 h • Toxicity: Bronchospasm, bradycardia, atrioventricular block, acute • Metoprolol, bisoprolol, nebivolol: Select group of b blockers that have been shown to reduce heart failure mortality •Digoxin(otherglycosides are used outside the USA) Na+/K+-ATPase inhibition results in reduced Ca2+ expulsion and increased Ca2+ stored in sarcoplasmic reticulum Increases cardiac contractility •cardiacparasympathomimeticeffect (slowed sinus heart rate, slowed atrioventricular conduction) Chronic symptomatic heart failure•rapidventricularrateinatrialfibrillation•hasnotbeen shown to reduce mortality but does reduce rehospitalization Oral,parenteral•duration36–40h•Toxicity: Nausea, vomiting,diarrhea•cardiacarrhythmias CARDIAC GLYCOSIDE Enalapril Generic, Vasotec, Vasotec I.V. Fosinopril Generic, Monopril Lisinopril Generic, Prinivil, Zestril


Pharmacology_Katzung

Pharmacology_Katzung. Enalapril Generic, Vasotec, Vasotec I.V. Fosinopril Generic, Monopril Lisinopril Generic, Prinivil, Zestril Quinapril Generic, Accupril Ramipril Generic, Altace Trandolapril Generic, Mavik Eprosartan Generic, Teveten Irbesartan Generic, Avapro Losartan Generic, Cozaar Telmisartan Generic, Micardis Bisoprolol Generic, Zebeta Carvedilol Generic, Coreg Metoprolol Generic, Lopressor, Toprol XL Eplerenone Generic, Inspra Isosorbide dinitrate Generic, Isordil Milrinone Generic, Primacor Ahmed A et al: Effectiveness of digoxin in reducing one-year mortality in chronic heart failure in the Digitalis Investigation Group trial. Am J Cardiol 2009;103:82. Borlaug BA, Colucci WS: Treatment and prognosis of heart failure with preserved ejection fraction. UpToDate, 2016. http://www.UpToDate.com. Bourge RC et al: Digoxin reduces 30-day all-cause hospital admission in older patients with chronic systolic heart failure. Am J Med 2013;126:701.


Pharmacology_Katzung

Pharmacology_Katzung. Bourge RC et al: Digoxin reduces 30-day all-cause hospital admission in older patients with chronic systolic heart failure. Am J Med 2013;126:701. Braunwald E: Heart failure. J Am Coll Cardiol HF:Heart Failure 2013;1:1. Cleland JCF et al: The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539. Cleland JCF et al: The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: A double blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 2011;378:676. Colucci WS: Pharmacologic therapy of heart failure with reduced ejection fraction. UpToDate, 2016. http://www.UpToDate.com. Colucci WS: Treatment of acute decompensated heart failure. Components of therapy. UpToDate, 2016. http://www.UpToDate.com. Elkayam U et al: Vasodilators in the management of acute heart failure. Crit Care Med 2008;36:S95.


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Pharmacology_Katzung. Elkayam U et al: Vasodilators in the management of acute heart failure. Crit Care Med 2008;36:S95. Fitchett DH, Udell JA, Inzucchi SE: Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. Eur J Heart Fail 2017;19:43. George M et al: Novel drug targets in clinical development for heart failure. Eur J Clin Pharmacol 2014;70:765. Givertz MM et al: Acute decompensated heart failure: Update on new and emerging evidence and directions for future research. J Card Fail 2013;19:371. Hasenfuss G, Teerlink JR: Cardiac inotropes: Current agents and future directions. Eur Heart J 2011;32:1838. Lam GK et al: Digoxin antibody fragment, antigen binding (Fab), treatment of preeclampsia in women with endogenous digitalis-like factor: A secondary analysis of the DEEP Trial. Am J Obstet Gynecol 2013;209:119. Lingrel JB: The physiological significance of the cardiotonic steroid/ouabainbinding site of the Na, K-ATPase. Annu Rev Physiol 2010;72:395.


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Pharmacology_Katzung. Lingrel JB: The physiological significance of the cardiotonic steroid/ouabainbinding site of the Na, K-ATPase. Annu Rev Physiol 2010;72:395. Lother A, Hein L: Pharmacology of heart failure: From basic science to novel therapies. Pharmacol Ther 2016;166:136. Malik FI et al: Cardiac myosin activation: A potential therapeutic approach for systolic heart failure. Science 2011;331:1439. Marso SP et al: Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311. Papi L et al: Unexpected double lethal oleander poisoning. Am J Forensic Med Pathol 2012;33:93. Parry TJ et al: Effects of neuregulin GGF2 (cimaglermin alfa) dose and treatment frequency on left ventricular function in rats following myocardial infarction. Eur J Pharmacol 2017;796:76. Ponikowski P et al: 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 2016;18:2129.


