This presentation discusses angiotensin-converting enzyme (ACE) inhibitors, which are used to treat hypertension and other cardiovascular conditions. It describes the structure and function of ACE, the drug classification of ACE inhibitors based on their zinc-binding groups, and the structure-activity relationships that determine ACE inhibitor potency. Examples of commonly used ACE inhibitors are provided, along with their chemical nature, bioavailability, time to peak action, elimination, dosing, and adverse effects. Clinical uses and drug interactions of ACE inhibitors are also summarized.

1. presentation by-
Diksha Kumari
18601911022
B.pharm, 3rd year,6th semester

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

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

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

5. 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.

6. captopril enalapril lisinopril fosinopril perindopril ramipril
Chemical
nature
Sulfhydryl Carboxyl Carboxyl Phosphina
te
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

7. 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

8. 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.

9. 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. 6th edition. 739-52