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

328 or membrane-stabilizing activity (McGavin and Keating,
2002). It has a higher degree of β 1
-selective activity than
atenolol, metoprolol, or betaxolol but less than nebivolol.
It is approved for the treatment of hypertension and has
been investigated in randomized, double-blind multicenter
trials in combination with ACE inhibitors and diuretics
in patients with moderate to severe chronic heart
failure (Simon et al., 2003). All-case mortality was significantly
lower with bisoprolol than placebo.
SECTION II
NEUROPHARMACOLOGY
Bisoprolol generally is well tolerated; side effects include
dizziness, bradycardia, hypotension, and fatigue. Bisoprolol is
well absorbed following oral administration, with bioavailability of
~90%. It is eliminated by renal excretion (50%) and liver metabolism
to pharmacologically inactive metabolites (50%). Bisoprolol has a
plasma t 1/2
of 11-17 hours. Bisoprolol can be considered a standard
treatment option when selecting a β blocker for use in combination
with ACE inhibitors and diuretics in patients with stable, moderate
to severe chronic heart failure and in treating hypertension (McGavin
and Keating, 2002; Simon et al., 2003). It has also been used to treat
arrhythmias and ischemic heart disease. Bisoprolol was associated
with a 34% mortality benefit in the Cardiac Insufficiency Bisoprolol
Study-II (CIBIS-II).
Betaxolol
Betaxolol (BETOPTIC, LOKREN, KERLONE, others) is a
selective β 1
receptor antagonist with no partial agonist
activity and slight membrane-stabilizing properties.
Absorption, Fate, and Excretion. Betaxolol is well absorbed with
high bioavailability and an elimination t 1/2
of 14-22 hours.
Therapeutic Uses. Betaxolol is used to treat hypertension, angina
pectoris, and glaucoma. It is usually well tolerated and side effects
are mild and transient. In glaucoma it reduces intraocular pressure by
reducing the production of aqueous humor in the eye.
β RECEPTOR ANTAGONISTS WITH
ADDITIONAL CARDIOVASCULAR
EFFECTS (“THIRD GENERATION”
β BLOCKERS)
In addition to the classical non-selective and β 1
-selective
adrenergic-receptor antagonists, there is also a series of
drugs that possess vasodilatory actions. These effects
are produced through a variety of mechanisms including
α 1
adrenergic receptor blockade (labetalol,
carvedilol, bucindolol, bevantolol, nipradilol), increased
production of NO (celiprolol, nebivolol, carteolol,
bopindolol, nipradolol), β 2
agonist properties (celiprolol,
carteolol, bopindolol), Ca 2+ entry blockade
(carvedilol, betaxolol, bevantolol), opening of K +
channels (tilisolol), or antioxidant action (carvedilol)
(Toda, 2003). These actions are summarized in Table
12–4 and Figure 12–9. Many third-generation β receptor
antagonists are not yet available in the U.S. but have
undergone clinical trials and are on the market in other
countries.
Labetalol
Labetalol (NORMODYNE, TRANDATE, others) is representative
of a class of drugs that act as competitive antagonists
at both α 1
and β receptors. Labetalol has two
optical centers, and the formulation used clinically contains
equal amounts of the four diastereomers. The
pharmacological properties of the drug are complex,
because each isomer displays different relative activities.
The properties of the mixture include selective
blockade of α 1
receptors (as compared with the α 2
subtype), blockade of β 1
and β 2
receptors, partial
agonist activity at β 2
receptors, and inhibition of
neuronal uptake of NE (cocaine-like effect) (Chapter 8).
The potency of the mixture for β receptor blockade
is 5-10 fold that for α 1
receptor blockade.
The pharmacological effects of labetalol have become clearer
since the four isomers were separated and tested individually. The
R,R isomer is about four times more potent as a β receptor antagonist
than is racemic labetalol and accounts for much of the β blockade
produced by the mixture of isomers; it no longer is in
development as a separate drug (dilevalol). As an α 1
antagonist, this
isomer is < 20% as potent as the racemic mixture. The R,S isomer is
almost devoid of both α and β blocking effects. The S,R isomer
has almost no β blocking activity, yet is about five times more potent
as an α 1
blocker than is racemic labetalol. The S,S isomer is devoid
of β blocking activity and has a potency similar to that of racemic
labetalol as an α 1
receptor antagonist. The R,R isomer has some
intrinsic sympathomimetic activity at β 2
adrenergic receptors; this
may contribute to vasodilation. Labetalol also may have some direct
vasodilating capacity.
The actions of labetalol on both α 1
and β receptors contribute
to the fall in blood pressure observed in patients with hypertension.
α 1
Receptor blockade leads to relaxation of arterial smooth muscle
and vasodilation, particularly in the upright position. The β 1
blockade
also contributes to a fall in blood pressure, in part by blocking
reflex sympathetic stimulation of the heart. In addition, the intrinsic
sympathomimetic activity of labetalol at β 2
receptors may contribute
to vasodilation.
Labetalol is available in oral form for therapy of chronic
hypertension and as an intravenous formulation for use in hypertensive
emergencies. Labetalol has been associated with hepatic injury
in a limited number of patients. Labetalol is one of the few β adrenergic
antagonists that has been recommended as treatment for acute
severe hypertension (hypertensive emergency). Its hypotensive
action begins within 2-5 minutes after IV administration, reaching its
peak at 5-15 minutes and lasting ~2-4 hours. Heart rate is either
maintained or slightly reduced and cardiac output is maintained.
Labetalol reduces systemic vascular resistance without reducing total