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

760 Exertional Angina. Ca 2+ channel antagonists also are
effective in the treatment of exertional, or exerciseinduced,
angina. Their utility may result from an
increase in blood flow owing to coronary arterial dilation,
from a decrease in myocardial oxygen demand
(secondary to a decrease in arterial blood pressure,
heart rate, or contractility), or both. Numerous doubleblind,
placebo-controlled studies have shown that these
drugs decrease the number of anginal attacks and attenuate
exercise-induced ST-segment depression.
The double product, calculated as heart rate × systolic
blood pressure, is an approximate if easily measured
index of myocardial O 2
demand. Because these
agents reduce the level of the double product at a given
external workload, and because the value of the double
product at peak exercise is not altered, the beneficial
effect of Ca 2+ channel blockers likely is due primarily
to a decrease in O 2
demand rather than to an increase in
coronary flow.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
As described earlier, Ca 2+ channel antagonists, particularly
the dihydropyridines, may aggravate anginal symptoms in some
patients when used without a β adrenergic receptor antagonist. This
adverse effect is not prominent with verapamil or diltiazem because
of their limited ability to induce marked peripheral vasodilation
and reflex tachycardia. Concurrent therapy with nifedipine and the
β receptor antagonist propranolol or with amlodipine and any of several
β receptor antagonists has proven more effective than either
agent given alone in exertional angina, presumably because the β
antagonist suppresses reflex tachycardia (Gibbons et al., 2003). This
concurrent drug therapy is particularly attractive because the dihydropyridines,
unlike verapamil and diltiazem, do not delay AV conduction
and will not enhance the negative dromotropic effects
associated with β receptor blockade. Although concurrent administration
of verapamil or diltiazem with a β receptor antagonist also may
reduce angina, the potential for AV block, severe bradycardia, and
decreased left ventricular function requires that these combinations
be used judiciously, especially if left ventricular function is compromised
prior to therapy. Amlodipine produces less reflex tachycardia
than does nifedipine probably because of a flatter plasma concentration
profile. Isradipine, approximately equivalent to nifedipine in
enhancing exercise tolerance, also produces less rise in heart rate,
possibly because of its slower onset of action.
Unstable Angina. Medical therapy for unstable angina
involves the administration of aspirin, which reduces mortality,
nitrates, β adrenergic receptor blocking agents, and
heparin, which are effective in controlling ischemic
episodes and angina. Because vasospasm occurs in some
patients with unstable angina (Yeghiazarians et al., 2000),
Ca 2+ channel blockers may offer an additional approach
to the treatment of unstable angina. However, there is
insufficient evidence to assess whether such treatment
decreases mortality except when the underlying
mechanism is vasospasm. In a randomized, double-blind
clinical trial, the short-acting dihydropyridine nifedipine
was found to be less effective than metoprolol, and there
are no studies supporting the administration of a dihydropyridine
to patients with unstable angina. In contrast,
therapy directed toward reduction of platelet function
and thrombotic episodes clearly decreases morbidity and
mortality in patients with unstable angina (see Chapters
34 and 30), and administration of statins also can reduce
adverse cardiac events.
Myocardial Infarction. There is no evidence that Ca 2+
channel antagonists are of benefit in the early treatment
or secondary prevention of acute MI. In several trials,
higher doses of the short-acting formulation of the dihydropyridine
nifedipine had a detrimental effect on mortality
(Opie et al., 2000; Furberg et al., 1995). Diltiazem
and verapamil may reduce the incidence of reinfarction
in patients with myocardial infarction who are not candidates
for a β adrenergic receptor antagonist (Gibbons
et al., 2003), but β adrenergic receptor antagonists remain
the drugs of first choice. Again, administration of statins
can lead to improvements in the rate of adverse cardiac
events, apparently independent of changes in serum lipid
levels.
Other Uses. The use of Ca 2+ channel antagonists as antiarrhythmic
agents is discussed in Chapter 29; their use for the treatment of
hypertension is discussed later; and use of amlodipine in the treatment
of heart failure is reviewed in Chapter 28. Clinical trials are
under way to evaluate the capacity of Ca 2+ channel blockers to slow
the progression of renal failure and to protect the transplanted kidney.
Verapamil has been demonstrated to improve left ventricular
outflow obstruction and symptoms in patients with hypertrophic cardiomyopathy.
Verapamil also has been used in the prophylaxis of
migraine headaches. While several studies suggest that dihydropyridines
may suppress the progression of mild atherosclerosis, there
is no evidence that this alters mortality or reduces the incidence of
ischemic events. Nimodipine has been approved for use in patients
with neurological deficits secondary to cerebral vasospasm after the
rupture of a congenital intracranial aneurysm. Nifedipine, diltiazem,
amlodipine, and felodipine appear to provide symptomatic relief in
Raynaud’s disease. The Ca 2+ channel antagonists cause relaxation
of the myometrium in vitro and may be effective in stopping preterm
uterine contractions in preterm labor (see Chapter 66).
β ADRENERGIC RECEPTOR ANTAGONISTS
β Adrenergic receptor antagonists are effective in reducing
the severity and frequency of attacks of exertional
angina and in improving survival in patients who have
had an MI. In contrast, these agents are not useful for
vasospastic angina and, if used in isolation, may worsen
the condition. Most β adrenergic receptor antagonists
apparently are equally effective in the treatment of