“INHIBITORS OF RENIN-

ANGIOENSIN SYSTEM”

Presented by
H.Javed Iqbal
 “COOMPONENTS OF RENIN-
ANGIOTENSIN SYSTEM”
1) Renin
2) Angiotensinogen
3) Angiotensin converting enzyme
4) Angiotensin II
5) Angiotensinase
6) Angiotensin receptors
 “RENIN”
 Glycoprotein, Acid protease or aspartyl
protease
 It contains two domains that form a cleft
 Synthesized, stored and secreted by granular
juxtaglomerular cells
 “Glomerulus showing the
juxtaglomerular apparatus”
 “Synthesis of Renin”

Preprorenin Prorenin Renin

 Catecholamines

AngiotensinII

“Regulation of renin secretion”

 “RENIN INHIBITORS”

 ALI SK IREN dose dependant

reduction of plasma renin activity.
 ALISKIREN dose dependant
reduction in blood pressure (essential
hypertension) similar to those produced by
angiotensin II receptor antagonists.
 “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
 “ANGIOTENSIN
CONVERTING ENZYME”
 “Angiotensin converting enzyme”
 Dipeptidyl carboxypeptidase ectoenzyme that
contains 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
“Angiotensin converting enzyme”
ACE2=?
 “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
ACE2
 Angiotensin-I } Angiotensin 1-9
ACE2
Angiotensin-II } Angiotensin 1-7
“ANGIOTENSIN II”
 “ANGIOTENSIN II”
Altered peripheral resistance Altered renal function
Mechanisms Mechanisms

1. Direct vasoconstriction 1. Direct effect to increase Na

2. Enhancement of peripheral reabsorption in proximal
NE neurotransmission tubules
a. Increase in NE release 2. Release of aldosterone from
b. Decreased NE reuptake adrenal cortex
c. Increase vascular 3. Altered renal homodynamic:
responsiveness a. Direct renal vasoconstriction
3. Increased sympathetic b. Enhanced noradrenergic
discharge (CNS) neurotransmission in kidney
4. Release of Catecholamines c. Increased renal sympathetic
from adrenal medulla tone (CNS)
Result Result

Rapid pressor response Slow pressor response

Continued
 “ANGIOTENSIN II”
Altered cardiovascular structure
Mechanisms

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)
Result

Vascular and Cardiac

hypertrophy and remodelling
Summary, Renin Angiotensin system
Continued
 “ACE INHIBITORS”
 They block the activity of ACE
 Currently 11 ACE inhibitors are available for clinical use in
USA
 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 on
absorption, half life, tissue distribution and mechanisms of
elimination )
 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.
 “ACE INHIBITORS”
(CLASSIFICATION)
Sr CLASS GROUP MEMBERS
#
1 Sulfhydryl containing ,similar 1)Fentiapril 2)Pivelopril
to CAPTOPRIL(Capoten) 3)Zofenopril 4)Alacepril

2 Dicarboxyl containing ,similar 1-Lisinopril(Zestril)

to ENALAPRIL(Vasotec)
3 Phosphorous containing,
similar to FOSINOPRIL
2-Benazepril
3-Quinapril (Accupril)
4-Moexipril 5-Ramipril
6-Trandolapril 7-Perindopril
Fosinopril (Monopril)
“ACE INHIBITORS”
 “CLINICAL USES OF ACE INHIBITORS”

 Hypertension
 Cardiac failure
 Following myocardial infarction( especially
when there is ventricular dysfunction, even
when it is mild)
 Patients at high risk of ischemic heart disease
 Diabetic nephropathy
 Progressive renal insufficiency
 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++ channel
blocker, 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
 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 via
a. Changes in preload and after load
b. By preventing growth effects of angiotensin II on
myocytes
c. By attenuating cardiac fibrosis induced by
angiotensin II and aldosterone
 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 start
immediately 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
 “ACE INHIBITORS”
(ADVERSE EFFECTS)
1. Hypotension
2. Cough
3. Hyperkalemia
4. Acute renal failure
5. Fetopathic potential
6. Skin rash
7. Proteinurea
8. Angioedema
9. Dysgeusia
10. Neutropenia
11. Hepatotoxicity
 “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
“ANGIOTENSIN
RECEPTORS”
 “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
“Multiple mechanisms of AT1
receptor- effector coupling”
 “ANGIOTENSIN
RECEPTOR BLOCKERS”
 “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 is
Candesartan = Omesartan> Irbesartan = Eprosartan>
Telmesartan= Walsartan > Losartan
 “THERAPEUTIC USES”
 All ARBs are approved for hypertension
 Losartan and Irbesartan are approved for
diabetic nephropathy also
 Losartan is approved for stroke prophylaxis
and is safe in the treatment of portal
hypertension associated with cirrhosis and
portal hypertension with renal insufficiency
 Valsartan is approved for heart failure patients
those are intolerant to ACE inhibitors
NOW DEBATE STARTS ?
 “ARBS and ACE inhibitors
equal or not”
1. 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 the
level of different substrates of
ACE e.g. bradykinin and certain
other enzymes
 WHAT LANCET SAYS ?
 The trial was conducted on 1800 patients with mean resting
diastolic 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 receiving
both drugs had lower BP than those on monotherapy
 Ambulatory diastolic BP, measured in some 350 patients, fell
to 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 might

expect from combining a renin inhibitor with a diuretic or a
calcium-channel blocker, as guidelines recommend.
 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."
 “Physiological regulation of electrolyte
balance, plasma volume and blood pressure
by renin-angiotensin system”