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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 medical diagnosis, diagnose, cure, therapy, treat, or preventive medicine, prevent disease. Drug therapy (pharmacotherapy) ...

medication
used primarily for the treatment of
high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term Long-Term Capital Management L.P. (LTCM) was a hedge fund''A financial History of the United States Volume II: 1970–2001'', Jerry W. Markham, Chapter 5: "Bank ...

high blood pressure
and
heart failure Heart failure (HF), also known as congestive heart failure (CHF) and (congestive) cardiac failure (CCF), is a set of manifestations caused by the failure of the heart The heart is a cardiac muscle, muscular Organ (biology), organ in mo ...
. They work by causing relaxation of blood vessels as well as a decrease in
blood volume Blood volume is the volume Volume is a scalar quantity expressing the amount Quantity or amount is a property that can exist as a multitude Multitude is a term for a group of people who cannot be classed under any other distinct category, ex ...
, which leads to lower
blood pressure Blood pressure (BP) is the pressure Pressure (symbol: ''p'' or ''P'') is the force In physics, a force is an influence that can change the motion (physics), motion of an Physical object, object. A force can cause an object with mas ...

blood pressure
and decreased
oxygen Oxygen is the chemical element Image:Simple Periodic Table Chart-blocks.svg, 400px, Periodic table, The periodic table of the chemical elements In chemistry, an element is a pure substance consisting only of atoms that all have the same ...

oxygen
demand from the
heart The heart is a muscular MUSCULAR (DS-200B), located in the United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain,Usage is mixed. The Guardian' and Telegraph' use ...

heart
. ACE inhibitors
inhibit Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor 400px, An enzyme binding site that would normally bind substrate can alternatively bind a competitive inhibitor, preventing substrate access. Dihydrofolate reductase is inhi ...
the activity of
angiotensin-converting enzyme Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system The renin–angiotensin system (RAS), or renin–angiotensin–aldosterone system (RAAS), is a endocrine system, hormone system that regulates blood ...
, 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 Blood pressure (BP) is the pressure Pressure (symbol: ''p'' or ''P'') is the force In phy ...
which converts
angiotensin I Angiotensin is a peptide hormonePeptide hormones or protein hormones are hormones whose molecules are peptides or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocri ...

angiotensin I
to
angiotensin II Angiotensin is a peptide hormonePeptide hormones or protein hormones are hormones whose molecules are peptides or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocri ...

angiotensin II
, and hydrolyses
bradykinin Bradykinin (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 Nitric oxide ( nitrogen oxide or nitrogen monoxide) ...

bradykinin
. 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 vessels ...
, and increase the level of
bradykinin Bradykinin (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 Nitric oxide ( nitrogen oxide or nitrogen monoxide) ...

bradykinin
, a
peptide Peptides (from Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to by speakers simply as Greek (, ), refers collectively to the dialects of the Greek language spoken ...
vasodilator Vasodilation is the widening of blood vessel The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. ...
. This combination is synergistic in lowering blood pressure. Frequently prescribed ACE inhibitors include
benazepril Benazepril, sold under the brand name Lotensin among others, is a medication used to treat high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term Disease, medical condition in which the blood pre ...

benazepril
,
zofenopril Zofenopril ( INN) is a medication A medication (also referred to as medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, therapy, treat, or preventive medicine, prevent disease. Dr ...

zofenopril
,
perindopril Perindopril is a medication A medication (also referred to as medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, therapy, treat, or preventive medicine, prevent disease. Drug th ...

perindopril
,
trandolapril Trandolapril is an ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication A medication (also referred to as medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to medical ...

trandolapril
,
captopril Captopril, sold under the brand name Capoten among others, is an angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a Chronic (medicine), ...

captopril
,
enalapril Enalapril, sold under the brand name Vasotec among others, is an ACE inhibitor medication used to treat high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term Disease, medical condition in whi ...

enalapril
,
lisinopril Lisinopril is a medication of the angiotensin-converting enzyme (ACE) inhibitor class used to treat high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term Disease, medical condition in which t ...

lisinopril
, and
ramipril Ramipril, sold under the brand name Altace among others, is a medication used to treat high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term Disease, medical condition in which the blood press ...

