ACE Inhibitor
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Transcript of ACE Inhibitor
ACE Inhibitors
PHRM 304
Schematic drawing shows the structure of ACE. There is a catalytic site on each extracellular lobe, each of which binds a zinc (Zn2+) atom.
ACE
• Angiotensin Converting Enzyme (ACE) catalyzes hydrolysis of dipeptide fragment
• Convert of angiotensin I (decapeptide) to angiotensin II (octapeptide)
• ACE inhibitors are competitive inhibitor
Competitive Inhibition
Non-competitive Inhibition
Angiotensins
• Angiotensin IDecapeptide
Aspartic acid – Arginine – Valine – Tyrosine – Isoleucine – Histidine – Proline – Phenyl alanine - Histidine - Leucine
• Angiotensin IIOctapeptide
Aspartic acid – Arginine – Valine – Tyrosine – Isoleucine – Histidine – Proline – Phenyl alanine
ACE
Angiotensinogen
Angiotensin I
Angiotensin II(Vasoconstrictor)
Potent effect
Bradykinin
Inactive Bradykinin
ACE
ProstaglandinRelease
Vasodilatation
+ +
Net result is vasoconstriction
Functions of ACE
Functions of ACE
ACE Side effects
• Dry cough in elderly (10-15% patient)• Common among women• Increase in bradykinin also increase
prostaglandin release which causes dry cough
ACE inhibitors
• 11 approved inhibitors are available• Based on chemical composition classified into
three groups
Captopril
I. Sulfhydryl-containing ACE inhibitors
Captopril was the first ACE inhibitor developed
Not a prodrug
This is the largest group, including:
Enalapril
Ramipril
Quinapril
Perindopril
Lisinopril
II. Dicarboxylate-containing ACE inhibitors
Enalapril
Esters are act as prodrug
Lisinopril (orally active without being prodrug)
Fosinopril, the only member
III. Phosphonate-containing ACE inhibitors
Active Sites in ACE
• To which angiotensin I or drug binds– Zinc ion (Zn+2)– Charged arginine unit (=NH2
+)– Hydrophobic pocket
Arginine
Sulfhydryl Carboxylic acid
Phosphonic acid
General structure of ACE inhibitors
COOH
Alanine
Lysine