Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of
medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...
used primarily for the treatment of
high blood pressure and
heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
.
They work by causing relaxation of blood vessels as well as a decrease in
blood volume
Blood volume (volemia) is the volume of blood (blood cells and plasma) in the circulatory system of any individual.
Humans
A typical adult has a blood volume of approximately 5 liters, with females and males having approximately the same blood ...
, which leads to lower
blood pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure ...
and decreased
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements ...
demand from the
heart
The heart is a muscular Organ (biology), organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as ca ...
.
ACE inhibitors
inhibit the activity of
angiotensin-converting enzyme
Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconst ...
, an important component of the
renin–angiotensin system
The renin–angiotensin system (RAS), or renin–angiotensin–aldosterone system (RAAS), is a hormone system that regulates blood pressure, fluid and electrolyte balance, and systemic vascular resistance.
When renal blood flow is reduced, ...
which converts
angiotensin I
Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adre ...
to
angiotensin II
Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adr ...
,
and hydrolyses
bradykinin
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor an ...
.
Therefore, ACE inhibitors decrease the formation of angiotensin II, a
vasoconstrictor
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...
, and increase the level of
bradykinin
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor an ...
, a
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...
vasodilator.
This combination is synergistic in lowering blood pressure.
As a result of inhibiting the ACE enzyme in the bradykinin system, the ACE inhibitor drugs allow for increased levels of bradykinin which would normally be degraded. Bradykinin produces prostaglandin. This mechanism can explain the two most common side effects seen with ACE Inhibitors: angioedema and cough.
Frequently prescribed ACE inhibitors include
benazepril,
zofenopril,
perindopril,
trandolapril,
captopril,
enalapril,
lisinopril, and
ramipril.
Medical use
ACE inhibitors were initially approved for the treatment of hypertension and can be used alone or in combination with other anti-hypertensive medications. Later, they were found useful for other cardiovascular and kidney diseases
including:
* Acute
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...
(heart attack)
*
Heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
(left ventricular systolic dysfunction)
* Kidney complications of
diabetes mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
(
diabetic nephropathy) by means of decreasing the blood pressure and increasing perfusion in glomerular arterioles.
In treating high blood pressure, ACE inhibitors are often the first drug choice, particularly when diabetes is present, but age can lead to different choices and it is common to need more than one drug to obtain the desired improvement. There are fixed-dose
combination drugs, such as
ACE inhibitor and thiazide combinations. ACE inhibitors have also been used in
chronic kidney failure
Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, v ...
and kidney involvement in
systemic sclerosis (hardening of tissues, as scleroderma renal crisis). In those with stable coronary artery disease, but no heart failure, benefits are similar to other usual treatments.
In 2012, there was a
meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...
published in the
BMJ that described the protective role of ACE inhibitors in reducing the risk of
pneumonia
Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...
when compared to
ARBs (Angiotensin II Receptor Blockers).
The authors found a decreased risk in patients with previous stroke (54% risk reduction), with heart failure (37% risk reduction), and of Asian descent (43% risk reduction vs 54% risk reduction in non-Asian population). However, no reduced pneumonia related mortality was observed.
Other
ACE inhibitors may also be used to help decrease excessive water consumption in people with
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...
resulting in
psychogenic polydipsia. A double-blind, placebo-controlled trial showed that when used for this purpose,
enalapril led to decreased consumption (determined by urine output and osmolality) in 60% of people; the same effect has been demonstrated in other ACE inhibitors.
Additionally ACEi are commonly used after renal transplant to manage post-transplant
erythrocytosis, a condition characterised by a persistently high
hematocrit greater than 51% which often develops 8–24 months after successful transplantation, as ACEi have been shown to decrease
erythropoietin production.
Adverse effects
Common side effects include: low blood pressure,
cough,
hyperkalemia
Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occa ...
,
headache
Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches.
Headaches can occur as a result ...
,
dizziness
Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness.
Dizziness is a common medical c ...
,
fatigue,
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...
, and
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
impairment.
[Rossi S, editor. ]Australian Medicines Handbook
Australian Medicines Handbook (AMH) is a peer-reviewed medicines prescribing guide for Australian health professionals. The handbook is available in paper and digital formats and is supplemented by the ''AMH Aged Care Companion'' and the ''AMH C ...
