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SCREENING OF ANTI ANGINAL
DRUGS
Presented by: SATISH. A. AKKI
1st M. Pharm
Department of pharmacology
SETs college of pharmacy
Dharwad
Subject: Pharmacological screening methods
& clinical evaluation
Subject incharge :Dr. PREETI.V.KULKARNI
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CONTENTS
IntroductionHeart blood supply
Ischaemic heart disease
What is angina?
Causes of anginaTypes of angina
Symptoms o angina
Pathophysiology of angina
Tests of anginaPreventive measures
Anti anginal drugs
Screening models
Reference
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Introduction
Angina pectoris was first described as a distinctclinical entity by WILLIAM HEBERDEN in the
latter half of the 18th century
In the second half of the 19th century, it was found
that amylnitrite could provide transient relief
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Heart blood supply
Coronary circulation(corona=crown)Two coronary arteries-right & left branch fromascending aorta
Left coronary artery1)anterior interventricular
2)circumflex branchesRight coronary artery-1)posterior interventricular
2)marginal branches
Coronary veins-coronary sinus
-great cardiac vein
-middle cardiac vein
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Coronary arteries
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Ischaemic heart disease
It is defined as acute or chronic form of cardiac disabilityarising from imbalance between the myocardial supply
and demand for oxygenated blood
Narrowing or obstruction of coronary arteries
Coronary artery disease
Etiopathogenesisatherosclerosis -90% cases
other causes -10% cases
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Atherosclerosis
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Effects of myocardial ischaemia
Asymptomatic stateAngina pectoris
Acute myocardial infarction
Chronic ischaemic heart disease
Sudden cardiac death
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Causes of angina pectoris
Non-atheroscleroticcoronary spasm
arteritis
embolism
Atherosclerosis
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Types of angina pectorisThree types- based on difference in pathogenesis1)Stable or typical angina
2)prinzmetals variant angina
3)Unstable or crescendo angina
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Symptoms Angina itself is a symptom (or set of symptoms), not a disease.
Pain in the center of the chest
Lightness
Pain may spread to the shoulders, neck or arms
Pain may be of any intensity from mild to severe
Shortness of breath
Anxiety or nervousness
Sweaty skin
It is always not easy to tell the difference between angina & heartattack
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Symptoms
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PATHOPHYSIOLSOGY OF ANGINA
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Exams and tests
ECGExercise stress test
Dobutamine echocardiogram stress test
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PreventionStop using nicotine in formControl high blood pressure
Lower blood fats
Control blood sugarMaintain healthy weight
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ANTIANGINAL DRUGS
1. nitrates:-
Short acting:-glyceryl trinitrate.Long acting:-isosorbide dinitrate,isosorbide mononitrate,erytritil
tetranitrate.
2. -blockers:- atenolol,metaprolol.propranolol
3.Ca-channel blockers:-
1. Phenyl alkyl amines:-varapamil.
2. Benzothiazepine:-diltiazem.
3. Dihydropyridines:-nifedipine,amlodipine etc
4.K-channel openers:-nicorandil.
5.others:-dipyridamol,oxyphedrine.
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SCREENING METHODS
Invitro models:
1.Isolated heart technique.
2.ca-antagonism in isolated rabbit aorta.
3.ca-antagonism in pitched rat.
4.Relaxation of bovine coronary aorta.
5.Coronary aorta ligation in isolated rat heart.
6.Isolated heart-lung prepration.7.Plastic casts from coronary vasculature in dogs.
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INVIVO MODELS1.Occlusion of coronary artery.
2.Microspheres induced acute ischaemia.3.Isoproterenol induced myocardial necrosis.
4.Stenosis induced coronary thrombosis model.
5.Electrical stimulation induced coronary thrombosis.6.Models for coronary flow measurement.
a.coronary in-flow measurement:-in anaesthetised dog.
b.coronary out-flow measurement.
i)electromagnetic flow meter
ii)other techniques-like inert gas technique,radioactive
technique.
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IN VITRO METHODS
*Isolated heart / langendorff technique.
- Principle ?
- Procedure.
