ACE inhibitor
Encyclopedia
ACE inhibitors or angiotensin-converting enzyme
Angiotensin-converting enzyme
Angiotensin I-converting enzyme , an exopeptidase, is a circulating enzyme that participates in the body's renin-angiotensin system , which mediates extracellular volume , and arterial vasoconstriction...

 inhibitors
are a group of drugs used primarily for the treatment of hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

 (high blood pressure) and congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...

. Originally synthesized from compounds found in pit viper venom
Snake venom
Snake venom is highly modified saliva that is produced by special glands of certain species of snakes. The glands which secrete the zootoxin are a modification of the parotid salivary gland of other vertebrates, and are usually situated on each side of the head below and behind the eye,...

, they inhibit
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...

 angiotensin-converting enzyme (ACE), a component of the blood pressure-regulating renin-angiotensin system
Renin-angiotensin system
The renin-angiotensin system or the renin-angiotensin-aldosterone system is a hormone system that regulates blood pressure and water balance....

.

Frequently prescribed ACE inhibitors include captopril
Captopril
Captopril is an angiotensin-converting enzyme inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the...

, enalapril
Enalapril
Enalapril is an angiotensin converting enzyme inhibitor used in the treatment of hypertension and some types of chronic heart failure. ACE raises blood pressure by constricting blood vessels. ACE inhibitors like enalapril prevent this effect. Enalapril has been shown to lower the death rate in...

, lisinopril
Lisinopril
Lisinopril is a drug of the angiotensin-converting enzyme inhibitor class that is primarily used in treatment of hypertension, congestive heart failure, and heart attacks and also in preventing renal and retinal complications of diabetes. Its indications, contraindications and side effects are as...

, and ramipril
Ramipril
Ramipril is an angiotensin-converting enzyme inhibitor, used to treat high blood pressure and congestive heart failure.-Mechanism of action:ACE inhibitors lower the...

.

Medical use

ACE inhibitors are used primarily to treat hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

, although they may also be prescribed for cardiac failure, diabetic nephropathy
Diabetic nephropathy
Diabetic nephropathy , also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse...

, renal disease, systemic sclerosis, left ventricular hypertrophy
Left ventricular hypertrophy
Left ventricular hypertrophy is the thickening of the myocardium of the left ventricle of the heart.-Causes:While ventricular hypertrophy occurs naturally as a reaction to aerobic exercise and strength training, it is most frequently referred to as a pathological reaction to cardiovascular...

 and other disorders.

Mechanism of action

Angiotensin-converting enzyme inhibitors reduce the activity of the renin-angiotensin-aldosterone system.

Renin-angiotensin-aldosterone system

One mechanism for maintaining the blood pressure is the release of a protein called renin
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...

 from cells in the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

 (to be specific, the juxtaglomerular apparatus
Juxtaglomerular apparatus
The juxtaglomerular apparatus is a microscopic structure in the kidney, which regulates the function of each nephron. The juxtaglomerular apparatus is named for its proximity to the glomerulus: it is found between the vascular pole of the renal corpuscle and the returning distal convoluted tubule...

). This produces another protein, angiotensin
Angiotensin
Angiotensin, a peptide hormone, causes blood vessels to constrict, and drives blood pressure up. It is part of the renin-angiotensin system, which is a major target for drugs that lower blood pressure. Angiotensin also stimulates the release of aldosterone, another hormone, from the adrenal cortex...

, which signals the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...

 to produce a hormone called aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...

. This system is activated in response to a fall in blood pressure (hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

), as well as markers of problems with the salt-water balance of the body, such as decreased sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...

 concentration in the distal tubule
Distal convoluted tubule
The distal convoluted tubule is a portion of kidney nephron between the loop of Henle and the collecting duct system.- Physiology :It is partly responsible for the regulation of potassium, sodium, calcium, and pH...

 of the kidney, decreased blood volume and stimulation of the kidney by the sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...

. In such situations, the kidneys release renin
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...