2006. Adelaide: Australian Medicines Handbook; 2006. .
The main adverse effects of ACE inhibition can be understood from their pharmacological action. The other reported adverse effects are liver problems and effects on the fetus.
Kidney problems may occur with all ACE inhibitors that directly follows from their mechanism of action. Patients starting on an ACE inhibitor usually have a modest reduction in
glomerular filtration rate (GFR).
However, the decrease may be significant in conditions of ''pre-existing'' decreased renal perfusions, such as renal artery stenosis, heart failure, polycystic kidney disease, or volume depletion. In these patients, the maintenance of GFR depends on angiotensin-II-dependent efferent vasomotor tone.
Therefore,
renal function
Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging.
Functions of a healthy kidney include maintaining a person's flui ...
should be closely monitored over the first few days after initiation of treatment with ACE inhibitor in patients with decreased renal perfusion.
A moderate reduction in renal function, no greater than 30% rise in serum
creatinine, that is stabilized after a week of treatment is deemed acceptable as part of the therapeutic effect, providing the residual renal function is sufficient.
Reduced GFR is especially a problem if the patient is concomitantly taking an
NSAID and a
diuretic
A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics i ...
.
When the three drugs are taken together, the risk of developing renal failure is significantly increased.
High blood potassium is another possible complication of treatment with an ACE inhibitor due to its effect on aldosterone. Suppression of angiotensin II leads to a decrease in aldosterone levels. Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors can cause retention of potassium. Some people, however, can continue to lose potassium while on an ACE inhibitor.
Hyperkalemia may decrease the velocity of impulse conduction in the nerves and muscles, including cardiac tissues. This leads to cardiac dysfunction and neuromuscular consequences, such as muscle weakness, paresthesia, nausea, diarrhea, and others. Close monitoring of potassium levels is required in patients receiving treatment with ACE inhibitors who are at risk of hyperkalemia.
Another possible adverse effect specific for ACE inhibitors, but not for other RAAS blockers, is an increase in
bradykinin
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor an ...
level.
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 has been disputed.
Many cases of cough in people on ACE inhibitors may not be from the medication itself, however. People who experience this cough are often switched to
angiotensin II receptor antagonists.
Some (0.7%)
develop
angioedema due to increased bradykinin levels. A genetic predisposition may exist.
A severe rare allergic reaction can affect the bowel wall and secondarily cause abdominal pain.
Blood
Hematologic effects, such as neutropenia, agranulocytosis and other blood dyscrasias, have occurred during therapy with ACE inhibitors, especially in people with additional risk factors.
Pregnancy
In pregnant women, ACE inhibitors taken during all the trimesters have been reported to cause
congenital malformations,
stillbirth
Stillbirth is typically defined as fetal death at or after 20 or 28 weeks of pregnancy, depending on the source. It results in a baby born without signs of life. A stillbirth can result in the feeling of guilt or grief in the mother. The term ...
s, and
neonatal deaths. Commonly reported fetal abnormalities include
hypotension
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...
,
renal dysplasia
Multicystic dysplastic kidney (MCDK) is a condition that results from the malformation of the kidney during fetal development. The kidney consists of irregular cysts of varying sizes. Multicystic dysplastic kidney is a common type of renal cyst ...
, anuria/oliguria,
oligohydramnios
Oligohydramnios is a medical condition in pregnancy characterized by a deficiency of amniotic fluid, the fluid that surrounds the fetus in the abdomen, in the amniotic sac. It is typically diagnosed by ultrasound when the amniotic fluid index ( ...
,
intrauterine growth retardation
Intrauterine growth restriction (IUGR), or fetal growth restriction, refers to poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's ...
,
pulmonary hypoplasia
Pulmonary hypoplasia is incomplete development of the lungs, resulting in an abnormally low number or size of bronchopulmonary segments or alveoli. A congenital malformation, it most often occurs secondary to other fetal abnormalities that i ...
,
patent ductus arteriosus
''Patent ductus arteriosus'' (PDA) is a medical condition in which the ''ductus arteriosus'' fails to close after birth: this allows a portion of oxygenated blood from the left heart to flow back to the lungs by flowing from the aorta, which has ...
, and incomplete ossification of the skull.
Overall, about half of newborns exposed to ACE inhibitors are adversely affected, leading to
birth defect
A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities ca ...
s.