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 Hemodynamics American and British English spelling differences#ae and oe, or haemodynamics are the Fluid dynamics, dynamics of blood flow. The circulatory sy ...

myocardial infarction
(heart attack) *
Heart failure Heart failure (HF), also known as congestive heart failure (CHF) and (congestive) cardiac failure (CCF), is a set of manifestations caused by the failure of the heart The heart is a cardiac muscle, muscular Organ (biology), organ in mo ...
(left ventricular systolic dysfunction) * Kidney complications of
diabetes mellitus Diabetes mellitus, commonly known as just diabetes, is a group of metabolic disorders characterized by a hyperglycemia, high blood sugar level over a prolonged period of time. Symptoms often include frequent urination, Polydipsia, increased th ...
(
diabetic nephropathy Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is one of the leading causes of chronic kidney disease (CKD) and end-stage renal d ...

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 A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form. Terms like "combination drug" or "combination drug product" can be common shorthand for a FDC product ...
, such as
ACE inhibitor and thiazide combination An ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication A medication (also referred to as medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to medical diagnosis, diagn ...
s. ACE inhibitors have also been used in
chronic kidney failure Chronic kidney disease (CKD) is a type of kidney disease The kidneys are two reddish-brown bean-shaped organs found in vertebrate Vertebrates () comprise all species of animal Animals (also called Metazoa) are multicellular eukary ...
and kidney involvement in
systemic sclerosis Systemic scleroderma, or systemic sclerosis, is an autoimmune Autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other body normal constituents. Any disease that results from such an aberrant ...
(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 The scientific method is an Empirical evidence, empirical method of acquiring knowledge that has characterized the development of science s ...
published in the
BMJ ''The BMJ'' is a weekly peer-reviewed Peer review is the evaluation of work by one or more people with similar competencies as the producers of the work ( peers). It functions as a form of self-regulation by qualified members of a profes ...
that described the protective role of ACE inhibitors in reducing the risk of
pneumonia Pneumonia is an inflammatory Inflammatory may refer to: * Inflammation, a biological response to harmful stimuli * The word ''inflammatory'' is also used to refer literally to fire and flammability, and figuratively in relation to comments t ...

pneumonia
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 A mental disorder, also called a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may b ...

schizophrenia
resulting in
psychogenic polydipsia Primary polydipsia, or psychogenic polydipsia, is a form of polydipsia characterised by excessive fluid intake in the absence of physiological stimuli to drink. Psychogenic polydipsia which is caused by psychiatric disorders, often schizophrenia ...
. A double-blind, placebo-controlled trial showed that when used for this purpose,
enalapril Enalapril, sold under the brand name Vasotec among others, is an ACE inhibitor medication used to treat high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term Disease, medical condition in whi ...

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 Polycythemia (also known as polycythaemia or polyglobulia) is a disease state in which the hematocrit (the volume percentage of red blood cells in the blood) and/or hemoglobin concentration are elevated in peripheral blood. It can be due to an inc ...
, a condition characterised by a persistently high
hematocrit The hematocrit () (Ht or HCT), also known by several other names, is the volume percentage (vol%) of red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in ...

hematocrit
greater than 51% which often develops 8-24 months after successful transplantation, as ACEi have been shown to decrease
erythropoietin Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein Glycoproteins are protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of f ...

erythropoietin
production.


Adverse effects

Common side effects include: low blood pressure,
cough A cough is a sudden expulsion of air through the large breathing passages that can help clear them of fluids, irritants, foreign particles and microbes A microorganism, or microbe,, ''mikros'', "small") and ''organism In biology, ...
,
hyperkalemia Hyperkalemia is an elevated level of potassium Potassium is a chemical element upright=1.0, 500px, The chemical elements ordered by link=Periodic table In chemistry Chemistry is the science, scientific study of the propertie ...
,
headache Headache is the symptom of pain Pain is a distressing feeling often caused by intense or damaging stimuli. The defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or ...

headache
,
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo Vertigo is a condition where a person has the sensation of moving or of surrounding objects moving when they are not. Often it feels like a spinnin ...
,
fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, often perceived as an urge to vomiting, vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, upper abdomen, or ...

nausea
, and
kidney The kidneys are two reddish-brown bean-shaped organs An organ is a group of tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A given organ's tissues can be broadly categorized ...

kidney
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 Ch ...
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 effect 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 Renal functions include maintaining an acid–base balance An acid dissociation constant, ''K''a, (also known as acidity constant, or acid-ionization constant) is a quantitative measure of the strength of an acid An acid is a molecu ...
(GFR). However, the decrease may be significant in conditions of ''pre-existing'' decreased renal perfusion, 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 fluid ...
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 Creatinine ( or ; from el, κρέας, kreas, flesh) is a breakdown product of creatine phosphate Phosphocreatine, also known as creatine phosphate (CP) or PCr (Pcr), is a phosphorylated creatine molecule that serves as a rapidly mobilizable ...

