ACE inhibitors

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Angiotensin converting enzyme inhibitors:

Angiotensin converting enzyme inhibitors presentation by- Diksha Kumari 18601911022 B.pharm , 3 rd year,6 th semester

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kininogen kallidin bradikinin Inactive fragments / kinins kallikrein Amino-peptidase (+)

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Important structural points- Positive amino group in active site Zinc(2+) ion, 2 amino acids away from cationic center. Hydrophobic centers for stabilizing the incoming substrate Protruding hydrogen’s to stabilize the carbonyl bond of peptide bond next to the labile peptide.

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Drug classification(based on groups which interact with zinc ion of ACE- Sulfhydryl group containing drugs Eg . Captopril Dicarboxylate group containing drugs Eg . Enalapril , lisinopril Phosphonate group containing drugs Eg . Fosinopril

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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.

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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

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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

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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.

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Reference - 1) Tripathi K.D,Essentials of medical pharmacology. Sixth edition.480-87 2)Williams, David A, Lemke, Thomas L. Foyes principles of medicinal chemistry. 6 th edition. 739-52 THANK YOU

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