ACE inhibitors are
ADEC pregnancy category
The pregnancy category of a medication is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does ''not'' include any risks conferred by pharmaceutical agents or their ...
D and should be avoided in women who are likely to become pregnant.
In the U.S., ACE inhibitors must be labeled with a
boxed warning concerning the risk of birth defects when taken during the second and third trimester. Their use in the first trimester is also associated with a risk of major
congenital malformation
A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities c ...
s, particularly affecting the
cardiovascular and
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
s.
Overdose
Symptoms and Treatment: There are few reports of ACE inhibitor overdose in the literature. The most likely manifestations are hypotension, which may be severe, hyperkalemia, hyponatremia and renal impairment with metabolic acidosis. Treatment should be mainly symptomatic and supportive, with volume expansion using normal saline to correct hypotension and improve renal function, and gastric lavage followed by activated charcoal and a cathartic to prevent further absorption of the drug. Captopril, enalapril, lisinopril and perindopril are known to be removable by hemodialysis.
Contraindications and precautions
The ACE inhibitors are contraindicated in people with:
* Pregnancy or breastfeeding
* Previous
angioedema associated with ACE inhibitor therapy
* Bilateral renal artery stenosis
* Hypersensitivity to ACE inhibitors
ACE inhibitors should be used with caution in people with:
* Impaired renal function
*
Aortic valve stenosis
Aortic stenosis (AS or AoS) is the narrowing of the exit of the left ventricle of the heart (where the aorta begins), such that problems result. It may occur at the aortic valve as well as above and below this level. It typically gets worse ...
or cardiac outflow obstruction
*
Hypovolemia or
dehydration
In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
*
Hemodialysis with high-flux polyacrylonitrile membranes
A combination of ACE inhibitor with other drugs may increase effects of these drugs, but also the risk of adverse effects.
The commonly reported adverse effects of drug combination with ACE are acute renal failure, hypotension, and hyperkalemia. The drugs interacting with ACE inhibitor should be prescribed with caution. Special attention should be given to combinations of ACE inhibitor with other RAAS blockers,
diuretics (especially potassium-sparing diuretics), NSAIDs,
anticoagulants,
cyclosporine,
DPP-4 inhibitors, and
potassium supplements.
Potassium supplementation should be used with caution and under medical supervision owing to the
hyperkalemic effect of ACE inhibitors.
Concomitant use with
cyclooxygenase inhibitors tends to decrease ACE inhibitor's hypotensive effect.
Mechanism of action
ACE inhibitors reduce the activity of the
renin–angiotensin–aldosterone system (RAAS) as the primary etiologic (causal) event in the development of hypertension in people with diabetes mellitus, as part of the insulin-resistance syndrome or as a manifestation of renal disease.
Renin–angiotensin–aldosterone system
The renin–angiotensin–aldosterone system is a major blood pressure regulating mechanism. Markers of electrolyte and water imbalance in the body such as
hypotension
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...
, low
distal tubule sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...
concentration, decreased blood volume and high
sympathetic tone trigger the release of the enzyme
renin
Renin (etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin–angiotensin–aldosterone system (RAAS)—also known as the ...
from the cells of
juxtaglomerular apparatus in the kidney.
Renin activates a circulating liver derived prohormone
angiotensinogen by proteolytic cleavage of all but its first ten
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
residues known as
angiotensin I
Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adre ...
.
ACE (angiotensin converting enzyme) then removes a further two residues, converting angiotensin I into
angiotensin II
Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adr ...
. ACE is found in the
pulmonary circulation and in the
endothelium
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...
of many blood vessels. The system increases 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
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...
).
Effects
ACE inhibitors block the conversion of angiotensin I (ATI) to angiotensin II (ATII).
They thereby lower
arteriolar resistance and increase venous capacity; decrease
cardiac output
In cardiac physiology, cardiac output (CO), also known as heart output and often denoted by the symbols Q, \dot Q, or \dot Q_ , edited by Catherine E. Williamson, Phillip Bennett is the volumetric flow rate of the heart's pumping output: th ...
,
cardiac index Cardiac index (CI) is a haemodynamic parameter that relates the cardiac output (CO) from left ventricle in one minute to body surface area (BSA), thus relating heart performance to the size of the individual. The unit of measurement is litres per mi ...
