SECTION III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM 15. Pharmacological Management of Chronic 20. Antihypertensive Drugs 225 Heart Failure 151 . David P Westfall Mitchell S. Finkel and Humayan Mirza 21. Diuretic Drugs 239 16. Antiarrhythmic Drugs 160 Peter A. Friedman and William O. Berndt Peter S. Fischbach and Benedict R. Lucchesi 22. Anticoagulant, Antiplatelet, and Fibrinolytic 17. Antianginal Drugs 196 (Thrombolytic) Drugs 256 Garrett J. Gross Jeffrey S. Fedan 18. The Renin–Angiotensin–Aldosterone System 23. Hypocholesterolemic Drugs and Coronary and Other Vasoactive Substances 206 Heart Disease 268 Lisa A. Cassis Richard J. Cenedella 19. Calcium Channel Blockers 218 Vijay C. Swamy and David J. Triggle 149 15 Pharmacological Management of Chronic Heart Failure Mitchell S. Finkel and Humayun Mirza DRUG LIST GENERIC NAME PAGE GENERIC NAME PAGE Amrinone 157 Hydralazine 155 Captopril 158 Losartan 156 Carvedilol 156 Metoprolol 156 Digitoxin 152 Milrinone 157 Dobutamine 157 Spironolactone 155 Digoxin 152 Valsartan 156 Furosemide 155 CHRONIC (CONGESTIVE) HEART gressive deterioration and early mortality in individuals FAILURE who have an EF below 40%. Patients who have a signiﬁcant loss of cardiac pump It is remarkable that the therapeutic approach to a function develop progressively severe symptoms of fa- decreased EF is the same regardless of the etiology. The tigue, dyspnea (shortness of breath), chest pain, syncope principles that guide the pharmacological management (loss of consciousness), and death. The management of of CHF is the same for patients who had damage from these patients requires an understanding that it is an on- a myocardial infarction (MI), viral infection, valvular going process in which the response to the initial injury disease, alcohol, and so on. This chapter reviews the rec- causes damage beyond the insult alone. The challenge ommended approach to the pharmacological manage- of the clinician is to keep the congestive heart failure ment of systolic dysfunction. An historic perspective (CHF) patient out of the hospital while reducing mor- will be followed to provide an appreciation of the evo- bidity and mortality in this high-risk population. lution in our understanding of the pathophysiology of Chronic CHF may be deﬁned as the clinical condi- this condition. tion in which an individual expels less than 40% of the The management of heart failure in the presence of blood from the left ventricle per heartbeat (ejection normal systolic function is not reviewed. This form of fraction [EF] 40%). A normal individual expels about heart failure commonly occurs in the elderly with 55 to 65% of the blood from the left ventricle per heart- chronic hypertension and left ventricular hypertrophy. beat (EF 55–65%). The rationale for choosing the The failure of the left ventricle to relax during diastole 40% EF is based on clinical ﬁndings demonstrating pro- (diastolic dysfunction) results in elevated end diastolic 151 152 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM pressures and volumes. The shortness of breath (dysp- trolled by phosphodiesterases and phosphatases that nea), chest pain, and fatigue that result from elevated prevent indeﬁnite phosphorylation and activation of pulmonary venous pressures are similar in both systolic regulatory proteins. -Adrenoceptor stimulation results and diastolic dysfunction. Also excluded from discus- in the phospholipase C–mediated breakdown of phos- sion are nondrug therapies for CHF, such as coronary phatidylcholine to inositol triphosphate and diacyl glyc- artery bypass, percutaneous coronary interventions, erol; these second messengers further enhance mobi- electronic pacemakers, and cardiac transplantation. lization of both transsarcolemmal calcium inﬂux and SR A considerable body of literature supports abnor- calcium efﬂux. malities in myocardial excitation–contraction coupling Binding of angiotensin II to its cardiac myocyte re- in CHF. An appreciation of the principles involved in ceptor acutely increases Ca inﬂux through sarcolem- this cell signaling process is crucial to understand cur- mal L-type calcium channels. The long-term effects of rent and future pharmacotherapies for CHF. A brief chronic angiotensin II receptor stimulation include car- overview of myocardial excitation–contraction coupling diac myocyte hypertrophy through enhanced expres- will be provided. sion of growth factor genes. The maintenance of a resting membrane potential in cardiac myocytes, as well as all cells, depends on meta- bolic energy (ATP) that is used by the Na –K ATPase MYOCARDIAL to drive the gradients for Na and K between the in- EXCITATION–CONTRACTION COUPLING tracellular and extracellular spaces. Cardiac glycosides The physiological processes that begin with cardiac sar- are known to bind to this protein. colemmal membrane depolarization and culminate in contraction are collectively deﬁned as myocardial exci- tation–contraction coupling. Depolarization of the car- CARDIAC