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

314 Billman, 2000; Brodde and Michel, 1999). β 3
Receptors also have
been identified in normal myocardial tissue in several species,
including humans (Moniotte et al., 2001). Signal transduction for β 3
receptors is complex and includes G s
but also G i
/G o
; stimulation of
cardiac β 3
receptors inhibits cardiac contraction and relaxation. The
physiological role of β 3
receptors in the heart remains to be established
(Morimoto et al., 2004). β Receptor antagonists reduce sinus
rate, decrease the spontaneous rate of depolarization of ectopic
pacemakers, slow conduction in the atria and in the AV node, and
increase the functional refractory period of the AV node.
Although high concentrations of many β blockers produce
quinidine-like effects (membrane-stabilizing activity), it is doubtful
that this is significant at usual doses of these agents. However, this
effect may be important when there is overdosage. Interestingly,
d-propranolol may suppress ventricular arrhythmias independently
of β receptor blockade.
The cardiovascular effects of β receptor antagonists are most
evident during dynamic exercise. In the presence of β receptor blockade,
exercise-induced increases in heart rate and myocardial contractility
are attenuated. However, the exercise-induced increase in
cardiac output is less affected because of an increase in stroke volume.
The effects of β receptor antagonists on exercise are somewhat
analogous to the changes that occur with normal aging. In healthy
elderly persons, catecholamine-induced increases in heart rate are
smaller than in younger individuals; however, the increase in cardiac
output in older people may be preserved because of an increase
in stroke volume during exercise. β Blockers tend to decrease work
capacity, as assessed by their effects on intense short-term or more
prolonged steady-state exertion. Exercise performance may be
impaired to a lesser extent by β 1
-selective agents than by non-selective
antagonists. Blockade of β 2
receptors tends to blunt the increase in
blood flow to active skeletal muscle during submaximal exercise.
Blockade of β receptors also may attenuate catecholamine-induced
activation of glucose metabolism and lipolysis.
Coronary artery blood flow increases during exercise or stress
to meet the metabolic demands of the heart. By increasing heart
rate, contractility, and systolic pressure, catecholamines increase
myocardial oxygen demand. However, in patients with coronary
artery disease, fixed narrowing of these vessels attenuates the expected
increase in flow, leading to myocardial ischemia. β Receptor antagonists
decrease the effects of catecholamines on the determinants of
myocardial O 2
consumption. However, these agents may tend to
increase the requirement for oxygen by increasing end-diastolic pressure
and systolic ejection period. Usually, the net effect is to improve
the relationship between cardiac O 2
supply and demand; exercise
tolerance generally is improved in patients with angina, whose
capacity to exercise is limited by the development of chest pain
(Chapter 28).
SECTION II
NEUROPHARMACOLOGY
Activity as Antihypertensive Agents. β Receptor antagonists
generally do not reduce blood pressure in patients
with normal blood pressure. However, these drugs
lower blood pressure in patients with hypertension.
Despite their widespread use, the mechanisms responsible
for this important clinical effect are not well
understood. The release of renin from the juxtaglomerular
apparatus is stimulated by the sympathetic
nervous system by means of β 1
receptors, and this effect
is blocked by β receptor antagonists (Chapter 25).
However, the relationship between this phenomenon
and the fall in blood pressure is not clear. Some investigators
have found that the antihypertensive effect of
propranolol is most marked in patients with elevated
concentrations of plasma renin, as compared with
patients with low or normal concentrations of renin.
However, β receptor antagonists are effective even in
patients with low plasma renin, and pindolol is an effective
antihypertensive agent that has little or no effect on
plasma renin activity.
Presynaptic β receptors enhance the release of NE from sympathetic
neurons, but the importance of diminished release of NE to
the antihypertensive effects of β antagonists is unclear. Although β
blockers would not be expected to decrease the contractility of vascular
smooth muscle, long-term administration of these drugs to
hypertensive patients ultimately leads to a fall in peripheral vascular
resistance (Man in’t Veld et al., 1988). The mechanism for this
important effect is not known, but this delayed fall in peripheral vascular
resistance in the face of a persistent reduction of cardiac output
appears to account for much of the antihypertensive effect of
these drugs. Although it has been hypothesized that central actions
of β blockers also may contribute to their antihypertensive effects,
there is relatively little evidence to support this possibility, and
drugs that poorly penetrate the blood-brain barrier are effective antihypertensive
agents.
As indicated, some β receptor antagonists have additional
effects that may contribute to their capacity to lower blood pressure.
These drugs all produce peripheral vasodilation; at least six properties
have been proposed to contribute to this effect, including production
of nitric oxide, activation of β 2
receptors, blockade of α 1
receptors, blockade of Ca 2+ entry, opening of K + channels, and
antioxidant activity. The ability of vasodilating β receptor antagonists
to act through one or more of these mechanisms is depicted in
Table 12–4 and Figure 12–9. These mechanisms appear to contribute
to the antihypertensive effects by enhancing hypotension, increasing
peripheral blood flow, and decreasing afterload. Two of these
agents (e.g., celiprolol and nebivolol) also have been observed to
produce vasodilation and thereby reduce preload.
Although further clinical trials are needed, these agents may
be associated with a lower incidence of bronchospasm, impaired
lipid metabolism, impotence, reduced regional blood flow, increased
vascular resistance, and withdrawal symptoms. A lower incidence
of these adverse effects would be particularly beneficial in patients
who have insulin resistance and diabetes mellitus in addition to
hypertension (Toda, 2003). The clinical significance in humans of
some of these relatively subtle differences in pharmacological properties
still is unclear. Particular interest has focused on patients with
congestive heart failure or peripheral arterial occlusive disease.
Propranolol and other non-selective β receptor antagonists
inhibit the vasodilation caused by isoproterenol and augment the
pressor response to epinephrine. This is particularly significant in
patients with pheochromocytoma, in whom β receptor antagonists
should be used only after adequate α receptor blockade has been