Enalapril

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Not to be confused with Allopurinol.
Enalapril
Enalapril-structural.svg
Enalapril VanDerVals transparent.png
Systematic (IUPAC) name
(2S)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]pyrrolidine-2-carboxylic acid
Clinical data
Trade names Vasotec
AHFS/Drugs.com monograph
MedlinePlus a686022
Pregnancy cat.
  • C,D
Legal status
  • Prescription only
Routes I.V. and P.O.
Pharmacokinetic data
Bioavailability 60% (oral)
Metabolism hepatic (to enalaprilat)
Half-life 11 hours (enalaprilat)
Excretion renal
Identifiers
CAS number 75847-73-3 YesY
ATC code C09AA02
PubChem CID 5388962
DrugBank DB00584
ChemSpider 4534998 YesY
UNII 69PN84IO1A YesY
KEGG D07892 YesY
ChEBI CHEBI:4784 YesY
ChEMBL CHEMBL578 YesY
Chemical data
Formula C20H28N2O5 
Mol. mass 376.447 g/mol
Physical data
Melt. point 143–144.5 °C (289–292 °F)
 YesY (what is this?)  (verify)
Enalapril 3D structure

Enalapril (marketed as Vasotec in the USA, Enaladex in some other countries, and Enacard for veterinary use[1]) is an angiotensin-converting-enzyme (ACE) inhibitor used in the treatment of hypertension, diabetic nephropathy, and some types of chronic heart failure. ACE converts the peptide hormone angiotensin I to angiotensin II. One of the actions of angiotensin II is the vasoconstriction of blood vessels resulting in an increase in blood pressure. ACE inhibitors such as enalapril prevent this effect. Enalapril has been shown to lower the death rate in systolic heart failure.[2] Enalapril was the first member of the group known as the dicarboxylate-containing ACE inhibitors.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[3]

Medical uses[edit]

Enalapril is used to treat hypertension, symptomatic heart failure, and treatment of asymptomatic left ventricular dysfunction. Enalapril has been proven to protect the function of the kidneys in hypertension, heart failure, and diabetes. Enalapril may be used by physicians in the absence of hypertension for its kidney protective effects. (Enalapril Maleate Tablet)

Pregnancy and breast feeding[edit]

Enalapril is pregnancy category D. There is evidence to suggest that enalapril will cause injury and death to a developing fetus. Patients are advised not to become pregnant while taking enalapril and to notify their doctor 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. (Enalapril Maleate Tablet)

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. (Enalapril Maleate Tablet)

Development[edit]

Enalapril as a treatment for high blood pressure works by modulating the renin-angiotensin-aldosterone system (RAAS).

Squibb developed the first 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.

Enalaprilat[edit]

Enalaprilat, the first dicarboxylate-containing ACE inhibitor, 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 similar potency to captopril.

Enalaprilat, however, had a problem of its own. The consequence of the structural modifications was it proved to have unfavourable ionisation characteristics to allow sufficient potency for oral administration (in tablets). Thus, it was only suitable for intravenous administration. This was overcome by the researchers at Merck by the esterification of enalaprilat with ethanol to produce enalapril.

As a prodrug, enalapril is metabolised in vivo to the active form enalaprilat by carboxylesterase 1 (CES1).[4] Peak plasma enalaprilat concentrations occur two to four hours after oral administration. Elimination thereafter is biphasic, with an initial phase which reflects renal filtration (elimination half-life two to six hours) and a subsequent prolonged phase (elimination half-life 36 hours), the latter representing equilibration of drug from tissue distribution sites.

The prolonged phase does not contribute to drug accumulation on repeated administration, but is thought to be of pharmacological significance in mediating drug effects. Renal impairment [particularly creatinine clearance < 20 ml/min (< 1.2 l/h)] results in significant accumulation of enalaprilat and necessitates dosage reduction. Accumulation is probably the cause of reduced elimination in healthy elderly individuals and in patients with concomitant diabetes, hypertension and heart failure.

Mechanism of action[edit]

Enalapril belongs to a class of medications called angiotensin converting enzyme inhibitors. Normally angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II constricts blood vessels, increasing blood pressure. By inhibiting ACE, Enalapril decreases levels of angiotensin II leading to less vasoconstriction and decreased blood pressure.(Enalapril Maleate Tablet)

Pharmacokinetics and pharmacodynamics[edit]

Onset of action: ~1 hour Peak effect: 4–6 hours Duration: 12–24 hours Absorption: 55% to 75% Protein binding: ~50% (Davies, 1984) Metabolism: Prodrug, undergoes hepatic biotransformation to enalaprilat Half-life elimination: Enalapril: Adults: Healthy: 2 hours; Congestive heart failure: 3.4–5.8 hours Enalaprilat: Adults: ~35 hours (Till, 1984; Ulm, 1982) Time to peak, serum: Oral: Enalapril: 0.5–1.5 hours; Enalaprilat (active metabolite): 3–4.5 hours Excretion: Urine (61%; 18% of which was enalapril, 43% was enalaprilat); feces (33%; 6% of which was enalapril, 27% was enalaprilat) (Ulm, 1982)

Synthesis[edit]

Enalapril reductive amination.png[5]

References[edit]

  1. ^ Enacard listed at http://www.drugs.com.
  2. ^ John J.V. McMurray (January 21, 2010). "Clinical Practice: Systolic Heart Failure". N Engl J Med 362 (3): 228–238. doi:10.1056/NEJMcp0909392. 
  3. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  4. ^ Thomsen R, Rasmussen HB, Linnet K; INDICES Consortium. (Jan 2014). "In vitro drug metabolism by human carboxylesterase 1: focus on angiotensin-converting enzyme inhibitors". Drug Metab Dispos 42 (1): 126–33. doi:10.1124/dmd.113.053512. PMID 24141856. 
  5. ^ Patchett, A. A.; in Chronicles of Drug Discovery, Vol. 3; Lednicer, D., ed., ACS Books, Washington, DC, 1993, 125.

Davies RO, Gomez HJ, Irvin JD, et al., "An Overview of the Clinical Pharmacology of Enalapril," Br J Clin Pharmacol, 1984, 18(Suppl 2):215-29.

"Enalapril Maleate Tablet." Daily Med. N.p., n.d. Web. 15 Apr. 2014. <http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=08f90170-f53c-4272-92ae-951cf115e271>.

Till AE, Gomez HJ, Hichens M, et al., "Pharmacokinetics of Repeated Single Oral Doses of Enalapril Maleate (MK-421) in Normal Volunteers," Biopharm Drug Dispos, 1984, 5(3):273–80.

Ulm EH, Hichens M, Gomez HJ, et al., "Enalapril Maleate and a Lysine Analogue (MK-521): Disposition in Man," Br J Clin Pharmacol, 1982, 14(3):357–62

External links[edit]

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