Enalapril
Encyclopedia
Enalapril is an angiotensin converting enzyme (ACE) inhibitor
used in the treatment of hypertension
and some types of chronic heart failure. ACE raises blood pressure by constricting blood vessels. ACE inhibitors like 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 of ACE inhibitors known as the dicarboxylate-containing ACE inhibitors.
(RAS) system.
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 product.
, 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 that it proved to have unfavourable ionisation characteristics to allow sufficient potency for oral administration (in tablets). Thus enalaprilat 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 esterase
s. Peak plasma enalaprilat concentrations occur 2 to 4 hours after oral enalapril administration. Elimination thereafter is biphasic, with an initial phase which reflects renal filtration (elimination half-life 2 to 6 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.
Enalapril is a prodrug that is converted by deesterification to converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies.
ACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
used in the treatment of hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
and some types of chronic heart failure. ACE raises blood pressure by constricting blood vessels. ACE inhibitors like 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 of ACE inhibitors known as the dicarboxylate-containing ACE inhibitors.
Development
Enalapril is a treatment for high blood pressure that works by modulating the renin-angiotensin-aldosteroneRenin-angiotensin system
The renin-angiotensin system or the renin-angiotensin-aldosterone system is a hormone system that regulates blood pressure and water balance....
(RAS) system.
Squibb developed the first inhibitor, captopril
Captopril
Captopril is an angiotensin-converting enzyme inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the...
, but it had adverse effects such as a metallic taste (which, as it turned out, was due to the sulfhydryl group). Merck & Co.
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
developed enalapril as a competing product.
Enalaprilat
EnalaprilatEnalaprilat
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 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
Enalaprilat
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...
, however, had a problem of its own. The consequence of the structural modifications was that it proved to have unfavourable ionisation characteristics to allow sufficient potency for oral administration (in tablets). Thus enalaprilat 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
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
, enalapril is metabolised in vivo to the active form enalaprilat by various esterase
Esterase
An esterase is a hydrolase enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis.A wide range of different esterases exist that differ in their substrate specificity, their protein structure, and their biological function.- EC classification/list...
s. Peak plasma enalaprilat concentrations occur 2 to 4 hours after oral enalapril administration. Elimination thereafter is biphasic, with an initial phase which reflects renal filtration (elimination half-life 2 to 6 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 is a prodrug that is converted by deesterification to converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies.