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Ramipril

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===Mechanism of Action===
===Mechanism of Action===
Angiotensin II has been implicated in cardiac, renal and vascular diseases. <ref>PMID:17083068</ref> 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.
Angiotensin II has been implicated in cardiac, renal and vascular diseases. <ref>PMID:17083068</ref> 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.
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Ramipril is quickly metabolized into Ramiprilat, the most active inhibitor of Ramipril. Ramiprilat binds to the active site of <scene name='Ramipril/Angio/1'>Angiotensin-Converting Enzyme</scene>, actively inhibiting ACE-1 from binding and converting Angiotensin I into Angiotensin II. ACE-1 <scene name='Ramipril/Ramiprilat_binding/1'> binds Ramiprilat</scene>using residues Glu 395, His 497, Lys 495, Gln 265, Tyr 504, Tyr 496 and Tyr 507, tightly affixing the inhibitor to the active site of ACE-1.
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Ramipril is quickly metabolized into Ramiprilat, the most active inhibitor of Ramipril. Ramiprilat binds to the active site of <scene name='Ramipril/Angio/1'>Angiotensin-Converting Enzyme</scene>, actively inhibiting ACE-1 from binding and converting Angiotensin I into Angiotensin II. ACE-1 <scene name='Ramipril/Ramiprilat_binding/1'> binds Ramiprilat</scene> using residues Glu 395, His 497, Lys 495, Gln 265, Tyr 504, Tyr 496 and Tyr 507, tightly affixing the inhibitor to the active site of ACE-1.
===Pharmacokinetics===
===Pharmacokinetics===

Revision as of 10:25, 29 November 2010

Ramiprilat, the metabolite of Ramipril, also known as Altace

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Better Known as: Altace

  • Marketed By: King Pharmaceuticals (Now part of Pfizer Inc.)
  • Major Indication: Hypertension & Congestive Heart Failure
  • Drug Class: ACE Inhibitor
  • Date of FDA Approval (Patent Expiration): 1991 (2007)
  • 2006 Sales: $650 Million
  • Why You Should Care: One of the best selling Angiotensin-Converting Enzyme Inhibitors of all time.
  • The following is a list of Pharmacokinetic Parameters. See: Pharmaceutical Drugs for more information

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. Ramipril is quickly metabolized into Ramiprilat, the most active inhibitor of Ramipril. Ramiprilat binds to the active site of , actively inhibiting ACE-1 from binding and converting Angiotensin I into Angiotensin II. ACE-1 using residues Glu 395, His 497, Lys 495, Gln 265, Tyr 504, Tyr 496 and Tyr 507, tightly affixing the inhibitor to the active site of ACE-1.

Pharmacokinetics

ACE-Inhibitor Pharmacokinetics Comparison at Equivalent Dosages [2][3][4][5][6]
Parameter Captopril Lisinopril Ramipril Enalapril Benazepril Perindopril Trandolapril
Tmax (hr) .98 6.5 .67 1.06 .5 .75 .72
Cmax (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
T1/2 (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)

References

  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. ↑ Sun JX, Cipriano A, Chan K, John VA. Pharmacokinetic interaction study between benazepril and amlodipine in healthy subjects. Eur J Clin Pharmacol. 1994;47(3):285-9. PMID:7867683
  3. ↑ Arafat T, Awad R, Hamad M, Azzam R, Al-Nasan A, Jehanli A, Matalka K. Pharmacokinetics and pharmacodynamics profiles of enalapril maleate in healthy volunteers following determination of enalapril and enalaprilat by two specific enzyme immunoassays. J Clin Pharm Ther. 2005 Aug;30(4):319-28. PMID:15985045 doi:10.1111/j.1365-2710.2005.00646.x
  4. ↑ Arafat T, Awad R, Hamad M, Azzam R, Al-Nasan A, Jehanli A, Matalka K. Pharmacokinetics and pharmacodynamics profiles of enalapril maleate in healthy volunteers following determination of enalapril and enalaprilat by two specific enzyme immunoassays. J Clin Pharm Ther. 2005 Aug;30(4):319-28. PMID:15985045 doi:10.1111/j.1365-2710.2005.00646.x
  5. ↑ Tamimi JJ, Salem II, Alam SM, Zaman Q, Dham R. Bioequivalence evaluation of two brands of lisinopril tablets (Lisotec and Zestril) in healthy human volunteers. Biopharm Drug Dispos. 2005 Nov;26(8):335-9. PMID:16075412 doi:10.1002/bdd.465
  6. ↑ Arner P, Wade A, Engfeldt P, Mouren M, Stepniewski JP, Sultan E, Bryce T, Lenfant B. Pharmacokinetics and pharmacodynamics of trandolapril after repeated administration of 2 mg to young and elderly patients with mild-to-moderate hypertension. J Cardiovasc Pharmacol. 1994;23 Suppl 4:S44-9. PMID:7527101


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