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Pharmacology_Katzung. Ponikowski P et al: 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 2016;18:2129. Pöss J, Link M, Böhm M: Pharmacological treatment of acute heart failure: Current treatment and new targets. Clin Pharmacol Ther 2013;94:499. Redfield MM: Heart failure with preserved ejection fraction. N Engl J Med 2016;375:1868. Seed A et al: Neurohumoral effects of the new orally active renin inhibitor, aliskiren, in chronic heart failure. Eur J Heart Fail 2007;9:1120. Taur Y, Frishman WH: The cardiac ryanodine receptor (RyR2) and its role in heart disease. Cardiol Rev 2005;13:142. Topalian S, Ginsberg F, Parrillo JE: Cardiogenic shock. Crit Care Med 2008;36:S66. Tran HA, Lin F, Greenberg BH: Potential new drug treatments for congestive heart failure. Exp Opin Invest Drugs 2016;25:811.


Pharmacology_Katzung

Pharmacology_Katzung. Tran HA, Lin F, Greenberg BH: Potential new drug treatments for congestive heart failure. Exp Opin Invest Drugs 2016;25:811. van Veldhuisen DJ et al: Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction. Data from SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure). J Am Coll Cardiol 2009;53:2150. Vardeny O, Tacheny T, Solomon SD: First in class angiotensin receptor neprilysin inhibitor in heart failure. Clin Pharmacol Ther 2013:94:445. Yancy CW et al: 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: An update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2016;68:1476.


Pharmacology_Katzung

Pharmacology_Katzung. Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2016;68:1476. Yancy CW et al: 2013 ACCF/AHA guidelines for the management of heart failure: A report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation 2013;128:1810.


Pharmacology_Katzung

Pharmacology_Katzung. The patient has a low ejection fraction with systolic heart failure, probably secondary to hypertension. His heart fail-ure must be treated first, followed by careful control of the hypertension. He was initially treated with a diuretic (furo-semide, 40 mg twice daily). On this therapy, he was less short of breath on exertion and could also lie flat without dyspnea. An angiotensin-converting enzyme (ACE) inhib-itor was added (enalapril, 20 mg twice daily), and over the next few weeks, he continued to feel better. Because of continued shortness of breath on exercise, digoxin at 0.25 mg/d was added with a further modest improvement in exercise tolerance. The blood pressure stabilized at 150/90 mm Hg, and the patient will be educated regarding the relation between his hypertension and heart failure and the need for better blood pressure control. Cautious addition of a β blocker (metoprolol) will be considered. Blood lipids, which are currently in the normal range, will be monitored.


Pharmacology_Katzung

Pharmacology_Katzung. Robert D. Harvey, PhD, & Augustus O. Grant, MD, PhD*


Pharmacology_Katzung

Pharmacology_Katzung. A 69-year-old retired teacher presents with a 1-month history of palpitations, intermittent shortness of breath, and fatigue. She has a history of hypertension. An electrocardiogram (ECG) shows atrial fibrillation with a ventricular response of 122 beats/min (bpm) and signs of left ventricular hypertrophy. She is anticoagulated with warfarin and started on sustained-release metoprolol, 50 mg/d. After 7 days, her rhythm reverts to normal sinus rhythm spontaneously. However, over the ensuing month, she continues to have intermittent palpita-tions and fatigue. Continuous ECG recording over a 48-hour period documents paroxysms of atrial fibrillation with heart rates of 88–114 bpm. An echocardiogram shows a left ven-tricular ejection fraction of 38% (normal ≥ 60%) with no localized wall motion abnormality. At this stage, would you initiate treatment with an antiarrhythmic drug to maintain normal sinus rhythm, and if so, what drug would you choose?


Pharmacology_Katzung

Pharmacology_Katzung. Cardiac arrhythmias are a common problem in clinical practice, occurring in up to 25% of patients treated with digitalis, 50% of anesthetized patients, and over 80% of patients with acute myocardial infarction. Arrhythmias may require treatment because rhythms that are too rapid, too slow, or asynchronous can reduce cardiac output. Some arrhythmias can precipitate more serious or even lethal rhythm disturbances; for example, early premature ventricular depolarizations can precipitate ventricular fibrillation. In such patients, antiarrhythmic drugs may be lifesaving. On the other hand, the hazards of antiarrhythmic drugs—and in particular the fact that they can precipitate lethal arrhythmias in some patients—have led to a reevaluation of their relative risks and benefits. In general, treatment of asymptomatic or minimally symptomatic arrhythmias should be avoided for this reason.