, which acts as an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 and cuts off all but the first 10 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 residues of angiotensinogen (a protein made in the liver, and which circulates in the blood). These 10 residues are then known as angiotensin I. Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme (ACE), which removes a further two residues, and is found in the pulmonary circulation
Pulmonary circulation
Pulmonary circulation is the half portion of the cardiovascular system which carries Oxygen-depleted Blood away from the heart, to the Lungs, and returns oxygenated blood back to the heart. Encyclopedic description and discovery of the pulmonary circulation is widely attributed to Doctor Ibn...

, as well as in the endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...

 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).

Effects

ACE inhibitors block the conversion of angiotensin I to angiotensin II. They, therefore, lower arteriolar
Arteriole
An arteriole is a small diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries.Arterioles have muscular walls and are the primary site of vascular resistance...

 resistance and increase venous capacity; increase cardiac output
Cardiac output
Cardiac output is the volume of blood being pumped by the heart, in particular by a left or right ventricle in the time interval of one minute. CO may be measured in many ways, for example dm3/min...

, cardiac index
Cardiac index
Cardiac index is a vasodynamic parameter that relates the cardiac output to body surface area , thus relating heart performance to the size of the individual...

, stroke work, and volume
Stroke volume
In cardiovascular physiology, stroke volume is the volume of blood pumped from one ventricle of the heart with each beat. SV is calculated using measurements of ventricle volumes from an echocardiogram and subtracting the volume of the blood in the ventricle at the end of a beat from the volume...

; lower renovascular resistance; and lead to increased natriuresis
Natriuresis
Natriuresis is the process of excretion of sodium in the urine via action of the kidneys. Natriuresis is promoted by Brain and Atrial natriuretic peptides, and it is inhibited by chemicals such as aldosterone...

 (excretion of sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...

 in the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...

).
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 enzyme.

Under normal conditions, angiotensin II will have the following effects:
  • Vasoconstriction (narrowing of blood vessels) by AII may lead to increased blood pressure and hypertension
    Hypertension
    Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

    . Further, constriction of the efferent arteriole
    Efferent arteriole
    The efferent arterioles are blood vessels that are part of the urinary tract of organisms. The efferent arterioles form from a convergence of the capillaries of the glomerulus...

    s of the kidney
    Kidney
    The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

     leads to increased perfusion pressure in the glomeruli
    Glomerulus
    A glomerulus is a capillary tuft that is involved in the first step of filtering blood to form urine.A glomerulus is surrounded by Bowman's capsule, the beginning component of nephrons in the vertebrate kidney. A glomerulus receives its blood supply from an afferent arteriole of the renal...

    .
  • It contributes to ventricular remodeling
    Ventricular remodeling
    Ventricular remodeling refers to the changes in size, shape, and function of the heart after injury to the ventricles. The injury is typically due to acute myocardial infarction , but may be from a number of causes that result in increased pressure or volume overload on the heart...

     and ventricular hypertrophy
    Ventricular hypertrophy
    Ventricular hypertrophy is the enlargement of ventricles in the heart. Although left ventricular hypertrophy is more common, enlargement can also occur in the right ventricle, or both ventricles.- Physiology :...

     of the heart.
  • Stimulation by AII of the adrenal cortex to release aldosterone
    Aldosterone
    Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...

    , a hormone that acts on kidney tubules, causes sodium and chloride ions retention and potassium excretion. Sodium is a "water-holding" molecule, 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
    Vasopressin
    Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...

     (also known as antidiuretic hormone (ADH)) also acts on the kidneys to increase water retention.
  • A decrease renal protein kinase C is caused.


With ACE inhibitor use, the production of angiotensin II is decreased, leading to decreased blood pressure.

Epidemiological
Epidemiology
Epidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a population. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive...

 and clinical studies have shown ACE inhibitors reduce the progress of diabetic nephropathy
Diabetic nephropathy
Diabetic nephropathy , also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse...

 independently from their blood pressure-lowering effect. This action of ACE inhibitors is used in the prevention of diabetic renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...

.

