Angina Screening - Satish

8/3/2019 Angina Screening - Satish

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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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Angina Screening - Satish

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