Enalapril

Better Known as: Vasotec

Marketed By: Merck & Co.
Major Indication: Hypertension & Congestive Heart Failure
Drug Class: ACE Inhibitor
Date of FDA Approval (Patent Expiration): 1985 (2000)
1996 Peak Sales: $2.5 Billion
Importance: One of the best selling Angiotensin-Converting Enzyme Inhibitors of all time. Was developed by Merck as a replacement for Captopril with a better side effect profile.
See Pharmaceutical Drugs for more information about other drugs and diseases.

Mechanism of Action

Angiotensin II has been implicated in cardiac, renal and vascular diseases. ^[1] Bradykinin, a small peptide that counterbalance the effects of Angiotensin II by acting as a strong vasodilator upon binding AT2, is degraded by the same ACE-1 enzyme. Since ACE-1 is the primary producer of Angiotensin II and degrader of Bradykinins, inhibition of ACE-1 has proven an effective treatment for Hypertension and Congestive Heart Failure. Enalapril is quickly metabolized into Enalaprilat, the more active metabolite of Enalapril predominantly by the Hepatic enzyme CYP3A4. Enalaprilat binds to the active site of , preventing ACE-1 from binding and converting Angiotensin I into Angiotensin II. to ACE-1 via electrostatic interactions with His 353, Ala 354 (Backbone oxygen), Glue 384, Lys 511, His 513, Tyr 520 and Tyr 523 along with the zinc cation. ^[2]

Pharmacokinetics

ACE-Inhibitor Pharmacokinetics Comparison at Equivalent Dosages
Parameter	Captopril	Lisinopril	Ramipril	Enalapril	Benazepril	Perindopril	Trandolapril
T_max (hr)	.98	6.5	.67	1.06	.5	.75	.72
C_max (ng/ml)	1210	79	16.4	314	149	105	1.68
Bioavailability (%)	72	25	28	60	97	24	10
Protein Binding (%)	97	0	73	20	97	20	80
T_1/2 (hr)	.56	10.1	1.93	1.6	10	.9	.68
AUC (ng/ml/hr)	1673	1016	21.9	450	140	182	1.86
IC₅₀ (nM)	1.1	5.5	5.0	5.4	1.7	2.4	2.5
Dosage (mg)	10	20	5	20	10	4	2
Metabolism	Hepatic (CYP2D6)	None	Hepatic	Hepatic (CYP3A4)	Hepatic	Hepatic	Hepatic (CYP2D6 & CYP2C9)

For Pharmacokinetic Data References, See: References

References

↑ Ferrario CM. Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research. J Renin Angiotensin Aldosterone Syst. 2006 Mar;7(1):3-14. PMID:17083068
↑ Natesh R, Schwager SL, Evans HR, Sturrock ED, Acharya KR. Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I-converting enzyme. Biochemistry. 2004 Jul 13;43(27):8718-24. PMID:15236580 doi:10.1021/bi049480n

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David Canner, Alexander Berchansky

[1] Ferrario CM. Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research. J Renin Angiotensin Aldosterone Syst. 2006 Mar;7(1):3-14. PMID:17083068

[2] Natesh R, Schwager SL, Evans HR, Sturrock ED, Acharya KR. Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I-converting enzyme. Biochemistry. 2004 Jul 13;43(27):8718-24. PMID:15236580 doi:10.1021/bi049480n

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