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

800 CHF and may represent one mechanism by which the
use of AT 1
-receptor antagonists are effective in the clinical
management of these patients.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
LV systolic dysfunction can be associated with hypervasopressinemia.
Numerous observational and case- controlled studies
have reported AVP levels nearly 2-fold above normal in CHF patients
(Finley et al., 2008). The mechanisms to account for dysregulated
AVP synthesis in CHF may involve impaired atrial stretch receptor
sensitivity, normally a counterregulatory mechanism for AVP secretion,
and increased adrenergic tone (Bristow et al., 2005). These
probably do not fully explain the relationship between CHF and AVP
levels; e.g., elevated levels of AVP have been observed in asymptomatic
patients with significantly decreased LV function, calling into
question the attributable role of sympathetically mediated adrenergic
tone as a cause of hypervasopressinemia (Francis et al., 1990).
In addition, there is evidence to suggest that CHF is a disease
of abnormal responsiveness to vasopressin rather than one of excessive
vasopressin production alone. For example, vasopressin infusion
in CHF patients decreases cardiac output and stroke volume and
causes an exaggerated increase in systemic vascular resistance and
pulmonary capillary wedge pressure (Finley et al., 2008). In turn,
V 2
antagonists attenuate the adverse pathophysiologic effects of
hypervasopressinemia by decreasing capillary wedge pressure, right
atrial pressure, and pulmonary artery systolic blood pressure
(Udelson et al., 2008). These agents also restore and maintain normal
serum sodium levels in decompensated CHF patients, but their
long- term use has not yet been convincingly linked to a decrease in
CHF- associated symptoms or mortality (Gheorghiade et al., 2004).
Generally, trials designed to measure the effect of
vasopressin- receptor antagonists have used agents selective for the
V 2
receptor, although some drugs with both V 2
and V 1a
receptor
affinity also have been studied. Tolvaptan (SAMSCA), which preferentially
binds the V 2
receptor over the V 1a
receptor (receptor affinity
~29:1), is perhaps the most widely tested vasopressin receptor antagonist
in patients with CHF and also is approved for hyponatremia.
Due to the risk of overly rapid correction of hyponatremia causing
osmotic demyelination, tolvaptan should be started only in a hospital
setting where Na + levels can be monitored closely and possible
drug interactions mediated by CYP and P-gp can be considered
(black box warning). Conivaptan, used mainly for the treatment of
hyponatremia rather than for CHF per se, differs from tolvaptan in
that it may be intravenously administered, demonstrates high affinity
for both V 2
- and V 1a
- vasopressin receptors, and has a t 1/2
that is
nearly twice as long.
In the randomized, placebo- controlled EVEREST trial, the
effect of tolvaptan (30 mg/day) in addition to standard therapy on
immediate symptom improvement was assessed in patients administered
the drug <48 hours into hospitalization for CHF
(Gheorghiade et al., 2007). Data from this study substantiated that
from the others, indicating that AVP antagonists decrease body
weight, self- reported dypsnea, and physician- assessed peripheral
edema, rales, and fatigue after a short course of therapy (<7 days).
Long-term outcomes (survival, hospitalizations) were not significantly
different from placebo. The identification of a CHF subgroup
that stands to benefit most from AVP antagonists, in addition to the
preferred agent and therapy duration, are questions of ongoing clinical
investigation.
β Adrenergic Receptor Antagonists
Sympathetic nervous system activation in CHF supports
circulatory function by enhancing contractility
(inotropy), augmenting ventricular relaxation and filling
(lusitropy), and increasing heart rate (chronotropy).
For many years, pharmacologic approaches to CHF
treatment targeted drugs with sympathomimetic properties.
This reflected the viewpoint that CHF is fundamentally
a disorder of impaired stroke volume and
cardiac output. For example, CHF symptom relief from
short- term dobutamine and dopamine use in patients
with ventricular dysfunction led to the belief that longterm
sympathomimetic use would further improve
clinical outcome. Under this model, the use of β receptor
antagonists was believed to be counterproductive;
however, the reverse appears to be the case. Long- term
sympathomimetic use is associated with increased
CHF mortality rates, whereas a survival benefit is associated
with chronic administration of β receptor antagonists.
Initially, clinical investigation of β receptor
antagonists in the treatment of CHF encountered skepticism,
but reports beginning in the early 1990s demonstrated
that β antagonists (e.g., metoprolol) improve
symptoms, exercise tolerance, and are measures of LV
function over several months in idiopathic dilated cardiomyopathy
patients with CHF (Waagstein et al.,
1993; Gottlieb et al., 1998; Swedberg, 1993; Bristow,
2000). Serial echocardiographic measurements in CHF
patients indicate that a decrease in systolic function
occurs immediately after initiation of a β antagonist
treatment, but this recovers and improves beyond baseline
over the ensuing 2-4 months (Hall et al., 1995).
This trend may be due to attenuation or prevention of
the β receptor–mediated adverse effects of catecholamines
on the myocardium (Eichhorn and Bristow,
1996).
Mechanism of Action. The mechanisms by which β
receptor antagonists influence outcome in CHF patients
are not fully delineated. By preventing myocardial
ischemia without significantly influencing serum
electrolytes, β receptor antagonists probably influence
mortality, in part, by decreasing the frequency of unstable
tachyarrhythmias to which CHF patients are particularly
prone. In addition, these agents may influence
survival by favorably affecting LV geometry, specifically
by decreasing LV chamber size and increasing LV
ejection fraction. Through inhibition of sustained sympathetic
nervous system activation, these agents prevent
or delay progression of myocardial contractile dysfunction
by inhibiting maladaptive proliferative cell