Enalapril

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Enalapril
Enalapril structure.svg
Enalapril ball-and-stick model.png
Clinical data
Trade names Vasotec, Renitec, Enacard, others
AHFS/Drugs.com Monograph
MedlinePlus a686022
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class ACE inhibitor
ATC code
Legal status
Legal status
  • US: WARNING [2] Rx-only [3]
  • EU:Rx-only [4]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 60% (by mouth)
Metabolism Liver (to enalaprilat)
Elimination half-life 11 hours (enalaprilat)
Excretion Kidney
Identifiers
  • (2S)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]pyrrolidine-2-carboxylic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.119.661 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H28N2O5
Molar mass 376.453 g·mol−1
3D model (JSmol)
Melting point 143 to 144.5 °C (289.4 to 292.1 °F)
  • O=C(O)[C@H]2N(C(=O)[C@@H](N[C@H](C(=O)OCC)CCc1ccccc1)C)CCC2
  • InChI=1S/C20H28N2O5/c1-3-27-20(26)16(12-11-15-8-5-4-6-9-15)21-14(2)18(23)22-13-7-10-17(22)19(24)25/h4-6,8-9,14,16-17,21H,3,7,10-13H2,1-2H3,(H,24,25)/t14-,16-,17-/m0/s1 Yes check.svgY
  • Key:GBXSMTUPTTWBMN-XIRDDKMYSA-N Yes check.svgY
   (verify)

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. [5] For heart failure, it is generally used with a diuretic, such as furosemide. [6] It is given by mouth or by injection into a vein. [5] Onset of effects are typically within an hour when taken by mouth and last for up to a day. [5]

Contents

Common side effects include headache, tiredness, feeling lightheaded with standing, and cough. [5] Serious side effects include angioedema and low blood pressure. [5] Use during pregnancy is believed to result in harm to the baby. [5] It is in the angiotensin-converting-enzyme (ACE) inhibitor family of medications. [5]

Enalapril was patented in 1978, and came into medical use in 1984. [7] It is on the World Health Organization's List of Essential Medicines. [8] In 2022, it was the 141st most commonly prescribed medication in the United States, with more than 4 million prescriptions. [9] [10] It is available as a generic medicine. [11]

Medical uses

Enalapril three-dimensional structure Enalapril 3D animation.gif
Enalapril three-dimensional structure

Enalapril is used to treat hypertension, symptomatic heart failure, and asymptomatic left ventricular dysfunction. [12] 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). [13] This renal protective effect is not seen in the absence of proteinuria/microalbuminuria, including in diabetic populations. [14] 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) [15] [13] [16] It is widely used in chronic kidney failure. [17] 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. [18]

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. [3] Angioedema and fatality therefrom are reportedly higher among black people. [3] Agranulocytosis has been observed with Enalapril. [19]

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. [3]

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. [3]

Pharmacokinetics

Pharmacokinetic data of enalapril: [3]

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. [21] [22] 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. [23] [24] : 12–13 

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. [24]

Merck introduced enalapril to market in 1981; it became Merck's first billion dollar-selling drug in 1988. [24] The patent expired in 2000, opening the way for generics. [25]

Society and culture

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. [26] The applicant for this medicinal product is Proveca Pharma Limited. [26] Aqumeldi was approved for medical use in the European Union in November 2023. [4]

Related Research Articles

<span class="mw-page-title-main">ACE inhibitor</span> Class of medications used primarily to treat high blood pressure

Angiotensin-converting-enzyme 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 decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.

<span class="mw-page-title-main">Renin</span> Aspartic protease protein and enzyme

Renin, also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin-angiotensin-aldosterone system (RAAS)—also known as the renin-angiotensin-aldosterone axis—that increases the volume of extracellular fluid and causes arterial vasoconstriction. Thus, it increases the body's mean arterial blood pressure.

<span class="mw-page-title-main">Renin–angiotensin system</span> Hormone system

The renin-angiotensin system (RAS), or renin-angiotensin-aldosterone system (RAAS), is a hormone system that regulates blood pressure, fluid, and electrolyte balance, and systemic vascular resistance.

<span class="mw-page-title-main">Bradykinin</span> Chemical compound

Bradykinin (BK) (from 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, and endothelium-derived hyperpolarizing factor and makes veins constrict, via prostaglandin F2, thereby leading to leakage into capillary beds, due to the increased pressure in the capillaries. Bradykinin consists of nine amino acids, and is a physiologically and pharmacologically active peptide of the kinin group of proteins.

<span class="mw-page-title-main">Captopril</span> Antihypertensive drug of the ACE inhibitor class

Captopril, sold under the brand name Capoten among others, is an angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first oral ACE inhibitor found for the treatment of hypertension. It does not cause fatigue as associated with beta-blockers. Due to the adverse drug event of causing hyperkalemia, as seen with most ACE Inhibitors, the medication is usually paired with a diuretic.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (ARBs), and beta blockers.

