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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