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IN VIVO MODELS
Occlusion of coronary artery
Principle
Procedure:
Dogs of either sex (30kg)
Anesthetized with pentobarbitone sodium(35mg/kg,i.p)
Trachea is cannulated
Saphenous vein is cannulated for administration of test compound
ECG is recorded continuously
Femoral vein is cannulated & connected to pressure transducer
Left ventricular pressure & heart rate are also measured using Millar microtipcatheter inserted via left coronary artery
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Heart is exposed through left thoracotomy
Left anterior descending coronary artery is exposed & then ligated for360min
Test substance or vehicle is administered by i.v bolus infusion
Hemodynamic parameters are monitored & at the end , animal aresacrificed
Area at risk of infarction is measured using coronary arteriogram
Left ventricle is cut into transverse section
Slices incubated in p-nitro-blue-tetrazolium (0.25g/l) in order to visualizeinfarct tissue
Blue stained is healthy, unstained is necrotic
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Mortality, hemodynamic parameters & infarct size isdetermined
Changes in parameters in treated animals are
compared to vehicle control
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Isoproterenol-induced myocardial necrosis
Principle
Procedure:
Wistar rats (150-200g)
Pretreated with test drug or standard orally for at least a week
Then, injected with 85mg/kg isoproterenol s.c on two consecutive days
Mortality & symptoms are recorded in each group &compare to group injectedwith isoproterenol only
After 48h of first dose of isoproterenol animals are sacrificed
Heart is removed, weighed & preserved for histological evaluation
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Before sacrificing the animal hemodynamicparameters can be recorded by cannulating the
carotid artery
Changes of parameters of drug treated animals are
compared to isoproterenol controls
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Stenosis-induced coronary thrombosis
Stenosis a Greek word-narrowing
Procedure:
Dogs(15-20kg)
anesthetized with pentobarbitone sodium (30-40mg/kg i.p)
Maintained on artificial respiration
Heart is exposed at the 4th & 5th inter costal space
An electromagnetic flow probe is placed on proximal part of left coronary arteryto measure coronary blood flow
Distal to flow meter, the vessel is clamped for 5sec
A small plastic constrictor is placed around the artery at the site of damage
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Constrictor is changed several times until required narrowing of the coronaryartery is achieved
In case the artery is occluded, the coronary artery is lifted to induce reflow
Dogs with regular repeated cyclic flow variations of same intensity within apretreatment phase of 60min are used for experimental purpose
Hemodynamic parameters are recorded
Test compound is administered i.v & the cyclic flow variations are registered for2-5hr & compared to pretreated values
In simple clamping of the coronary artery does not produce cyclic variations
Cyclic flow variations are registered & compared to the drug treated group
El t i l ti l ti i d d
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Electrical stimulation-induced
thrombosisElectric stimulation can induce thrombosis in the coronary artery of pig
Procedure:
German landrace pigs(20-40kg)
Anesthetized with ketamine(2mg/kg,i.m), metomidate(10mg/kg,i.p),&xylazine(1-2mg/kg,i.m)
Maintained on artificial respiration
Heart is exposed through left thoracotomy
An electromagnetic flow meter is placed on the proximal part of the left coronaryartery to measure coronary blood flow
A vanadium steel electrode is placed in the vessel with the intimal lining &connected with teflon-coated wire of 9-volt battery, potentiometer &
amperometer
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The intima is stimulated with 150A for 6hrs during which time an occluding
thrombosis occurs
Test drug is administered either s.c with electrical stimulation or 30 min after
Hemodynamic parameters are measured by cannulating the femoral artery &connecting it to pressure transducer
The time interval until the thrombotic occlusion of the vessel occurs & thethrombus size are determined
At the end of experiment animals are sacrificed
% change in mean values for occlusion time & thrombus size in drug treated group
is compared to the control group
Also changes in hemodynamic parameters is compared to pretreated values
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References:K. D. Tripathi, Essentials of Medical Pharmacology, 5th
Edition, 2003, Jaypee Series, p. 437-40.
H. P. Rang, M. M. Dale, J. M. Ritter, P. K. Moore,Pharmacology, 5th Edition, 2003, Churchill Livingstone, p.494-98.
Harsh Mohan, Textbook of pathology, 5th
Edition, 2005,Jaypee Brothers Medical Publishers (P) ltd, p.316-18.
H. Gerard Vogel and Wolfgang H. Vogel, Drug Discovery andEvaluation: Pharmacological Assays, 2nd Edition, 2002,Springer Publications, p. 595-643.
S. K. Gupta, Drug Screening Methods, 1st Edition, 2004,Jaypee Series, p.
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