CLINICAL USE OF ACE INHIBITORS

Levinra V Vijiakumar
Fakultas Kedokteran Universitas Udayana

ABSTRACT

High blood pressure or hypertension is a leading cause of death in the world today. This
condition is often called a silent killer because its symptoms can go undetected until
damage to the body has occurred. Because of this, it is one of the most significantly underdiagnosed and under-treated medical conditions. If left uncontrolled, it can raise the risk of
dementia, heart attack, heart failure, kidney failure, stroke and vision loss. ACE (angiotensinconverting enzyme) inhibitors are used by millions of people every day. They are used
primarily to treat people who have high blood pressure and/or heart failure (congestive heart
failure). The ACE inhibitors are also widely used to treat people after a heart attack (in the
absence of heart failure) and people with diabetes with or without kidney disease. ACE
inhibitors are just one class of prescription medicines used to treat high blood pressure, heart
failure, and other heart-related ailments. Several other classes are also commonly used to
treat high blood pressure. These include diuretics, angiotensin-receptor blockers, betablockers and calcium-channel blockers. Those drugs plus the ACE inhibitors are often used in
combination, two or more at a time. Indeed, many people with high blood pressure will
require two or more drugs to bring their blood pressure down to a normal level. ACE
inhibitors and other drugs are also used to treat heart failure.

Keywords: Hypertension, ACE inhibitors, heart failure.

1. INTRODUCTION
The role of ACE inhibitors for the treatment of cardiovascular disease has expanded
since the development of the first orally effective agents in the late 1970s.1,2 For the basic
scientist the development of ACE inhibitors has been a useful means of examining the role of
the renin-angiotensin system (RAS) in physiological preparations and animal models of
disease.1 ACE inhibitors have stimulated interest in the molecular biology of the RAS in the
vascular and other systems.1,2
For the practising clinician ACE inhibitors are an essential tool for the treatment of
hypertension and heart failure.1,2,5 The impact on the management of heart failure has been
large because ACE inhibitors not only improve systems but also delay progression and
death.1,2 ACE inhibitors also have the potential to improve the quality and duration of life in
heart failure and may reduce health costs.1,2 A series of landmarks studies starting in 1987
with CONSENSUS and culminating in the AIRE (Autoimmune Regulator) study have shown
that ACE inhibitors should be used not only in all grades of heart failure associated with left
ventricular dilatation and systolic dysfunction but also in patients with substantial left
ventricular dysfunction after infarction.1
ACE inhibitors are also found to be beneficial in atherosclerotic coronary disease and
atherosclerotic complications.1,2 Mechanisms exist by which ACE inhibitors could retard the
progression of atheroma, reduce the risks of plaque rupture, or ameliorate the consequences
of ruptured plaque.1 We now have the means to determine whether the protective effect is
mediated through reduction in angiotensin II or increases in bradykinin/prostaglandin/nitric
oxide or other effects of ACE inhibitors.1,2
Undoubtedly, given the right conditions, innovative new classes of drugs will
continue to advance our knowledge in many areas of medicine.1 This opportunity is
particularly welcome in an area such as heart failure that despite being widespread and
important has been relatively neglected until now.1

CLINICAL USE OF ACE INHIBITORS

2

Figure 1. Classification and management of blood pressure for adults.

An ACE inhibitor (or angiotensin-converting-enzyme inhibitor) is a pharmaceutical
drug used primarily for the treatment of hypertension (high blood pressure) and congestive
heart failure.3,5,6 ACE inhibitors inhibit angiotensin-converting enzyme (a component of the
blood pressure-regulating renin-angiotensin system), thereby decreasing the tension of blood
vessels and blood volume, thus lowering blood pressure.3,6 Frequently prescribed ACE
inhibitors include perindopril, captopril, enalapril, lisinopril, and ramipril.3 ACE inhibitors
are used primarily to treat hypertension, although they may also be prescribed for cardiac
failure, diabetic nephropathy, chronic renal failure, renal involvement in systemic sclerosis
(scleroderma renal crisis), left ventricular systolic dysfunction, and acute myocardial
infarction.3,6
Angiotensin-converting enzyme (ACE) inhibitors reduce the activity of the reninangiotensin-aldosterone system.3,6 One mechanism for maintaining the blood pressure is the
release of a protein called renin from cells in the kidney (to be specific, the juxtaglomerular
apparatus).3,6 This produces another protein, angiotensin, which signals the adrenal gland to
produce a hormone called aldosterone.3,6 This system is activated in response to a fall in
blood pressure (hypotension), as well as markers of problems with the salt-water balance of
the body, such as decreased sodium concentration in the distal tubule of the kidney, decreased
3

