Lehne: Pharmacology for Nursing Care, 8th Edition

Chapter 44: Drugs Acting on the Renin-Angiotensin-Aldosterone System

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Chapter 44 begins with a review of the physiology of the renin-angiotensinaldosterone system and its role in the regulation of blood pressure. As the chapter
continues, a discussion of the drugs that affect it will follow.

The renin-angiotensin-aldosterone system (RAAS) helps regulate blood pressure,

blood volume, and fluid and electrolyte balance. The RAAS exerts its effects
through angiotensin II and aldosterone.
The most prominent actions of angiotensin II are vasoconstriction and
stimulation of aldosterone release.
The compound acts directly on vascular smooth muscle (VSM) to cause
contraction. Vasoconstriction is prominent in arterioles and less so in veins.
In addition to its direct action on blood vessels, angiotensin II can cause
vasoconstriction indirectly by acting on (1) sympathetic neurons to promote
norepinephrine release, (2) the adrenal medulla to promote epinephrine release,
and (3) the central nervous system to increase sympathetic outflow to blood
vessels.
Angiotensin II acts on the adrenal cortex to promote synthesis and secretion of
aldosterone.
Angiotensin II may cause pathologic structural changes in the heart and blood
vessels. In the heart, it may cause hypertrophy (increased cardiac mass) and
remodeling (redistribution of mass within the heart).
After release from the adrenal cortex, aldosterone acts on the distal tubules of
the kidney to cause retention of sodium and excretion of potassium and
hydrogen. Aldosterone can promote cardiac remodeling and fibrosis.
Renin catalyzes the formation of angiotensin I from angiotensinogen. This
reaction is the rate-limiting step in angiotensin II formation.
Release of renin can be triggered by multiple factors. Release increases in
response to a decline in blood pressure, blood volume, plasma sodium content, or
renal perfusion pressure.
Release of renin is suppressed by factors opposite to those that cause release; that
is, renin secretion is inhibited by elevation of blood pressure, blood volume, and
the plasma sodium content.
ACE catalyzes the conversion of angiotensin I (inactive) o angiotensin II (highly
active).
ACE is located on the luminal surface of all blood vessels.
The RAAS is poised to help regulate blood pressure: factors that lower blood
pressure turn the system on; factors that raise blood pressure turn it off.
The RAAS, acting through angiotensin II, raises blood pressure through two basic
processes: vasoconstriction and renal retention of water and sodium.
Copyright 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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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
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44-3

wheals and edema of the tongue, glottis, and pharynx.

The chapter then discusses the angiotensin II receptor blockers, their uses, and their
possible side effects.

ARBs block the actions of angiotensin II.

Because both the ACE inhibitors and ARBs interfere with angiotensin II, they
have similar effects. They differ primarily in that ARBs do not cause cough or
hyperkalemia, but they may increase the risk of cancer.
ARBs block access of angiotensin II to its receptors in blood vessels, the adrenals,
and all other tissues.
By blocking angiotensin II receptors on blood vessels, ARBs cause dilation of
arterioles and veins.
By blocking angiotensin II receptors in the heart, ARBs can prevent angiotensin II
from inducing pathologic changes in cardiac structure.
By blocking angiotensin II receptors in the adrenals, ARBs reduce the release of
aldosterone and thus can increase renal excretion of sodium and water.
These drugs are used to treat hypertension, heart failure, and diabetic
nephropathy; they also play a role in MI and stroke prevention.
ARBs do not cause clinically significant hyperkalemia.
Like the ACE inhibitors, ARBs can cause angioedema, although the incidence
may be lower with ARBs. ARBs can injure the developing fetus if taken during
the second or third trimester of pregnancy and therefore are contraindicated
during this period.
ARBs can cause renal failure in patients with bilateral renal artery stenosis or
stenosis in the artery to a single remaining kidney.
Some evidence, but no solid proof, indicates that ARBs may increase the risk of
cancer, especially cancer of the lung. However, even if the risk is real, it is probably
very small.

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,
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cough, or hyperkalemia is low. At high therapeutic doses, some patients

experience diarrhea.
The chapter then reviews the aldosterone antagonists, their method of action, and
their expected side effects.

Aldosterone antagonists are drugs that block receptors for aldosterone.

Two such agents are available: eplerenone and spironolactone. The two drugs
have similar structures and actions, and both are used for the same disorders:
hypertension and heart failure.
Eplerenone is a first-in-class selective aldosterone receptor blocker. The drug is
used for hypertension and heart failure and has one significant side effect:
hyperkalemia.
Eplerenone produces selective blockade of aldosterone receptors, having little or
no effect on receptors for other steroid hormones (e.g., glucocorticoids,
progesterone, androgens).
For the treatment of hypertension, eplerenone may be used alone or in
combination with other antihypertensive agents.
In patients with heart failure, eplerenone can improve symptoms, reduce
hospitalizations, and prolong life.
Eplerenone is generally well tolerated. The incidence of adverse effects is nearly
identical to that of placebo. A few adverse effectsdiarrhea, abdominal pain,
cough, fatigue, gynecomastia, flulike syndromeoccur slightly more often with
eplerenone (1% to 2%) than with placebo.
Inhibitors of CYP3A4 can increase levels of eplerenone, thereby posing a risk of
toxicity.

Copyright 2013, 2010 by Saunders, an imprint of Elsevier Inc.