GLYCOSIDES diac myocyte sarcolemmal membrane during the action potential results in the intracellular entry of extracellu- Historical Background lar calcium. The major regulators of the transsarcolem- mal entry of calcium include L-type calcium channels In “An Account of the Foxglove” William Withering re- and autonomic receptors (Fig. 15.1). These membrane- lated his experiences while in private practice more bound proteins all contribute to the inﬂux of a minute than 200 years ago. He traveled between two towns quantity of calcium from outside the cell into the myo- where he took care of the wealthy patients on a fee-for- cyte. The entry of this small quantity of calcium causes service basis in one town and the poor people for free the release of the large reservoir of calcium stored in in the other. He encountered during one of his com- the sarcoplasmic reticulum (SR) through the SR cal- mutes a practitioner of the healing arts who was re- cium release channel (ryanodine receptor). This large ferred to as a witch. She provided care for people with reservoir of calcium interacts with tropomyosin to allow obvious signs and symptoms of ﬂuid overload who were the actin and myosin ﬁlaments to overlap, resulting in diagnosed with dropsy (later called CHF). She gave systolic myocardial contraction. Diastolic relaxation re- these patients a group of herbs that contained digitalis, sults from the resequestration of this large reservoir of and it was Withering who identiﬁed Digitalis purpura as calcium back into the sarcoplasmic reticulum through the active plant in this mixture. Unfortunately, he the SR calcium adenosine triphosphatase (ATPase). lacked any insight into potential mechanisms of action. Calcium exits the cell through the Na –Ca exchanger Although Withering thought that digitalis worked by in- and sarcolemmal Ca ATPase. ducing emesis, he was actually describing digitalis toxic- Autonomic receptors further regulate calcium inﬂux ity and not the mechanism of action at all. through the sarcolemma (Fig. 15.1). -Adrenergic stim- ulation results in the association of a catalytic subunit of Digitalization a G protein coupled to the -receptor. This stimulates the enzyme adenylyl cyclase to convert ATP to cyclic Digitalis remains notorious today for its very narrow adenosine monophosphate (cAMP). Increasing cAMP dosage window for therapeutic efﬁcacy without toxicity. production results in a cAMP-dependent phosphoryla- A unique process, digitalization, for dosing digitalis tion of the L-type calcium channel and a subsequent in- (digoxin [Lanoxin]; digitoxin [Crystodigin]) has been crease in the probability of the open state of the chan- widely accepted over the years as a means of minimiz- nel. This translates to an increase in transsarcolemmal ing toxicity. This process is to start patients on several calcium inﬂux during phase 2 (the plateau phase) of the repeated doses of digitalis over 24 to 36 hours before es- cardiac muscle action potential. The effects of transient tablishing a lower daily maintenance dose. Digitalis has increases in intracellular levels of cAMP are tightly con- become the mainstay of therapy for CHF despite its 15 Pharmacological Management of Chronic Heart Failure 153 L-Type Calcium Channel Ca2+ ATP cAMP Adenylate cyclase ATPase Ca2+ Ca2+ G-protein β-Adrenergic Ryanodine Receptor Receptor Ca2+ Ca2+ ATPase α-Adrenergic Receptor Sarcoplasmic Reticulum 2Ca2+ 3Na+ Ca2+ Angiotensin II Receptor 2K+ ATPase 3Na Contractile Proteins FIGURE 15.1 Principles of excitation-contraction coupling in the cardiac myocyte. Calcium enters the myocyte through L-type calcium channels that are modulated by - and -adrenergic receptors. This small quantity of calcium triggers release of the large reservoir of intracellular calcium stored in the SR by activation of the SR calcium release channel (ryanodine receptor). Calcium is resequestered in the SR by the SR calcium–ATPase. Calcium is extruded from the cell largely through the Na –Ca exchanger and the sarcolemmal calcium ATPase. -Adrenergic agonists (e.g., dobutamine) bind to the -adrenoceptor and activate a stimulatory G protein to couple with . adenylyl cyclase to convert ATP to cAMP Phosphodiesterase inhibitors (e.g., milrinone) increase intracellular cAMP levels by blocking the degradation of cAMP by phosphodiesterases. -Adrenergic antagonists (e.g., metoprolol, carvedilol) bind to the same site and prevent endogenous catecholamines (e.g., norepinephrine) from binding to that site and activating a stimulatory G protein. -Adrenergic antagonists (e.g., prazosin) and angiotensin II receptor blockers (e.g., valsartan, losartan) similarly prevent the endogenous mediators (i.e., norepinephrine, angiotensin II, respectively) from increasing intracellular ionized free calcium levels in the cardiac myocyte. ACE inhibitors (e.g., captopril, fosinopril, lisinopril) block conversion of inert angiotensin I to active angiotensin II by ACE. Digitalis glycosides initially increase intracellular Na levels by binding to the Na –K ATPase. The increase in intracellular Na causes the Na –Ca exchanger to extrude Na from the myocyte in exchange for extracellular Ca . This increases intracellular ionized free calcium levels sufﬁciently to enhance contractility. 