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8/14/2019 Ace Inhibitors by h.javeed Iqbal
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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