Pharmacology_Katzung

Pharmacology_Katzung. Arrhythmias can be treated with the drugs discussed in this chapter and with nonpharmacologic therapies such as pacemakers, cardioversion, catheter ablation, and surgery. This chapter * The authors thank Joseph R. Hume, PhD, for his contributions to previous editions. describes the pharmacology of drugs that suppress arrhythmias by a direct action on the cardiac cell membrane. Other modes of therapy are discussed briefly (see Box: The Nonpharmacologic Therapy of Cardiac Arrhythmias, later in the chapter).


Pharmacology_Katzung

Pharmacology_Katzung. The electrical impulse that triggers a normal cardiac contraction originates at regular intervals in the sinoatrial (SA) node (Figure 14–1), usually at a frequency of 60–100 bpm. This impulse spreads rapidly through the atria and enters the atrioventricular (AV) node, which is normally the only conduction pathway between the atria and ventricles. Conduction through the AV node is slow, requiring about 0.15 seconds. (This delay provides time for atrial contraction to propel blood into the ventricles.) The impulse then propagates down the His-Purkinje system and invades all parts of the ventricles, beginning with the endocardial surface near the apex and ending with the epicardial surface at the base of the heart. Activation of the entire ventricular myocardium is complete


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 14–1 Schematic representation of the heart and normal cardiac electrical activity (intracellular recordings from areas indicated and electrocardiogram [ECG]). Sinoatrial (SA) node, atrioventricular (AV) node, and Purkinje cells display pacemaker activity (phase 4 depolarization). The ECG is the body surface manifestation of the depolarization and repolarization waves of the heart. The P wave is generated by atrial depolarization, the QRS by ventricular muscle depolarization, and the T wave by ventricular repolarization. Thus, the PR interval is a measure of conduction time from atrium to ventricle, and the QRS duration indicates the time required for all of the ventricular cells to be activated (ie, the intraventricular conduction time). The QT interval reflects the duration of the ventricular action potential.


Pharmacology_Katzung

Pharmacology_Katzung. in less than 0.1 second. As a result, ventricular contraction is synchronous and hemodynamically effective. Arrhythmias represent electrical activity that deviates from the above description as a result of an abnormality in impulse initiation and/or impulse propagation. Ionic Basis of Membrane Electrical Activity


Pharmacology_Katzung

Pharmacology_Katzung. Ionic Basis of Membrane Electrical Activity The electrical excitability of cardiac cells is a function of the unequal distribution of ions across the plasma membrane—chiefly sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl−)—and the relative permeability of the membrane to each ion. The gradients are generated by transport mechanisms that move these ions across the membrane against their concentration gradients. The most important of these transport mechanisms is the Na+/K+-ATPase, or sodium pump, described in Chapter 13. It is responsible for keeping the intracellular sodium concentration low and the intracellular potassium concentration high relative to their respective extracellular concentrations. Other transport mechanisms maintain the gradients for calcium and chloride.


Pharmacology_Katzung

Pharmacology_Katzung. As a result of the unequal distribution, when the membrane becomes permeable to a given ion, that ion tends to move down its concentration gradient. However, because of its charged nature, ion movement is also affected by differences in the electrical charge across the membrane, or the transmembrane potential. The potential difference that is sufficient to offset or balance the concentration gradient of an ion is referred to the equilibrium potential (Eion) for that ion, and for a monovalent cation at physiologic temperature, it can be calculated by a modified version of the Nernst equation: where Ce and Ci are the extracellular and intracellular ion concentrations, respectively. Thus, the movement of an ion across the membrane of a cell is a function of the difference between the transmembrane potential and the equilibrium potential. This is also known as the “electrochemical gradient” or “driving force.”


Pharmacology_Katzung

Pharmacology_Katzung. The relative permeability of the membrane to different ions determines the transmembrane potential. However, ions contributing to this potential difference are unable to freely diffuse across the lipid membrane of a cell. Their permeability relies on aqueous channels (specific pore-forming proteins). The ion channels that are thought to contribute to cardiac action potentials are illustrated in Figure 14–2. Most channels are relatively ion-specific, and the current generated by the flux of ions through them is controlled by “gates” (flexible portions of the peptide chains that make up the channel proteins). Sodium, calcium, and some potassium channels are thought to have two types of gates—one that opens or activates the channel and another that closes or inactivates the channel. For the majority of the channels responsible for the cardiac action potential, the movement of these gates is controlled by voltage changes across the cell membrane; that is, they are voltage-sensitive.


Pharmacology_Katzung

Pharmacology_Katzung. the majority of the channels responsible for the cardiac action potential, the movement of these gates is controlled by voltage changes across the cell membrane; that is, they are voltage-sensitive. However, certain channels are primarily ligandrather than voltage-gated. Furthermore, the activity of many voltage-gated ion channels can be modulated by a variety of other factors, including permeant ion concentrations, tissue metabolic activity, and second messenger signaling pathways.