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, prophylaxis of cardiovascular events) is justified because it improves clinical outcomes, independent 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 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.

The ACE inhibitor enalapril
Enalapril
Enalapril is an angiotensin converting enzyme inhibitor used in the treatment of hypertension and some types of chronic heart failure. ACE raises blood pressure by constricting blood vessels. ACE inhibitors like enalapril prevent this effect. Enalapril has been shown to lower the death rate in...

 has also been shown to reduce cardiac cachexia
Cachexia
Cachexia or wasting syndrome is loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite in someone who is not actively trying to lose weight...

 in patients with chronic heart failure. Cachexia is a poor prognostic sign in patients with chronic heart failure.
ACE inhibitors are now used to reverse frailty and muscle wasting in elderly patients without heart failure.

Adverse effects

Common adverse drug reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

s include: hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

, cough
Cough
A cough is a sudden and often repetitively occurring reflex which helps to clear the large breathing passages from secretions, irritants, foreign particles and microbes...

, hyperkalemia
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...

, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...

, dizziness
Vertigo (medical)
Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear...

, fatigue
Fatigue (physical)
Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...

, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

, and renal impairment. Some evidence also suggests ACE inhibitors might increase inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

-related pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

.

A persistent dry cough is a relatively common adverse effect believed to be associated with the increases in bradykinin
Bradykinin
Bradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...

 levels produced by ACE inhibitors, although the role of bradykinin in producing these symptoms remains disputed by some authors. Patients who experience this cough are often switched to angiotensin II receptor antagonist
Angiotensin II receptor antagonist
Angiotensin II receptor antagonists, also known as angiotensin receptor blockers , AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system...

s.

Rash and taste disturbances, infrequent with most ACE inhibitors, are more prevalent in captopril
Captopril
Captopril is an angiotensin-converting enzyme inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the...

 and is attributed to its sulfhydryl moiety. This has led to decreased use of captopril in clinical setting, although it is still used in scintigraphy
Scintigraphy
Scintigraphy is a form of diagnostic test used in nuclear medicine, wherein radioisotopes are taken internally, and the emitted radiation is captured by external detectors to form two-dimensional images...

 of the kidney.

Renal impairment is a significant adverse effect of all ACE inhibitors, but the reason is still unknown. Some suggest it is associated with their effect on angiotensin II-mediated homeostatic
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...

 functions, such as renal blood flow. Renal blood flow may be affected by angiotensin II because it vasoconstricts the efferent arteriole
Efferent arteriole
The efferent arterioles are blood vessels that are part of the urinary tract of organisms. The efferent arterioles form from a convergence of the capillaries of the glomerulus...

s of the glomeruli
Glomerulus
A glomerulus is a capillary tuft that is involved in the first step of filtering blood to form urine.A glomerulus is surrounded by Bowman's capsule, the beginning component of nephrons in the vertebrate kidney. A glomerulus receives its blood supply from an afferent arteriole of the renal...

 of the kidney, thereby increasing glomerular filtration rate (GFR). Hence, by reducing angiotensin II levels, ACE inhibitors may reduce GFR, a marker of renal function
Renal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...

. To be specific, they can induce or exacerbate renal impairment in patients with renal artery stenosis
Renal artery stenosis
Renal artery stenosis is the narrowing of the renal artery, most often caused by atherosclerosis or fibromuscular dysplasia. This narrowing of the renal artery can impede blood flow to the target kidney...

. This is especially a problem if the patient is concomitantly taking an NSAID
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...

 and a diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...

. When the three drugs are taken together, there is a very high risk of developing renal failure.

ACE inhibitors may cause hyperkalemia
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...

. 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.

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
Angioedema
Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...

 due to increased bradykinin levels. There appears to be a genetic predisposition toward this adverse effect in patients who degrade bradykinin more slowly than average.

In pregnant women
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...

