Enalapril, sold under the brand name Vasotec among others, is an ACE inhibitor medication used to treat high blood pressure,

diabetic kidney disease Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease ...

, and heart failure. 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 i ...

, such as

furosemide Furosemide is a loop diuretic medication used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It may also be used for the treatment of high blood pressure. It can be taken by injection into a vein or by m ...

. 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 nutri ...

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

feeling lightheaded with standing Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when standing up or sitting down. Primary orthostatic hypertension is also often referred to as neurogenic orthostatic hyp ...

, 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 is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...

. Use during

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

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 2020, it was the 329th most commonly prescribed medication in the United States, with more than 800thousand prescriptions. As of August 2021, enalapril 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 ...

in the US.

Structure Activity Relationship

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

Medical uses

Enalapril is used to treat hypertension, symptomatic heart failure, and asymptomatic left ventricular dysfunction.U.S. National Library of Medicine. Last Revised October 1, 201
MedlinePlus: Enalapril
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 kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...

. Furthermore, enalapril is an emerging treatment for psychogenic polydipsia. 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.

Pregnancy and breastfeeding

Enalapril is pregnancy category D. Some evidence suggests it will cause injury and death to a developing fetus. Patients are advised not to become pregnant while taking enalapril and to notify their doctors immediately if they become pregnant. In pregnancy, enalapril may result in damage to the fetus's kidneys and resulting oligohydramnios (not enough amniotic fluid). Enalapril is secreted in breast milk and is not recommended for use while breastfeeding.

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 importa ...

(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.

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 a ...

is converted to angiotensin II by an angiotensin-converting enzyme (ACE). Angiotensin II constricts blood vessels, increasing blood pressure. Enalaprilat, 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 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

History

Squibb developed the first ACE inhibitor, captopril, but it had adverse effects such as a metallic taste (which, as it turned out, was due to the sulfhydryl group). Merck & Co. developed enalapril as a competing prodrut. Enalaprilat was developed partly to overcome these limitations of captopril. The sulfhydryl moiety was replaced by a carboxylate 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 researchers at Merck by the

esterification In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

of enalaprilat with ethanol 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 April 23, 2016

References

External links

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