blood volume and stimulation of the kidney by the sympathetic nervous system.3,6 In such
situations, the kidneys release renin, which acts as an enzyme and cuts off all but the first 10
amino acid residues of angiotensinogen (a protein made in the liver, and which circulates in
the blood).3,6 These 10 residues are then known as angiotensin I. Angiotensin converting
enzyme (ACE) then removes a further two residues which converts angiotensin I into
angiotensin II. Angiotensin II is found in the pulmonary circulation, as well as in the
endothelium of many blood vessels. The system in general aims to increase blood pressure by
increasing the amount of salt and water the body retains, although angiotensin is also very
good at causing the blood vessels to tighten (a potent vasoconstrictor).3,6
ACE inhibitors block the conversion of angiotensin I to angiotensin II. Therefore,
lower arteriolar resistance and increase venous capacity; increase cardiac output, cardiac
index, stroke work, and volume; lower renovascular resistance; and lead to increased
natriuresis (excretion of sodium in the urine). Renin will increase in concentration in the
blood due to negative feedback of conversion of AI to AII. Angiotensin I will increase for the
same reason. AII will decrease. Aldosterone will decrease. Bradykinin will increase due to
less inactivation that is done by ACE.3,6
Under normal conditions, angiotensin II will have the following effects: Vasoconstriction
(narrowing of blood vessels) and vascular smooth muscle hypertrophy (enlargement) induced
by AII may lead to increased blood pressure and hypertension. Further, constriction of the
efferent arterioles of the kidney leads to increased perfusion pressure in the glomeruli. It
contributes to ventricular remodeling and ventricular hypertrophy of the heart through
stimulation of the proto-oncogens c-fos, c-jun, c-myc, transforming growth factor beta (TGFB), through fibrogenesis and apoptosis (programmed cell death). Stimulation by AII of the
adrenal cortex to release aldosterone, a hormone that acts on kidney tubules, causes sodium
and chloride ions retention and potassium excretion. Sodium is a "water-holding" ion, so
water is also retained, which leads to increased blood volume, hence an increase in blood
pressure. Stimulation of the posterior pituitary to release vasopressin (antidiuretic hormone,
ADH) also acts on the kidneys to increase water retention. If ADH production is excessive in
heart failure, Na+ level in the plasma may fall (hyponatremia), and this is a sign of increased
risk of death in heart failure patients. A decrease renal protein kinase C is caused. With ACE
inhibitor use, the production of angiotensin II is decreased, leading to decreased blood
pressure.3,6

ADVERSE EFFECTS
Common adverse drug reactions include: hypotension, cough, hyperkalemia,
headache, dizziness, fatigue, nausea, and renal impairment.3,6 Some evidence also suggests
ACE inhibitors might increase inflammation-related pain, perhaps mediated by the buildup of
bradykinin that accompanies ACE inhibition.3,6 A persistent dry cough is a relatively
common adverse effect believed to be associated with the increases in bradykinin levels
produced by ACE inhibitors, although the role of bradykinin in producing these symptoms
remains disputed by some authors.3,6 Patients who experience this cough are often switched
to angiotensin II receptor antagonists.3,6 Rash and taste disturbances, infrequent with most
ACE inhibitors, are more prevalent in captopril and are attributed to its sulfhydryl moiety.3,6
This has led to decreased use of captopril in clinical setting, although it is still used in
scintigraphy of the kidney.3,6 Renal impairment is a significant adverse effect of all ACE
inhibitors, but the reason is still unknown.3,6 Some suggest it is associated with their effect on
angiotensin II-mediated homeostatic functions, such as renal blood flow.3,6 Renal blood flow
may be affected by angiotensin II because it vasoconstricts the efferent arterioles of the
glomeruli of the kidney, thereby increasing glomerular filtration rate (GFR).3,6 Hence, by
reducing angiotensin II levels, ACE inhibitors may reduce GFR, a marker of renal function.3,6
To be specific, they can induce or exacerbate renal impairment in patients with renal artery
stenosis.3,6 This is especially a problem if the patient is concomitantly taking an NSAID and a
diuretic.3,6 When the three drugs are taken together, there is a very high risk of developing
renal failure.3,6 ACE inhibitors may cause hyperkalemia.3,6 Suppression of angiotensin II
leads to a decrease in aldosterone levels.3,6 Since aldosterone is responsible for increasing the
excretion of potassium, ACE inhibitors can cause retention of potassium.3,6 Some people,
however, can continue to lose potassium while on an ACE inhibitor.3,6 A severe allergic
reaction that rarely can affect the bowel wall and secondarily cause abdominal pain can
occur.3,6 This "anaphylactic" reaction is very rare as well.3,6 Some patients develop
angioedema due to increased bradykinin levels.3,6 There appears to be a genetic
predisposition toward this adverse effect in patients who degrade bradykinin more slowly
than average.3,6 In pregnant women, ACE inhibitors taken during the first trimester have
been reported to cause major congenital malformations, stillbirths, and neonatal deaths.3,4,6
Commonly reported fetal abnormalities include hypotension, renal dysplasia, anuria/oliguria,
oligohydramnios, intrauterine growth retardation, pulmonary hypoplasia, patent ductus
arteriosus, and incomplete ossification of the skull.3,4,6 Overall, about half of newborns
exposed to ACE inhibitors are adversely affected.3,4,6
5

