|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.
A prototype for others
Most importantly, perhaps, the QSAR-based modifications in structure serendipitously led to an improved understanding of the structure of ACE, which aided in the development of subsequent carboxylate-containing ACE inhibitors.
Enalapril, a prodrug, is converted by de-esterification to converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies.
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