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

316 The β receptors mediate activation of hormone-sensitive lipase
in fat cells, leading to release of free fatty acids into the circulation
(Chapter 8). This increased flux of fatty acids is an important source
of energy for exercising muscle. β Receptor antagonists can attenuate
the release of free fatty acids from adipose tissue. Non-selective
β receptor antagonists consistently reduce HDL cholesterol, increase
LDL cholesterol, and increase triglycerides. In contrast, β 1
-selective
antagonists, including celiprolol, carteolol, nebivolol, carvedilol, and
bevantolol, reportedly improve the serum lipid profile of dyslipidemic
patients. While drugs such as propranolol and atenolol increase triglycerides,
plasma triglycerides are reduced with chronic celiprolol,
carvedilol, and carteolol (Toda, 2003).
In contrast to classical β blockers, which decrease insulin sensitivity,
the vasodilating β receptor antagonists (e.g., celiprolol,
nipradilol, carteolol, carvedilol, and dilevalol) increase insulin sensitivity
in patients with insulin resistance. Together with their cardioprotective
effects, improvement in insulin sensitivity from
vasodilating β receptor antagonists may partially counterbalance the
hazard from worsened lipid abnormalities associated with diabetes.
If β blockers are to be used, β 1
-selective or vasodilating β receptor
antagonists are preferred. In addition, it may be necessary to use
β receptor antagonists in conjunction with other drugs, (e.g.,
HMGCoA reductase inhibitors) to ameliorate adverse metabolic
effects (Dunne et al., 2001).
β Receptor agonists decrease the plasma concentration of K +
by promoting the uptake of the ion, predominantly into skeletal muscle.
At rest, an infusion of epinephrine causes a decrease in the plasma
concentration of K + . The marked increase in the concentration of epinephrine
that occurs with stress (such as myocardial infarction) may
cause hypokalemia, which could predispose to cardiac arrhythmias.
The hypokalemic effect of epinephrine is blocked by an experimental
antagonist, ICI 118551, which has a high affinity for β 2
and β 3
receptors. Exercise causes an increase in the efflux of K + from skeletal
muscle. Catecholamines tend to buffer the rise in K + by increasing
its influx into muscle. β Blockers negate this buffering effect.
Other Effects. β Receptor antagonists block catecholamine-induced
tremor. They also block inhibition of mast-cell degranulation by catecholamines.
SECTION II
NEUROPHARMACOLOGY
ADVERSE EFFECTS AND PRECAUTIONS
The most common adverse effects of β receptor antagonists
arise as pharmacological consequences of blockade
of β receptors; serious adverse effects unrelated to
β receptor blockade are rare.
Cardiovascular System. Because the sympathetic nervous
system provides critical support for cardiac performance
in many individuals with impaired myocardial
function, β receptor antagonists may induce congestive
heart failure in susceptible patients. Thus, β receptor
blockade may cause or exacerbate heart failure in
patients with compensated heart failure, acute myocardial
infarction, or cardiomegaly. It is not known
whether β receptor antagonists that possess intrinsic
sympathomimetic activity or peripheral vasodilating
properties are safer in these settings. Nonetheless, there
is convincing evidence that chronic administration of β
receptor antagonists is efficacious in prolonging life in
the therapy of heart failure in selected patients (discussed
later in this chapter and in Chapter 28).
Bradycardia is a normal response to β receptor
blockade; however, in patients with partial or complete
AV conduction defects, β antagonists may cause lifethreatening
bradyarrhythmias. Particular caution is indicated
in patients who are taking other drugs, such as
verapamil or various anti-arrhythmic agents, which may
impair sinus-node function or AV conduction.
Some patients complain of cold extremities while taking
β receptor antagonists. Symptoms of peripheral vascular disease
may worsen, although this is uncommon, or Raynaud’s phenomenon
may develop. The risk of worsening intermittent claudication
probably is very small with this class of drugs, and the clinical
benefits of β antagonists in patients with peripheral vascular disease
and coexisting coronary artery disease may be very important.
Abrupt discontinuation of β receptor antagonists after longterm
treatment can exacerbate angina and may increase the risk of
sudden death. The underlying mechanism is unclear, but it is well
established that there is enhanced sensitivity to β receptor agonists
in patients who have undergone long-term treatment with certain
β receptor antagonists after the blocker is withdrawn abruptly. For
example, chronotropic responses to isoproterenol are blunted in
patients who are receiving β receptor antagonists; however, abrupt
discontinuation of propranolol leads to greater-than-normal sensitivity
to isoproterenol. This increased sensitivity is evident several
days after stopping propranolol and may persist for at least 1 week.
Such enhanced sensitivity can be attenuated by tapering the dose
of the β blocker for several weeks before discontinuation.
Supersensitivity to isoproterenol also has been observed after abrupt
discontinuation of metoprolol, but not of pindolol. This enhanced β
responsiveness may result from up-regulation of β receptors. The
number of β receptors on circulating lymphocytes is increased in
subjects who have received propranolol for long periods; pindolol
has the opposite effect. Optimal strategies for discontinuation of β
blockers are not known, but it is prudent to decrease the dose gradually
and to restrict exercise during this period.
Pulmonary Function. A major adverse effect of β receptor
antagonists is caused by blockade of β 2
receptors in
bronchial smooth muscle. These receptors are particularly
important for promoting bronchodilation in patients
with bronchospastic disease, and β blockers may cause
a life-threatening increase in airway resistance in such
patients. Drugs with selectivity for β 1
receptors or those
with intrinsic sympathomimetic activity at β 2
receptors
seem less likely to induce bronchospasm. Since the
selectivity of current β blockers for β 1
receptors is modest,
these drugs should be avoided if at all possible in
patients with asthma. However, in selected patients with
chronic obstructive pulmonary disease and cardiovascular