, ACE inhibitors taken during the first trimester have been reported to cause major congenital malformations, stillbirth
Stillbirth
A stillbirth occurs when a fetus has died in the uterus. The Australian definition specifies that fetal death is termed a stillbirth after 20 weeks gestation or the fetus weighs more than . Once the fetus has died the mother still has contractions and remains undelivered. The term is often used in...

s, and neonatal deaths. Commonly reported fetal abnormalities include hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

, renal dysplasia, anuria/oliguria, oligohydramnios
Oligohydramnios
Oligohydramnios is a condition in pregnancy characterized by a deficiency of amniotic fluid. It is the opposite of polyhydramnios.-Diagnosis:Diagnosis is made by ultrasound measurement of the amniotic fluid index...

, intrauterine growth retardation, pulmonary hypoplasia
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 interfere with normal development of the lungs...

, patent ductus arteriosus
Patent ductus arteriosus
Patent ductus arteriosus is a congenital disorder in the heart wherein a neonate's ductus arteriosus fails to close after birth. Early symptoms are uncommon, but in the first year of life include increased work of breathing and poor weight gain...

, and incomplete ossification of the skull.

Contraindications and precautions

The ACE inhibitors are contraindicated in patients with:
  • Previous angioedema
    Angioedema
    Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...

     associated with ACE inhibitor therapy
  • Renal artery stenosis
    Renal artery stenosis
    Renal artery stenosis is the narrowing of the renal artery, most often caused by atherosclerosis or fibromuscular dysplasia. This narrowing of the renal artery can impede blood flow to the target kidney...

     (bilateral, or unilateral with a solitary functioning kidney)
  • Hypersensitivity to ACE inhibitors


ACE inhibitors should be used with caution in patients with:
  • Impaired renal function
  • Aortic valve stenosis
    Aortic valve stenosis
    Aortic valve stenosis is a disease of the heart valves in which the opening of the aortic valve is narrowed. The aortic valve is the valve between the left ventricle of the heart and the aorta, which is the largest artery in the body and carries the entire output of blood.-Pathophysiology:The...

     or cardiac outflow obstruction
  • Hypovolemia
    Hypovolemia
    In physiology and medicine, hypovolemia is a state of decreased blood volume; more specifically, decrease in volume of blood plasma...

     or dehydration
    Dehydration
    In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...

  • Hemodialysis
    Hemodialysis
    In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...

     with high-flux polyacrylonitrile membranes


ACE inhibitors are ADEC
Australian Drug Evaluation Committee
The Australian Drug Evaluation Committee or ADEC, was a committee that provided independent scientific advice to the Australian Government regarding therapeutic drugs. The committee was originally formed in 1963 and more recently authorised under the Therapeutic Goods Act 1989 as part of the...

 pregnancy category
Pregnancy category
The pregnancy category of a pharmaceutical agent 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 metabolites that are present in breast...

 D, and should be avoided in women who are likely to become pregnant. In the U.S., ACE inhibitors are required to be labeled with a "black box
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...

" 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 malformations, particularly affecting the cardiovascular
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...

 and central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

s.

Potassium supplementation should be used with caution and under medical supervision owing to the hyperkalemic
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...

 effect of ACE inhibitors.

Sulfhydryl-containing agents

  • Captopril
    Captopril
    Captopril is an angiotensin-converting enzyme inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the...

     (trade name Capoten), the first ACE inhibitor
  • Zofenopril
    Zofenopril
    Zofenopril is an angiotensin converting enzyme inhibitor with cardioprotective properties indicated for the treatment of hypertension....


Dicarboxylate-containing agents

This is the largest group, including:
  • Enalapril
    Enalapril
    Enalapril is an angiotensin converting enzyme inhibitor used in the treatment of hypertension and some types of chronic heart failure. ACE raises blood pressure by constricting blood vessels. ACE inhibitors like enalapril prevent this effect. Enalapril has been shown to lower the death rate in...

     (Vasotec/Renitec)
  • Ramipril
    Ramipril
    Ramipril is an angiotensin-converting enzyme inhibitor, used to treat high blood pressure and congestive heart failure.-Mechanism of action:ACE inhibitors lower the...

