Page 201 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 11 Antihypertensive Agents 187

in hypertension (and, in part, in angina) is inhibition of calcium Angiotensin II has vasoconstrictor and sodium-retaining activity.
influx into arterial smooth muscle cells. Angiotensin II and III both stimulate aldosterone release. Angio-
Verapamil, diltiazem, and the dihydropyridine family (amlo- tensin may contribute to maintaining high vascular resistance in
dipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, hypertensive states associated with high plasma renin activity, such
and nitrendipine [withdrawn in the USA]) are all equally effective as renal arterial stenosis, some types of intrinsic renal disease, and
in lowering blood pressure, and many formulations are currently malignant hypertension, as well as in essential hypertension after
approved for this use in the USA. Clevidipine is a newer member of treatment with sodium restriction, diuretics, or vasodilators. How-
this group that is formulated for intravenous use only. ever, even in low-renin hypertensive states, these drugs can lower
Hemodynamic differences among calcium channel blockers blood pressure (see below).
may influence the choice of a particular agent. Nifedipine and the A parallel system for angiotensin generation exists in several
other dihydropyridine agents are more selective as vasodilators and other tissues (eg, heart) and may be responsible for trophic changes
have less cardiac depressant effect than verapamil and diltiazem. such as cardiac hypertrophy. The converting enzyme involved in
Reflex sympathetic activation with slight tachycardia maintains or tissue angiotensin II synthesis is also inhibited by ACE inhibitors.
increases cardiac output in most patients given dihydropyridines. Three classes of drugs act specifically on the renin-angiotensin
Verapamil has the greatest depressant effect on the heart and may system: ACE inhibitors; the competitive inhibitors of angiotensin
decrease heart rate and cardiac output. Diltiazem has intermedi- at its receptors, including losartan and other nonpeptide antagonists;
ate actions. The pharmacology and toxicity of these drugs are and aliskiren, an orally active renin antagonist (see Chapter 17). A
discussed in more detail in Chapter 12. Doses of calcium channel fourth group of drugs, the aldosterone receptor inhibitors (eg,
blockers used in treating hypertension are similar to those used in spironolactone, eplerenone), is discussed with the diuretics. In
treating angina. Some epidemiologic studies reported an increased addition, β blockers, as noted earlier, can reduce renin secretion.
risk of myocardial infarction or mortality in patients receiving
short-acting nifedipine for hypertension. It is therefore recom-
mended that short-acting oral dihydropyridines not be used for ANGIOTENSIN-CONVERTING ENZYME
hypertension. Sustained-release calcium blockers or calcium block- (ACE) INHIBITORS
ers with long half-lives provide smoother blood pressure control
and are more appropriate for treatment of chronic hypertension. Captopril and other drugs in this class inhibit the converting
Intravenous nicardipine and clevidipine are available for the treat- enzyme peptidyl dipeptidase that hydrolyzes angiotensin I to
ment of hypertension when oral therapy is not feasible; parenteral angiotensin II and (under the name plasma kininase) inactivates
verapamil and diltiazem can also be used for the same indication. bradykinin, a potent vasodilator that works at least in part by
Nicardipine is typically infused at rates of 2–15 mg/h. Clevidipine stimulating release of nitric oxide and prostacyclin. The hypoten-
is infused starting at 1–2 mg/h and progressing to 4–6 mg/h. It has sive activity of captopril results both from an inhibitory action
a rapid onset of action and has been used in acute hypertension on the renin-angiotensin system and a stimulating action on
occurring during surgery. Oral short-acting nifedipine has been the kallikrein-kinin system (Figure 11–5). The latter mechanism
used in emergency management of severe hypertension. has been demonstrated by showing that a bradykinin receptor
antagonist, icatibant (see Chapter 17), blunts the blood pressure-
lowering effect of captopril.
■ INHIBITORS OF ANGIOTENSIN Enalapril is an oral prodrug that is converted by hydrolysis to
a converting enzyme inhibitor, enalaprilat, with effects similar to
Renin, angiotensin, and aldosterone play important roles in those of captopril. Enalaprilat itself is available only for intravenous
some people with essential hypertension. Approximately 20% use, primarily for hypertensive emergencies. Lisinopril is a lysine
of patients with essential hypertension have inappropriately low derivative of enalaprilat. Benazepril, fosinopril, moexipril, per-
and 20% have inappropriately high plasma renin activity. Blood indopril, quinapril, ramipril, and trandolapril are other long-
pressure of patients with high-renin hypertension responds well to acting members of the class. All are prodrugs, like enalapril, and are
drugs that interfere with the system, supporting a role for excess converted to the active agents by hydrolysis, primarily in the liver.
renin and angiotensin in this population. Angiotensin II inhibitors lower blood pressure principally by
decreasing peripheral vascular resistance. Cardiac output and heart
Mechanism & Sites of Action rate are not significantly changed. Unlike direct vasodilators, these
agents do not result in reflex sympathetic activation and can be
Renin release from the kidney cortex is stimulated by reduced renal used safely in persons with ischemic heart disease. The absence
arterial pressure, sympathetic neural stimulation, and reduced of reflex tachycardia may be due to downward resetting of the
sodium delivery or increased sodium concentration at the distal baroreceptors or to enhanced parasympathetic activity.
renal tubule (see Chapter 17). Renin acts upon angiotensinogen Although converting enzyme inhibitors are most effective in
to yield the inactive precursor decapeptide angiotensin I. Angio- conditions associated with high plasma renin activity, there is no
tensin I is then converted, primarily by endothelial ACE, to the good correlation among subjects between plasma renin activity
arterial vasoconstrictor octapeptide angiotensin II (Figure 11–5), and antihypertensive response. Accordingly, renin profiling is
which is in turn converted in the adrenal gland to angiotensin III. unnecessary.