Download - ACE Inhibitors
Angiotensin converting enzyme inhibitors
presentation by-Diksha Kumari18601911022B.pharm, 3rd year,6th semester
kininogen
kallidin
bradikinin
Inactive fragments
/kinins
kallikrein
Amino-peptidase
(+)
Important structural points-
1. Positive amino group in active site2. Zinc(2+) ion, 2 amino acids away from cationic
center.3. Hydrophobic centers for stabilizing the
incoming substrate4. Protruding hydrogen’s to stabilize the carbonyl
bond of peptide bond next to the labile peptide.
Drug classification(based on groups which interact with zinc ion of ACE-1. Sulfhydryl group
containing drugsEg. Captopril
2. Dicarboxylate group containing drugsEg. Enalapril, lisinopril
3. Phosphonate group containing drugsEg. Fosinopril
Structure activity relationship
•The N ring must contain a carboxylic acid to mimic the C-terminal carboxylate of ACE substrate.•Large hydrophobic heterocyclic rings(i.e., the N-ring) increases potency and after pharmacokinetic factors.•The zinc binding groups can be either sulfhydryl(A), a carboxylic acid(B), or a phosphinic acid(C).•X is usually methyl to mimic the side chain of alanine within the di-carboxylate series, when X= n-butyl amine it produces an orally active drug.•Optimum activity occurs when stereochemistry of inhibitor is consistent with L-amino acids stereochemistry present in normal substrate.
captopril
enalapril
lisinopril
fosinopril
perindopril
ramipril
Chemical nature
Sulfhydryl
Carboxyl Carboxyl Phosphinate
Carboxyl carboxyl
Activity status
Active Prodrug Active Prodrug Prodrug Prodrug
Bio-availability(as active form)
70% 50% 25% 30% 20% 60%
Time to peak action
1hr 4-6hr 6-8hr 3-5hr 6hr 3-6hr
Elimination
2hr 11hr 12hr 12hr 25-30hr 8-48hr
Mode of excretion
Renal Renal Renal Renal/hepatic
Renal Renal
Duration of action
6-12hr 24hr >=24hr 24hr >24hr >24hr
Daily dose(mg)
25-150 2.5-40 5-40 10-40 2-8 1.25-10
1-Treatment of hypertension.2-Treatment of heart failure.3-Secondry prevention after myocardial infarction.4-Diabetic nephropathy in insulin-dependent diabetes mellitus.
Clinical use-
Adverse effects-•Hypotension•Hyperkalamia •Cough•Rashes•Angio-edema•Foetopathic•Headache •Dizziness•Acute renal failure
Drug interactions-• Antacids decrease the bio-availability of ACE inhibitors•With diuretics they cause potential excessive deduction in blood pressure•With NSAIDs they show decreased hypotensive effects•With potassium sparing diuretics they cause hyperkalamia •On administration with iron salts there are reduction in efficacy of the drugs•With allupurinol there is increased risk of hypersensitivity.
Reference-
1) Tripathi K.D,Essentials of medical pharmacology. Sixth edition.480-872)Williams, David A, Lemke, Thomas L. Foyes principles of
medicinal chemistry. 6th edition. 739-52
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