154 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM toxicity, the lack of understanding of its mode of action, channel results in closing of the L-type sarcolemmal and the lack of any deﬁnitive evidence describing its Ca channel. Ca channel inhibition slows the heart safety and efﬁcacy. rate and/or converts the rhythm to a sinus mechanism. Digitalis works directly on the heart through an ac- tion on the sodium–potassium (Na –K ) ATPase. Since Toxicity all living cells have a resting membrane potential, there Digitalis toxicity includes nausea, vomiting, anorexia, is an electrochemical gradient across the cell membrane fatigue, and a characteristic visual disturbance (green- that is not at a steady state electrically. There is an im- yellow halos around bright objects). Cardiac toxicities balance in that all cells are intracellularly negative com- have included tachyarrhythmias and bradyarrhythmias, pared to the outside of the cell. The maintenance of this including supraventricular and ventricular tachycardia gradient requires metabolic energy to maintain this dif- and atrioventricular (A-V) block. The most classic (but ference in ions. This electrochemical gradient is lost af- not most frequent) manifestations of digitalis toxicity ter death. The activity of the Na –K ATPase results in include atrial tachycardia with A-V block. Treatment serum sodium levels of roughly 140 to 145 mmol and for digitalis toxicity ranges from mild cases that respond serum potassium around 5 mmol. Inside cells the Na to simply stopping the drug to the use of antidigitalis concentration is low and the K concentration is high. antibodies in life-threatening situations. The availability The reason for this difference between the intracellular of a radioimmunoassay for digitalis levels and antidigi- and extracellular sodium and potassium is the action of talis antibodies, useful in reversing digitalis’s actions, the Na –K ATPase enzyme. Digitalis binds to this en- have minimized the frequency of fatal toxicity. zyme and inhibits its activity. This results in an elevation in intracellular Na that leads to an increase in extru- sion of Na through the Na –Ca exchanger, which Clinical Use functions to maintain a relatively constant level of both Randomized clinical trials have been conducted to ex- Na and Ca in the cell. The Na –Ca exchanger nor- plore the safety and efﬁcacy of digitalis in the manage- mally extrudes Ca in exchange for Na . However, in ment of CHF. The ﬁrst major trial showed an improve- the presence of increased intracellular Na , it will ex- ment in quality of life but no mortality beneﬁt. A second trude Na by exchanging it for extracellular Ca . This major clinical trial revealed that treatment with digitalis reversal in the activity of the Na –Ca exchanger re- diminished the combined end points of death and hos- sults in an increase in intracellular ionized free Ca pitalizations but did not speciﬁcally improve overall that enhances myocardial contractility. survival. Thus, no studies have demonstrated that digi- The current hypothesis regarding the cellular basis talis therapy improves survival in CHF patients. for the positive inotropic effect of digitalis helps to ex- However, digitalis does decrease morbidity by dimin- plain some of the wide individual variability in the ishing the number of admissions to the hospital for dosage required to develop digitalis toxicity. Dif- symptoms such as dyspnea (shortness of breath) and fa- ferences in pH, ischemia, Na , K , and Ca can each tigue. Current guidelines for the treatment of CHF in- alter the likelihood of developing toxicity within the dicate that physicians must at least consider including same patient and between individuals. digitalis in the regimen. The consensus now is to pre- scribe a dose that achieves a digitalis blood level of 0.8 to 1.2 ng/dL. This lower dose reduces the incidence of side effects while optimizing the beneﬁt. DIURETICS One cannot discuss the management of heart failure without including comments about the kidney. The rela- Mechanism of Action tionship between the heart and the kidney makes intu- Digitalis has the unique characteristic of increasing con- itive sense when one considers the importance of the tractility (positive inotropy) while decreasing heart rate kidney in maintaining an appropriate volume status (negative chronotropy). This pharmacological proﬁle throughout the body. An analogy that may be useful to results from indirect as well as direct effects of digitalis consider is the situation in which an individual turns on glycosides on the heart. Digitalis is a fat-soluble steroid the faucet at home to ﬁnd that little water is ﬂowing. that crosses the blood-brain barrier and enhances