Professional Documents
Culture Documents
44-2
The chapter then moves to a discussion of the individual drugs that affect the
RAAS, beginning with the ACE inhibitors.
The ACE inhibitors are important drugs for treating hypertension, heart failure,
diabetic nephropathy, and myocardial infarction (MI). In addition, they are used to
prevent adverse cardiovascular events in patients at risk.
Their most prominent adverse effects are cough, angioedema, first-dose
hypotension, and hyperkalemia.
ACE inhibitors produce their beneficial effects and adverse effects by (1)
reducing levels of angiotensin II (through inhibition of ACE) and (2) increasing
levels of bradykinin (through inhibition of kinase II). By reducing levels of
angiotensin II, ACE inhibitors can dilate blood vessels (primarily arterioles and,
to a lesser extent, veins), reduce blood volume (through effects on the kidney)
and, an important effect, prevent or reverse pathologic changes in the heart and
blood vessels mediated by angiotensin II and aldosterone. All ACE inhibitors are
approved for hypertension. ACE inhibitors offer several advantages over most
other antihypertensive drugs. In contrast to the sympatholytic agents, ACE
inhibitors do not interfere with cardiovascular reflexes.
They can be used safely in patients with bronchial asthma.
ACE inhibitors reduce the risk of cardiovascular mortality caused by hypertension.
ACE inhibitors produce multiple benefits in heart failure.
ACE inhibitors can reduce mortality after an acute MI (heart attack).
ACE inhibitors can benefit patients with diabetic nephropathy. They may slow the
progression of established nephropathy, although they do not protect against early
kidney damage.
A precipitous drop in blood pressure may occur after the first dose of an ACE
inhibitor. This reaction is caused by widespread vasodilation secondary to abrupt
lowering of angiotensin II levels. All ACE inhibitors can cause a persistent, dry,
irritating, nonproductive cough. The underlying cause is accumulation of bradykinin
secondary to inhibition of kinase II.
Cough occurs in about 10% of patients and is the most common reason for
discontinuing therapy. Cough begins to subside 3 days after discontinuing an ACE
inhibitor and is gone within 10 days.
Inhibition of aldosterone release (secondary to inhibition of angiotensin II
production) can cause potassium retention by the kidney. Patients should be
instructed to avoid potassium supplements and potassium-containing salt
substitutes unless they are prescribed.
ACE inhibitors can cause severe renal insufficiency in patients with bilateral
renal artery stenosis or stenosis in the artery to a single remaining kidney.
ACE inhibitors can cause major fetal malformations and should be avoided during
pregnancy. Until recently, it was thought that this risk was limited to exposure
during the second and third trimesters. However, new data indicate that exposure
during the first trimester may be dangerous as well.
Angioedema is a potentially fatal reaction that develops in up to 1% of patients.
Symptoms, which result from increased capillary permeability, include giant
Copyright 2013, 2010 by Saunders, an imprint of Elsevier Inc.
44-3
The chapter then presents information about the direct renin inhibitors.
Direct renin inhibitors (DRIs) are drugs that act on renin to inhibit the conversion
of angiotensinogen to angiotensin I.
Aliskiren was the first DRI on the market. Blood pressure reduction with DRIs
equals that seen with ACE inhibitors. Aliskiren causes less cough and angioedema
than the ACE inhibitors but poses similar risks to the developing fetus.
Aliskiren binds tightly with renin, thereby inhibiting the cleavage of
angiotensinogen into angiotensin I. Because this reaction is the first and ratelimiting step in the production of angiotensin II and aldosterone, aliskiren can
reduce the influence of the entire RAAS.
Aliskiren is approved only for treatment of hypertension. It may be used alone or
in combination with other antihypertensives.
Aliskiren is generally well tolerated. At usual doses the risk of angioedema,
Copyright 2013, 2010 by Saunders, an imprint of Elsevier Inc.
44-4