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

signaling in the myocardium, reducing catecholamineinduced
cardiomyocyte toxicity, and decreasing
myocyte apoptosis (Communal et al., 1998; Bisognano
et al., 2000). β Receptor antagonists may also induce
positive LV remodeling by decreasing oxidative stress
in the myocardium (Sawyer and Colucci, 2000).
Metoprolol. Metoprolol (LOPRESSOR, TOPROL XL, others)
is a β 1
-selective receptor antagonist. The short- acting
form of this drug has a drug elimination t 1/2
of ~6 hours,
and therefore appropriate dosing is three to four times
daily. Conversely, the extended- release formulation is
sufficiently dosed once daily.
A number of clinical trials have demonstrated the beneficial
effects of β- antagonist therapy in CHF. In the Metoprolol Randomized
Intervention Trial in Congestive Heart Failure (MERIT- HF Study
Group 1999), patients with low LV ejection fraction and severe CHF
receiving metoprolol succinate (target dose, 200 mg/day) received a
34% all- cause mortality benefit, an effect attributable to reductions in
sudden death and death from worsening CHF. Despite the high target
drug dose, the majority of patients achieved this therapeutic goal.
Carvedilol. Carvedilol (COREG, others) is a nonselective
β receptor antagonist and α 1
-selective antagonist that
is FDA approved for the management of mild- to- severe
CHF.
The U.S. Carvedilol Trial randomized patients with symptomatic
but compensated CHF (New York Heart Association [NYHA]
classes II to IV) and low LV ejection fraction to receive carvedilol or
placebo (Packer et al., 1996). Carvedilol (25 mg twice daily) was
associated with a 65% reduction in all- cause mortality that was independent
of age, sex, CHF etiology, or LV ejection fraction. The mortality
benefit and improvement in LV ejection fraction was carvedilol
concentration dependent (Bristow et al., 1996). Exercise capacity
(e.g., 6-minute walk test) did not improve with carvedilol, however,
but therapy did appear to slow the progression of CHF in a subgroup
of patients with good exercise capacity and mild symptoms at baseline
(Colucci et al., 1996).
In the Carvedilol Post Infarct Survival Control in LV
Dysfunction Trial (Dargie, 2001), patients with recent MI (3-21 days
prior to enrollment) and impaired LV systolic function were randomized
to carvedilol (25 mg twice daily) or placebo. Patients with symptomatic
CHF and those with asymptomatic LV dysfunction were
included. Although there was no difference in the primary endpoint
of all- cause mortality, carvedilol therapy was associated with a significant
reduction in the combined endpoint of all- cause mortality
and nonfatal MI. At the opposite end of the spectrum, patients with
symptomatic CHF at rest or with minimal exertion and impaired LV
systolic function were randomized to carvedilol versus placebo in the
Carvedilol Prospective Randomized Cumulative Survival Study
(Packer et al., 2002b). Consistent with previous trials, there was a
35% decrease in all- cause mortality. Although the patients included
in the trial had established CHF, it merits emphasis that the placebo
group mortality at 1 year was ~18%, a finding suggestive that the
patient cohort was not representative of patients with advanced CHF.
Clinical Use of β Adrenergic Receptor
Antagonists in Heart Failure
Data from more than 15,000 patients with mild- tomoderate
chronic CHF enrolled in various clinical trials
have established that β receptor antagonists
improve disease- associated symptoms, hospitalization,
and mortality. Accordingly, β antagonists are recommended
for use in patients with an LV ejection fraction
<35% and NYHA class II or III symptoms in
conjunction with an ACE inhibitor or AT 1
receptor
antagonist, and diuretics as required to palliate symptoms.
Interpretation of these and other clinical guidelines
should, however, consider the following areas of
uncertainty.
The role of β receptor antagonists in severe CHF
or under circumstances of an acute clinical decompensation
is not yet clear. Likewise, the utility of β
blockade in patients with asymptomatic LV dysfunction
has not been systematically evaluated. The marked
heterogeneous pharmacologic characteristics (e.g.,
receptor selectivity, pharmacokinetics) of specific
agents within this general drug class, as discussed in
Chapter 12, play a key role in predicting the overall efficacy
of a particular βreceptor antagonist.
β receptor antagonist therapy is customarily initiated
at very low doses, generally less than one- tenth of
the final target dose, and titrated cautiously upward.
Even when initiated properly, a tendency to retain fluid
exists that may require diuretic dose adjustment.
Insufficient evidence exists to support the unrestricted
administration of β receptor antagonists in patients
with severe (NYHA class IIIB and IV), new- onset, or
acutely decompensated CHF.
Cardiac Glycosides
The English botanist, chemist, and physician Sir
William Withering is credited with the first published
observation in 1785 that digitalis purpurea, a derivative
of the purple foxglove flower, could be used for the
treatment of “cardiac dropsy,” or congestive heart failure.
The benefits of cardiac glycosides in CHF have
been extensively studied (Eichhorn and Gheorghiade,
2002) and are generally attributed to:
• Inhibition of the plasma membrane Na + , K + -ATPase
in myocytes
• A positive inotropic effect on the failing myocardium
• Suppression of rapid ventricular rate response in
CHF-associated atrial fibrillation
• Regulation of downstream deleterious effects of
sympathetic nervous system overactivation
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CHAPTER 28
PHARMACOTHERAPY OF CONGESTIVE HEART FAILURE