DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 28–1
Causes of Diuretic Resistance in Heart Failure
Noncompliance with medical regimen; excess
dietary Na + intake
Decreased renal perfusion and glomerular filtration
rate due to:
Excessive vascular volume depletion and hypotension
due to aggressive diuretic or vasodilator therapy
Decline in cardiac output due to worsening heart
failure, arrhythmias, or other primary cardiac causes
Selective reduction in glomerular perfusion pressure
following initiation (or dose increase) of
ACE-inhibitor therapy
Nonsteroidal anti-inflammatory drugs
Primary renal pathology (e.g., cholesterol emboli, renal
artery stenosis, drug-induced interstitial nephritis,
obstructive uropathy)
Reduced or impaired diuretic absorption due to gut
wall edema and reduced splanchnic blood flow
arteriole vasoconstriction, appears responsible (in part)
for the development of complications common to the
use of diuretics in decompensated CHF patients, particularly
prerenal azotemia. The role of adenosine in
the macula densa and juxtaglomerular (granular) cells
(see Figure 26–2) suggests other effects of A 1
antagonists
on the renin- angiotensin system.
As an example of the use of A 1
antagonists, the administration
of KW-3902 (ROLOFYLLINE) (30 mg) to patients with decompensated
CHF already treated with loop diuretics is associated with
increased volume reduction, improved renal function, and lower
diuretic dosing, as compared to placebo (Givertz et al., 2007).
Favorable effects on urine output and renal function also have been
observed in similar patients with the A 1
receptor antagonist BG9179
(NAXIFYLLINE) (Gottlieb et al., 2002). A large clinical trial failed to
show significant benefits of rolofylline in patients with CHF, and
clinical development of the drug was stopped in 2009. No A 1
antagonists
are currently marketed in the U.S.
Aldosterone Antagonists
and Clinical Outcome
LV systolic dysfunction deceases renal blood flow and
results in overactivation of the renin–angiotensin–
aldosterone axis and may increase circulating plasma
aldosterone levels in CHF to 20-fold above normal
(Figure 28–3). The pathophysiologic effects of hyperaldosteronemia
are diverse (Table 28–2) and extend
beyond Na + and fluid retention; importantly, however,
the precise mechanism by which aldosterone receptor
blockade improves outcome in CHF remains unresolved
(Weber, 2004).
In the Randomized Aldactone Evaluation Study, CHF
patients with low LV ejection fraction receiving spironolactone
(25 mg/day) had a significant (~30%) reduction in mortality (from
progressive heart failure or sudden cardiac death) and fewer CHFrelated
hospitalizations compared with the placebo group (Pitt et al.,
1999). Treatment was well tolerated overall; most notably, however,
10% of men reported gynecomastia and 2% of all patients developed
severe hyperkalemia (>6.0 mEq/L) on spironolactone (Pitt et al.,
1999). Data from this and other clinical studies (Pitt et al., 2003)
suggest that despite maximum ACE inhibition, clinically important
aldosterone levels are still achieved in CHF. This may account for the
beneficial effects observed in these trials where aldosteronereceptor
antagonists were used in combination with ACE inhibitor
therapy. Combination therapy in those with renal impairment, however,
increases the probability of drug- induced hyperkalemia.
The role of aldosterone antagonists in patients with asymptomatic
LV dysfunction or in those with minimal CHF- associated
symptoms has not been established.
Vasodilators
The rationale for oral vasodilator drugs in the pharmacotherapy
of CHF derives from experience with parenterally
administered phentolamine and nitroprusside
in patients with advanced disease and elevated systemic
vascular resistance (Cohn and Franciosa, 1977).
Although numerous vasodilators have since been developed
that improve CHF symptoms, only the
hydralazine–isosorbide dinitrate combination, ACE
inhibitors, and AT 1
receptor blockers (ARBs) demonstrably
improve survival. The therapeutic use of
vasodilators in the treatment of hypertension and
myocardial ischemia is considered in detail in Chapter 27.
This chapter will focus on the uses for some of these
same vasodilator drugs in the treatment of CHF.
Table 28–3 summarizes properties of vasodilators commonly
used to treat CHF.
Nitrovasodilators. Nitrovasodilators are nitric oxide
(NO) donors that activate soluble guanylate cyclase in
vascular smooth muscle cells, leading to vasodilation.
The mechanism underlying the variable response profiles
to nitrovasodilators in different vascular beds
remains controversial; e.g., nitroglycerin preferentially
induces epicardial coronary artery vasodilation.
Furthermore, the mechanisms by which nitrovasodilators
are converted to their active forms in vivo depend
on the particular agent. Unlike nitroprusside, which is
converted to NO • by cellular reducing agents such as
glutathione, nitroglycerin and other organic nitrates
undergo a more complex enzymatic biotransformation
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CHAPTER 28
PHARMACOTHERAPY OF CONGESTIVE HEART FAILURE