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INHIBITORS OF RENIN-

ANGIOENSIN SYSTEM

Presented by

H.Javed Iqbal

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COOMPONENTS OF RENIN-

ANGIOTENSIN SYSTEM

1) Renin

2) Angiotensinogen

3) Angiotensin converting enzyme4) Angiotensin II

5) Angiotensinase

6) Angiotensin receptors

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RENIN

Glycoprotein, Acid protease or aspartyl

protease

It contains two domains that form a cleftSynthesized, stored and secreted by granular

juxtaglomerular cells

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Glomerulus showing the

juxtaglomerular apparatus

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Synthesis of Renin

Preprorenin Prorenin Renin

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Regulation of renin secretion

AngiotensinII

Catecholamines

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RENIN INHIBITORS

ALI SKIREN dose dependantreduction of plasma renin activity.

ALISKIREN dose dependant

reduction in blood pressure (essential

hypertension) similar to those produced by

angiotensin II receptor antagonists.

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ANGIOTENSINOGEN

It is a substrate for renin

Glycoprotein in nature

Circulating levels is less than the Km of the Ranin-

angiotensin reaction Its level is stimulated

a) during pregnancy

b) In woman taking oral contraceptives

c) by inflammation

d) by glucocorticoides

e) by angiotensin II

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ANGIOTENSIN

CONVERTING ENZYME

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Angiotensin converting enzyme

Dipeptidyl carboxypeptidase ectoenzyme thatcontains 1277 amino acids and two domains

Each domain has a catalytic site and zinc binding

region. It is identical to kinase-II

ACE has a large amino terminal domain(extracellular) and one small carboxyl terminal

intracellular domain

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ACE2=?

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ANGIOTENSIN CONVERTING

ENZYME-2

Highly expressed in vascular endothelial cells of

heart, kidney and testes

Only one active site and function as carboxypeptidase

No effect on bradykinin activity

Not prevented by ACE inhibitors

Angiotensin-I

}Angiotensin-II }

Angiotensin 1-9

Angiotensin 1-7

ACE2

ACE2

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ANGIOTENSIN II

ANGIOTENSIN II

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Continued

ANGIOTENSIN II

1. Direct vasoconstriction

2. Enhancement of peripheral

NE neurotransmission

a. Increase in NE release

b. Decreased NE reuptakec. Increase vascular

responsiveness

3. Increased sympathetic

discharge (CNS)

4. Release of Catecholaminesfrom adrenal medulla

1. Direct effect to increase Na

reabsorption in proximal

tubules

2. Release of aldosterone from

adrenal cortex

3. Altered renal homodynamic:

a. Direct renal vasoconstriction

b. Enhanced noradrenergic

neurotransmission in kidney

c. Increased renal sympathetictone (CNS)

Altered peripheral resistance Altered renal function

Mechanisms Mechanisms

Result

Rapid pressor response

Result

Slow pressor response

ANGIOTENSIN II

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ANGIOTENSIN II

1. Non hemodynamically mediated effects

a. Increased expression of proto-oncogenes

b. Increased production of growth factors

c. Increased synthesis of extracellular matrix

proteins

2. Hemodynamically-mediated effects:

a. Increase after load (cardiac)

b. Increased wall tension (vascular)

Altered cardiovascular structure

Mechanisms

Result

Vascular and Cardiac

hypertrophy and remodelling

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Continued

Summary, Renin Angiotensin system

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ACE INHIBITORS

They block the activity of ACE

Currently 11 ACE inhibitors are available for clinical use inUSA

They differ with regard to three properties:

1. Potency

2. Whether the effect is direct or by active metabolite

3. Pharmacokinetics (extent of absorption, effect of food onabsorption, half life, tissue distribution and mechanisms ofelimination )

No ACE inhibitor is superior to other but According to Quality-of-Life hypertension Study Group

CAPTOPRIL has more favorable effect on quality of life.

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ACE INHIBITORS(CLASSIFICATION)

Sr#

CLASS GROUP MEMBERS

1 Sulfhydryl containing ,similarto CAPTOPRIL(Capoten)

1)Fentiapril 2)Pivelopril

3)Zofenopril 4)Alacepril

2 Dicarboxyl containing ,similarto ENALAPRIL(Vasotec)

1-Lisinopril(Zestril)

2-Benazepril

3-Quinapril (Accupril)

4-Moexipril 5-Ramipril

6-Trandolapril 7-Perindopril

3 Phosphorous containing,similar to FOSINOPRIL

Fosinopril (Monopril)

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ACE INHIBITORS

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CLINICAL USES OF ACE INHIBITORS

Hypertension

Cardiac failure

Following myocardial infarction( especiallywhen there is ventricular dysfunction, evenwhen it is mild)