vagal The ﬁrst assumption is that a leak somewhere in the sys- tone. The slowing and/or conversion of a patient with tem is responsible for the lower water pressure. An ap- supraventricular arrhythmia (e.g., atrial ﬁbrillation, propriate response is to turn off the water to the house. supraventricular tachycardia) with digitalis results from In an analogous manner, the kidney perceives low car- enhancement of vagal tone. This increased vagal activity diac output from a failing heart as a leak. The kidney be- increases acetylcholine release, which in turn is coupled gins to elaborate hormones designed to retain ﬂuid. to the opening of a K channel. Opening of this K Many of the problems in CHF result from an inappro- 15 Pharmacological Management of Chronic Heart Failure 155 priate neurohumoral activation by the kidney in re- ing duct of the kidney. Aldosterone enhances salt and sponse to perceived volume depletion from hemor- water retention at the expense of enhanced renal K rhage. Mechanisms that result in vasoconstriction are and H excretion. Spironolactone enhances diuresis by normally compensatory in the short term for acute blocking sodium and water retention while retaining bleeding. These same adaptive mechanisms become potassium. An obvious potential side effect is hyper- damaging in chronic heart failure. kalemia, which is aggravated by the potassium-retaining The usefulness of diuretics in the management of properties of the ACE inhibitors. The likely concomi- CHF cannot be overstated. Before diuretics were avail- tant use of the loop diuretic furosemide, which depletes able, rotating tourniquets were used to diminish venous K , dictates careful monitoring of serum potassium to return by ligating the lower extremities. Less venous avoid life-threatening rhythm disturbances. blood returned to the right side of the heart and pooled There is also evidence for the existence of mineralo- in the legs. This procedure diminished the effective in- corticoid receptors on cardiac myocytes. This raises the travascular volume that would otherwise have accumu- intriguing possibility that spironolactone could mediate lated in the lungs. The availability of loop diuretics (par- important direct effects on the myocardium in CHF. ticularly furosemide) has resulted in the virtual elimination of this practice. HYDRALAZINE AND NITRATES Loop Diuretics A major advance in the pharmacological management of CHF has been the demonstration that afterload re- Diuretics and their mechanisms of action will be dis- duction improved survival. The concept of afterload cussed in detail in Chapter 21. Loop diuretics, such as reduction was developed for the treatment of mitral re- furosemide (Lasix), block the Na –K –2Cl symporter gurgitation. It was noted that a decrease in systemic vas- in the ascending limb of the loop of Henle. The resultant cular resistance, as reﬂected in lower arterial blood pres- effect is delivery of more Na to the distal tubule and sure, resulted in an increase in the percentage of blood enhanced urinary loss of Na and water. Unfortunately, that ﬂowed from the left ventricle to the aorta as op- the resultant increase in urinary excretion of H and K posed to the left atrium (decreased regurgitant fraction). can lead to arrhythmias. The potential for arrhythmias is The decrease in backup of blood into the lungs provided exacerbated by the loss of Mg and Ca and an un- considerable symptomatic relief from dyspnea, fatigue, derlying vulnerability of the myocardium in CHF. and chest pain. It was reasoned that patients with CHF However, loop diuretics are still part of the mainstay of often also have mitral regurgitation and might similarly therapy for CHF despite these potential problems and beneﬁt from more forward (left ventricle to aorta), as the absence of well-controlled multicenter clinical trials. opposed to backward (left ventricle to left atrium), The rationale for their use is so compelling that blood ﬂow. A VA Cooperative Study in which vasodila- placebo-controlled studies appear unethical. Moreover, tors were added to digitalis and furosemide was the ﬁrst furosemide was accepted as the standard of care in all to demonstrate a signiﬁcant improvement in survival in of the clinical trials that form the basis for recom- CHF. Patients were given either prazosin as an - mended therapy for CHF. The use of the potassium- adrenoceptor blocking agent or the combination of sparing diuretic spironolactone has been shown to im- the direct vasodilator hydralazine and a nitric oxide– prove survival and is discussed below. mediated vasodilator, that is, one of the nitrates. There were fewer deaths among the patients on the combina- Spironolactone tion of hydralazine and nitrates. Patients taking prazosin did not beneﬁt, probably because chronic therapy with Spironolactone (Aldactone) is the only diuretic that has prazosin results in tachyphylaxis. The mechanisms of ac- been shown in a double-blind multicenter prospective tion of