Enalapril, sold under the brand name Vasotec among others, is an

ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decr ...

medication used to treat

high blood pressure Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms itself. It is, however, a major ri ...

, diabetic kidney disease, and

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

. For heart failure, it is generally used with a

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics ...

, such as

furosemide Furosemide, sold under the brand name Lasix among others, is a loop diuretic medication used to treat edema due to heart failure, liver scarring, or kidney disease. Furosemide may also be used for the treatment of high blood pressure. It can ...

. It is given by mouth or by

injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

. Onset of effects are typically within an hour when taken by mouth and last for up to a day. Common side effects include

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

tiredness Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated with medical conditions ...

, feeling lightheaded with standing, and cough. Serious side effects include

angioedema Angioedema is an area of swelling (edema) of the lower layer of skin and 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 associated with hives, which are ...

and

low blood pressure Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...

. Use during

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

is believed to result in harm to the baby. It is in the angiotensin-converting-enzyme (ACE) inhibitor family of medications. Enalapril was patented in 1978, and came into medical use in 1984. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. In 2022, it was the 141st most commonly prescribed medication in the United States, with more than 4million prescriptions. It is available as a

generic medicine A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

Medical uses

Enalapril is used to treat hypertension, symptomatic heart failure, and asymptomatic left ventricular dysfunction. ACE-inhibitors (including enalapril) have demonstrated ability to reduce the progression and worsening of existing chronic kidney disease in the presence of proteinuria/microalbuminuria (protein in the urine, a biomarker for chronic kidney disease). This renal protective effect is not seen in the absence of proteinuria/microalbuminuria, including in diabetic populations. The benefit has been particularly demonstrated in patients with hypertension and/or diabetes, and is likely to be seen in other populations (although further studies and subgroup analyses of existing studies are needed) It is widely used in

chronic kidney failure Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...

. Furthermore, enalapril is an emerging treatment for

psychogenic polydipsia Primary polydipsia and psychogenic polydipsia are forms of polydipsia characterised by excessive fluid intake in the absence of physiological stimuli to drink. Psychogenic polydipsia caused by psychiatric disordersoftentimes schizophreniais frequ ...

. A double-blind, placebo-controlled trial showed that when used for this purpose, enalapril led to decreased water consumption (determined by urine output and osmolality) in 60% of patients.

Side effects

The most common side effects of enalapril include increased

serum creatinine Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass). Biological relevance Serum creatinine (a blood measurement) is an impor ...

(20%), dizziness (2–8%), low blood pressure (1–7%), syncope (2%), and dry cough (1–2%). The most serious common adverse event is

(swelling) (0.68%) which often affects the face and lips, endangering the patient's airway. Angioedema can occur at any point during treatment with enalapril, but is most common after the first few doses. Angioedema and fatality therefrom are reportedly higher among black people. Agranulocytosis has been observed with Enalapril. Some evidence suggests enalapril will cause injury and death to a developing fetus. In pregnancy, enalapril may result in damage to the fetus's kidneys and resulting

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. The limiting case is anhydramnios, where there is a complete absence of ...

(not enough amniotic fluid). Enalapril is secreted in breast milk and is not recommended for use while breastfeeding.

Mechanism of action

Normally,

angiotensin I Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adren ...

is converted to

angiotensin II Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the ...

by an

angiotensin-converting enzyme Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasocon ...

(ACE). Angiotensin II constricts blood vessels, increasing blood pressure.

Enalaprilat Enalaprilat is the active metabolite of enalapril. It is the first dicarboxylate-containing ACE inhibitor and was developed partly to overcome these limitations of captopril. The thiol functional group of captopril was replaced with a carboxylic ...

, the active metabolite of enalapril, inhibits ACE. Inhibition of ACE decreases levels of angiotensin II, leading to less vasoconstriction and decreased blood pressure.

Pharmacokinetics

Pharmacokinetic Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific subs ...

data of enalapril: * Onset of action: about 1 hour * Peak effect: 4–6 hours * Duration: 12–24 hours * Absorption: ~60% * Metabolism: prodrug, undergoes biotransformation to

enalaprilat Enalaprilat is the active metabolite of enalapril. It is the first dicarboxylate-containing ACE inhibitor and was developed partly to overcome these limitations of captopril. The thiol functional group of captopril was replaced with a carboxylic ...

Structure activity relationship

Enalapril has an L-proline moiety as a part of the molecule which is responsible for the oral

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of the drug. It is a pro-drug, which means that it exerts its function after being metabolized. The "-OCH2CH3" part of the molecule will split during the metabolism and at the carbon will be a carboxylate, which then interacts with the Zn+2 site of the ACE enzyme. This structural feature and mechanism of metabolism that must occur before the drug can inhibit the enzyme explains why it has a greater duration of action than another similar drug used for the same indication, Captopril. Duration of effect is dose-related; at recommended doses, antihypertensive and haemodynamic effects have been shown to be maintained for at least 24 hours. Enalapril has a slower onset of action than Captopril but a greater duration of action. However, unlike Captopril, Enalapril does not have a thiol moiety.

History

Squibb developed the first ACE inhibitor,

captopril Captopril, sold under the brand name Capoten among others, is an ACE inhibitor, angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first oral ACE inh ...

, but it had adverse effects such as a metallic taste (which, as it turned out, was due to the

sulfhydryl In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...

group). Merck developed enalapril as a competing product.

was developed first, partly to overcome these limitations of captopril. The

moiety was replaced by a

carboxylate In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an anion, an ion with negative charge. Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,... ...

moiety, but additional modifications were required in its structure-based design to achieve a potency similar to captopril. Enalaprilat, however, had a problem of its own in that it had poor oral availability. This was overcome by the Merck researchers through the

esterification In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

of enalaprilat with

ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...

to produce enalapril. Merck introduced enalapril to market in 1981; it became Merck's first billion dollar-selling drug in 1988. The patent expired in 2000, opening the way for generics.Staff, Drug Discovery Online.
Patent expiry looms: 18 blockbusters expose $37 billion to generic competition by 2005
Page accessed 23 April 2016

Society and culture

Legal status

In September 2023, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as the Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regar ...

(CHMP) of the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

adopted a positive opinion, recommending the granting of a pediatric use marketing authorization for the medicinal product Aqumeldi, intended for the treatment of heart failure in children from birth to less than 18 years of age. The applicant for this medicinal product is Proveca Pharma Limited. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Aqumeldi was approved for medical use in the European Union in November 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

References

{{Authority control ACE inhibitors Carboxylate esters Enantiopure drugs Prodrugs Pyrrolidines World Health Organization essential medicines Wikipedia medicine articles ready to translate Ethyl esters Carboxylic acids