Enalapril, sold under the brand name Vasotec among others, is an ACE inhibitor medication used to treat high blood pressure, diabetic kidney disease, and heart failure.[ Onset of effects are typically within an hour when taken by mouth and last for up to a day.][
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Common side effects include headache, fatigue, feeling lightheaded with standing, and cough.[ Serious side effects include angioedema and low blood pressure.][ Use during pregnancy is believed to result in harm to the baby.][ It is in the ACE inhibitor family of medications.][
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Enalapril was patented in 1978, and came into medical use in 1984.
Medical uses
Enalapril is used to treat hypertension, symptomatic heart failure, and asymptomatic left ventricular dysfunction.
Side effects
The most common side effects of enalapril include increased serum creatinine (20%), dizziness (2–8%), low blood pressure (1–7%), syncope (2%), and dry cough (1–2%). The most serious common adverse event is angioedema (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.
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 (not enough amniotic fluid). Enalapril is secreted in breast milk and is not recommended for use while breastfeeding.
Mechanism of action
Normally, angiotensin I 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
Pharmacokinetics data of enalapril:
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Onset of action: about 1 hour
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Peak effect: 4–6 hours
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Duration: 12–24 hours
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Absorption: ~60%
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Metabolism: prodrug, undergoes biotransformation to enalaprilat
[Menard J and Patchett A. Angiotensin-Converting Enzyme Inhibitors. Pp 14-76 in Drug Discovery and Design. Volume 56 of Advances in Protein Chemistry. Eds Richards FM, Eisenberg DS, and Kim PS. Series Ed. Scolnick EM. Academic Press, 2001. . Pg 30 ]
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. Duration of effect is dose-related; at recommended doses, antihypertensive and haemodynamic effects have been shown to be maintained for at least 24 hours.
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 developed enalapril as a competing product.
Enalaprilat was developed first, partly to overcome these limitations of captopril. The Thiol 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 Merck researchers through the esterification of enalaprilat with ethanol to produce enalapril.[
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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 (CHMP) of the European Medicines Agency 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.[ 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.]
