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

758 increased modestly. After oral administration of nifedipine,
arterial dilation increases peripheral blood flow;
venous tone does not change.
The other dihydropyridines—amlodipine, felodipine,
isradipine, nicardipine, nisoldipine, nimodipine, and
clevidipine— share many of the cardiovascular effects
of nifedipine.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Amlodipine is a dihydropyridine that has a slow absorption
and a prolonged effect. With a plasma t 1/2
of 35-50 hours, plasma
levels and effect increase over 7-10 days of daily administration of
a constant dose. Amlodipine produces both peripheral arterial vasodilation
and coronary dilation, with a hemodynamic profile similar to
that of nifedipine. However, there is less reflex tachycardia with
amlodipine, possibly because the long t 1/2
produces minimal peaks
and troughs in plasma concentrations (van Zwieten and Pfaffendorf,
1993). Felodipine may have even greater vascular specificity than
does nifedipine or amlodipine. At concentrations producing vasodilation,
there is no negative inotropic effect. Like nifedipine, felodipine
indirectly activates the sympathetic nervous system, leading to an
increase in heart rate. Nicardipine has anti-anginal properties similar
to those of nifedipine and may have selectivity for coronary vessels.
Isradipine also produces the typical peripheral vasodilation seen with
other dihydropyridines, but because of its inhibitory effect on the SA
node, little or no rise in heart rate is seen. This inhibitory effect does
not extend to the cardiac myocytes, however, because no cardiodepressant
effect is seen.
Despite the negative chronotropic effect, isradipine appears to
have little effect on the AV node, so it may be used in patients with
AV block or combined with a β adrenergic receptor antagonist. In
general, because of their lack of myocardial depression and, to a
greater or lesser extent, lack of negative chronotropic effect, dihydropyridines
are less effective as monotherapy in stable angina than
are verapamil, diltiazem, or a β adrenergic receptor antagonist.
Nisoldipine is more than 1000 times more potent in preventing contraction
of human vascular smooth muscle than in preventing contraction
of human cardiac muscle in vitro, suggesting a high degree
of vascular selectivity (Godfraind et al., 1992). Although nisoldipine
has a short elimination t 1/2
, a sustained-release preparation that is efficacious
as an anti-anginal agent has been developed. Nimodipine has
high lipid solubility and was developed as an agent to relax the cerebral
vasculature. It is effective in inhibiting cerebral vasospasm and
has been used primarily to treat patients with neurological defects
associated with cerebral vasospasm after subarachnoid hemorrhage.
Clevidipine is a novel dihydropyridine L-type Ca 2+ channel
blocker—available for intravenous administration—that has a very
rapid (t 1/2
~2 minutes) onset and offset of action. It is metabolized by
esterases in blood, similar to the fate of esmolol. Clevidipine preferentially
affects arterial smooth muscle compared to targeting veins
or the heart. It may be useful in controlling blood pressure in severe
or perioperative hypertension when oral therapy is not possible or
desirable. Infusions are typically started at a rate of 1-2 μg/kg/min
and titrated to the desired effect on blood pressure. Cumulative experience
with the drug in clinical settings is relatively limited.
Verapamil is a less potent vasodilator in vivo
than are the dihydropyridines. Like dihydropyridines,
verapamil causes little effect on venous resistance vessels
at concentrations that produce arteriolar dilation.
With doses of verapamil sufficient to produce peripheral
arterial vasodilation, there are more direct negative
chronotropic, dromotropic, and inotropic effects than
with the dihydropyridines. Intravenous verapamil
causes a decrease in arterial blood pressure owing to a
decrease in vascular resistance, but the reflex tachycardia
is blunted or abolished by the direct negative
chronotropic effect of the drug. This intrinsic negative
inotropic effect is partially offset by both a decrease in
afterload and the reflex increase in adrenergic tone.
Thus, in patients without congestive heart failure, ventricular
performance is not impaired and actually may
improve, especially if ischemia limits performance. In
contrast, in patients with congestive heart failure,
intravenous verapamil can cause a marked decrease in
contractility and left ventricular function. Oral administration
of verapamil reduces peripheral vascular resistance
and blood pressure, often with minimal changes
in heart rate. The relief of pacing-induced angina seen
with verapamil is due primarily to a reduction in
myocardial oxygen demand.
Intravenous administration of diltiazem can result
initially in a marked decrease in peripheral vascular
resistance and arterial blood pressure, which elicits a
reflex increase in heart rate and cardiac output. Heart
rate then falls below initial levels because of the direct
negative chronotropic effect of the agent. Oral administration
of diltiazem decreases both heart rate and mean
arterial blood pressure. While diltiazem and verapamil
produce similar effects on the SA and AV nodes, the
negative inotropic effect of diltiazem is more modest.
The effects of Ca 2+ channel blockers on diastolic ventricular
relaxation (the lusitropic state of the ventricle) are complex. The
direct effect of several of these agents, especially when given into the
coronary arteries, is to impair relaxation (Walsh and O’Rourke,
1985). Clinical studies suggest an improvement in peak left ventricular
filling rates when verapamil, nifedipine, nisoldipine, or nicardipine
are given systemically, but one must be cautious in extrapolating
this change in filling rates to enhancement of relaxation. Because
ventricular relaxation is so complex, the effect of even a single agent
may be pleiotropic. If reflex stimulation of sympathetic tone
increases cyclic AMP levels in myocytes, increased lusitropy will
result that may outweigh a direct negative lusitropic effect. Likewise,
a reduction in afterload will improve the lusitropic state. In addition,
if ischemia is improved, the negative lusitropic effect of asymmetrical
left ventricular contraction will be reduced. The sum total of
these effects in any given patient cannot be determined a priori.
Thus, caution should be exercised in the use of Ca 2+ channel blockers
for this purpose; the ideal is to determine the end result objectively
before committing the patient to therapy.