Drugs Affecting the Renin-Angiotensin
System
The renin-angiotensin system maintains blood pressure and fluid
balance (see Fig. 16-7
).
The major end product of the system, angiotensin II, is a potent vasoconstrictor
that also stimulates the release of aldosterone from the adrenal cortex. Aldosterone
causes salt and water retention by the kidney. The mechanism by which angiotensin
II is produced is as follows. The juxtaglomerular cells of the renal cortex secrete
the proteolytic enzyme renin, which cleaves angiotensinogen, a protein produced in
the liver, producing the decapeptide angiotensin I. Angiotensin I is converted almost
immediately to angiotensin II by ACE. This converting enzyme is located predominantly
in the endothelial tissue of the lung. In addition to its direct vasoconstrictive
activity, angiotensin II enhances the prejunctional release of norepinephrine from
the adrenergic nerve ending and increases efferent sympathetic nerve activity. Angiotensin
II also affects sodium and water homeostasis by directly decreasing tubular reabsorption
of sodium, increasing antidiuretic and adrenocorticotropic hormone secretion, and
stimulating the secretion of aldosterone. ACE is also a kinase that degrades the
vasodilator bradykinin. ACE inhibition blocks angiotensin II formation and delays
bradykinin breakdown along with effects on associated prostaglandins.[427]
A few patients with hypertensive vascular disease have high circulating
plasma renin levels, but many more, 70% of patients, respond to the antihypertensive
effects of ACEIs, and there is no dramatic difference in hypertensive response among
patients with low or high renin levels.[339]
The
ACEIs have proved to be useful in the treatment of hypertension and CHF and have
decreased mortality after MI.[428]
Captopril (Capoten),
was the first active oral agent available, followed by enalapril (Vasotec) and lisinopril
(Prinivil, Zestril). Four new ACEIs have been marketed: benazepril (Lotensin),
fosinopril (Monopril), quinapril (Accupril), and ramipril (Altace). The ACEIs affect
the renin-angiotensin-aldosterone system by inhibiting ACE activity.[427]
[429]
[430]
Enalapril
is the only ACEI available in a parenteral dosage at this time. Lisinopril offers
once-daily dosing.
Although all the ACEIs are approved for the treatment of hypertension,
only captopril and enalapril are approved for the treatment of CHF. Both agents
can decrease morbidity and mortality in patients with CHF. Captopril is associated
with more frequent adverse effects than enalapril, may have a few more drug interactions,
and has a dosing regimen of two or three times daily, compared with enalapril, which
has a dosing regimen of once or twice daily.
Some adverse effects observed with ACEIs are common to the entire
class, such as cough, angioedema, acute renal failure, and hyperkalemia. Angioedema,
especially after the first dose, affects the face, extremities, lips, mucous membranes,
tongue, glottis, or larynx.[427]
[431]
[432]
Some occurrences may be fatal.[427]
[431]
[432]
[433]
Rash and taste disturbance are more frequent with captopril than with the other
ACEIs. Because impairment of renal function with an ACEI is usually reversible after
withdrawal of the drug, renal function must be monitored,[431]
[432]
and because hyperkalemia may result from inhibition
of aldosterone secretion, serum potassium levels should be monitored.[427]
[430]
[431]
[432]
ACEIs can cause fetal morbidity and mortality in humans. These agents should not
be used at all during the second or third trimester of pregnancy.[433]
The adverse effect profile of the ACEIs has led to the development of angiotensin
II receptor antagonists. Losartan was the first of this new class of antihypertensive
agents that now includes candesartan, irbesartan, olmesartan, and valsartan. Initial
trials have not demonstrated angiotensin II receptor antagonists to be superior to
ACEIs; however, the addition of these agents during chronic ACEI therapy reduced
all-cause mortality and hospitalization in patients with heart failure.[434]
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