<span class="mw-page-title-main">Fosinopril</span> Antihypertensive drug of the ACE inhibitor class

Fosinopril is an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of chronic heart failure. Fosinopril is the only phosphonate-containing ACE inhibitor marketed, by Bristol-Myers Squibb under the trade name Monopril. Fosinopril is a cascading pro-drug. The special niche for the medication that differentiates it from the other members of the ACE Inhibitor drug class is that was specifically developed for the use for patients with renal impairment. This was through manipulation of the metabolism and excretion, and is seen that fifty percent of the drug is hepatobiliary cleared, which can compensate for diminished renal clearance. The remaining fifty percent is excreted in urine. It does not need dose adjustment.

<span class="mw-page-title-main">Angiotensin II receptor blocker</span> Group of pharmaceuticals that modulate the renin–angiotensin system

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 antagonists, are a group of pharmaceuticals that bind to and inhibit the angiotensin II receptor type 1 (AT1) and thereby block the arteriolar contraction and sodium retention effects of renin–angiotensin system.

<span class="mw-page-title-main">Enalaprilat</span> Active metabolite of the drug enalapril

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 acid group, but additional modifications were required to achieve a potency similar to captopril.

<span class="mw-page-title-main">Lisinopril</span> Medication used to treat hypertension and heart failure

Lisinopril is a medication belonging to the drug class of angiotensin-converting enzyme (ACE) inhibitors and is used to treat hypertension, heart failure, and heart attacks. For high blood pressure it is usually a first-line treatment. It is also used to prevent kidney problems in people with diabetes mellitus. Lisinopril is taken orally. Full effect may take up to four weeks to occur.

<span class="mw-page-title-main">Ramipril</span> ACE inhibitor medication

Ramipril, sold under the brand name Altace among others, is an ACE inhibitor type medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It can also be used as a preventative medication in patients over 55 years old to reduce the risk of having a heart attack, stroke or cardiovascular death in patients shown to be at high risk, such as some diabetics and patients with vascular disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth.

<span class="mw-page-title-main">Candesartan</span> Angiotensin II receptor antagonist

Candesartan is an angiotensin receptor blocker used mainly for the treatment of high blood pressure and congestive heart failure. Candesartan has a very low maintenance dose. Like olmesartan, the metabolism of the drug is unusual as it is a cascading prodrug. Candesartan has good bioavailibility and is the most potent by weight of the AT-1 receptor antagonists.

<span class="mw-page-title-main">Quinapril</span> ACE inhibitor used in the treatment of hypertension and congestive heart failure

Quinapril, sold under the brand name Accupril by the Pfizer corporation. It a medication used to treat high blood pressure (hypertension), heart failure, and diabetic kidney disease. It is a first line treatment for high blood pressure. It is taken by mouth.

<span class="mw-page-title-main">Benazepril</span> Medication used to treat high blood pressure and heart failure

Benazepril, sold under the brand name Lotensin among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combinations benazepril/hydrochlorothiazide and benazepril/amlodipine.

<span class="mw-page-title-main">Valsartan</span> Angiotensin II receptor antagonist

Valsartan, sold under the brand name Diovan among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It belongs to a class of medications referred to as angiotensin II receptor blockers (ARBs). It is a reasonable initial treatment for high blood pressure. It is taken by mouth.

<span class="mw-page-title-main">Perindopril</span> High blood pressure medication

Perindopril is a medication used to treat high blood pressure, heart failure, or stable coronary artery disease. As a long-acting ACE inhibitor, it works by relaxing blood vessels and decreasing blood volume. As a prodrug, perindopril is hydrolyzed in the liver to its active metabolite, perindoprilat. It was patented in 1980 and approved for medical use in 1988.

<span class="mw-page-title-main">Aliskiren</span> Medication

Aliskiren is the first in a class of drugs called direct renin inhibitors. It is used for essential (primary) hypertension. While used for high blood pressure, other better studied medications are typically recommended due to concerns of higher side effects and less evidence of benefit.

<span class="mw-page-title-main">Renin inhibitor</span> Compound inhibiting the activity of renin

Renin inhibitors are pharmaceutical drugs inhibiting the activity of renin that is responsible for hydrolyzing angiotensinogen to angiotensin I, which in turn reduces the formation of angiotensin II that facilitates blood pressure.

The angiotensin receptor blockers (ARBs), also called angiotensin (AT1) receptor antagonists or sartans, are a group of antihypertensive drugs that act by blocking the effects of the hormone angiotensin II in the body, thereby lowering blood pressure. Their structure is similar to Ang II and they bind to Ang II receptors as inhibitors, e.g., [T24 from Rhys Healthcare].

<span class="mw-page-title-main">Sacubitril/valsartan</span> Combination medication

Sacubitril/valsartan, sold under the brand name Entresto among others, is a fixed-dose combination medication for use in heart failure. It consists of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan. The combination is sometimes described as an "angiotensin receptor-neprilysin inhibitor" (ARNi). In 2016, the American College of Cardiology/American Heart Association Task Force recommended it as a replacement for an ACE inhibitor or an angiotensin receptor blocker in people with heart failure with reduced ejection fraction.

