Angiotensin Converting Enzyme inhibitor (ACEI)

1. Angiotensin Converting Enzyme inhibitor (ACEI) Vilasinee Hirunpanich B. Pharm(Hon), M.Sc in Pharm(Pharmacology)

2. Renin angiotensin system (RAS) • Control the balance of electrolyte, blood volume, BP • Release from juxtaglomerular cell of cortex renin

3. Factors which stimulate renin release • BP drop • Beta-adrenergic receptor stimulation • The stimulation of sympathetic system • The decrease of Na+-load

4. Function of renin

7. Angiotensin converting enzyme inhibitors (ACEI) • Inhibit enzyme ACE • Decrease ATII • Decrease the destroy of bradykinin • Increase NO, PGI2 and PGE2

8. angiotensinogen kinogen renin kallikrin Angiotensin I bradykinin ACEI. PG syn. Angiotensin II inactive  Aldosterone release vasodilation vasodilation  Na+&H2O retention  PVR PVR  BP BP

9. Pharmacological effects

10. Vascular smooth muscle • Vasodilate & venodilate • Dilate afferent and efferent arteriole at renal • Increase capillary compliance

11. 2. Cardiovascular effect • Decrease both preload and afterload • Increase cardiac out put • Decrease left ventricular hypertrophy (LVH) • No reflex tachycardia

12. 3. renal • Increase renal blood flow • Decrease excretion of protein in urine which good for pts with DM • Inhibit the secretion of aldosterone

13. 4. CNS • Decrease NE release • Increase parasympathetic system so not increase reflex tachycardia • May increase cerebral blood flow

14. Pharmacokinetic

15. Divided into 3 groups • Direct action but internalized metabolite to disulfide group • Ex. captopril • 2. Prodrug (ester dicarboxylic acid) • They have the effects when they are changed to active metabolized • Ex enalapril, benazepril, cilazapril • 3. Soluble in water and not change in the body • Ex lisinopril

16. กลไกการยับยั้ง ACE ของยา ACEI

17. structure

18. Drugs • captoril • Contain sulhydril (SH) in the structure • Bioavailability 70% • Food interfere with absorption …AC • Metabolized into disulfide group

19. Enalapril • The first prodrug which was used in clinic • It is metabolized into dicarboxylic group …enalaprilat which is the active metabolized. • Elanaprilat has long T1/2 than parent drug.

20. Lisinopril • Direct action in the body • Excrete by renal

21. Other drugs • Benazepril • Cilazapril (Inhibace) • Delapril (Cupressin) • Fosinopril (Monopril) • Perindopril (Coversyl) • Ramipril (Ramace, Tritace)

22. ADR • 1. Dry cough • Common SE • Cause by increase cough reflex, from the accumulation of bradykinin and others substance such as substance P, PG • 2. Hypotension…esp. first dose • 3. Hyperkalemia esp. used with K+ sparing diuretic • 4. Fetopathic • category X…….not use in pregnant women

23. ADR (cont) • 6. Renal failure • bilateral renal artery stenosis • Severe single renal artery stenosis Need ATII 7. Angioedema...บวมของจมูกปากลิ้นกล่องเสียง (พบน้อย) 8. Rash ……..SH group, bradykinin accumulation 9. loss of taste….most in captopril 10. Protein in urine (less)

24. Angiotensin receptor blocker(ARB) • Lorsartan • Valsartan • Candesartan • Eprosartan • Irbesartan • telmisartan

25. Mechanism of action • Direct inhibit at angiotensin II receptor (type I) • More selective than ACEI • No or less Side effect of dry cough and angioedema

26. Angiotensin I ACEI Angiotensin II Cellular response ARB vasoconstriction Aldosterone release Cardiac hypertrophy Na+ reabsorption

27. Limitation of ACEI • Bilatery artery stenosis, unilatery artery stenosis • Pragnancy women….esp 1st trimester • Chronic cough • Black people…low renin activity

28. Drug interaction • Beta-blocker …decrease renin release • K+-sparing diuretic……increase K+ • NSAID……decrease PG synthesis, bradykinin • Probenecid….inhibit abs • Antacid……decrease abs

29. Clinical uses • Treatment HT with other condition Ex • HT with Dyslipidemia, Gout, DM, renal • CHF • Atherosclerosis • LVH