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 Nonsteroidal anti-inflammatory drugs (NSAIDs) are members of a drug class A drug is any chemical substance A chemical substance is a form of matter In classical physics and general chemistry, matter is any substance that has mass a ...
and a
diuretic A diuretic () is any substance that promotes diuresis Diuresis () is increased urination Urination is the release of urine from the urinary bladder through the urethra to the outside of the body. It is the urinary system's form of excreti ...
. When the three drugs are taken together, the risk of developing renal failure is significantly increased.
High blood potassium Hyperkalemia is an elevated level of potassium Potassium is a chemical element Image:Simple Periodic Table Chart-blocks.svg, 400px, Periodic table, The periodic table of the chemical elements In chemistry, an element is a pure substanc ...
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 (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 Nitric oxide ( nitrogen oxide or nitrogen monoxide) ...

bradykinin
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 antagonist Losartan, the first ARB, 250px, right Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonist ...
s. Some (0.7%) develop
angioedema Angioedema is an area of swelling (edema) of the dermis, lower layer of skin and subcutaneous tissue, tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is assoc ...

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 A birth defect, also known as a congenital disorder, is a condition present at birth Birth is the act or process of bearing or bringing forth offspring, also referred to in technical contexts as parturition. In mammals, the process is initiate ...
,
stillbirth Stillbirth is typically defined as fetal A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo An embryo is the early stage of development of a multicellular organism ...
s, and
neonatal death Perinatal mortality (PNM) refers to the death of a fetus A fetus American and British English spelling differences#ae and oe, or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring of an animal that develops from an embr ...
s. 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 Systole, systolic blood pressure (the top number) and ...
, renal dysplasia, 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 (AF ...
,
intrauterine growth retardation Intrauterine growth restriction (IUGR) refers to poor growth of a fetus while in the mother's womb during pregnancy. The causes can be many, but most often involve poor maternal nutrition or lack of adequate oxygen supply to the fetus A fetus ...
,
pulmonary hypoplasia Pulmonary hypoplasia is incomplete development of the lung The lungs are the primary organs An organ is a group of tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A give ...
,
patent ductus arteriosus ''Patent ductus arteriosus'' (PDA) is a medical condition in which the ''ductus arteriosus The ductus arteriosus, also called the ductus Botalli, named after the Italian physiologist Leonardo Botallo, is a blood vessel in the developing fetus c ...

patent ductus arteriosus
, 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 a condition present at birth Birth is the act or process of bearing or bringing forth offspring, also referred to in technical contexts as parturition. In mammals, the process is initiat ...
s. ACE inhibitors are ADEC
pregnancy category The pregnancy category of a medication is an assessment of the risk of fetal A fetus American and British English spelling differences#ae and oe, or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from ...
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 In the United States The United States of America (USA), commonly known as the United States (U.S. or US), or America, is a country Contiguous United States, primarily located in North America. It consists of 50 U.S. state, states, a Washin ...
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 a condition present at birth Birth is the act or process of bearing or bringing forth offspring, also referred to in technical contexts as parturition. In mammals, the process is initiate ...
s, particularly affecting the
cardiovascular The circulatory system, also called the cardiovascular system or the vascular system, is an organ system An organ system is a biological system A biological system is a complex biological network, network which connects several biological ...
and
central nervous system The central nervous system (CNS) is the part of the nervous system In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecu ...

central nervous system
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 Angioedema is an area of swelling (edema) of the dermis, lower layer of skin and subcutaneous tissue, tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is assoc ...

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 A ventricle is one of two large chambers toward the bottom of the heart The heart is a muscle, muscular Organ (anatomy), organ in most animals, which pumps ...
or cardiac outflow obstruction *
Hypovolemia Hypovolemia, also known as volume depletion or volume contraction, is a state of abnormally low extracellular fluid in the body. This may be due to either a loss of both salt and water or a decrease in blood volume. Hypovolemia refers to the loss ...
or
dehydration In physiology, dehydration is a lack of total body water In physiology Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology Biology is the natural science that studie ...

dehydration
*
Hemodialysis Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidney The kidneys are two reddish-brown bean-shaped organs An organ is a group of tissues with similar functions. Plan ...