Pharmacology_Katzung

Pharmacology_Katzung. Pumps and exchangers that contribute indirectly to the membrane potential by creating ion gradients (as discussed above) can also contribute directly because of the current they generate through the unequal exchange of charged ions across the membrane. Such transporters are referred to as being “electrogenic.” An important example is the sodium-calcium exchanger (NCX). Throughout most of the cardiac action potential, this exchanger couples the movement of one calcium ion out of the cell for every three sodium ions that move in, thus generating a net inward or depolarizing current. Although this current is typically small during diastole, when intracellular calcium levels are low, spontaneous release of calcium from intracellular storage sites can generate a depolarizing current that contributes to pacemaker activity as well as arrhythmogenic events called delayed afterdepolarizations (see below). The Active Cell Membrane


Pharmacology_Katzung

Pharmacology_Katzung. The Active Cell Membrane In atrial and ventricular cells, the diastolic membrane potential (phase 4) is typically very stable. This is because it is dominated by a potassium permeability or conductance that is due to the activity of channels that generate an inward-rectifying potassium current (IK1). This keeps the membrane potential near the potassium SCN5A/Nav 1.5 Ca2+ L-type CACNA1/Cav 1.2 current T-type CACNA1G,H/Cav 3.1, 3.2 transient lto,f KCND3/Kv 4.3 outward lto,s KCNA4/Kv 1.4 lKur KCNA5/Kv 1.5 lK,ACh KCNJ3, 5/Kir 3.1, 3.4 lCl CFTR/CFTR inward rectifier, lK1 KCNJ2/Kir 2.1 pacemaker current, lf HCN2, 4/HCN2, 4 Na+/Ca2+ exchange SLC8A1/NCX 1 Na+/K+-ATPase NKAIN1-4/Na, K-pump


Pharmacology_Katzung

Pharmacology_Katzung. Na+/K+-ATPase NKAIN1-4/Na, K-pump FIGURE 14–2 Schematic diagram of the ion permeability changes and transport processes that occur during an action potential and the diastolic period following it. Yellow indicates inward (depolarizing) membrane currents; blue indicates outward (repolarizing) membrane currents. Multiple subtypes of potassium and calcium currents, with different sensitivities to blocking drugs, have been identified. The right side of the figure lists the genes and proteins responsible for each type of channel or transporter.


Pharmacology_Katzung

Pharmacology_Katzung. equilibrium potential, EK (about –90 mV when Ke = 5 mmol/L and Ki = 150 mmol/L). It also explains why small changes in extracellular potassium concentration have significant effects on the resting membrane potential of these cells. For example, increasing extracellular potassium shifts the equilibrium potential in a positive direction, causing depolarization of the resting membrane potential. It is important to note, however, that potassium is unique in that changes in the extracellular concentration can also affect the permeability of potassium channels, which can produce some nonintuitive effects (see Box: Effects of Potassium).


Pharmacology_Katzung

Pharmacology_Katzung. The upstroke (phase 0) of the action potential is due to the inward sodium current (INa). From a functional point of view, the behavior of the channels responsible for this current can be described in terms of three states (Figure 14–3). It is now recognized that these states actually represent different conformations of the channel protein. Depolarization of the membrane by an impulse propagating from adjacent cells results in opening of the activation (m) gates of sodium channels (Figure 14–3, middle), and sodium permeability is markedly increased. Extracellular sodium is then able to diffuse down its electrochemical gradient into the cell, causing the membrane potential to move very rapidly toward the sodium equilibrium potential, ENa (about +70 mV when Nae = 140 mmol/L and Nai = 10 mmol/L). As a result, the maximum upstroke velocity of the action potential is very fast. This intense influx of sodium is very brief because opening of the m gates upon depolarization is promptly


Pharmacology_Katzung

Pharmacology_Katzung. 10 mmol/L). As a result, the maximum upstroke velocity of the action potential is very fast. This intense influx of sodium is very brief because opening of the m gates upon depolarization is promptly followed by closure of the h gates and inactivation of these channels (Figure 14–3, right). This inactivation contributes to the early repolarization phase of the action potential (phase 1). In some cardiac myocytes, phase 1 is also due to a brief increase in


Pharmacology_Katzung

Pharmacology_Katzung. Changes in serum potassium can have profound effects on electrical activity of the heart. An increase in serum potas-sium, or hyperkalemia, can depolarize the resting mem-brane potential due to changes in EK. If the depolarization is great enough, it can inactivate sodium channels, resulting in increased refractory period duration and slowed impulse propagation. Conversely, a decrease in serum potassium, or hypokalemia, can hyperpolarize the resting membrane potential. This can lead to an increase in pacemaker activity due to greater activation of pacemaker channels, especially in latent pacemakers (eg, Purkinje cells), which are more sensitive to changes in serum potassium than normal pacemaker cells. If one only considers what happens to the potassium electrochemical gradient, changes in serum potassium can also produce effects that appear somewhat paradoxical, especially as they relate to action potential duration. This is because changes in serum potassium also affect the


