ACE Inhibitors (angiotensin-converting enzyme inhibitors)

ACE INHIBITORS
Since their introduction in 1980, angiotensin-converting
enzyme (ACE) inhibitors, because of their unique
pharmacologic properties, have proven superior to other
vasodilators in the management of heart failure and have
come to play a key role in the therapy of hypertension.
They are particularly useful in hypertensive patients with
diabetes and proteinuria.

Mechanism of Action
The sodium concentration in the distal kidney tubules,
sensed by the macula densa, controls the release of renin
from the specialized juxtaglomerular cells located in the
media of the afferent kidney arterioles. Renin is an enzyme
that profoundly affects the cardiovascular system. It is a
protease that cleaves the leucine 10–valine 11 bond from the
circulating precursor angiotensinogen to form the decapeptide
angiotensin I. ACE in the lungs cleaves histidineleucine
from angiotensin I, resulting in the formation of
angiotensin II, which produces the effects listed below.
1. Vasoconstriction that is more intense than that caused
by norepinephrine. This vasoconstriction occurs
mainly in arterioles and, to a small degree, in veins.
This action is more pronounced in skin and in the
kidney but with some sparing of vessels in the brain
and muscle.
2. Renal effects that include marked sodium reabsorption
in the proximal kidney tubules.
3. Adrenal effects that cause the release of aldosterone,
which enhances sodium and water reabsorption and
potassium excretion in the renal tubule distal to the
macula densa. Angiotensin II promotes release of
catecholamines from the adrenal glands.
4. There is an increase in sympathetic outflow that
facilitates ganglionic stimulation of the sympathetic
nervous system.

Stimuli to the release of renin include: (1) a decrease in
renal blood flow, hypotension, and reduction of intravascular
volume; (2) sodium depletion or sodium diuresis;
and (3) beta-adrenergic receptor activation.
ACE inhibitors are competitive inhibitors of angiotensin-
converting enzyme and therefore prevent the
conversion of angiotensin I to angiotensin II. This action
causes the salutary effects listed below.
1. There is dilatation of arteries which causes a reduction
in total systemic vascular resistance resulting in a fall in
blood pressure and a reduction in afterload. This allows
the left ventricle to pump blood more easily into the
arterial system. Thus, the left ventricle has less work to
do and this action prevents or improves heart failure
(see the section Pathophysiology in the chapter Heart
Failure).
2. There is potentiation of sympathetic activity and the
release of norepinephrine is attenuated. This action
causes further vasodilatation and reduction in afterload.
The effect on the sympathetic nervous system and
increased vagal tone prevents the increase in heart rate
that is observed with other vasodilating agents. This
important action is helpful in the management of heart
failure where tachycardia causes increased work for the
heart, and in hypertensive patients it prevents hypertrophy.
Other vasodilating drugs are deleterious in these
two conditions.
3. There is a reduction in aldosterone secretion that
promotes sodium excretion and potassium retention.
This action also prevents or improves heart failure.
Unfortunately, aldosterone secretion is not completely
suppressed. Agents that completely suppress aldosterone
are being investigated.
4. Converting enzyme is the same as kininase II, which
causes degradation of bradykinin to inactive peptides.
The accumulation of bradykinin appears to stimulate
the release of the important vasodilator nitric oxide
(NO) and prostacyclin, which protect the endothelial
lining of arteries. This accumulation also contributes to
arterial dilation and a further decrease in peripheral
vascular resistance and afterload. Thus, ACE inhibitors
are more beneficial than angiotensin receptor blockers
that do not have this salutary effect on bradykinin.
Excessive bradykinin, however, may cause angioedema
in susceptible individuals.
5. ACE inhibitors inhibit vascular superoxide production,
and because superoxide reacts with nitric NO, ACE
inhibitors appear to increase NO bioactivity. This
action, although modest, is important in patients with
coronary artery disease (CAD).
6. The modulation and adequacy of the neurohormonal
response to the long-term administration of ACE
inhibitors in heart failure appear to be associated with
ACE gene polymorphism. Patients with heart failure
and aldosterone escape have been shown to have a
higher prevalence of DD genotype compared with
patients who have normal aldosterone levels. A small
study indicated that the antihypertensive response to
ACE inhibition is more pronounced in subjects with
ACE DD genotype than in those with ACE II genotype.
7. The ACE inhibitor captopril has been shown to
modestly reduce high blood uric acid levels. This
action may be important in an individual who is given
diuretics that increase uric acid levels. Captopril may
counteract some of this adverse effect.

Available ACE inhibitors
Below is a list of available ACE inhibitors.
1. Captopril — dosage 12.5–50 mg two or three times
daily for hypertension and heart failure. The discovery
of captopril, the first ACE inhibitor used in clinical
practice, provided a major change in the management
of heart failure.
2. Benazepril — dosage 5–30 mg daily
3. Cilazapril — dosage 1.25–5 mg daily
4. Enalapril — dosage 5–40 mg once daily
5. Fosinopril — dosage 5–50 mg once daily
6. Lisinopril — dosage 5–40 mg once daily
7. Perindopril — dosage 2–8 mg once daily
8. Quinapril — dosage 5–40 mg once daily
9. Ramipril — dosage 2.5 mg or up to 15 mg once daily
10. Trandolapril — dosage 0.5–4 mg once daily
Although there are more than ten ACE inhibitors
currently available, it is unfortunate that their actions,
indications, and adverse effects are similar. The newer
agents have no beneficial effects over and above that of the
older agents captopril, enalapril, and lisinopril that were
available during the 1980s; thus the newer agents offer is
little added benefit to patients. Although there are subtle
differences in absorption, elimination by the liver or kidney,
and duration of action, these differences do not cause
beneficial effects and do not merit further discussion.

Adverse Effects
Below is a list of adverse affects of ACE inhibitors.
1. Hypotension may occur if the dose of ACE inhibitor
is excessive, particularly if a diuretic is used before the
addition off the ACE inhibitor. Lightheadedness,
dizziness, and a faint feeling may occur. The initial
dose should be small in elderly patients and in patients
with heart failure.
2. Kidney failure may become worse if hypotension
occurs or if the patient has severe obstruction in one
renal artery or tight renal artery stenosis. Fortunately,
renal artery stenosis is uncommon.
3. Hyperkalemia may occur if kidney failure is progressive
or if a potassium-sparing diuretic, potassium
supplements, or salt substitutes are added to the
treatment regimen.
4. Cough occurs in up to 20% of patients; it is
sufficiently bothersome to promote the discontinuation
of medications in about 10% of treated patients.
Cough occurs because of the accumulation of
bradykinin.
5. Loss of taste has been reported in up to 7% of
patients.
6. Extensive skin rash with severe itching may occur in
greater than 10% of patients.
7. Angioedema is a life-threatening complication that
occurs in approximately 0.8% of patients. Bradykinin
and kallidin mediate hereditary angioedema. ACE
inhibition results in the accumulation of bradykinin
which can cause angioedema. Swelling of the eyelids,
lips, and tongue may occur. Most important, swelling
of the upper airway may obstruct air entry to the lung
and death can occur if treatment is not immediately
available.

Interactions
Lithium levels may increase, and interactions may occur
with immunosuppressive agents and those that alter the
immune response.

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