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 A diuretic () is any substance that promotes diuresis, the increased production of urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. U ...
(especially potassium-sparing diuretics), NSAIDs,
anticoagulants Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in hematophagy, blood-eating animals such as leeches and mosquitoes, ...
,
cyclosporine Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken by mouth or by injection into a vein for rheumatoid arthritis Rheumatoid a ...
,
DPP-4 inhibitors 300px, DPP-4 inhibitors and GLP-1 Inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors or gliptins) are a class of oral hypoglycemics that block Block or blocked may refer to: Arts, entertainment and media Broadcasting * Block programming, t ...
, and potassium supplements. Potassium supplementation should be used with caution and under medical supervision owing to the
hyperkalemic Hyperkalemia is an elevated level of potassium (K+) in the Serum (blood), blood. Normal potassium levels are between 3.5 and 5.0Molar concentration, mmol/L (3.5 and 5.0Equivalent (chemistry), mEq/L) with levels above 5.5mmol/L defined as hyperkale ...
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 Systole, systolic blood pressure (the top number) and ...
, low
distal tubule The distal convoluted tubule (DCT) is a portion of kidney The kidneys are two reddish-brown bean-shaped organs An organ is a group of tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ sys ...
sodium Sodium is a chemical element In chemistry, an element is a pure Chemical substance, substance consisting only of atoms that all have the same numbers of protons in their atomic nucleus, nuclei. Unlike chemical compounds, chemical eleme ...
concentration, decreased blood volume and high sympathetic tone trigger the release of the enzyme
renin Renin (#Discovery and naming, 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 system, renin–angiotensin ...

renin
from the cells of
juxtaglomerular apparatus The juxtaglomerular apparatus (also known as the juxtaglomerular complex) is a structure in the kidney The kidneys are two reddish-brown bean-shaped organ (anatomy), organs found in vertebrates. They are located on the left and right in the re ...
in the kidney. Renin activates a circulating liver derived prohormone
angiotensin Angiotensin is a peptide hormonePeptide hormones or protein hormones are hormones whose molecules are peptides or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocr ...
ogen by proteolytic cleavage of all but its first ten
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
residues known as
angiotensin I Angiotensin is a peptide hormonePeptide hormones or protein hormones are hormones whose molecules are peptides or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocri ...

angiotensin I
.
ACE An ace is a playing card A playing card is a piece of specially prepared , heavy paper, thin cardboard, , cotton-paper blend, or thin plastic that is marked with distinguishing motifs. Often the front (face) and back of each card has a to ...
(angiotensin converting enzyme) then removes a further two residues, converting angiotensin I into
angiotensin II Angiotensin is a peptide hormonePeptide hormones or protein hormones are hormones whose molecules are peptides or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocri ...

angiotensin II
. ACE is found in the
pulmonary circulation The mammalian heart is divided between the systemic and the pulmonary circulation, generally agreed upon as left and right sided circuits. The right circuit is the portion of the circulatory system The circulatory system, also called the ca ...
and in the
endothelium Endothelium is a single layer of squamous Epithelium () is one of the four basic types of animal Animals (also called Metazoa) are multicellular eukaryotic organisms that form the Kingdom (biology), biological kingdom Animalia. Wit ...
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 vessels ...
).


Effects

ACE inhibitors block the conversion of angiotensin I (ATI) to angiotensin II (ATII). They thereby lower resistance and increase venous capacity; decrease
cardiac output Cardiac output (CO), also known as heart output denoted by the symbols Q, or \dot Q_ , is a term used in cardiac physiology Cardiac physiology or heart function is the study of healthy, unimpaired function of the heart: involving blood flow; ...
,
cardiac indexCardiac index (CI) is a haemodynamic parameter that relates the cardiac output Cardiac output (CO), also known as heart output denoted by the symbols Q, or \dot Q_ , is a term used in cardiac physiology that describes the volume of blood bein ...
, stroke work, and
volume Volume is a scalar quantity expressing the amount Quantity or amount is a property that can exist as a multitude Multitude is a term for a group of people who cannot be classed under any other distinct category, except for their shared fact ...
; lower resistance in blood vessels in the kidneys; and lead to increased
natriuresisNatriuresis is the process of sodium excretion in the urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being ...
(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 (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide Peptides (from Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to by speakers simply as ...