, stroke work, and
volume
Volume is a measure of occupied three-dimensional space. It is often quantified numerically using SI derived units (such as the cubic metre and litre) or by various imperial or US customary units (such as the gallon, quart, cubic inch). ...
; lower resistance in blood vessels in the kidneys; and lead to increased
natriuresis (excretion of sodium in the urine). Renin increases in concentration in the blood as a result of negative feedback of conversion of ATI to ATII. ATI increases for the same reason; ATII and aldosterone decrease.
Bradykinin
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor an ...
increases because of less inactivation by ACE.
Under normal conditions, angiotensin II has these effects:
* Vasoconstriction (narrowing of blood vessels) and vascular smooth muscle hypertrophy (enlargement) induced by ATII 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 In cardiology, ventricular remodeling (or cardiac remodeling) refers to changes in the size, shape, structure, and function of the heart. This can happen as a result of exercise (physiological remodeling) or after injury to the heart muscle (pathol ...
and
ventricular hypertrophy of the heart through stimulation of the
proto-oncogenes
c-fos,
c-jun
Transcription factor Jun is a protein that in humans is encoded by the ''JUN'' gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only la ...
,
c-myc,
transforming growth factor beta (TGF-B), through fibrogenesis and apoptosis (programmed cell death).
* Stimulation by ATII of the
adrenal cortex
The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is ...
to release
aldosterone
Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...
, 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
During the course of ACE inhibitor use, the production of ATII is decreased,
which prevents aldosterone release from the adrenal cortex.
This allows the kidney to excrete sodium ions along with obligate water, and retain potassium ions. This decreases blood volume, leading to decreased blood pressure.
Epidemiological
Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and determinants of health and disease conditions in a defined population.
It is a cornerstone of public health, and shapes policy decisions and evid ...
and clinical studies have shown ACE inhibitors reduce the progress of
diabetic nephropathy independently from their blood pressure-lowering effect.
This action of ACE inhibitors is used in the prevention of diabetic
renal failure
Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
.
ACE inhibitors have been shown to be effective for indications other than hypertension even in patients with normal blood pressure. The use of a maximum dose of ACE inhibitors in such patients (including for prevention of diabetic nephropathy, congestive heart failure, and prophylaxis of cardiovascular events) is justified, because it improves clinical outcomes independently of the blood pressure-lowering effect of ACE inhibitors. Such therapy, of course, requires careful and gradual titration of the dose to prevent the effects of rapidly decreasing blood pressure (dizziness, fainting, etc.).
ACE inhibitors have also been shown to cause a central enhancement of
parasympathetic nervous system
The parasympathetic nervous system (PSNS) is one of the three divisions of the autonomic nervous system, the others being the sympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part o ...
activity in healthy volunteers and patients with heart failure. This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials.
ACE Inhibitors also reduce plasma
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...
levels, and its resulting vasoconstriction effects, in heart failure patients, thus breaking the vicious circles of
sympathetic and renin angiotensin system activation, which sustains the downward spiral in cardiac function in congestive heart failure
The ACE inhibitor
enalapril has also been shown to reduce cardiac
cachexia
Cachexia () is a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, most commonly cancer, congestive heart fa ...
in patients with chronic heart failure. Cachexia is a poor prognostic sign in patients with chronic heart failure.
ACE inhibitors are under early investigation for the treatment of frailty and muscle wasting (sarcopenia) in elderly patients without heart failure.
Examples
Currently, there are 10 ACE inhibitors approved for use in the
United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country Continental United States, primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., ...
by the
FDA:
captopril (1981),
enalapril (1985),
lisinopril (1987),
benazepril (1991),
fosinopril
Fosinopril is an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of chronic heart failure. Fosinopril is the only phosphonate-containing ACE inhibitor marketed, by Bristol-Myers Squibb under the ...
(1991),
quinapril
Quinapril, sold under the brand name Accupril among others, is a medication used to treat high blood pressure (hypertension), heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken ...
(1991),
ramipril (1991),
perindopril (1993),
moexipril (1995) and
trandolapril (1996).
ACE inhibitors are easily identifiable by their common suffix, '-pril'. ACE inhibitors can be divided into three groups based on their molecular structure of the
enzyme binding sites (
sulfhydryl,
phosphinyl,
carboxyl) to the active center of ACE:
Sulfhydryl-containing agents
*
Alacepril
Alacepril (INN) is an ACE inhibitor medication indicated as a treatment for hypertension. The medication metabolizes to captopril
Captopril, sold under the brand name Capoten among others, is an ACE inhibitor, angiotensin-converting enzyme (A ...
