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

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

Factors which stimulate renin release 1.BP drop 2.Beta-adrenergic receptor stimulation 3.The stimulation of sympathetic system 4.The decrease of Na + -load

Function of renin

Angiotensin converting enzyme inhibitors (ACEI) Inhibit enzyme ACE Decrease ATII Decrease the destroy of bradykinin Increase NO, PGI 2 and PGE 2

angiotensinogen Angiotensin I Angiotensin II vasodilation  PVR  BP renin  Aldosterone release  Na + &H 2 O retention kinogen bradykinin inactive  PG syn. vasodilation  PVR  BP kallikrin ACEI.

Vasodilate & venodilate Dilate afferent and efferent arteriole at renal Increase capillary compliance 1.Vascular smooth muscle

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

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

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

Divided into 3 groups 1.Direct action but internalized metabolite to disulfide group Ex. captopril 2. Prodrug (esterdicarboxylic 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

กลไกการยับยั้ง ACE ของ ยา ACEI

structure

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

Enalapril The first prodrug which was used in clinic It is metabolized into dicarboxylic group … enalaprilat which is the active metabolized. Elanaprilat has long T 1/2 than parent drug.

Lisinopril Direct action in the body Excrete by renal

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

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

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

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

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

Angiotensin I ACEI Angiotensin II Cellular response vasoconstric tion Cardiac hypertrophy Aldosterone release ARB Na + reabsorption

Limitation of ACEI 1.Bilatery artery stenosis, unilatery artery stenosis 2. Pragnancy women….esp 1 st trimester 3.Chronic cough 4.Black people…low renin activity

Drug interaction 1.Beta-blocker…decrease renin release 2.K + -sparing diuretic……increase K + 3.NSAID……decrease PG synthesis, bradykinin 4.Probenecid….inhibit abs 5.Antacid……decrease abs

Clinical uses Treatment HT with other condition Ex 1.HT with Dyslipidemia, Gout, DM, renal 2.CHF 3.Atherosclerosis 4.LVH