Bradykinin
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 arteriole The efferent arterioles are blood vessel The blood vessels are the components of the circulatory system The circulatory system, also called the cardiovascular system or the vascular system, is an organ system An organ system is a biolo ...
s of the kidney leads to increased perfusion pressure in the
glomeruli ''Glomerulus'' () is a common term used in anatomy Anatomy (Greek ''anatomē'', 'dissection') is the branch of biology concerned with the study of the structure of organism In biology, an organism (from Ancient Greek, Greek: ὀργαν ...
. * It contributes to ventricular remodeling and
ventricular hypertrophy Ventricular hypertrophy (VH) is thickening of the walls of a ventricle (lower chamber) of the heart The heart is a muscular MUSCULAR (DS-200B), located in the United Kingdom The United Kingdom of Great Britain and Northern Ireland ...
of the heart through stimulation of the proto-oncogenes c-fos, c-jun, c-myc, transforming growth factor beta (TGF-B), through fibrogenesis and apoptosis (programmed cell death). * Stimulation by ATII of the adrenal cortex to release aldosterone, a hormone that acts on kidney tubules, causes sodium and chloride ions retention and potassium excretion. Sodium is a "water-holding" ion, so water is also retained, which leads to increased blood volume, hence an increase in blood pressure. * Stimulation of the posterior pituitary to release vasopressin (antidiuretic hormone, ADH) also acts on the kidneys to increase water retention. If ADH production is excessive in heart failure, Na+ level in the plasma may fall (hyponatremia), and this is a sign of increased risk of death in heart failure patients. * A decrease renal protein kinase C 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. Epidemiology, Epidemiological and clinical studies have shown ACE inhibitors reduce the progress of
diabetic nephropathy Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is one of the leading causes of chronic kidney disease (CKD) and end-stage renal d ...

diabetic nephropathy
independently from their blood pressure-lowering effect. This action of ACE inhibitors is used in the prevention of diabetic renal failure. 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 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 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 Enalapril, sold under the brand name Vasotec among others, is an ACE inhibitor medication used to treat high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term Disease, medical condition in whi ...

enalapril
has also been shown to reduce cardiac cachexia 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

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 * Captopril (trade name Capoten), the first ACE inhibitor. *Zefnopril These agents appear to show antioxidative 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 (Accupril) * Perindopril (Coversyl/Aceon/Perindo) * Lisinopril (Listril/Lopril/Novatec/Prinivil/Zestril, Lisidigal) * Benazepril (Lotensin) * Imidapril (Tanatril) * Trandolapril (Mavik/Odrik/Gopten) * Cilazapril (Inhibace)


Phosphonate-containing agents

* Fosinopril (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

* Casokinins and lactokinins, breakdown products of casein and whey, occur naturally after ingestion of milk products, especially cultured milk. Their role in blood pressure control is uncertain. * The lactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic ''Lactobacillus helveticus'' or derived from casein 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 Captopril, sold under the brand name Capoten among others, is an angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a Chronic (medicine), ...

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, 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 Ramipril, sold under the brand name Altace among others, is a medication used to treat high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term Disease, medical condition in which the blood press ...

ramipril
(Altace), demonstrated an ability to reduce the mortality rates of patients suffering from a
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow Hemodynamics American and British English spelling differences#ae and oe, or haemodynamics are the Fluid dynamics, dynamics of blood flow. The circulatory sy ...

myocardial infarction
, 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 not having suffered from 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 Perindopril is a medication A medication (also referred to as medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, therapy, treat, or preventive medicine, prevent disease. Drug th ...

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.


Angiotensin II receptor antagonists

ACE inhibitors possess many common characteristics with another class of cardiovascular drugs,
angiotensin II receptor antagonist Losartan, the first ARB, 250px, right Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonist ...
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 blockage is dose-dependent, 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, chronic
heart failure Heart failure (HF), also known as congestive heart failure (CHF) and (congestive) cardiac failure (CCF), is a set of manifestations caused by the failure of the heart The heart is a cardiac muscle, muscular Organ (biology), organ in mo ...
, 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. 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 afflicted with
diabetic nephropathy Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is one of the leading causes of chronic kidney disease (CKD) and end-stage renal d ...

diabetic nephropathy
, and pediatric IgA nephropathy.


History

Leonard T. Skeggs and his colleagues (including Norman Shumway) discovered ACE in blood plasma, 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 Teprotide, bradykinin-potentiating factor (BPF) present in the venom of ''Bothrops jararaca'', a South American pit viper, in 1965. Ferreira then went to John Vane'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 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 (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 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-proline-proline (IPP) from the dairy protein. Valine-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. 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 * Loop diuretic, also used to treat congestive heart failure (CHF), CHF * Renin inhibitor


References


External links

*
ACE Inhibitors: Summary of Recommendations – Consumer Reports Best Buy Drugs – free public education project
{{DEFAULTSORT:Ace Inhibitor ACE inhibitors