prazosin, hydralazine, and organic nitrates are clinical trial to improve survival in CHF. The addition discussed in more detail elsewhere. of spironolactone to digitalis and an angiotensin- converting enzyme (ACE) inhibitor signiﬁcantly im- proved survival among patients with chronic severe ANGIOTENSIN-CONVERTING ENZYME heart failure. This study was conducted with patients INHIBITORS who were not taking a -adrenoceptor blocking agent. It is unclear at present whether the addition of spirono- The relative ease of administration and superior efﬁ- lactone to a combination of digitalis, ACE inhibitor, and cacy of angiotensin-converting enzyme inhibitors and a -blocker will also confer additional beneﬁt. angiotensin II receptor blockers (ARB) have largely Spironolactone competitively inhibits the binding of relegated hydralazine and nitrate therapy to second- aldosterone to cytosolic mineralocorticoid receptors in line therapies for CHF. The demonstration of the sur- the epithelial cells in the late distal tubule and collect- vival beneﬁt conferred by vasodilator therapy resulted 156 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM in a paradigm shift in the approach to CHF. It was rec- cular system (i.e., vasoconstrictors vs. vasodilators). The ognized that the way to improve survival in heart failure use of an ACE inhibitor results in the elaboration of was not by directly addressing the weakened heart more kinins and less angiotensin II. Thus, the beneﬁts pump but rather by reversing the inappropriate periph- of ACE inhibitors may derive from their elaboration of eral vasoconstriction that results from neurohumoral more kinins in addition to their inhibition of an- activation. giotensin II formation. Captopril (Capoten) was the original prototype Efforts to elucidate the mechanisms responsible for product, and it was administered three times a day. the pharmacological efﬁcacy of ACE inhibitors have A once-a-day preparation was subsequently patented been further complicated by the discovery of alterna- and marketed. Prospective multicenter double-blind tive pathways for forming angiotensin II independent of placebo-controlled clinical trials have repeatedly the conversion of angiotensin I to angiotensin II. Other demonstrated an early and persistent survival beneﬁt cellular enzymes, such as chymases and trypsin, can also with ACE inhibitors in CHF patients. ACE inhibitors elaborate angiotensin II. And ﬁnally, at least two dis- were found superior to hydralazine and nitrates in a di- tinct angiotensin II receptors have been cloned and se- rect comparison. ACE inhibitors are now clearly the quenced; they are confusingly named the type 1 and agents of ﬁrst choice in the pharmacological manage- type 2 angiotensin II (AT-1;AT-2) receptors. ment of CHF. There are also a number of additional rea- Elaboration of angiotensin II can result in either of sons to use ACE inhibitors. The HOPE trial and other two effects on an individual cell, depending on the rela- studies demonstrated additional survival and renal pro- tive numbers of AT-1 and AT-2 receptors. Relatively se- tective beneﬁts of ACE inhibition in diabetic and/or hy- lective AT-1 receptor blockers have been developed in pertensive patients long before they develop CHF. an effort to achieve superior efﬁcacy with enhanced se- Our understanding of the mechanism of action of lectivity. Thus far, clinical studies indicate that ARBs ACE inhibitors has evolved along with our growing ap- may be as effective as ACE inhibitors and have fewer preciation of the physiological and pathophysiological side effects. The consensus in their use is to try an ACE role of angiotensin II. Initially, angiotensin II was shown inhibitor as the ﬁrst-line therapy before using an ARB, to be elaborated in response to low blood ﬂow to the such as valsartan or losartan. However, ACE inhibitors kidney in animal models of hypertension. Low ﬂow to can induce a very troubling cough in susceptible indi- the kidney occurs when damage to the heart results in a viduals as a result of the increase in kinins. ARBs serve low cardiac output. The low EF criterion for CHF noted as a very good substitute for such patients. previously is a noninvasively determined surrogate marker for a low cardiac output. The low ﬂow to the kid- ney is perceived as bleeding. The appropriate response -ADRENOCEPTOR BLOCKING DRUGS by the kidney to low ﬂow is to elaborate renin. Renin cir- culates to the liver. Renin in the liver converts an- For many years the prevailing view was that -blockers giotensinogen to angiotensin I. Angiotensin I travels to are contraindicated in CHF. The physiological rationale the lung, where it is converted to angiotensin II by ACE. for not using -blockers in heart failure was certainly Angiotensin II binds to its receptor and increases in- well founded. Heart failure patients have a decrease in tracellular ionized free calcium. This increase in intra- cardiac output. Since cardiac output is a function of cellular ionized free