     (Altace/Prilace/Ramace/Ramiwin/Triatec/Tritace)
  • Quinapril
    Quinapril
    Quinapril is an angiotensin-converting enzyme inhibitor used in the treatment of hypertension and congestive heart failure.-Pharmacology:Quinapril is a prodrug...

     (Accupril)
  • Perindopril
    Perindopril
    Perindopril, or perindopril arginine, is a long-acting ACE inhibitor. Perindopril is used to treat high blood pressure, heart failure or stable coronary artery disease. It is also available in a generic form, perindopril erbumine...

     (Coversyl/Aceon)
  • Lisinopril
    Lisinopril
    Lisinopril is a drug of the angiotensin-converting enzyme inhibitor class that is primarily used in treatment of hypertension, congestive heart failure, and heart attacks and also in preventing renal and retinal complications of diabetes. Its indications, contraindications and side effects are as...

     (Listril/Lopril/Novatec/Prinivil/Zestril)
  • Benazepril
    Benazepril
    Benazepril, brand name Lotensin, is a medication used to treat high blood pressure , congestive heart failure, and chronic renal failure...

     (Lotensin)
  • Imidapril
    Imidapril
    Imidapril is an ACE inhibitor....

      (Tanatril)
  • Zofenopril
    Zofenopril
    Zofenopril is an angiotensin converting enzyme inhibitor with cardioprotective properties indicated for the treatment of hypertension....

     (Zofecard)
  • Trandolapril
    Trandolapril
    Trandolapril is an ACE inhibitor used to treat high blood pressure, it may also be used to treat other conditions.It is marketed by Abbott Laboratories with the brand name Mavik.- Pharmacology :...

     (Mavik/Odrik/Gopten)

Phosphonate-containing agents

  • Fosinopril
    Fosinopril
    Fosinopril is an angiotensin converting enzyme inhibitor used for the treatment of hypertension and some types of chronic heart failure. Fosinopril is the only phosphinate-containing ACE inhibitor marketed...

     (Fositen/Monopril) is the only member of this group

Naturally occurring

  • Casokinin
    Kinin
    A kinin is any of various structurally related polypeptides, such as bradykinin and kallikrein. They are members of the autacoid family.They act locally to induce vasodilation and contraction of smooth muscle.It is a component of the kinin-kallikrein system....

    s and lactokinins, breakdown products of casein
    Casein
    Casein is the name for a family of related phosphoprotein proteins . These proteins are commonly found in mammalian milk, making up 80% of the proteins in cow milk and between 60% and 65% of the proteins in human milk....

     and whey
    Whey
    Whey or Milk Serum is the liquid remaining after milk has been curdled and strained. It is a by-product of the manufacture of cheese or casein and has several commercial uses. Sweet whey is manufactured during the making of rennet types of hard cheese like cheddar or Swiss cheese...

    , occur naturally after ingestion of milk
    Milk
    Milk is a white liquid produced by the mammary glands of mammals. It is the primary source of nutrition for young mammals before they are able to digest other types of food. Early-lactation milk contains colostrum, which carries the mother's antibodies to the baby and can reduce the risk of many...

     products, especially cultured milk. Their role in blood pressure control is uncertain.
  • The lactotripeptides
    Lactotripeptides
    Lactotripeptides are two naturally occurring milk peptides: Isoleucine-Proline-Proline and Valine-Proline-Proline . These lactotripeptides are derived from casein, which is a milk protein also found in dairy products. Although most normal dairy products contain lactotripeptides, they are inactive...

     Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic
    Probiotic
    Probiotics are live microorganisms thought to be beneficial to the host organism. According to the currently adopted definition by FAO/WHO, probiotics are: "Live microorganisms which when administered in adequate amounts confer a health benefit on the host"...