*
Captopril (trade name Capoten), the first ACE inhibitor.
*
Zofenopril
These agents appear to show
antioxidative
Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricants, ...
properties but may be involved in adverse events such as
skin eruptions.
Dicarboxylate-containing agents
This is the largest group, including:
*
Enalapril (Vasotec/Renitec/Berlipril/Enap/Enalapril Profarma)
*
Ramipril (Altace/Prilace/Ramace/Ramiwin/Triatec/Tritace/Ramitac)
*
Quinapril
Quinapril, sold under the brand name Accupril among others, is a medication used to treat high blood pressure (hypertension), heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken ...
(Accupril)
*
Perindopril (Coversyl/Aceon/Perindo)
*
Lisinopril (Listril/Lopril/Novatec/Prinivil/Zestril, Lisidigal)
*
Benazepril (Lotensin)
*
Imidapril
Imidapril (trade name Tanatril) is an ACE inhibitor used as an antihypertensive drug and for the treatment of chronic heart failure.
It was patented in 1982 and approved for medical use in 1993.
Contraindications
Contraindications are hypersen ...
(Tanatril)
*
Trandolapril (Mavik/Odrik/Gopten)
*
Cilazapril (Inhibace)
Phosphonate-containing agents
*
Fosinopril
Fosinopril is an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of chronic heart failure. Fosinopril is the only phosphonate-containing ACE inhibitor marketed, by Bristol-Myers Squibb under the ...
(Fositen/Monopril) is the only member of this group
Naturally occurring
* A comprehensive resource on anti-hypertensive peptides is available in form of a database. It contains around 1700 unique antihypertensive peptides
*
Arfalasin (HOE 409) is angiotensin antagonist.
Dairy products
* Caso
kinins and lactokinins, breakdown products of
casein
Casein ( , from Latin ''caseus'' "cheese") is a family of related phosphoproteins ( αS1, aS2, β, κ) that are commonly found in mammalian milk, comprising about 80% of the proteins in cow's milk and between 20% and 60% of the proteins in hum ...
and
whey
Whey is the liquid remaining after milk has been curdled and strained. It is a byproduct of the manufacturing of cheese or casein and has several commercial uses. Sweet whey is a byproduct resulting from the manufacture of rennet types of har ...
, occur naturally after ingestion of
milk
Milk is a white liquid food produced by the mammary glands of mammals. It is the primary source of nutrition for young mammals (including breastfed human infants) before they are able to digest solid food. Immune factors and immune-modulat ...
products, especially
cultured milk
Fermented milk products or fermented dairy products, also known as cultured dairy foods, cultured dairy products, or cultured milk products, are dairy foods that have been fermented with lactic acid bacteria such as ''Lactobacillus'', ''Lactococc ...
. Their role in blood pressure control is uncertain.
* The
lactotripeptides Lactotripeptides are two naturally occurring milk peptides: Isoleucine-Proline-Proline (IPP) and Valine-Proline-Proline (VPP). These lactotripeptides are derived from casein, which is a milk protein also found in dairy products. Although most normal ...
Val-Pro-Pro and Ile-Pro-Pro produced by the
probiotic
Probiotics are live microorganisms promoted with claims that they provide health benefits when consumed, generally by improving or restoring the gut microbiota. Probiotics are considered generally safe to consume, but may cause bacteria-host i ...
''
Lactobacillus helveticus'' or derived from
casein
Casein ( , from Latin ''caseus'' "cheese") is a family of related phosphoproteins ( αS1, aS2, β, κ) that are commonly found in mammalian milk, comprising about 80% of the proteins in cow's milk and between 20% and 60% of the proteins in hum ...
have been shown to have ACE-inhibiting and antihypertensive functions.
In one study, ''L. helveticus'' PR4 was isolated from Italian cheeses.
Comparative information
All ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The main differences lie with
captopril, the first ACE inhibitor. Captopril has a shorter duration of action and an increased incidence of adverse effects. It is also the only ACE inhibitor capable of passing through the
blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of the central nervous system where ne ...
, although the significance of this characteristic has not been shown to have any positive clinical effects.
