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

318 treatment for patients with all grades of heart failure
secondary to left ventricular systolic dysfunction. The
drugs have been shown to improve myocardial function,
to improve life quality, and to prolong life. From
the point of view of the history of therapeutic advances
in the treatment of congestive heart failure, it is interesting
to note how this drug class has moved from being
completely contraindicated to being the standard of
care in many settings.
SECTION II
NEUROPHARMACOLOGY
Large trials have been conducted with carvedilol, bisoprolol,
metoprolol, xamoterol, bucindolol, betaxol, nebivolol, and talinolol
(Cleland, 2003). Carvedilol, metoprolol, and bisoprolol all have been
shown to reduce the mortality rate in large cohorts of patients with
stable chronic heart failure regardless of severity (Bolger and Al-
Nasser, 2003; Cleland, 2003). In the initial use of β blockers for
treating heart failure, the beginning effects often are neutral or even
adverse. Benefits accumulate gradually over a period of weeks to
months, although benefits from the third-generation vasodilator β
blocker carvedilol may be seen within days in patients with severe
heart failure. There also is a reduction in the hospitalization of
patients along with a reduction in mortality with fewer sudden deaths
and deaths caused by progressive heart failure. These benefits extend
to patients with asthma and with diabetes mellitus (Cruickshank,
2002; Dunne et al., 2001; Salpeter, 2003; Self et al., 2003). Patients
in atrial fibrillation and heart failure can also benefit from β blockade
(Kühlkamp et al., 2002). On the other hand, patients with heart failure
and atrial fibrillation are associated with a higher mortality, and
the benefit derived from β blockers may not be comparable to those
in sinus rhythm (Fung et al., 2003). Long-term β blockade reduces
cardiac volume, myocardial hypertrophy, and filling pressure, and
increases ejection fraction (e.g., ventricular remodeling). β Receptor
antagonists impact mortality even before beneficial effects on ventricular
function are observed, possibly due to prevention of arrhythmias
or a reduction in acute vascular events.
Some patients are unable to tolerate β blockers. Hopefully,
ongoing trials will identify the common characteristics that define
this population so that β blockers can be avoided in these patients
(Bolger and Al-Nasser, 2003). Because of the real possibility of
acutely worsening cardiac function, β receptor antagonists should
be initiated only by clinicians experienced in patients with congestive
heart failure. As might be anticipated, starting with very low
doses of drug and advancing doses slowly over time, depending on
each patient’s response, are critical for the safe use of these drugs in
patients with congestive heart failure.
It is unknown whether it is necessary to block only the
β 1
adrenergic receptor or whether non-selective agents would be
more desirable in the management of heart failure. Blockade of
β 2
adrenergic receptors can enhance peripheral vasoconstriction and
bronchoconstriction and therefore have a deleterious effect. On the
other hand, blocking β 2
receptors might be advantageous due to more
effectively protecting cardiac cells from catecholamine excess and
hypokalemia. Some propose that non-selective β antagonists that
block both β 1
and β 2
receptors and also have peripheral vasodilatory
actions (third-generation β blockers) may offer the best myocardial,
metabolic, and hemodynamic benefit (Chapter 28) (Cleland, 2003).
Some experts have recommended that β blockers be considered as
part of the standard treatment regimen for all patients with mild to
moderate heart failure (Goldstein, 2002; Maggioni et al., 2003).
β Adrenergic Receptor Signaling in Heart Failure and
Its Treatment. The underlying cellular or subcellular
mechanisms leading to the beneficial effects of β blockers
are unclear. Sympathetic nervous system activity is
increased in patients with congestive heart failure
(Bristow et al., 1985). Infusions of β agonists are toxic
to the heart in several animal models. Also, overexpression
of β receptors in transgenic mice leads to a dilated
cardiomyopathy (Engelhardt et al., 1999). A number of
changes in β receptor signaling occur in the
myocardium of patients with heart failure and in a variety
of animal models (Post et al., 1999). Decreased
numbers and functioning of β 1
receptors consistently
have been found in heart failure, leading to attenuation
of β receptor–mediated stimulation of positive inotropic
responses in the failing heart. These changes may be
due in part to increased expression of β adrenergic
receptor kinase-1 (βARK-1, GRK2) (Lefkowitz et al.,
2000). See also Chapters 3 and 8.
It is of potential interest that expression of β 2
receptors is relatively
maintained in these settings of heart failure. While both β 1
and
β 2
receptors activate adenylyl cyclase by means of G s
, there is evidence
suggesting that β 2
receptors also stimulate G i
, which may attenuate
contractile responses and lead to activation of other effector
pathways downstream of G i
(Lefkowitz et al., 2000).
Overexpression of β 2
adrenergic receptors in mouse heart is associated
with increased cardiac force without the development of cardiomyopathy
(Liggett et al., 2000). The stimulation of β 3
adrenergic
receptors inhibits contraction and relaxation (Gauthier et al., 2000).
In contrast to β 1
and β 2
receptors, β 3
receptors are upregulated in heart
failure (Moniotte et al., 2001). This has led to the hypothesis that in
severe congestive heart failure, as β 1
and β 2
receptor pathways by G s
become less responsive, the inhibitory effects of the β 3
receptor pathway
may contribute to the detrimental effects of sympathetic stimulation
in congestive heart failure (Morimoto et al., 2004). Thus, the
blockade of β 3
receptors by β antagonists (e.g., carvedilol) could
improve the acute tolerability and benefit of β 1
and β 2
receptor antagonists
(Moniotte et al., 2001; Morimoto et al., 2004).
The mechanisms by which β receptor antagonists decrease
mortality in patients with congestive heart failure are still unclear.
Perhaps this is not surprising, given that the mechanism by which
this class of drugs lowers blood pressure in patients with hypertension
remains elusive despite years of investigation (Chapter 27). This
is much more than an academic undertaking; a deeper understanding
of involved pathways could lead to selection of the most appropriate
drugs available as well as the development of novel
compounds with especially desirable properties. The potential differences
among β 1
, β 2
, and β 3
receptor function in heart failure is one
example of the complexity of adrenergic pharmacology of this syndrome.
There is evidence for multiple affinity states of the β 1
receptor,
for cell–type specific coupling of β receptor subtypes to