Pharmacology_Katzung

Pharmacology_Katzung. in serum potassium can also produce effects that appear somewhat paradoxical, especially as they relate to action potential duration. This is because changes in serum potassium also affect the potas-sium conductance (increased potassium increases the con-ductance, decreased potassium decreases the conductance), and this effect often predominates. As a result, hyperkalemiacan reduce action potential duration, and hypokalemiacan prolong action potential duration. This effect of potassium probably contributes to the observed increase in sensitivity to potassium channel-blocking antiarrhythmic agents (quini-dine or sotalol) during hypokalemia, resulting in accentuated action potential prolongation and a tendency to cause torsades de pointes arrhythmia.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 14–3 A schematic representation of Na+ channels cycling through different conformational states during the cardiac action potential. Transitions between resting, activated, and inactivated states are dependent on membrane potential and time. The activation gate is shown as m and the inactivation gate as h. Potentials typical for each state are shown under each channel schematic as a function of time. The dashed line indicates that part of the action potential during which most Na+ channels are completely or partially inactivated and unavailable for reactivation. potassium permeability due to the activity of channels generating transient outward currents.


Pharmacology_Katzung

Pharmacology_Katzung. Although a small fraction of the sodium channels activated during the upstroke may actually remain open well into the later phases of the action potential, sustained depolarization during the plateau (phase 2) is due primarily to the activity of calcium channels. Because the equilibrium potential for calcium, like sodium, is very positive, these channels generate a depolarizing inward current. Cardiac calcium channels activate and inactivate in what appears to be a manner similar to sodium channels, but in the case of the most common type of calcium channel (the “L” type), the transitions occur more slowly and at more positive potentials. After activation, these channels eventually inactivate and the permeability to potassium begins to increase, leading to final repolarization (phase 3) of the action potential. Two types of potassium channels are particularly important in phase 3 repolarization. They generate what are referred to as the rapidly activating (IKr) and slowly activating


Pharmacology_Katzung

Pharmacology_Katzung. of the action potential. Two types of potassium channels are particularly important in phase 3 repolarization. They generate what are referred to as the rapidly activating (IKr) and slowly activating (IKs) delayed rectifier potassium currents. Repolarization, especially late in phase 3, is also aided by the inward rectifying potassium channels that are responsible for the resting membrane potential.


Pharmacology_Katzung

Pharmacology_Katzung. It is noteworthy that other delayed rectifier-type potassium currents also play important roles in repolarization of certain cardiac cell types. For example, the ultra-rapidly activating delayed rectifier potassium current (IKur) is particularly important in repolarizing the atrial action potential. The resting membrane potential and repolarization of atrial myocytes are also affected by potassium channels that are gated by the parasympathetic neurotransmitter acetylcholine.


Pharmacology_Katzung

Pharmacology_Katzung. Purkinje cells are similar to atrial and ventricular cells in that they generate an action potential with a fast upstroke due to the activity of sodium channels. However, unlike atrial and ventricular cells, the membrane potential during phase 4 exhibits spontaneous depolarization. This is due to the presence of pacemaker channels that generate an inward depolarizing pacemaker current. This is sometimes referred to as the “funny” current (If), because the channels involved have the unusual property of being activated by membrane hyperpolarization. Under some circumstances, Purkinje cells can act as pacemakers for the heart by spontaneously depolarizing and initiating an action potential that is then propagated throughout the ventricular myocardium. However, under normal conditions, the action potential in Purkinje cells is triggered by impulses that originate in the SA node and are conducted to these cells through the AV node.


Pharmacology_Katzung

Pharmacology_Katzung. Pacemaking activity in the SA node is due to spontaneous depolarization during phase 4 of the action potential as well (Figure 14–1). This diastolic depolarization is mediated in part by the activity of pacemaker channels. It is also thought to be due to the net inward current generated by the sodium-calcium exchanger, which is activated by the spontaneous release of calcium from intracellular storage sites. Unlike the action potential in Purkinje cells, spontaneous depolarization in the SA node triggers the upstroke of an action potential that is primarily due to an increase in permeability to calcium, not sodium. Because the calcium channels involved open or activate slowly, the maximum upstroke velocity of the action potential in SA node cells is relatively slow. Repolarization occurs when the calcium channels subsequently close due to inactivation and delayed rectifier-type potassium channels open.