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 with a
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...
and to slow the subsequent development of heart failure. This finding was made after it was discovered that regular use of ramipril reduced mortality rates even in test subjects who didn't have hypertension.
Some believe ramipril's additional benefits may be shared by some or all drugs in the ACE-inhibitor class. However, ramipril currently remains the only ACE inhibitor for which such effects are actually evidence-based.
A meta-analysis confirmed that ACE inhibitors are effective and certainly the first-line choice in hypertension treatment. This meta-analysis was based on 20 trials and a cohort of 158,998 patients, of whom 91% were hypertensive. ACE inhibitors were used as the active treatment in seven trials (n=76,615) and angiotensin receptor blocker (ARB) in 13 trials (n=82,383).
ACE inhibitors were associated with a statistically significant 10% mortality reduction: (HR 0.90; 95% CI, 0.84–0.97; P=0.004). In contrast, no significant mortality reduction was observed with ARB treatment (HR 0.99; 95% CI, 0.94–1.04; P=0.683). Analysis of mortality reduction by different ACE inhibitors showed that perindopril-based regimens are associated with a statistically significant 13% all-cause mortality reduction.
Taking into account the broad spectrum of the hypertensive population, one might expect that an effective treatment with ACE inhibitors, in particular with
perindopril, would result in an important gain of lives saved.
Equivalent doses in hypertension
The ACE inhibitors have different strengths with different starting dosages. Dosage should be adjusted according to the clinical response.
Combination with angiotensin II receptor antagonists
ACE inhibitors possess many common characteristics with another class of cardiovascular drugs,
angiotensin II receptor antagonists, which are often used when patients are intolerant of the adverse effects produced by ACE inhibitors. ACE inhibitors do not completely prevent the formation of angiotensin II, as blockage is dose-dependent, so angiotensin II receptor antagonists may be useful because they act to prevent the action of angiotensin II at the AT
1 receptor, leaving AT
2 receptor unblocked; the latter may have consequences needing further study.
The combination therapy of angiotensin II receptor antagonists with ACE inhibitors may be superior to either agent alone. This combination may increase levels of bradykinin while blocking the generation of angiotensin II and its activity at the AT
1 receptor. This 'dual blockade' may be more effective than using an ACE inhibitor alone, because angiotensin II can be generated via non-ACE-dependent pathways. Preliminary studies suggest this combination of pharmacologic agents may be advantageous in the treatment of
essential hypertension, chronic
heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
,
and
nephropathy.
However, the more recent ONTARGET study showed no benefit of combining the agents and more adverse events. While statistically significant results have been obtained for its role in treating hypertension, clinical significance may be lacking.
There are warnings about the combination of ACE inhibitors with ARBs.
Patients with heart failure may benefit from the combination in terms of reducing
morbidity and
ventricular remodeling In cardiology, ventricular remodeling (or cardiac remodeling) refers to changes in the size, shape, structure, and function of the heart. This can happen as a result of exercise (physiological remodeling) or after injury to the heart muscle (pathol ...
.
The most compelling evidence for the treatment of nephropathy has been found: This combination therapy partially reversed the
proteinuria and also exhibited a renoprotective effect in patients with
diabetic nephropathy,
and pediatric
IgA nephropathy.
History
Leonard T. Skeggs
Leonard or ''Leo'' is a common English language, English masculine given name and a surname.
The given name and surname originate from the Old High German ''Leonhard'' containing the prefix ''levon'' ("lion") from the Greek wikiwikiweb:Λέων, � ...
and his colleagues (including
Norman Shumway) discovered ACE in
plasma in 1956.
It was also noted that those who worked in banana plantations in South-western Brazil collapsed after being bitten by a
pit viper, leading to a search for a blood pressure lowering component in its venom.
Brazilian scientist
Sérgio Henrique Ferreira reported a
bradykinin-potentiating factor (BPF) present in the venom of ''
Bothrops jararaca
''Bothrops jararaca'' — known as the ''jararaca'' or ''yarara'' — is a highly venomous pit viper species endemic to South America in southern Brazil, Paraguay, and northern Argentina. The specific name, ''jararaca'', is derived from the Tu ...
'', a South American pit viper, in 1965.
