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

containing these two compounds in combination is marketed as
BiDil) reduces CHF mortality in patients with systolic dysfunction
(Cohn et al., 1986). In V- HeFT I, the mortality benefit was agent
specific: the α 1
receptor antagonist prazosin offered no advantage
over placebo when compared with isosorbide plus hydralazine.
Hydralazine provides additional hemodynamic improvement
for patients with advanced CHF (with or without nitrates) already
treated with conventional doses of an ACE inhibitor, digoxin, and
diuretics (Cohn, 1994). The hypothesis that hydralazine- mediated
antioxidant effects benefit CHF patients at elevated risk for vascular
endothelial dysfunction is supported by the African- American Heart
Failure Trial, in which isosorbide dinitrate- hydralazine substantially
decreased all- cause mortality in self- described black patients, a
group associated with impaired vascular endothelial function and
diminished bioavailable levels of NO when compared to white counterparts
(Taylor et al., 2007).
There are several important considerations for hydralazine
use. First, ACE inhibitors appear to be superior to hydralazine for
mortality reduction in severe CHF. Second, side effects requiring
dose adjustment of hydralazine withdrawal are common. In V- HeFT I,
e.g., only 55% of patients were taking full doses of both hydralazine
and isosorbide dinitrate after 6 months. The lupus- like side effects
associated with hydralazine are relatively uncommon and may be
more likely to occur in selected patients with the “slow- acetylator”
phenotype (see Chapter 27). Finally, hydralazine is a medication
taken three or four times daily, and adherence may be difficult for
CHF patients, who are often prescribed multiple medications concurrently.
The oral bioavailability and pharmacokinetics of hydralazine
are not altered significantly in CHF, unless severe hepatic congestion
or hypoperfusion is present. Intravenous hydralazine is available but
provides little practical advantage over oral formulations except for
urgent use in pregnant patients. In these individuals, hydralazine is
often used owing to contraindications that exist for use of most other
vasodilators in pregnancy. Hydralazine is typically started at a dose
of 10-25 mg three or four times per day and uptitrated to a maximum
of 100 mg three or four times daily, as tolerated. At total daily
doses >200 mg, hydralazine is associated with an increased risk of
lupus-like effects.
Targeting Neurohormonal Regulation:
The Renin–Angiotensin–Aldosterone
Axis and Vasopressin Antagonists
Renin–Angiotensin–Aldosterone Axis Antagonists.
The renin–angiotensin–aldosterone axis plays a central
role in the pathophysiology of CHF (Figure 28–3).
AngII is a potent arterial vasoconstrictor and an important
mediator of Na + and water retention through its effects
on glomerular filtration pressure and aldosterone secretion.
AngII also modulates neural and adrenal medulla
catecholamine release, is arrhythmogenic, promotes
vascular hyperplasia and myocardial hypertrophy,
and induces myocyte death. Consequently, reduction of
the effects of AngII constitutes a cornerstone of CHF
management (Weber, 2004).
ACE inhibitors suppress AngII (and aldosterone) production,
decrease sympathetic nervous system activity, and potentiate the
effects of diuretics in CHF. However, AngII levels frequently return
to baseline values following chronic treatment with ACE inhibitors
(see Chapter 26), due in part to AngII production via ACEindependent
enzymes. The sustained clinical effectiveness of ACE
inhibitors despite this AngII “escape” suggests that alternate mechanisms
contribute to the clinical benefits of ACE inhibitors in CHF.
ACE is identical to kininase II, which degrades bradykinin and other
kinins that stimulate production of NO, cyclic GMP, and vasoactive
eicosanoids. These oppose AngII- induced vascular smooth muscle
cell and cardiac fibroblasts proliferation and inhibit unfavorable
extracellular matrix deposition.
ACE inhibitors are preferential arterial vasodilators.
ACE- inhibitor–mediated decreases in LV afterload
result in increased stroke volume and cardiac output; ultimately,
the magnitude of these effects is associated with
the observed change in mean arterial pressure. Heart rate
typically is unchanged with treatment, often despite
decreases in systemic arterial pressure, a response that
probably is a consequence of decreased sympathetic
nervous system activity from ACE inhibition.
Most clinical actions of AngII, including its deleterious
effects in CHF, are mediated through the AT 1
angiotensin receptor, whereas AT 2
receptor activation
appears to counterbalance the downstream biologic
effects of AT 1
receptor stimulation. Owing to enhanced
target specificity, AT 1
receptor antagonists more efficiently
block the effects of AngII than do ACE
inhibitors. In addition, the elevated level of circulating
AngII that occurs secondary to AT 1
receptor blockade
results in a relative increase in AT 2
receptor activation.
Unlike ACE inhibitors, AT 1
blockers do not influence
bradykinin metabolism (see the next section).
Angiotensin-Converting Enzyme Inhibitors. The first orally
administered ACE inhibitor, captopril (CAPOTEN, others),
was introduced in 1977. Since then, six additional
ACE inhibitors— enalapril (VASOTEC, others), ramipril
(ALTACE, others), lisinopril (PRINIVIL, ZESTRIL, others),
quinapril (ACCUPRIL, others), trandolapril (MAVIK, others)
and fosinopril (MONOPRIL, others) have been FDAapproved
for the treatment of CHF. Data from numerous
clinical trials involving well over 100,000 patients
support ACE inhibition in the management of CHF of
any severity, including those with asymptomatic LV
dysfunction.
ACE- inhibitor therapy typically is initiated at a low dose
(e.g., 6.25 mg of captopril, 5 mg of lisinopril) to avoid iatrogenic
hypotension, particularly in the setting of volume contraction.
Hypotension following drug administration usually can be reversed
by intravascular volume expansion, but, of course, this may be
797
CHAPTER 28
PHARMACOTHERAPY OF CONGESTIVE HEART FAILURE