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

exertional angina (Gibbons et al., 2003). Timolol, metoprolol,
atenolol, and propranolol have been shown to
exert cardioprotective effects. The effectiveness of β
adrenergic receptor antagonists in the treatment of exertional
angina is attributable primarily to a fall in myocardial
O 2
consumption at rest and during exertion,
although there also is some tendency for increased flow
toward ischemic regions. The decrease in myocardial O 2
consumption is due to a negative chronotropic effect
(particularly during exercise), a negative inotropic effect,
and a reduction in arterial blood pressure (particularly
systolic pressure) during exercise. Not all actions of β
adrenergic receptor antagonists are beneficial in all
patients. The decreases in heart rate and contractility
cause increases in the systolic ejection period and left
ventricular end-diastolic volume; these alterations tend
to increase O 2
consumption. However, the net effect of
β receptor blockade usually is to decrease myocardial
O 2
consumption, particularly during exercise.
Nevertheless, in patients with limited cardiac reserve
who are critically dependent on adrenergic stimulation,
β receptor blockade can result in profound decreases in
left ventricular function. Despite this, several β adrenergic
receptor antagonists have been shown to reduce mortality
in patients with congestive heart failure, and
treatment of patients with heart failure with β adrenergic
antagonist drugs has become standard therapy for
many such patients (see Chapters 12 and 28). Numerous
β receptor antagonists are approved for clinical use in
the U.S. Their pharmacology and the criteria for
choosing a β 1
-selective agent, an agent with intrinsic
sympathomimetic activity, or a nonspecific agent are
considered in detail in Chapter 12.
Therapeutic Uses
Unstable Angina. β Adrenergic receptor antagonists
are effective in reducing recurrent episodes of
ischemia and the risk of progression to acute MI
(Braunwald et al., 2002). Clinical trials have lacked
sufficient statistical power to demonstrate beneficial
effects of β receptor antagonists on mortality. On the
other hand, if the underlying pathophysiology is coronary
vasospasm, nitrates and Ca 2+ channel blockers
may be effective, and β receptor antagonists should be
used with caution. In some patients, there is a combination
of severe fixed disease and superimposed
vasospasm; if adequate anti-platelet therapy and
vasodilation have been provided by other agents and
angina continues, the addition of a β receptor antagonist
may be helpful.
Myocardial Infarction. β Adrenergic receptor antagonists
that do not have intrinsic sympathomimetic activity
improve mortality in MI. They should be given early
and continued indefinitely in patients who can tolerate
them (Gibbons et al., 2003).
COMPARISON OF ANTI-ANGINAL
THERAPEUTIC STRATEGIES
In evaluating trials in which different forms of antianginal
therapy are compared, careful attention must be
paid to the patient population studied and to the pathophysiology
and stage of the disease. An important
placebo effect may be seen in these trials. The efficacy
of anti-anginal treatment will depend on the severity of
angina, the presence of coronary vasospasm, and
myocardial O 2
demand. Optimally, the dose of each
agent should be titrated to maximum benefit.
Task forces from the ACC and the AHA (Gibbons
et al., 2003; updated in 2007) have published guidelines
that are useful in the selection of appropriate initial
therapy for patients with chronic stable angina pectoris.
Patients with coronary artery disease should be treated
with aspirin and a β receptor blocking drug (particularly
if there is a history of prior MI). The ACC/AHA
guidelines also note that solid data support the use of
ACE inhibitors in patients with coronary artery disease
who also have left ventricular dysfunction and/or diabetes.
Therapy of hypercholesterolemia also is indicated.
Nitrates, for treatment of angina symptoms, and
Ca 2+ antagonists also may be used (Gibbons et al.,
2003). Table 27–3 summarizes the issues that the
ACC/AHA task force considered to be relevant in
choosing between β receptor antagonists and Ca 2+
channel blockers in patients with angina and other medical
conditions. A meta-analysis of publications that
compared two or more anti-anginal therapies has been
conducted (Heidenreich et al., 1999). Comparison of β
adrenergic receptor antagonists with Ca 2+ channel
blockers showed that β receptor antagonists are associated
with fewer episodes of angina per week and a
lower rate of withdrawal because of adverse events.
However, there were no differences in time to ischemia
during exercise or in the frequency of adverse events
when Ca 2+ channel blockers other than nifedipine were
compared with β adrenergic receptor antagonists. There
were no significant differences in outcome between the
studies comparing long-acting nitrates and Ca 2+ channel
blockers and the studies comparing long-acting
nitrates with β receptor antagonists.
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CHAPTER 27
TREATMENT OF MYOCARDIAL ISCHEMIA AND HYPERTENSION