calcium causes vasoconstriction by stroke volume times heart rate (CO SV HR), an in- vascular smooth muscle cells, aldosterone secretion by creased heart rate would be necessary to maintain an adrenal glomerulosa cells, increased central sympa- adequate cardiac output in the presence of the rela- thetic outﬂow, and enhanced thirst. This system is acti- tively ﬁxed decrease in stroke volume observed in CHF. vated as part of the normal host response to stressful A rapid increase in heart rate does play an important injury, such as bleeding or trauma. The systemic an- role in the physiological response to acute hemorrhage. giotensin II levels rise acutely to retain ﬂuid and im- Thus, a decrease in heart rate, along with a depression in prove short-term survival following injury. Unfor- contractility produced by -blockers, would be ex- tunately, these short-term adaptive mechanisms are not pected to precipitate catastrophic decompensation; and designed to protect against the long-term consequences this certainly can happen in the acute setting. of chronic low blood ﬂow from CHF. The extraordinary Several subsequent studies have led to the incorpo- success of ACE inhibitors in CHF clearly demonstrates ration of -blocker therapy, using either carvedilol or the harmful effects of chronic angiotensin II activation. metoprolol, into the standard of care for CHF. Patients Further reﬁnement of this basic understanding fol- already taking digitalis, furosemide, and an ACE in- lowed. First of all, ACE inhibitors not only block the hibitor were prescribed a -blocker in these studies. conversion of angiotensin I to angiotensin II; they also Surprisingly, the long-term use of -blockers in CHF block the breakdown of bradykinin. Kinins are va- improved ventricular function and prolonged survival. sodilators and serve as part of the yin–yang of the vas- The assumption that an increased heart rate is neces- 15 Pharmacological Management of Chronic Heart Failure 157 sary to maintain an adequate cardiac output in the face agement of CHF. This rationale favors the use of the of a reduced stroke volume is clearly not true in CHF. combined nonselective - and -blocker carvedilol over The beneﬁts of the use of -blockade appear to ex- the relatively selective 1-antagonist metoprolol. In ad- ceed by far the risks of bronchospasm in patients diag- dition, in CHF the number of 1-receptors decreases nosed with chronic obstructive pulmonary disease while the number of 2-receptors increases, and the ratio (COPD) and/or suppression of hypoglycemic responses of 1- to 2-receptors changes. Thus, the 1-selectivity of in diabetics. COPD is very different from bronchospas- metoprolol may not confer any advantage over the less tic asthma. Young people with asthma have highly reac- speciﬁc -blocker carvedilol. It is clear from clinical trial tive airways and can die within hours of a broncho- data that -adrenoceptor blockers are not all the same. spasm in response to an exposure to an external agent. Use of some has produced improvements in survival, This highly reversible dynamic condition contrasts and others have produced no improvements at all. The sharply with the destruction of connective tissue in lung mechanisms responsible for these beneﬁts are not yet parenchyma and dead airway sacs that are not very re- established. Speculation includes up-regulation of active. This is a very different phenomenon. -adrenoceptors, improved G-protein coupling, altered -Blockers are adrenoceptor antagonists that bind to regulation of nitric oxide, and so on. the -receptor at the same site as do endogenous -adrenergic agonists, such as norepinephrine. Norepi- nephrine binds to the adrenergic receptor, which acti- cAMP-ELEVATING AGENTS vates a G protein, which participates in the conversion of ATP to cAMP via adenylyl cyclase. cAMP activates pro- The immediate effect of increasing intracellular cAMP tein kinase A (protein kinase A, or PKA) to phosphory- levels is an increase in contractility. This has been ob- late proteins, such as the sarcolemmal L-type Ca chan- served repeatedly in acutely ill patients in the intensive nel, that subsequently increase calcium, increase heart care unit with the intravenous infusion of either rate, conduction, and contraction. -Blockers bind to the -adrenergic agonists (e.g., dobutamine) or the phos- same receptor as does norepinephrine but do not facili- phodiesterase inhibitors milrinone (Corotrope) and am- tate G protein coupling. Occupation of the binding site rinone (Inocor). Binding of dobutamine to cardiac myo- by the -blocker prevents norepinephrine from binding cyte adrenoceptors results in G-protein coupling, to it and stimulating cAMP formation. activation of adenylyl cyclase, and the conversion of Circulating plasma norepinephrine levels correlate ATP to cAMP. inversely with survival in CHF; that is, higher levels of Administration of either milrinone or amrinone in- norepinephrine are associated with a decrease in sur- creases cAMP levels