Patients at high risk of ischemic heart disease

Diabetic nephropathyProgressive renal insufficiency

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1) IN HYPERTENSION

Ace inhibitors alone normalize BP in approximately

50% patients with mild moderate hypertension

90% hypertensive patients are controlled by the

combination of ACE inhibitors + Ca++ channelblocker, or adrenergic receptor blocker or a diuretic

ACE inhibitors are superior in controlling BP in

diabetic patients

a. they reduce cardiovascular events

b. improve endothelial function

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2)IN CARDIAC FAILURE

They improve the ventricular geometry by

reducing the ventricular dilation and tend to

restore the heart to its normal shape

They reverse remodelling viaa. Changes in preload and after load

b. By preventing growth effects of angiotensin II on

myocytes

c. By attenuating cardiac fibrosis induced byangiotensin II and aldosterone

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3)IN ACUTE MYOCARDIAL

INFARCTION

Ace inhibitors reduce overall mortality when

treatment is begun during the peri-infarction period.

According to ACE Inhibitor Myocardial Infarction

Collaborative Group,(1998) ACE inhibitors startimmediately during the acute phase of myocardial

infarction and can be administered with thrombolytic

agents, aspirin, and B-adrenergic receptor antagonists

In high risk patients (e.g. Large infarct, systolic

ventricular dysfunction) ACE inhibitors

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ACE INHIBITORS(ADVERSE EFFECTS)

1. Hypotension

2. Cough

3. Hyperkalemia

4. Acute renal failure

5. Fetopathic potential6. Skin rash

7. Proteinurea

8. Angioedema

9. Dysgeusia10. Neutropenia

11. Hepatotoxicity

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ACE INHIBOTORS(DRUG INTERACTION)

Antacids reduce the bioavailability

NSAIDS reduce the antihypertensive response

to ACE inhibitors

K-sparing diuretics or K supplement may

cause ACE inhibitors induced hyperkalemia

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ANGIOTENSIN

RECEPTORS

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ANGIOTENSIN RECEPTORS

Two subtypes of receptors, termed AT1 and AT2

AT1receptors have high affinity for Losartan and

low affinity for PD 123177.

In terms of affinity,AT2 receptors is directly

opposite to AT1 receptors

AT1 receptors predominate in vascular smooth

muscles while AT2 are in brain, reproductive

tissues and in adrenal medulla

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Multiple mechanisms of AT1

receptor- effector coupling

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ANGIOTENSIN

RECEPTOR BLOCKERS

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ANGIOTENSIN RECEPTOR

BLOCKERS

Available ARBs have more affinity for AT1 receptors

and more than 10,000 fold selective for At1 receptors

than that of AT2 receptors

The rank order affinity of At1 receptor for ARBs isCandesartan = Omesartan> Irbesartan = Eprosartan>

Telmesartan= Walsartan > Losartan

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THERAPEUTIC USES

All ARBs are approved for hypertension

Losartan and Irbesartan are approved fordiabetic nephropathy also

Losartan is approved for stroke prophylaxisand is safe in the treatment of portalhypertension associated with cirrhosis and

portal hypertension with renal insufficiencyValsartan is approved for heart failure patients

those are intolerant to ACE inhibitors

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NOW DEBATE STARTS ?

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ARBS and ACE inhibitors

equal or not1. Block the AT1ceptors more

effectively regardless of

biosynthesis pathway of

Angiotensin II

2. They permit the activation of

AT2 receptors, they also

increase AGII level by

increasing the level of renin.

3. They do not increase the level

of AG(1-7)

4. They are not the enzymes, so do

not have any substrate

1. Ace inhibitors reduce the

biosynthesis of AG II produced

by the action of ACE only

2. They block the conversion of

AGI to AGII.They also increase

the level of renin

4. Ace is involved in the clearance

of AG(1-7)

5. ACE inhibitors increase thelevel of different substrates of

ACE e.g. bradykinin and certain

other enzymes

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WHAT LANCET SAYS ?

The trial was conducted on 1800 patients with mean restingdiastolic BP between 95 and 110 mm HG to receive aliskiren,Valsartan, both drugs, or placebo.

After 4 weeks, doses were titrated to the maximum. After 8 weeks of treatment, patients receiving either drug had

lower resting BP than those on placebo, and patients receivingboth drugs had lower BP than those on monotherapy

Ambulatory diastolic BP, measured in some 350 patients, fellto a greater extent with combination therapy (mean reduction,10.3) than with monotherapy (mean reduction, 7.1).

The observed BP reductions are less than what one mightexpect from combining a renin inhibitor with a diuretic or acalcium-channel blocker, as guidelines recommend.

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WHAT LANCET SAYS ?

(CONCLUSION)

Because of the potential life-threatening side-

effects ... this concept of treatment is unlikely

to make it to general practice or even to

primary prevention in specialist care."

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Physiological regulation of electrolyte

balance, plasma volume and blood pressure