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
Pregnancy
category
Routes of
administration
by mouth
ATC code
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 60% (by mouth)
Metabolism liver (to enalaprilat)
Biological half-life 11 hours (enalaprilat)
Excretion kidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.119.661
Chemical and physical data
Formula C20H28N2O5
Molar mass 376.447 g/mol
3D model (Jmol)
Melting point 143 to 144.5 °C (289.4 to 292.1 °F)
  (verify)

Enalapril, sold under the brand name Vasotec among others, is a medication used to treat high blood pressure, diabetic kidney disease, and heart failure.[1] For heart failure it is generally used with a diuretic such as furosemide.[2] It is given by mouth or injection into a vein. Onset of effects are typically within an hour when taken by mouth and last for up to day.[1]

Common side effects include headache, tiredness, lightheadedness 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. Enalapril is in the angiotensin-converting-enzyme inhibitor (ACEi) family of medications.[1]

Enalapril was patented in 1978 and came into medical use in 1984.[3] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[4] The wholesale cost in the developing world is about 0.08 to 0.80 USD per month.[5] In the United States it costs about 25 to 50 USD per month.[6]

Medical uses[edit]

Enalapril 3D structure

Enalapril is used to treat hypertension, symptomatic heart failure, and asymptomatic left ventricular dysfunction.[7] It has been proven to protect the function of the kidneys in hypertension, heart failure, and diabetes, and may be used in the absence of hypertension for its kidney protective effects.[8] It is widely used in chronic kidney failure.[9] Furthermore, enalapril is an emerging treatment for psychogenic polydipsia. A double-blind, placebo-controlled trial showed that when used for this purpose, enalapril lead to decreased water consumption (determined by urine output and osmality) in 60% of patients.[10]

Pregnancy and breastfeeding[edit]

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.[11]

Side effects[edit]

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.[11] Angioedema and fatality therefrom is reportedly higher among black people.[11]

Mechanism of action[edit]

Normally, angiotensin I is converted to angiotensin II by an angiotensin-converting enzyme (ACE). Angiotensin II constricts blood vessels, increasing blood pressure. By inhibiting the ACE, enalaprilat, the active metabolite of enalapril, decreases levels of angiotensin II leading to less vasoconstriction and decreased blood pressure.[11]

Pharmacokinetics and pharmacodynamics[edit]

Pk and Pd are as follows:[11]

  • Onset of action: about 1 hour
  • Peak effect: 4–6 hours
  • Duration: 12–24 hours
  • Absorption: ~60%
  • Metabolism: prodrug, undergoes biotransformation to enalaprilat[12]

History[edit]

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 prodrug.[13][14]:12–13

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 of enalaprilat with ethanol to produce enalapril.[14]:13

Merck introduced enalapril to market in 1981; it became Merck's first billion-dollar selling drug in 1988.[14]:13 The patent expired in 2000, opening the way for generics.[15]

References[edit]

  1. ^ a b c d "Enalaprilat/Enalapril Maleate". The American Society of Health-System Pharmacists. Retrieved 8 December 2016. 
  2. ^ WHO Model Formulary 2008 (PDF). World Health Organization. 2009. p. 286. ISBN 9789241547659. Retrieved 8 December 2016. 
  3. ^ Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 467. ISBN 9783527607495. 
  4. ^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Retrieved 8 December 2016. 
  5. ^ "Enalapril". International Drug Price Indicator Guide. Retrieved 8 December 2016. 
  6. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 120. ISBN 9781284057560. 
  7. ^ U.S. National Library of Medicine. Last Revised October 1, 2010 MedlinePlus: Enalapril
  8. ^ John J.V. McMurray (January 21, 2010). "Clinical Practice: Systolic Heart Failure". N Engl J Med. 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 there was a relative risk reduction for death of 16 to 40%. 
  9. ^ He YM et al. Enalapril versus losartan for adults with chronic kidney disease: a systematic review and meta-analysis. Nephrology (Carlton). 2013 Sep;18(9):605-14. doi: 10.1111/nep.12134. PMID 23869492
  10. ^ Greendyke, R. M.; Bernhardt, A. J.; Tasbas, H. E.; Lewandowski, K. S. (1998-04-01). "Polydipsia in chronic psychiatric patients: therapeutic trials of clonidine and enalapril". Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology. 18 (4): 272–281. doi:10.1016/S0893-133X(97)00159-0. ISSN 0893-133X. PMID 9509495. 
  11. ^ a b c d e FDA Label: Enalapril Maleate Tablet Last updated April 2011
  12. ^ 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
  13. ^ Jenny Bryan for The Pharmaceutical Journal, 17 Apr 2009 From snake venom to ACE inhibitor — the discovery and rise of captopril
  14. ^ a b c Jie Jack Li, History of Drug Discovery. Chapter 1 in Drug Discovery: Practices, Processes, and Perspectives. Eds. Jie Jack Li, E. J. Corey. John Wiley & Sons, Apr 3, 2013 ISBN 9781118354469
  15. ^ Staff, Drug Discovery Online. Patent expiry looms: 18 blockbusters expose $37 billion to generic competition by 2005 Page accessed April 23, 2016

External links[edit]

Package insert at DailyMed: dailymed-nlm-nih.gov