by preventing its degradation by vival. It appears that norepinephrine levels are more cardiac myocyte phosphodiesterases. Both classes of than just markers of disease severity: norepinephrine is cAMP-elevating agents have been shown to be helpful actually directly toxic to cardiac myocytes, at least in cul- for the acute short-term management of the decompen- ture. The addition of either an - or -blocker confers sated patient. Unfortunately, the long-term continuous partial protection from norepinephrine damage. use of either of these classes of agents in the outpatient Combined - and -blockade confers additive protec- setting has been associated with an increase in mortal- tion. These data from animal studies may be relevant to ity in CHF. However, the use of these drugs in appro- human heart failure, since they suggest that both - and priately selected patients is highly effective for sympto- - adrenoceptor blockade may be beneﬁcial in the man- matic relief. Study Questions 1. A 40-year-old man goes to the emergency depart- been more active and has noted improvement in his ment because of an intractable cough for the past dyspnea and fatigue that prompted his initial pres- few days. No one else in his household has any entation 10 days ago. He appreciates all of the care cough, fever, upper respiratory infection, and so on. that he received and apologizes for making a fuss He was released from the hospital a week ago with over the cough. He states that his wife made him the diagnosis of idiopathic dilated cardiomyopathy come in because she was concerned that it might be following an extensive evaluation that revealed nor- his heart. He states that the cough is different from mal coronary anatomy and a left ventricular EF of the congested feeling he had 10 days ago. On exam- 38%. He was discharged with prescriptions for digi- ination, he was afebrile; his heart rate was 60 beats talis, furosemide, captopril, and carvedilol. He has per minute; blood pressure, 100/60. Neck veins were 158 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM ﬂat; carotid upstrokes were normal. Chest and lungs (D) Binding to and inhibiting the Na–K ATPase were clear. Heart revealed a regular rate and enzyme in cardiac myocytes rhythm without murmurs, gallops, or rubs. Abdo- (E) Deactivation of the angiotensin receptor men was soft and not tender. Bowel sounds were 4. The combination of hydralazine and nitrates has present without organomegaly. Extremities revealed been shown to improve survival in patients of heart no cyanosis, clubbing, or edema. Chest radiograph failure. All of the following statements about this and electrocardiogram revealed no acute changes combination are true except: and no active disease. The physician was satisﬁed (A) The combination serves to decrease both after- that he was hemodynamically stable and the cough load and preload. was not resulting from worsening heart failure. (B) Prazosin is as effective as the combination in What is a reasonable next step? treatment of congestive heart failure. (A) Admit to the hospital to exclude (rule out) a (C) The concept of afterload reduction is princi- myocardial infarction pally derived from patients of signiﬁcant mitral re- (B) Apply a PPD skin test to exclude tuberculosis gurgitation. (C) Substitute an angiotensin II receptor blocker (D) The VA cooperative study was a landmark trial for the ACE inhibitor demonstrating the beneﬁcial effect of hydralazine (D) Provide reassurance and continue with current and nitrate combination in patients of heart failure. medications 5. -Blockers have been effective in the treatment of (E) Immediately stop the -adrenergic blocker, heart failure. They primarily exert their effect by carvedilol (A) Binding to the receptor that binds norepineph- 2. A 67 year old woman has had fatigue and short- rine ness of breath over the past few months. She has (B) Inducing a prominent diuretic effect diabetes and hypertension for which she has been (C) Increasing contractility treated for 25 years with appropriate medications. (D) Improving asthma control She is status post three myocardial infarctions (MI (E) Increasing heart rate to meet the additional 3) and has known inoperable coronary artery demands placed upon the heart in CHF disease and CHF. She has been very compliant with her complicated medical regimen, which in- ANSWERS cludes digitalis, an ACE inhibitor (fosinopril), loop 1. C. The most likely diagnosis is ACE inhibitor– diuretic (furosemide), -adrenergic receptor induced cough. A reasonable approach is to substi- blocker (carvedilol) and aldosterone antagonist tute an ARB (angiotensin II receptor blocker) such (spironolactone). On examination she was noted as valsartan or losartan for the ACE inhibitor, cap- to be in acute respiratory distress with a respira- topril. Reassure and encourage the patient and tory rate of 24, a heart rate of 60, and blood pres- spouse that you think the cough will resolve a few sure of 110/60. She was anxious and