     Lactobacillus helveticus
    Lactobacillus helveticus
    Lactobacillus helveticus is a lactic-acid producing rod shaped bacterium of the genus Lactobacillus. It is most commonly used in the production of American Swiss cheese and Emmental cheese but is also sometimes used in making other styles of cheese, such as Cheddar, Parmesan, romano, provolone,...

    or derived from casein
    Casein
    Casein is the name for a family of related phosphoprotein proteins . These proteins are commonly found in mammalian milk, making up 80% of the proteins in cow milk and between 60% and 65% of the proteins in human milk....

     have been shown to have ACE-inhibiting and antihypertensive functions.

Comparative information

All ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The main point-of-difference lies with captopril
Captopril
Captopril is an angiotensin-converting enzyme inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the...

, the first ACE inhibitor, which has a shorter duration of action and increased incidence of certain adverse effects.

Certain agents in the ACE inhibitor class have been proven, in large clinical studies, to reduce mortality in patients after myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

, and prevent development of heart failure. The ACE inhibitor most prominently recognized for these qualities is ramipril
Ramipril
Ramipril is an angiotensin-converting enzyme inhibitor, used to treat high blood pressure and congestive heart failure.-Mechanism of action:ACE inhibitors lower the...

 (Altace). Because ramipril has been shown to reduce mortality rates even among patient groups not suffering from hypertension, some (mostly drug-company representatives) believe ramipril's benefits may extend beyond those of the general abilities it holds in common with other members of the ACE inhibitor class.

ACEI equivalents

The ACE inhibitors have different strengths with different starting dosages. Dosage should be adjusted according to the clinical response.
ACE inhibitors dosages for hypertension
| Dosage
Note: bid = 2 times a day, tid = 3 times a day, d = daily
Drug dosages from Drug Lookup, Epocrates Online.
Name Equivalent daily dose | Start Usual Maximum
Benazepril 10 mg | 10 mg 20–40 mg 80 mg
Captopril 50 mg (25 mg bid) | 12.5–25 mg bid-tid 25–50 mg bid-tid 450 mg/d
Enalapril 5 mg | 5 mg 10–40 mg 40 mg
Fosinopril 10 mg | 10 mg 20–40 mg 80 mg
Lisinopril 10 mg | 10 mg 10–40 mg 80 mg
Moexipril 7.5 mg | 7.5 mg 7.5–30 mg 30 mg
Perindopril 4 mg | 4 mg 4–8 mg 16 mg
Quinapril 10 mg | 10 mg 20–80 mg 80 mg
Ramipril 2.5 mg | 2.5 mg 2.5–20 mg 20 mg
Trandolapril 2 mg | 1 mg 2–4 mg 8 mg
5 mg | 5 mg 10 mg 20 mg Name Equivalent daily dose | Start Usual Maximum
Note: bid = 2 times a day, tid = 3 times a day, d = daily
Drug dosages from Drug Lookup, Epocrates Online.
ACE inhibitors dosages for hypertension

Angiotensin II receptor antagonists

ACE inhibitors possess many common characteristics with another class of cardiovascular drugs, angiotensin II receptor antagonist
Angiotensin II receptor antagonist
Angiotensin II receptor antagonists, also known as angiotensin receptor blockers , AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system...

s, 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 there are other conversion pathways, so angiotensin II receptor antagonists may be useful because they act to prevent the action of angiotensin II at the AT1 receptor, leaving AT2 receptor unblocked; the latter may have consequences needing further study.

Use in combination

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 AT1 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
Essential hypertension
Essential hypertension is the form of hypertension that by definition, has no identifiable cause. It is the most common type of hypertension, affecting 95% of hypertensive patients, it tends to be familial and is likely to be the consequence of an interaction between environmental and genetic...

, chronic heart failure, and nephropathy
Nephropathy
Nephropathy refers to damage to or disease of the kidney. An older term for this is nephrosis.-Causes:Causes of nephropathy include administration of analgesics, xanthine oxidase deficiency, and long-term exposure to lead or its salts...

. However, more studies are needed to confirm these highly preliminary results. While statistically significant results have been obtained for its role in treating hypertension, clinical significance may be lacking.