Ferreira then went to
John Vane
Sir John Robert Vane (29 March 1927 – 19 November 2004) was a British pharmacologist who was instrumental in the understanding of how aspirin produces pain-relief and anti-inflammatory effects and his work led to new treatments for heart and b ...
's laboratory as a postdoctoral fellow with his already-isolated BPF. The conversion of the inactive angiotensin I to the potent angiotensin II was thought to take place in the plasma. However, in 1967,
Kevin K. F. Ng and
John R. Vane
Sir John Robert Vane (29 March 1927 – 19 November 2004) was a British pharmacologist who was instrumental in the understanding of how aspirin produces pain-relief and anti-inflammatory effects and his work led to new treatments for heart and b ...
showed plasma ACE is too slow to account for the conversion of angiotensin I to angiotensin II ''in vivo''. Subsequent investigation showed rapid conversion occurs during its passage through the pulmonary circulation.
Bradykinin is rapidly inactivated in the circulating blood, and it disappears completely in a single pass through the pulmonary circulation. Angiotensin I also disappears in the pulmonary circulation because of its conversion to angiotensin II. Furthermore, angiotensin II passes through the lungs without any loss. The inactivation of bradykinin and the conversion of angiotensin I to angiotensin II in the lungs was thought to be caused by the same enzyme.
In 1970, Ng and Vane, using BPF provided by Ferreira, showed the conversion is inhibited during its passage through the pulmonary circulation.
BPFs are members of a family of peptides whose potentiating action is linked to inhibition of bradykinin by ACE. Molecular analysis of BPF yielded a nonapeptide BPF
teprotide
Teprotide is nonapeptide which has been isolated from the snake '' Bothrops jararaca''. It is an angiotensin converting enzyme inhibitor (ACE inhibitor) which inhibits the conversion of angiotensin I to angiotensin II and may potentiate some of t ...
(SQ 20,881), which showed the greatest ACE inhibition potency and hypotensive effect ''in vivo''. Teprotide had limited clinical value as a result of its peptide nature and lack of activity when given orally. In the early 1970s, knowledge of the structure-activity relationship required for inhibition of ACE was growing.
David Cushman,
Miguel Ondetti and colleagues used peptide analogues to study the structure of ACE, using carboxypeptidase A as a model. Their discoveries led to the development of captopril, the first orally-active ACE inhibitor, in 1975.
Captopril was approved by the United States
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
in 1981. The first nonsulfhydryl-containing ACE inhibitor, enalapril, was marketed two years later. At least 12 other ACE inhibitors have since been marketed.
In 1991, Japanese scientists created the first milk-based ACE inhibitor, in the form of a fermented milk drink, using specific cultures to liberate the
tripeptide isoleucine
Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depr ...
-
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...
-proline (IPP) from the dairy protein.
Valine
Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...
-proline-proline (VPP) is also liberated in this process—another milk tripeptide with a very similar chemical structure to IPP. Together, these peptides are now often referred to as
lactotripeptides Lactotripeptides are two naturally occurring milk peptides: Isoleucine-Proline-Proline (IPP) and Valine-Proline-Proline (VPP). These lactotripeptides are derived from casein, which is a milk protein also found in dairy products. Although most normal ...
. In 1996, the first human study confirmed the blood pressure-lowering effect of IPP in fermented milk.
Although twice the amount of VPP is needed to achieve the same ACE-inhibiting activity as the originally discovered IPP, VPP also is assumed to add to the total blood pressure lowering effect.
Since the first lactotripeptides discovery, more than 20 human clinical trials have been conducted in many different countries.
Note
See also
*
Angiotensin II receptor blocker
**
Discovery and development of angiotensin receptor blockers
The angiotensin receptor blockers (ARBs), also called angiotensin (AT1) receptor antagonists or sartans, are a group of antihypertensive drugs that act by blocking the effects of the hormone angiotensin II (Ang II) in the body, thereby lowering bl ...
*
Loop diuretic
Loop diuretics are diuretics that act on the Na-K-Cl cotransporter along the thick ascending limb of the loop of Henle in the kidney. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure o ...
, also used to treat
CHF
*
Renin inhibitor
References
External links
*
ACE Inhibitors: Summary of Recommendations – Consumer Reports Best Buy Drugs – free public education projectFrom snake venom to ACE inhibitor — the discovery and rise of captopril
{{DEFAULTSORT:Ace Inhibitor
ACE inhibitors