CONTRAINDICATIONS AND PRECAUTIONS

The ACE inhibitors are contraindicated in patients with previous angioedema
associated with ACE inhibitor therapy, renal artery stenosis (bilateral or unilateral with a
solitary functioning kidney) or hypersensitivity to ACE inhibitors.3,6 ACE inhibitors should
be used with caution in patients with impaired renal function, aortic valve stenosis or cardiac
outflow obstruction, hypovolemia or dehydration, or hemodialysis with high-flux
polyacrylonitrile membranes.3,6 ACE inhibitors should be avoided in women who are likely
to become pregnant.3,4,6 In the U.S., ACE inhibitors are labeled with a warning concerning
the risk of birth defects when taken during the second and third trimester.3,4,6 Their use in the
first trimester is also associated with a risk of major congenital malformations, particularly
affecting the cardiovascular and central nervous systems.3,4,6 Potassium supplementation
should be used with caution and under medical supervision owing to the hyperkalemic effect
of ACE inhibitors.3,6
CLINICAL USE
The ACE inhibitors have different strengths with different starting dosages. Dosage
should be adjusted according to the clinical response.3,5,6,7

Figure 2. ACE inhibitors with different starting dosages.

All ACE inhibitors have similar antihypertensive efficacy when equivalent doses are
administered.

3,5,6,7

The main differences lie with captopril, the first ACE inhibitor.

3,5,6,7

Captopril has a shorter duration of action and an increased incidence of adverse effects. 3,5,6,7
Captopril is also the only ACE inhibitor which is capable of passing through the bloodbrain
barrier, although the significance of this characteristic has not been shown to have any
positive clinical effects. 3,5,6,7 In a large clinical study, one of the agents in the ACE inhibitor
class, ramipril (Altace), demonstrated an ability to reduce the mortality rates of patients who
suffered a myocardial infarction, and to slow the subsequent development of heart failure.
3,5,6,7

This finding was made after it was discovered that regular use of ramipril reduced

mortality rates even in test subjects who did not suffer from hypertension. 3,5,6,7 Some believe
that ramipril's additional benefits may be shared by some or all drugs in the ACE inhibitor
class.

3,5,6,7

However, ramipril currently remains the only ACE inhibitor for which such

effects are actually evidence-based. 3,5,6,7

CONCLUSION
An ACE inhibitor (or angiotensin-converting-enzyme inhibitor) is a pharmaceutical
drug used primarily for the treatment of hypertension (high blood pressure) and congestive
heart failure. Frequently prescribed ACE inhibitors include perindopril, captopril, enalapril,
lisinopril, and ramipril. Angiotensin-converting enzyme (ACE) inhibitors reduce the activity
of the renin-angiotensin-aldosterone system. Common adverse drug reactions include:
hypotension, cough, hyperkalemia, headache, dizziness, fatigue, nausea, and renal
impairment. A persistent dry cough is a relatively common adverse effect believed to be
associated with the increases in bradykinin levels produced by ACE inhibitors. Patients who
experience this cough are often switched to angiotensin II receptor antagonists. A severe
allergic reaction that rarely can affect the bowel wall and secondarily cause abdominal pain
can occur. This "anaphylactic" reaction is very rare as well. Some patients develop
angioedema due to increased bradykinin levels. In pregnant women, ACE inhibitors taken
during the first trimester have been reported to cause major congenital malformations,
stillbirths, and neonatal deaths. ACE inhibitors should be avoided in women who are likely to
become pregnant. The ACE inhibitors have different strengths with different starting dosages.
Dosage should be adjusted according to the clinical response. Potassium supplementation
should be used with caution and under medical supervision owing to the hyperkalemic effect
of ACE inhibitors. All ACE inhibitors have similar antihypertensive efficacy when equivalent
doses are administered.
7

REFERENCES

1.

Cleland G F, 1994. ACE inhibitors: current understanding and future directions.

Retrieved on 3rd November 2012 from
http://heart.bmj.com/content/72/3_Suppl/S1.full.pdf

2.

Ervin G, Erdos, 2006. The ACE and I: how ACE inhibitors came to be. Retrieved
on 3rd November 2012 from http://www.fasebj.org/content/20/8/1034.full.pdf

3.

CRH, 2011. Using ACE inhibitors to treat: High Blood Pressure and Heart
Disease. Retrieved on 3rd November 2012 from
http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/ACEI-fullreport.pdf

4.

Cooper W O, Diaz S H, Arbogast P G, 2006. Major Congenital Malformations

after First-Trimester Exposure to ACE Inhibitors. Retrieved on 3rd November
2012 from http://www.medlive.cn/uploadfile/2011/1019/20111019075810477.pdf

5.

Olson K L, Karpiuk E, 2008. Hypertension:CIinical Practice Updates. Retrieved

on 3rd November 2012 from
http://www.accp.com/docs/bookstore/psap/p7b01sample01.pdf

6.

Prabhu M, Palaian S, Malhotra A, 2005. Therapeutic dimensions of ACE

inhibitors: A review of literature and clinical trials. Retrieved on 3rd November
2012 from http://www.kumj.com.np/issue/11/296-304.pdf

7.

McMurray J, Solal A C, Dietz R, 2005. Practical recommendations of the use of

ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor
blockers in heart failure: Putting guidelines into practice. Retrieved on 3rd
November 2012 from http://pharmacoclin.hug-ge.ch/formation/McMurray.pdf