Patients with heart failure may benefit from the combination in terms of reducing morbidity and ventricular remodeling
Ventricular remodeling
Ventricular remodeling refers to the changes in size, shape, and function of the heart after injury to the ventricles. The injury is typically due to acute myocardial infarction , but may be from a number of causes that result in increased pressure or volume overload on the heart...

.

The most compelling evidence for the treatment of nephropathy has been found: This combination therapy partially reversed the proteinuria
Proteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...

 and also exhibited a renoprotective effect in patients afflicted with diabetic nephropathy
Diabetic nephropathy
Diabetic nephropathy , also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse...

, and pediatric IgA nephropathy
IgA nephropathy
IgA nephropathy is a form of glomerulonephritis...

.

History

The first step in the development of ACE inhibitors was the discovery of ACE in plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

  by Leonard T. Skeggs and his colleagues in 1956. Brazilian scientist Sergio Ferreira reported a bradykinin-potentiating factor (BPF) present in the venom of Bothrops jararaca
Bothrops jararaca
Bothrops jararaca is a venomous pit viper species found in southern Brazil, Paraguay and northern Argentina. The species name is derived from the Tupi words yarará and ca, which means "large snake." Within its range it is often abundant and is an important cause of snakebite...

, a South American pit viper, in 1965. Ferreira then went to John Vane's laboratory as a postdoctoral 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 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
Bradykinin
Bradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...

 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 due to 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 Sérgio Henrique Ferreira
Sérgio Henrique Ferreira
Sérgio Henrique Ferreira , Brazil, Brazilian physician and pharmacologist, noted for his discovery of Bradykinin potentiating factor, which led to better anti-hypertension drugs.Ferreira received his M.D...

, 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
Teprotide is nonapeptide which has been isolated from the snake Bothrops jararaca. It is an angiotensin converting enzyme inhibitor , which inhibits the conversion of angiotensin I to angiotensin II and may potentiate some of the pharmacological actions of bradykinin...

 (SQ 20,881), which showed the greatest ACE inhibition potency and hypotensive effect in vivo. Teprotide had limited clinical value due to 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
David Cushman
David Cushman was an American chemist famous for his role in the invention of captopril, the first of the ACE inhibitors used in the treatment of cardiovascular disease. With Miguel A...

, Miguel Ondetti
Miguel Ondetti
Miguel Angel Ondetti was an Argentinean-born American chemist that first synthesized captopril, the first ACE inhibitor that was used to treat heart disease...

 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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 in 1981. The first nonsulfhydryl-containing ACE inhibitor, enalapril, was marketed two years later. At least twelve 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
Tripeptide
A tripeptide is a peptide consisting of three amino acids joined by peptide bonds.Examples of tripeptides are:*Eisenin is a peptide with immunological activity that is isolated from the Japanese marine alga, Eisenia bicyclis, which more commonly is known as, Arame*GHK-Cu is a human copper binding...

 isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....

-proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...

-proline (IPP) from the dairy protein. Valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...

-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
Lactotripeptides are two naturally occurring milk peptides: Isoleucine-Proline-Proline and Valine-Proline-Proline . These lactotripeptides are derived from casein, which is a milk protein also found in dairy products. Although most normal dairy products contain lactotripeptides, they are inactive...

. 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.

See also

  • Angiotensin II receptor antagonist
    Angiotensin II receptor antagonist
    Angiotensin II receptor antagonists, also known as angiotensin receptor blockers , AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system...

  • Discovery and development of angiotensin receptor blockers
    Discovery and development of angiotensin receptor blockers
    The angiotensin receptor blockers , also called angiotensin receptor antagonists or sartans, are a group of anti-hypertensive drugs that act by blocking the effects of the hormone angiotensin II in the body, thereby lowering blood pressure...

  • Discovery and development of renin inhibitors
    Discovery and development of renin inhibitors
    Renin inhibitors are antihypertensive drugs that inhibit the first and rate-limiting step of the renin-angiotensin-aldosterone system . Since the 1970s scientists have been trying to develop potent inhibitors with acceptable oral bioavailability. The process was difficult and took about three decades...

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