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

positive inotropy, although β 2
receptor activation may
cause a decrease in systemic vascular resistance and,
therefore, mean arterial pressure. Despite increases in
cardiac output, there is relatively little chronotropic
effect.
Continuous dobutamine infusions are typically
initiated at 2-3 μg/kg/min without a loading dose and
uptitrated until the desired hemodynamic response is
achieved. Pharmacologic tolerance may limit infusion
efficacy beyond 4 days, and, therefore, addition or substitution
with a class III PDE inhibitor may be necessary
to maintain adequate circulatory support. The
major side effects of dobutamine are tachycardia and
supraventricular or ventricular arrhythmias, which may
require a reduction in dosage. Recent βreceptor antagonist
use is a common cause of blunted clinical responsiveness
to dobutamine.
Phosphodiesterase Inhibitors. The cyclic AMP–PDE
inhibitors decrease cellular cyclic AMP degradation,
resulting in elevated levels of cyclic AMP in cardiac and
smooth muscle myocytes. The physiologic effects of
this are positive myocardial inotropism and dilation of
resistance and capacitance vessels. Collectively, therefore,
PDE inhibition improves cardiac output through
ionotropy and by decreasing preload and afterload (thus
giving rise to the term inodilator). The clinical application
of early- generation PDE inhibitors (e.g., theophylline,
caffeine) is limited by low cardiovascular
specificity and an unfavorable side- effect profile,
whereas inamrinone, milrinone, and other more
recently developed PDE inhibitors are preferred.
Inamrinone and Milrinone. Parenteral formulations of inamrinone
(previously named amrinone) and milrinone are approved for shortterm
circulation support in advanced CHF. Both drugs are bipyridine
derivatives and are selective PDE3 inhibitors, the cyclic
GMP–inhibited cyclic AMP–PDE. These drugs directly stimulate
myocardial contractility and accelerate myocardial relaxation. In
addition, they cause balanced arterial and venous dilation with a consequent
fall in systemic and pulmonary vascular resistances and left
and right- heart filling pressure. As a result of its effect on LV contractility,
the increase in cardiac output from milrinone is superior to
that from nitroprusside, despite comparable reductions in systemic
vascular resistance. Conversely, the arterial and venodilatory effects
of milrinone are greater than those of dobutamine at concentrations
that produce similar increases in cardiac output.
Parenteral administration of inamrinone and milrinone in
patients with CHF from systolic dysfunction should be initiated
with a loading dose followed by continuous infusion. For inamrinone,
a 0.75-mg/kg bolus injection administered over 2-3 minutes
is typically followed by a 2-20-μg/kg/min infusion. The loading
dose of milrinone is ordinarily 50 μg/kg, and the continuous infusion
rate ranges from 0.25-1 μg/kg/min. The elimination half- lives
of inamrinone and milrinone in normal individuals are 2-3 hours
and 0.5-1 hour, respectively, but are nearly doubled in patients with
severe CHF. Clinically significant thrombocytopenia occurs in
~10% of those receiving inamrinone but is rare with milrinone.
Because of enhanced selectivity for PDE3, short t 1/2
, and favorable
side- effect profile, milrinone is the agent of choice among currently
available PDE inhibitors for short- term, parenteral inotropic support.
However, vasodilation- mediated reductions in mean arterial
pressure are one practical barrier to milrinone administration in
patients with marginal systemic arterial blood pressure from low
cardiac output.
Sildenafil. In contrast to inamrinone and milrinone, sildenafil (REVA-
TIO) inhibits PDE5, which is the most common PDE isoform in lung
tissue. This characteristic of PDE5 likely accounts for the enhanced
pulmonary artery specificity observed with sildenafil use. In fact,
until recently, the primary clinical application of sildenafil in CHF
has mainly been limited to those with isolated right ventricular systolic
failure from pulmonary artery hypertension. However, recently
published reports suggest that sildenafil favorably influences exercise
capacity and right- heart hemodynamics in patients with pulmonary
hypertension from LV systolic dysfunction as well (Lewis
et al., 2007). Preclinical experimental models also have raised the
possibility that PDE5 inhibition is directly cardioprotective via attenuation
of adrenergic stimulation- induced myocardial contraction and
by suppressing pressure- overload mediated myocardial hypertrophy
and attendant ventricular dysfunction (Kass et al., 2007). The pharmacology
of PDE5 inhibitors is presented in Chapter 27.
Chronic Positive Inotropic Therapy
Several orally administered agents with combined
inotropic and vasodilator properties are available for
clinical use. Although improvements in CHF symptoms,
functional status, and hemodynamic profile have
been reported, the effect of long- term therapy on mortality
is disappointing. In fact, the dopaminergic agonist
ibopamine; PDE inhibitors milrinone, inamrinone,
and vesnarinone; and pimobendan are associated
with increased mortality (Hampton et al., 1997; Packer
et al., 1991; Cohn et al., 1998). At present, digoxin
remains the only oral inotropic agent available for CHF
patient use.
Continuous or intermittent outpatient therapy with intravenous
dobutamine or milrinone, administered by a portable or
home- based infusion pump through a central venous catheter, is
available for end- stage CHF patients with symptoms refractory to
optimized medical therapy.
Diastolic Heart Failure
Data from population studies suggest that up to 40% of
CHF patients have preserved LV systolic function. The
pathogenesis of diastolic CHF includes structural and
functional abnormalities of the ventricle(s) that are
associated with impaired ventricular relaxation and LV
distensibility. These abnormalities are reflected in the
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CHAPTER 28
PHARMACOTHERAPY OF CONGESTIVE HEART FAILURE