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

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O
O
O
OH
H
N
O
OH
H
N
O
BISOPROLOL
BETAXOLOL
CN
SECTION II
N
H
N
H
OH
BUCINDOLOL
O
F
O
OH
CH
CH 2 NH CH 2
NEBIVOLOL
OH
CH
O
F
NEUROPHARMACOLOGY
N
H
OH
O CH 2 CH CH 2 NH CH 2 CH 2 O
CARVEDILOL
CH 3 O
N
NH
O
O
CELIPROLOL
Figure 12–8. Structural formulas of some “third-generation” β adrenergic receptor antagonists with additional cardiovascular effects.
O
OH
NH
Several β blockers (e.g., pindolol and acebutolol) activate
β receptors partially in the absence of catecholamines;
however, the intrinsic activities of these drugs are less
than that of a full agonist such as isoproterenol. These
partial agonists are said to have intrinsic sympathomimetic
activity. Substantial sympathomimetic activity
would be counterproductive to the response desired from
a β antagonist; however, slight residual activity may, e.g.,
prevent profound bradycardia or negative inotropy in a
resting heart. The potential clinical advantage of this
property, however, is unclear and may be disadvantageous
in the context of secondary prevention of myocardial
infarction (described under Therapeutic Uses). In
addition, other β receptor antagonists have been found
to have the property of inverse agonism (Chapter 3).
These drugs can decrease basal activity of β receptor signaling
by shifting the equilibrium of spontaneously
active receptors toward the inactive state (Chidiac et al.,
1994). Several β receptor antagonists also have local
anesthetic or membrane-stabilizing activity, similar to
lidocaine, that is independent of β blockade. Such drugs
include propranolol, acebutolol, and carvedilol. Pindolol,
metoprolol, betaxolol, and labetalol have slight membrane-stabilizing
effects. Although most β receptor
antagonists do not block α adrenergic receptors,
labetalol, carvedilol, and bucindolol are examples of
agents that block both α 1
and β adrenergic receptors. In
addition to carvedilol, labetalol, and bucindolol, many
other β receptor antagonists have vasodilating properties
due to various mechanisms discussed below. These
include celiprolol, nebivolol, nipradilol, carteolol, betaxolol,
bopindolol, and bevantolol (Toda, 2003).
Pharmacological Properties
As in the case of α receptor blocking agents, the pharmacological
properties of α receptor antagonists can be
explained largely from knowledge of the responses
elicited by the receptors in the various tissues and the
activity of the sympathetic nerves that innervate these
tissues (Table 8–1). For example, β receptor blockade
has relatively little effect on the normal heart of an
individual at rest, but has profound effects when
sympathetic control of the heart is dominant, as during
exercise or stress.
In this chapter, β adrenergic receptor antagonists are classified
as non–subtype-selective (“first generation”), β 1
-selective (“second
generation”), and non–subtype or subtype-selective with
additional cardiovascular actions (“third generation”). These latter