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LWBK340-c24_p555-594.qxd 30/06/2009 01:43 PM Page 572 Aptara

572 PA R T IV / Pathophysiology and Management of Heart Disease

reverses vasoconstriction (reducing afterload), and inhibit en- activity associated with the syndrome of HF. -Adrenergic blockers
docrine, paracrine, and cellular growth effect of AT. 71 ACE-I should be administered routinely to clinically stable patients who are
also diminish release of aldosterone (inhibiting sodium reten- on standard therapy (usually ACE-I and diuretic). ACC/AHA stages
tion) and produce venodilation (reducing preload). In addition B, C, and D therapy should be initiated at low doses and up-titrated
to blocking AT formation, this drug class increases levels of slowly, generally no sooner than at 2-week intervals (Table 24-10). 1
bradykinin, promotes vasodilatation, and inhibits maladaptive Table 24-11 describes strategies for management of side effects dur-
growth, including ventricular remodeling, hypertrophy, fibro- ing titration of -adrenergic blockers. -Adrenergic blockers have
sis, and improves endothelial and vascular function. The unique been shown in multiple studies to reduce mortality, morbidity, and
characteristics of this class of neurohormonal inhibitors support improve symptoms. 84–89 The safety of beta-blockers in asympto-
the use of ACE-I as first-line drugs in all patients with HF or matic LV dysfunction has not been tested.
asymptomatic LV systolic dysfunction. 1,72 Clinical benefits also
extend to patients with evidence of atherosclerotic disease. The Diuretics. The kidney is the target organ of many of the
doses used should be titrated to target levels. NSAIDs should be neurohormonal and hemodynamic changes that occur in HF. 90
avoided in patients in HF, and particularly in those patients us- Diuretics and dietary salt restriction exert their primary benefit
ing ACE-I therapy. by decreasing extracellular fluid and intravascular blood vol-
ume. The elimination of dependent edema helps reduce tissue
AT Receptor Blockers. AT receptor blockers differ in their pressure, oppose venous pooling, and therefore improve the ca-
mechanism of action compared to ACE-I. Rather than inhibiting pacitance of the venous system. Similarly, the decrease in in-
the production of angiotensin by blockade of the ACE, ARBs travascular volume also reduces ventricular preload directly,
block the cell surface receptor for AT 1 . 70 Hemodynamic effects thereby helping to diminish the filling pressures in the pul-
are similar to those of ACE-I with respect to reducing preload and monary and systemic circulations. Thiazide diuretics may be
afterload and increasing cardiac output. The potential concern of helpful in patients with mild fluid overload and normal renal
this class of drug is that the blockade of AT 1 elevates serum AT, function, but most patients require loop diuretics. Administra-
which, because the AT 2 receptors are not blocked, can increase tion of the aldosterone antagonist spironolactone should
counter regulatory actions of AT 2 activation. 73 be considered (see previous section). With advanced HF and
There is ongoing interest in and investigation of combination compromised renal function, multiple diuretics with different
therapy with ACE-I and ARBs, 74 but at the present time this sites of renal action are usually needed. 1
combination cannot be recommended as routine therapy. ACE-I
rather than ARBs continue to be the agent of choice for blockade Digitalis Glycosides. The cardiac glycosides have important
of the RAAS in HF, and the use of ARBs are usually reserved for effects in HF, including augmenting contractility (positive inotropy),
patients truly intolerant to ACE inhibitor because of cough. 73,75
Aldosterone Antagonists. ACE-I do completely block the ef- Table 24-10 ■ PHARMACOLOGIC THERAPIES
fect of the RAAS. After several months of ACE-I treatment, there
can be an increase in aldosterone levels. Aldosterone promotes Maximum
sodium retention (edema) and release of cytokines and growth Medication Start (mg) Target (mg) (mg)
factors, and causes myocardial and vascular fibrosis (autocrine or Angiotensin Converting Enzyme
paracrine effects), baroreceptor dysfunction, and progressive re- Inhibitors and Vasodilators
modeling. 76–78 The addition of low-dose spironolactone to stan- Captopril 6.25–12.5 tid 50 tid 100 tid
dard therapy for patients with ACC/AHA stage C and/or D Enalapril 2.5–5 bid 10 bid 20 bid
Lisinopril
2.5–5 qd
40 bid
20 qd
(NYHA Classes III and IV) promotes a therapeutic effect and re- Ramipril 1.25–2.5 bid 5 bid 10 bid
79
duces morbidity and mortality. The benefit of this class of drug Quinipril 5 bid 20 bid 20 bid
is not primarily a diuretic effect; spironolactone lessens myocar- Fosinorpil 2.5–5 bid 20 bid 20 bid
dial fibrosis, significantly reduces plasma BNP levels, and im- Hydralazine 25 qid 50–75 bid to tid 100 qid
20–80 tid
80 tid
proves LV remodeling and cardiac sympathetic nerve activity Isosorbide dinitrate 10–20 tid 60–120 qd 240 qd
Isosorbide mononitrate
30 qd
(which may reduce ventricular arrhythmias and SCD). 79
Diuretics
Furosemide* 20–40 qd As required 480 qd
-Adrenergic Blockers. Cardiac myocytes have three adren- Torsemide* 10–20 qd As required 200 qd
ergic receptors ( 1 , 2 , and 1 ) that are coupled with positive in- Hydochlorothiazide † 25 qd As required 200 qd
otropic and chronotropic response, cardiac myocyte growth, toxicity, Metolazone* † ‡ 2.5 qd As required 5 qd
and apoptosis. 80 Although 1 and 2 receptors are present in the Spironolactone 25 qd As required 50 bid
normal human myocardium, because 1 receptors are down- -Blockers
3.125 bid
50 bid
regulated, 2 receptors predominate in the failing myocardium. Carvedilol 6.25–25 qd 6.35–25 bid 200 qd
Metoprolol succinate
50–200 qd
Neurohormonal activity in HF can be blunted by -adrenergic Bisoprolol 1.25 qd 10 qd 10 qd
81
blockers. Second- and third-generation -adrenergic blockers have Angiotensin II Receptor Blockers
82
been used in HF. Metoprolol and bisoprolol are second-generation Ibersartan 150 qd 300 qd 300 qd
selective 1 -adrenergic blockers. 83 Carvedilol is a nonselective Candesartan 16 qd 32 qd 32 qd
-adrenergic (blocking 1 and 2 receptors), as well as an -blocking Losartan 12.5–25 50 qd 50–100 qd
agent. At low doses, carvedilol exhibits 1 selectivity; at higher target Valsartan 80 qd 160 qd 320 qd
doses, it blocks all three adrenergic receptors, allowing for renal and
*Watch potassium carefully; may cause hypokalemia
systemic vasodilatation. -Adrenergic blockers protect the failing
†
Give 30 minutes before loop diuretic
myocardium from the deleterious effects of the neurohormonal ‡ May increase serum potassium; do not give if serum potassium 4.7 mEq/L