h_aceis

Timeline:

  • Human ACE is a large protein with 1278 AA residues that cleaves dipeptide units from substrates with diverse AA sequences, but preferred substrates have only one free carboxyl group in the carboxyl-terminal AA, & proline must not be the penultimate AA:
    • eg. angiotensin I but not II;
    • bradykinin & other potent vasodilator peptides;
  • In 1967, pit viper venoms were found to have substances that intensify responses to bradykinin (bradykinin potentiating factors - BPF's) which proved to be a family of 5-13 AA peptides that inhibited kininase II which was shown to be ACE.
  • An orally active ACE inhibitor (captopril) [Capoten] was discovered (1977) based on analysis of these BFP's leading to search for carboxy alkanoyl & mercapto alkanoyl derivatives, approved for use in severe HT in Aust. in 1982.
    • bioavailability varies with food → take 1hr prior to meals;
    • peak [] within 1hr; duration of action 6hrs;
    • cleared rapidly mainly by kidneys (40% intact) T1/2 = 2hrs;
    • bd or tds dose needed commencing with 6.25mg tds if CCF;
  • Enalapril [Renitec] was the 2nd to be released in Australia as ACE inhib.
    • A prodrug which is rapidly absorbed with bioavailability minimally affected by food, & hydrolysed by a serum esterase to active enalaprilate such that slower onset & a peak decr. BP at 4-6hrs post-ingestion & compared with captopril:
      • considerably more potent;
      • longer duration of action of 12hrs although 70% effect @ 24hrs;
      • enalaprilate binds more strongly to ACE → longer persistence;
      • decr. incidence rashes, taste disturbance but still rare neutropenia/proteinuria;
      • THUS: once-daily dose possible in HT but bd if CCF;
  • Lisinopril (Aust. 1992)[Zestril/Prinivil] is a lysine analogue of enalaprilate has a long duration of action (peak 6-8hrs & still @ 24hrs) after slow & incomplete absorbtion from GIT & cleared by kidney with T1/2 = 12hrs;
    • However, it also has other actions:
      • short-term Rx (10-12wks) → decr. C.O.
      • decr. venous return;
      • redistribution i/vasc. volume from pulm.bed → periphery;
      • ? -ve inotropic effect;
  • Perindopril (Aust.1992)[Coversyl] prodrug conv. by hep. esterases → perindoprilat;
    • more potent & longer lasting than enalapril as almost 100% effect @24hrs;
    • ? greater tissue penetration → incr. renal ACE inhib.?;
    • although rapidly cleared from plasma, pharmac. T1/2 = 24hrs as bound to ACE;
    • elimination mainly renal;
    • ? incr. arterial compliance with long term Rx by decr. vasc.sm.muscle & collagen;
  • Ramipril (Aust.1992)[Tritace/Ramace] prodrug conv. by hep.esterases → ramiprilat;
    • ? similar profile & P/K to perindopril;
h_aceis.txt · Last modified: 2008/09/15 11:03 (external edit)