uncomfortable days after stopping the ACE inhibitor. There is gen- but polite and cooperative. Neck veins were ele- erally no beneﬁt to trying any other ACE inhibitor, vated to 8 cm with the patient partially supine. as the side effect is a class effect resulting from en- Lungs revealed rales to the angles of the scapulae hanced kinin activity from ACE inhibition. bilaterally. Heart revealed a third heart sound and Myocardial infarction is extremely unlikely in this a high pitched holosystolic murmur at the apex patient based on the catheterization data showing consistent with mitral regurgitation. Abdomen was normal coronary anatomy. Abrupt withdrawal of a protuberant with a ﬂuid shift consistent with as- -blocker may precipitate tachycardia and hyper- cites. Extremities revealed 2 to 3 pretibial pit- tension and should be avoided. ting edema bilaterally. What can the physician of- 2. A. This woman with CHF has obviously decom- fer this woman? pensated despite compliance with standard care. (A) Intravenous (cAMP elevating) positive in- She is symptomatic and may beneﬁt from a short otropic agents course of high-intensity intravenous therapy with a (B) Vasodilator therapy with hydralazine cAMP-elevating agent (e.g., dobutamine, milrinone, (C) -Adrenergic blockade with prazosin amrinone). This may be a reversible event or part of (D) Stop the diuretic, furosemide the inevitable decline of the disease process. (E) Stop the ACE inhibitor, fosinopril Approximately 45% of CHF patients die suddenly 3. Digitalis functions to improve congestive heart fail- of a presumed electrical event (e.g., ventricular ure by tachycardia, asystole). The others die slowly of pro- (A) Induction of emesis gressive deterioration. Many patients at the end (B) Activation of -adrenergic receptors stages of CHF prefer to try repeated outpatient in- (C) Improving survival in patients of heart failure otropic (cAMP elevating) therapy for symptomatic 15 Pharmacological Management of Chronic Heart Failure 159 relief even though it may be associated with a Cohn JN et al. Effect of vasodilator therapy on mortal- higher incidence of sudden death. ity in chronic congestive heart failure: Results of a 3. D. Inhibition of Na–K ATPase leads to an eleva- Veterans Administration Cooperative Study. N Engl tion of intracellular Na . This results in an increase J Med 1986;314:1547–1552. in intracellular Ca and an enhanced myocardial CONSENSUS Trial Study Group. Effects of enalapril contractibility. There is no deﬁnitive evidence that on mortality in severe congestive heart failure: digitalis improves survival of patients in heart fail- Results of the Cooperative North Scandinavian ure, but it clearly improves the symptoms of this Enalapril Survival Study (CONSENSUS). N Engl J condition. Med 1987;316:1429–1435. 4. B. Prazosin has been shown not to be as effective Hunt SA et al. ACC/AAAHA guidelines for the evalu- as the combination of hydralazine and nitrates. ation and management of CHF in the adult: 5. A. The salutary effect of -blockers appears to be Executive summary: A report of the American due solely to its binding to the -receptor, which College of Cardiology/American Heart Association prevents norepinephrine binding and stimulates Task Force on Practice Guidelines. Circulation cAMP formation. The other choices do not occur. 2001;104:2996–3007. Packer M et al. Effect of carvedilol on survival in se- SUPPLEMENTAL READING vere chronic heart failure. N Engl J Med Brophy JM, Joseph L, and Rouleau JL. Beta-blockers 2001;344:1651–1658. in congestive heart failure: A Bayesian meta- Pitt B et al. The effect of spironolactone on morbidity analysis. Ann Intern Med 2001;134:550–560. and mortality in patients with severe heart failure. Digitalis Investigation Group. The effects of digoxin on N Engl J Med 1999;341:709–717. mortality and morbidity in patients with heart fail- ure. N Engl J Med 1997;336:525–533. Case Study Therapy for Inoperable Coronary Artery Disease A 75-year-old man has inoperable coronary ar- tery disease with an EF of 31%. He is receiv- ing digoxin, furosemide, and an ACE inhibitor. He ANSWER: Start a low-dose -adrenergic blocker. Presently the choices are either the 1-selective adrenergic blocker, metoprolol, or the combined is unable to walk more than 50 feet on ﬂat ground nonselective - and -adrenergic blocker carvedilol. before getting short of breath (dyspnea on exertion The target heart rate at rest should be in the range at 50 feet). His heart rate at rest is 85 beats per of 50 to 60 beats per minute. The target blood pres- minute and his blood pressure while seated is sure should be in the range of 90 to 110 systolic, or 130/85. His neck veins are ﬂat; carotid upstrokes are orthostatic symptoms of light-headedness develop. normal; lungs are clear; and heart examination re- veals no murmurs, gallops, or rubs. His extremities reveal no cyanosis, clubbing, or edema. The remain- der of the physical examination is unremarkable. What is your next therapeutic option?