Enalapril

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| _other_data=(2S)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]pyrrolidine-2-carboxylic acid

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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.<ref name=AHFS2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> For heart failure, it is generally used with a diuretic, such as furosemide.<ref name=WHO2008>Template:Cite book</ref> It is given by mouth or by injection into a vein.<ref name=AHFS2016/> Onset of effects are typically within an hour when taken by mouth and last for up to a day.<ref name=AHFS2016/>

Common side effects include headache, tiredness, feeling lightheaded with standing, and cough.<ref name=AHFS2016/> Serious side effects include angioedema and low blood pressure.<ref name=AHFS2016/> Use during pregnancy is believed to result in harm to the baby.<ref name=AHFS2016/> It is in the angiotensin-converting-enzyme (ACE) inhibitor family of medications.<ref name=AHFS2016/>

Enalapril was patented in 1978, and came into medical use in 1984.<ref name=Fis2006>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref> In 2022, it was the 141st most commonly prescribed medication in the United States, with more than 4Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is available as a generic medicine.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

File:Enalapril 3D animation.gif

Enalapril three-dimensional structure

Enalapril is used to treat hypertension, symptomatic heart failure, and asymptomatic left ventricular dysfunction.<ref name=MedlinePlus>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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).<ref name="pmid26597926">Template:Cite journal</ref> This renal protective effect is not seen in the absence of proteinuria/microalbuminuria, including in diabetic populations.<ref name="pmid26868137">Template:Cite journal</ref> 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)<ref name="pmid30948820">Template:Cite journal</ref><ref name="pmid26597926"/><ref name="McMurray">Template:Cite journal</ref> It is widely used in chronic kidney failure.<ref name="pmid23869492">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.<ref name="Vasotec FDA label"/> Angioedema and fatality therefrom are reportedly higher among black people.<ref name="Vasotec FDA label"/> Agranulocytosis has been observed with Enalapril.<ref>Template:Cite journal</ref>

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.<ref name="Vasotec FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Mechanism of action

Template:See also 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.<ref name="Vasotec FDA label"/>

Pharmacokinetics

Pharmacokinetic data of enalapril:<ref name="Vasotec FDA label"/>

• Onset of action: about 1 hour
• Peak effect: 4–6 hours
• Duration: 12–24 hours
• Absorption: ~60%
• Metabolism: prodrug, undergoes biotransformation to enalaprilat<ref>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. Template:ISBN. Pg 30 Template:Webarchive</ref>

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> 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, 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.<ref>Template:Cite journal</ref><ref name=HistDD>Template:Cite book</ref>Template:Rp

Enalaprilat was developed first, 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 Merck researchers through the esterification of enalaprilat with ethanol to produce enalapril.<ref name=HistDD/>

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

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.<ref name="Aqumeldi: Pending EC decision" /> The applicant for this medicinal product is Proveca Pharma Limited.<ref name="Aqumeldi: Pending EC decision">{{#invoke:citation/CS1|citation |CitationClass=web }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Aqumeldi was approved for medical use in the European Union in November 2023.<ref name="Aqumeldi EPAR">{{#invoke:citation/CS1|citation |CitationClass=web }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>