Angiotensin Converting Enzyme inhibitor (ACEI)

Vilasinee HirunpanichB. 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, PGI2 and PGE2

angiotensinogen

Angiotensin I

Angiotensin II

vasodilation

PVR

BP

renin

Aldosterone release

Na+&H2O 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 (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

กลไกการยั�บยั�ง ACE ของ ยัา 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 T1/2 than parent drug.

Lisinopril

• Direct action in the body• Excrete by renal

Other drugs

BenazeprilCilazapril (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 stenosisSevere single renal artery stenosis

Need ATII

7. Angioedema...บวมของจม�ก ปาก ล�น กล�องเสี�ยัง (พบน�อยั)

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

vasoconstriction Cardiac

hypertrophy

Aldosterone release

ARB

Na+ reabsorption

Limitation of ACEI

1. Bilatery artery stenosis, unilatery artery stenosis

2. Pragnancy women….esp 1st 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