Pharmacology_Katzung

Pharmacology_Katzung. A similar process is involved in generating action potentials in the AV node. Although the intrinsic rate of spontaneous diastolic depolarization in the AV node is typically faster than that of Purkinje cells, it is still slower than the rate of depolarization in the SA node. Therefore, action potentials in the AV node are normally triggered by impulses that originate in the SA node and are conducted to the AV node through the atria. It is important to recognize that action potential upstroke velocity is a key determinant of impulse conduction velocity. Because the action potential upstroke in AV node cells is mediated by calcium channels, which open or activate relatively slowly, impulse conduction through the AV node is slow. This contributes to the delay between atrial and ventricular contraction.


Pharmacology_Katzung

Pharmacology_Katzung. Electrical activity in the SA node and AV node is significantly influenced by the autonomic nervous system (see Chapter 6). Sympathetic activation of β adrenoceptors speeds pacemaker activity in the SA node and impulse propagation through the AV node by enhancing pacemaker and calcium channel activity, respectively. Conversely, parasympathetic activation of muscarinic receptors slows pacemaker activity and conduction velocity by inhibiting the activity of these channels, as well as by increasing the potassium conductance by turning on acetylcholine-activated potassium channels. The Effect of Membrane Potential on Excitability


Pharmacology_Katzung

Pharmacology_Katzung. A key factor in the pathophysiology of arrhythmias and the actions of antiarrhythmic agents is the relationship between the membrane potential and the effect it has on the ion channels responsible for excitability of the cell. During the plateau of atrial, ventricular, or Purkinje cell action potentials, most sodium channels are inactivated, rendering the cell refractory or inexcitable. Upon repolarization, recovery from inactivation takes place (in the terminology of Figure 14–3, the h gates reopen), making the channels available again for excitation. This is a timeand voltage-dependent process. The actual time required for enough sodium channels to recover from inactivation in order that a new propagated response can be generated is called the refractory period. Full recovery of excitability typically does not occur until action potential repolarization is complete. Thus, refractoriness or excitability can be affected by factors that alter either action potential duration or the


Pharmacology_Katzung

Pharmacology_Katzung. typically does not occur until action potential repolarization is complete. Thus, refractoriness or excitability can be affected by factors that alter either action potential duration or the resting membrane potential. This relationship can also be significantly impacted by certain classes of antiarrhythmic agents. One example is drugs that block sodium channels. They can reduce the extent and rate of recovery from inactivation (Figure 14–4). Changes in refractoriness caused by either altered recovery from inactivation or altered action potential duration can be important in the genesis or suppression of certain arrhythmias. A reduction in the number of available sodium channels can reduce excitability. In some cases, it may result in the cell being totally refractory or inexcitable. In other cases, there may be a reduction in peak sodium permeability. This can reduce the


Pharmacology_Katzung

Pharmacology_Katzung. Drug Control Drug Control Channels available, percent of maximumRecovery time constant (ms) 100 0 100,000 10,000 1000 100 10 0


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 14–4 Dependence of sodium channel function on the membrane potential preceding the stimulus. Left: The fraction of sodium channels available for opening in response to a stimulus is determined by the membrane potential immediately preceding the stimulus. The decrease in the fraction available when the resting potential is depolarized in the absence of a drug (control curve) results from the voltage-dependent closure of h gates in the channels. The curve labeled Drug illustrates the effect of a typical local anesthetic antiarrhythmic drug. Most sodium channels are inactivated during the plateau of the action potential. Right: The time constant for recovery from inactivation after repolarization also depends on the resting potential. In the absence of drug, recovery occurs in less than 10 ms at normal resting potentials (−85 to −95 mV). Depolarized cells recover more slowly (note logarithmic scale). In the presence of a sodium channel-blocking drug, the time constant of recovery


Pharmacology_Katzung

Pharmacology_Katzung. 10 ms at normal resting potentials (−85 to −95 mV). Depolarized cells recover more slowly (note logarithmic scale). In the presence of a sodium channel-blocking drug, the time constant of recovery is increased, but the increase is far greater at depolarized potentials than at more negative ones.


Pharmacology_Katzung

Pharmacology_Katzung. maximum upstroke velocity of the action potential, which will in phase 3 of the action potential, or delayed afterdepolarizations turn reduce action potential conduction velocity. (DADs), which occur during phase 4. EADs are usually triggered In cells like those found in the SA and AV nodes, where excit-by factors that prolong action potential duration. When this pro-ability is determined by the availability of calcium channels, excit-longation occurs in ventricular cells, there is often a corresponding ability is most sensitive to drugs that block these channels. As a increase in the QT interval of the electrocardiogram (ECG). Such an result, calcium channel blockers can decrease pacemaker activity in the SA node as well as conduction velocity in the AV node.


