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					                                                 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?

				
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