References

  1. 1 2 "Enalapril Use During Pregnancy". Drugs.com. 28 February 2020. Retrieved 13 March 2020.
  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  3. 1 2 3 4 5 6 "Vasotec- enalapril maleate tablet". DailyMed. 12 November 2018. Retrieved 26 April 2020.
  4. 1 2 "Aqumeldi EPAR". European Medicines Agency. 15 November 2023. Retrieved 20 January 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  5. 1 2 3 4 5 6 7 "Enalaprilat/Enalapril Maleate". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  6. ↑ World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 286. hdl: 10665/44053 . ISBN   9789241547659.
  7. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 467. ISBN   9783527607495. Archived from the original on 20 December 2016.
  8. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  9. ↑ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  10. ↑ "Enalapril Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
  11. ↑ "Enalapril maleate: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 24 September 2021.
  12. ↑ "Enalapril". MedlinePlus. U.S. National Library of Medicine. October 2010. Archived from the original on 8 February 2015.
  13. 1 2 Xie X, Liu Y, Perkovic V, Li X, Ninomiya T, Hou W, et al. (May 2016). "Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients With CKD: A Bayesian Network Meta-analysis of Randomized Clinical Trials". American Journal of Kidney Diseases. 67 (5): 728–741. doi: 10.1053/j.ajkd.2015.10.011 . PMID   26597926.{{cite journal}}: CS1 maint: overridden setting (link)
  14. ↑ Bangalore S, Fakheri R, Toklu B, Messerli FH (February 2016). "Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials". BMJ (Clinical Research Ed.). 352: i438. doi:10.1136/bmj.i438. PMC   4772784 . PMID   26868137.
  15. ↑ Mishima E, Haruna Y, Arima H (April 2019). "Renin-angiotensin system inhibitors in hypertensive adults with non-diabetic CKD with or without proteinuria: a systematic review and meta-analysis of randomized trials". Hypertension Research. 42 (4): 469–482. doi:10.1038/s41440-018-0116-3. PMID   30948820. S2CID   96434746.
  16. ↑ McMurray JJ (January 2010). "Clinical practice. Systolic heart failure". The New England Journal of Medicine. 362 (3): 228–238. doi:10.1056/NEJMcp0909392. PMID   20089973. Two large trials showed that when patients with NYHA class II, III, or IV heart failure were treated with enalapril, as compared with placebo, in addition to diuretics and digoxin, the rates of admission to the hospital were reduced, and the relative risk reduction for death was 16 to 40%.
  17. ↑ He YM, Feng L, Huo DM, Yang ZH, Liao YH (September 2013). "Enalapril versus losartan for adults with chronic kidney disease: a systematic review and meta-analysis". Nephrology. 18 (9): 605–614. doi:10.1111/nep.12134. PMID   23869492. S2CID   31791094.
  18. ↑ Greendyke RM, Bernhardt AJ, Tasbas HE, Lewandowski KS (April 1998). "Polydipsia in chronic psychiatric patients: therapeutic trials of clonidine and enalapril". Neuropsychopharmacology. 18 (4): 272–281. doi: 10.1016/S0893-133X(97)00159-0 . PMID   9509495.
  19. ↑ Todd PA, Goa KL (March 1992). "Enalapril. A reappraisal of its pharmacology and therapeutic use in hypertension". Drugs. 43 (3): 346–381. doi:10.2165/00003495-199243030-00005. PMID   1374319. S2CID   262278681.
  20. ↑ 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. ISBN   9780080493381. Pg 30 Archived 10 September 2017 at the Wayback Machine
  21. ↑ "Enalapril 10mg Tablets - Summary of Product Characteristics. Section 5.1 Pharmacodynamic properties". emc (electronic medicines compendium). 21 February 2023.
  22. ↑ Given BD, Taylor T, Hollenberg NK, Williams GH (1984). "Duration of action and short-term hormonal responses to enalapril (MK 421) in normal subjects". Journal of Cardiovascular Pharmacology. 6 (3): 436–441. doi: 10.1097/00005344-198405000-00010 . PMID   6202969.
  23. ↑ Bryan J (April 2009). "From snake venom to ACE inhibitor--The discovery and rise of captopril". Pharmaceutical Journal. 282 (7548): 455.
  24. 1 2 3 Li JJ (April 2013). "Chapter 1: History of Drug Discovery". In Li JJ, Corey EJ (eds.). Drug Discovery: Practices, Processes, and Perspectives. John Wiley & Sons. ISBN   9781118354469.
  25. ↑ Staff, Drug Discovery Online. Patent expiry looms: 18 blockbusters expose $37 billion to generic competition by 2005 Archived 12 May 2016 at the Wayback Machine Page accessed 23 April 2016
  26. 1 2 "Aqumeldi: Pending EC decision". European Medicines Agency. 15 September 2023. Retrieved 21 September 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
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