Pharmacology_Katzung

Pharmacology_Katzung. Many factors can precipitate or exacerbate arrhythmias: ischemia, hypoxia, acidosis or alkalosis, electrolyte abnormalities, excessive catecholamine exposure, autonomic influences, drug toxicity (eg, digitalis or antiarrhythmic drugs), overstretching of cardiac fibers, and the presence of scarred or otherwise diseased tissue. However, all arrhythmias result from (1) disturbances in impulse formation and/or (2) disturbances in impulse conduction. Disturbances of Impulse Formation Pacemaking activity is regulated by both sympathetic and parasympathetic activity (see above). Therefore, factors that antagonize or enhance these effects can alter normal impulse formation, producing either bradycardia or tachycardia. Genetic mutations have also been found to alter normal pacemaking activity. Under certain circumstances, abnormal activity can be generated by latent pacemakers, cells that show slow phase 4 depolarization even under normal conditions (eg, Purkinje cells). Such cells are


Pharmacology_Katzung

Pharmacology_Katzung. Under certain circumstances, abnormal activity can be generated by latent pacemakers, cells that show slow phase 4 depolarization even under normal conditions (eg, Purkinje cells). Such cells are Early afterdepolarization (arises from the plateau) Delayed afterdepolarization (arises from the resting potential) Prolonged plateau 0 mV –70 0 mV –70 0.5 sec FIGURE 14–5 Two forms of abnormal activity, early (top) and particularly prone to accelerated pacemaker activity, especially under delayed afterdepolarizations (bottom). In both cases, abnormal conditions such as hypokalemia. Abnormalities in impulse formation depolarizations arise during or after a normally evoked action can also be the result of afterdepolarizations (Figure 14–5). These can potential. They are therefore often referred to as “triggered” automaticity; be either early afterdepolarizations (EADs), which occur during that is, they require a normal action potential for their initiation.


Pharmacology_Katzung

Pharmacology_Katzung. It is now possible to define the molecular basis of several con-genital and acquired cardiac arrhythmias. The best example is the polymorphic ventricular tachycardia known as torsades de pointes (Figure 14–8), which is associated with prolongation of the QT interval (especially at the onset of the tachycardia), syncope, and sudden death. This represents prolongation of the action potential of at least some ventricular cells (Figure 14–1). The effect can, in theory, be attributed to either increased inward current (gain of function) or decreased outward current (loss of function) during the plateau of the action potential. Action potential prolongation is thought to generate early afterdepo-larizations (Figure 14–5) that then trigger torsades de pointes. Recent molecular genetic studies have identified up to 300 different mutations in at least eight ion channel genes that produce congenital long QT (LQT) syndrome (Table 14–1). Loss-of-function mutations in potassium channel genes


Pharmacology_Katzung

Pharmacology_Katzung. have identified up to 300 different mutations in at least eight ion channel genes that produce congenital long QT (LQT) syndrome (Table 14–1). Loss-of-function mutations in potassium channel genes (HERG, KCNE2, KCNQ1, KCNE1, and KCNJ2) result in decreased outward plateau current, while gain-of-function mutations in the sodium channel gene (SCN5A) or calcium channel gene (CACNA1c) cause increases in inward plateau current. The identification of the precise molecular mechanisms underlying various forms of the LQT syndromes now raises the possibility that specific therapies may be developed for individu-als with defined molecular abnormalities. Indeed, preliminary reports suggest that the sodium channel blocker mexiletine can correct the clinical manifestations of congenital LQT subtype 3, while β-blockers have been used to prevent arrhythmias trig-gered by sympathetic stimulation in patients with LQT subtype 1. The molecular basis of several other congenital cardiac arrhythmias


Pharmacology_Katzung

Pharmacology_Katzung. 3, while β-blockers have been used to prevent arrhythmias trig-gered by sympathetic stimulation in patients with LQT subtype 1. The molecular basis of several other congenital cardiac arrhythmias associated with sudden death has also recently been identified. At least three forms of short QT syndrome have been identified that are linked to gain-of-function mutations in different potassium channel genes (KCNH2, KCNQ1, and KCNJ2). Catecholaminergic polymorphic ventricular tachycardia, a disease that is characterized by stressor emotion-induced syncope, can be caused by mutations in at least two different genes (hRyR2 and CASQ2) of proteins expressed in the sarcoplasmic reticulum that control intracellular calcium homeostasis. Mutations in two different ion channel genes (HCN4 and SCN5A) have been linked to congenital forms of sick sinus syndrome. Several forms of Brugada syndrome, which is characterized by ventricular fibrillation associated with persistent ST-segment elevation, and


Pharmacology_Katzung

Pharmacology_Katzung. have been linked to congenital forms of sick sinus syndrome. Several forms of Brugada syndrome, which is characterized by ventricular fibrillation associated with persistent ST-segment elevation, and progressive cardiac conduction disorder (PCCD), which is characterized by impaired conduction in the His-Purkinje system and right or left bundle block leading to complete AV block, have been linked to loss-of-function mutations in the sodium channel gene (SCN5A). At least one form of familial atrial fibrillation is caused by a gain-of-function mutation in a potassium channel gene (KCNQ1).


