|Systematic (IUPAC) name|
(Diagrams above are enalapril and enalaprilat, respectively. Data below refers to enalapril unless indicated)
|Legal status||℞ Prescription only|
|Routes||I.V. and P.O.|
|Metabolism||hepatic (to enalaprilat)|
|Half-life||11 hours (enalaprilat)|
|Mol. mass||376.447 g/mol|
|(what is this?)|
Enalapril (marketed as Vasotec in the USA, Enaladex in some other countries, and Enacard for veterinary use) 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. Enalapril was the first member of the group known as the dicarboxylate-containing ACE inhibitors.
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, 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 various esterases. 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.
FDA approved indications for Enalapril include the treatment of hypertension, treatment of 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 renal (kidney) protective effects. (Enalapril Maleate Tablet)
Mechanism of Action
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)
Enalapril is available in 2.5 mg tabs, 5 mg tabs, 10 mg tabs, and 20 mg tabs in the United States. The recommended dose to treat hypertension is 10-40 mg by mouth once daily. For congestive heart failure, the recommend dose is 2.5-20 mg by mouth twice daily. For nephropathy (kidney damage), the recommended dose is 5-20 mg by mouth daily. The dose does not need to be adjusted in patients with severe liver disease. Patients with severe renal disease should be slowly titrated on the medication using the lowest dose which controls blood pressure.(Enalapril Maleate Tablet)
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)
Pregnancy and Lactation
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)
Pharmacokinetics and Pharmacodynamics
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)
- Enacard listed at http://www.drugs.com.
- McMurray JJV, Systolic heart failure, N Engl J Med, 362:228, Jan. 21, 2010).
- 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