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

peripheral blood flow. Cerebral, renal, and coronary blood flow is
maintained. It can be used in the setting of pregnancy-induced hypertensive
crisis because little placental transfer occurs due to the poor
lipid solubility of labetalol.
Absorption, Fate, and Excretion. Although labetalol is completely
absorbed from the gut, there is extensive first-pass clearance; bioavailability
is only ~20-40%, is highly variable, and may be increased by
food intake. The drug is rapidly and extensively metabolized in the
liver by oxidative biotransformation and glucuronidation; very little
unchanged drug is found in the urine. The rate of metabolism of
labetalol is sensitive to changes in hepatic blood flow. The elimination
t 1/2
of the drug is ~8 hours. The t 1/2
of the R,R isomer of labetalol
(dilevalol) is ~15 hours. Labetalol provides an interesting and challenging
example of pharmacokinetic-pharmacodynamic modeling
applied to a drug that is a racemic mixture of isomers with different
kinetics and pharmacological actions (Donnelly and Macphee, 1991).
Carvedilol
Carvedilol (COREG) is a third-generation β receptor
antagonist that has a unique pharmacological profile. It
blocks β 1
, β 2
, and α 1
receptors similarly to labetalol,
but also has antioxidant and anti-inflammatory effects
(Dandona et al., 2007). It has membrane-stabilizing
activity but it lacks intrinsic sympathomimetic activity.
Carvedilol produces vasodilation. Additional properties
(e.g., antioxidant and anti-inflammatory effects) may
contribute to the beneficial effects seen in treating congestive
heart failure and in its cardioprotective effects.
The drug is FDA-approved for use in hypertension,
congestive heart failure, and left ventricular dysfunction
following MI.
Carvedilol possesses two distinct antioxidant properties: it is
a chemical antioxidant that can bind to and scavenge reactive oxygen
species (ROS), and it can suppress the biosynthesis of ROS and
oxygen radicals. Carvedilol is extremely liphophic and is able to protect
cell membranes from lipid peroxidation. It prevents low density
lipoprotein (LDL) oxidation, which in turn induces the uptake of
LDL into the coronary vasculature. Carvedilol also inhibits ROSmediated
loss of myocardial contractility, stress-induced hypertrophy,
apoptosis, and the accumulation and activation of neutrophils.
At high doses, carvedilol exerts Ca 2+ channel-blocking activity.
Carvedilol does not increase β receptor density and is not associated
with high levels of inverse agonist activity (Cheng et al., 2001;
Dandona et al., 2007; Keating and Jarvis, 2003).
Carvedilol has been tested in numerous double-blind, randomized
studies, including the U.S. Carvedilol Heart Failure Trials
Program, Carvedilol or Metoprolol European Trial (COMET)
(Poole-Wilson et al., 2003), Carvedilol Prospective Randomised
Cumulative Survival (COPERNICUS) trial, and the Carvedilol Post
Infarct Survival Control in LV Dysfunction (CAPRICORN) trial
(Cleland, 2003). These trials showed that carvedilol improves ventricular
function and reduces mortality and morbidity in patients with
mild to severe congestive heart failure. Several experts recommend
it as the standard treatment option in this setting. In addition,
carvedilol combined with conventional therapy reduces mortality
and attenuates myocardial infarction. In patients with chronic heart
failure, carvedilol reduces cardiac sympathetic drive, but it is not
clear if blockade of α 1
receptor–mediated vasodilation is maintained
over long periods of time.
Absorption, Fate, and Excretion. Carvedilol is rapidly absorbed
following oral administration, with peak plasma concentrations
occurring in 1-2 hours. It is highly lipophilic and thus is extensively
distributed into extravascular tissues. It is > 95% protein bound and
is extensively metabolized in the liver, predominantly by CYP2D6
and CYP2C9. The t 1/2
is 7-10 hours. Stereoselective first-pass metabolism
results in more rapid clearance of S(–)-carvedilol than R(+)-
carvedilol. No significant changes in the pharmacokinetics of
carvedilol were seen in elderly patients with hypertension, and no
change in dosage is needed in patients with moderate to severe renal
insufficiency (Cleland, 2003; Keating and Jarvis, 2003). Because of
carvedilol’s extensive oxidative metabolism by the liver, its pharmacokinetics
can be profoundly affected by drugs that induce or inhibit
oxidation. These include the inducer, rifampin, and inhibitors such
as cimetidine, quinidine, fluoxetine, and paroxetine.
Bucindolol
Bucindolol (SANDONORM) is a third-generation nonselective
β adrenergic antagonist with weak α 1
adrenergic
blocking properties. The intrinsic sympathomimetic
activity of bucindolol may be dependent on β 1
receptors.
Bucindolol increases left ventricular systolic ejection fraction
and decreases peripheral resistance, thereby reducing afterload.
It increases plasma HDL cholesterol, but does not affect plasma
triglycerides. A large comprehensive clinical trial, the β Blocker
Evaluation of Survival Trial (BEST), was terminated early because
of the inability to demonstrate a survival benefit with bucindolol versus
placebo. In subsequent analyses from BEST, however, benefits
have been demonstrated in discrete subgroups, including a genetically
identified subgroup. An evaluation was made of the therapeutic
responses to bucindolol among patients with genetic variations or
polymorphisms in two adrenergic receptors: β 1
389 arg/gly and α 2C
322-325 WT/Del. Researchers identified three distinct genotypes
that predict the effect of bucindolol: very favorable (47% of BEST
patients), favorable (40%), and unfavorable (13%). In the study,
patients with the very favorable genotype experienced significant
improvements in clinical end points compared to placebo, including
reductions in all-cause mortality, cardiovascular mortality, heart failure
hospitalization, and cardiovascular hospitalization. A New Drug
Application (NDA) has been filed with the FDA and is currently
under review.
Bucindolol is well absorbed after oral administration, reaching
maximum plasma levels in 2 hours. It is highly protein bound
(87%), extensively metabolized by the liver to 5-hydroxybucindolol,
and has a t 1/2
of ~8 hours.
Celiprolol
Celiprolol (SELECTOL) is a third-generation cardioselective
β receptor antagonist. It has low lipid solubility and
possesses weak vasodilating and bronchodilating
effects attributed to partial selective β 2
agonist activity
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CHAPTER 12
ADRENERGIC AGONISTS AND ANTAGONISTS