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

pharmacology of these drugs is presented earlier in this
chapter. The basis for their use in hypertension comes
from the understanding that hypertension generally is
the result of increased peripheral vascular resistance.
Because contraction of vascular smooth muscle is
dependent on the free intracellular concentration of
Ca 2+ , inhibition of transmembrane movement of Ca 2+
through voltage-sensitive Ca 2+ channels can decrease
the total amount of Ca 2+ that reaches intracellular sites.
Indeed, all of the Ca 2+ channel blockers lower blood
pressure by relaxing arteriolar smooth muscle and
decreasing peripheral vascular resistance (Weber, 2002).
As a consequence of a decrease in peripheral vascular
resistance, the Ca 2+ channel blockers evoke a
baroreceptor-mediated sympathetic discharge. In the
case of the dihydropyridines, tachycardia may occur
from the adrenergic stimulation of the SA node; this
response is generally quite modest except when the
drug is administered rapidly. Tachycardia is typically
minimal to absent with verapamil and diltiazem
because of the direct negative chronotropic effect of
these two drugs. Indeed, the concurrent use of a β
receptor antagonist drug may magnify negative
chronotropic effects of these drugs or cause heart block
in susceptible patients. Consequently, the concurrent
use of β receptor antagonists with either verapamil or
diltiazem may be problematic.
Ca 2+ channel blockers are effective when used
alone or in combination with other drugs for the treatment
of hypertension; this view has been strengthened
by a number of recent large clinical trials (Dahlöf et al.,
2005; Jamerson et al., 2008).
Oral administration of nifedipine as an approach to urgent
reduction of blood pressure has been abandoned. Sublingual administration
does not achieve the maximum plasma concentration any
more quickly than does oral administration. Moreover, in the absence
of deleterious consequences of high arterial pressure, data do not support
the rapid lowering of blood pressure. There is no place in the
treatment of hypertension for the use of nifedipine or other dihydropyridine
Ca 2+ channel blockers with short half-lives when administered
in a standard (immediate-release) formulation, because of the
oscillation in blood pressure and concurrent surges in sympathetic
reflex activity within each dosage interval. As noted earlier, parenteral
administration of the novel dihydropyridine clevidipine may be useful
in treating severe or perioperative hypertension.
Compared with other classes of antihypertensive agents,
there may be a greater frequency of achieving blood pressure control
with Ca 2+ channel blockers as monotherapy in elderly subjects
and in African-Americans, population groups in which the low renin
status is more prevalent. However, intrasubject variability is more
important than relatively small differences between population
groups. Ca 2+ channel blockers are effective in lowering blood pressure
and decreasing cardiovascular events in the elderly with isolated
systolic hypertension (Staessen et al., 1997). Indeed, these drugs
may be a preferred treatment in patients with isolated systolic
hypertension.
ANGIOTENSIN-CONVERTING
ENZYME INHIBITORS
Angiotensin II is an important regulator of cardiovascular
function (see Chapter 26). The ability to reduce levels
of AngII with orally effective inhibitors of ACE
represents an important advance in the treatment of
hypertension. Captopril was the first such agent to be
developed for the treatment of hypertension. Since then,
enalapril, lisinopril, quinapril, ramipril, benazepril,
moexipril, fosinopril, trandolapril, and perindopril also
have become available. These drugs have proven to
be very useful for the treatment of hypertension because
of their efficacy and their very favorable profile of
adverse effects, which enhances patient adherence.
Chapter 26 presents the pharmacology of ACE inhibitors
in detail.
The ACE inhibitors appear to confer a special
advantage in the treatment of patients with diabetes,
slowing the development and progression of diabetic
glomerulopathy. They also are effective in slowing the
progression of other forms of chronic renal disease,
such as glomerulosclerosis, and many of these patients
also have hypertension. An ACE inhibitor is the preferred
initial agent in these patients. Patients with
hypertension and ischemic heart disease are candidates
for treatment with ACE inhibitors; administration of
ACE inhibitors in the immediate post-MI period has
been shown to improve ventricular function and reduce
morbidity and mortality (see Chapter 28).
The endocrine consequences of inhibiting the
biosynthesis of AngII are of importance in a number
of facets of hypertension treatment. Because ACE
inhibitors blunt the rise in aldosterone concentrations
in response to Na + loss, the normal role of aldosterone
to oppose diuretic-induced natriuresis is diminished.
Consequently, ACE inhibitors tend to enhance the efficacy
of diuretic drugs. This means that even very small
doses of diuretics may substantially improve the antihypertensive
efficacy of ACE inhibitors; conversely,
the use of high doses of diuretics together with ACE
inhibitors may lead to excessive reduction in blood
pressure and to Na + loss in some patients.
The attenuation of aldosterone production by ACE
inhibitors also influences K + homeostasis. There is only
a very small and clinically unimportant rise in serum
K + when these agents are used alone in patients with
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CHAPTER 27
TREATMENT OF MYOCARDIAL ISCHEMIA AND HYPERTENSION