Pharmacology_Katzung

Pharmacology_Katzung. effect can be caused by genetic mutations associated with congenital long QT (LQT) syndrome (see Box: Molecular & Genetic Basis of Cardiac Arrhythmias). A number of drugs (antiarrhythmic as well as non-antiarrhythmic agents) can produce “acquired” or drug-induced LQT syndrome, which is typically due to block of rapidly activating delayed rectifier potassium channels. Many forms of LQT syndrome are exacerbated by other factors that prolong action potential duration, including hypokalemia and slow heart rates. DADs, on the other hand, often occur when there is an excess accumulation of intracellular calcium (see Chapter 13), especially at fast heart rates. They are thought to be responsible for arrhythmias associated with digitalis toxicity, excess catecholamine stimulation, and myocardial ischemia. Disturbances of Impulse Conduction


Pharmacology_Katzung

Pharmacology_Katzung. Disturbances of Impulse Conduction The most common form of conduction disturbance affects the AV node, causing various degrees of heart block. The result can be a simple slowing of impulse propagation through the AV node, which is reflected by an increase in the PR interval of the ECG. At the extreme, the result can be complete heart block, where no impulses are conducted from the atria to the ventricles. In this situation, ventricular activity is generated by a latent pacemaker, such as a Purkinje cell. Because the AV node is typically under the tonic influence of the parasympathetic nervous system, which slows conduction, AV block can sometimes be relieved by antimuscarinic agents like atropine.


Pharmacology_Katzung

Pharmacology_Katzung. A serious form of conduction abnormality involves reentry (also known as “circus movement”). In this situation, one impulse reenters and excites areas of the heart more than once. The path of the reentering impulse may be confined to very small areas, such as within or near the AV node or where a Purkinje fiber makes contact with the ventricular wall (Figure 14–6), or it may involve large portions of the atria or ventricles. Some forms of reentry are strictly anatomically determined. For example, in Wolff-Parkinson-White syndrome, the reentry circuit consists of atrial tissue, the AV node, ventricular tissue, and an accessory AV connection (bundle of Kent, a bypass tract). Depending on how many round trips through the pathway a reentrant impulse makes before dying out, the arrhythmia may be manifest as one or a few extra beats or as a sustained tachycardia. Circulating impulses can also give off “daughter impulses” that can spread to the rest of the heart. In cases such as atrial or


Pharmacology_Katzung

Pharmacology_Katzung. be manifest as one or a few extra beats or as a sustained tachycardia. Circulating impulses can also give off “daughter impulses” that can spread to the rest of the heart. In cases such as atrial or ventricular fibrillation, multiple reentry circuits may meander through the heart in apparently random paths, resulting in the loss of synchronized contraction.


Pharmacology_Katzung

Pharmacology_Katzung. An example of how reentry can occur is illustrated in Figure 14–6. In this scenario, there are three key elements: (1) First is an obstacle (anatomic or physiologic) to homogeneous impulse conduction, thus establishing a circuit around which the reentrant wave front can propagate. (2) The second element is unidirectional block at some point in the circuit. That is, something has occurred such that an impulse reaching the site initially encounters refractory tissue. This can occur under conditions such as ischemia, TABLE 14–1 Molecular and genetic basis of some cardiac arrhythmias.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 14–1 Molecular and genetic basis of some cardiac arrhythmias. 1Ankyrins are intracellular proteins that associate with a variety of transport proteins including Na+ channels, Na+/K+-ATPase, Na+, Ca2+ exchange, and Ca2+ release channels. 2Also known as Andersen syndrome. 3Also known as Timothy syndrome; multiple organ dysfunction, including autism. 4CPVT, catecholaminergic polymorphic ventricular tachycardia; mutations in intracellular ryanodine Ca2+ release channel or the Ca2+ buffer protein, calsequestrin, may result in enhanced sarcoplasmic reticulum Ca2+ leakage or enhanced Ca2+ release during adrenergic stimulation, causing triggered arrhythmogenesis. 5HCN4 encodes a pacemaker current in sinoatrial nodal cells; mutations in sodium channel gene (SCN5A) cause conduction defects. GF, gain of function; LF, loss of function; LQT, long QT syndrome; PCCD, progressive cardiac conduction disorder; SQT, short QT syndrome. A. Normal conduction B. Unidirectional block