Evaluation of Anti-Anginal Agents.

Dr. Jayesh U Patil

3
rd
Yr Resident
T.N.M.C. Mumbai
20 July 2013

Ischemic Heart Disease: Classical Angina (Stable Angina Pectoris), Variant
/Prinzmetal/Vasospastic Angina, Unstable Angina, Myocardial Infarction,Silent
Ischemia
Stable Angina: Exacerbated by stress relieved by rest, due to underlying Fixed
Obstruction- Atheromatous Plaque, Predictable, Managed with Nitrates , Beta
Blockers, CCBs etc.
Variant /Prinzmetal/Vasospastic Angina: Unpredictable, may occur at rest/ during
sleep, occurs due to localized vasospasm, Managed with Nitrates, CCBs. Beta-
blockers are avoided.
Unstable Angina: Rapid increase in the duration and severity of attacks, mostly due
to rupture of an atheromatous plaque. Managed as an Acute Coronary Syndrome
with anti-platelet agents (Aspirin, Clopidogrel etc.) Nitrates, Beta Blockers, Morphine
Sulphate , & Anticoagulants (Heparin, Enoxaparin etc). Thrombolytics should be
avoided. Early PCI is warranted.
Drug Therapy for Angina:
Nitrates : Glyceryl Trinitrate (GTN), Isosorbide Mononitrate, Isosorbide
Dinitrate, Erythityl Tetranitrate, Pentaerythitol Tetranitrate.
Beta Blockers: Propranolol, Metoprolol, Atenolol etc.
Calcium Channel Blockers: Verapamil, Diltiazem, Nifedipine, Felodipine,
Amlodipine, Nitredipine, Nimodipine, Lacidipine, Lercanidipine, Clevidipine,
Benidipine.
Potassium Channel Openers: Nicorandil
Others : Trimetazidine, Ranolazine, Ivabradine.


IN-Vitro Models :
Langendorff Heart Preparation: Retrograde perfusion in isolated Guinea Pig Hearts.
Highly reproducible model for evaluating effect of drugs on Coronary blood flow.
Advantages, Disadvantages.


Coronary Artery Ligation in Isolated working Rat Heart: Modification of
Langendorff Heart Preparation. In working heart preparations of rats, ischemia can
be induced by clamping the left coronary artery close to its origin.


Relaxation of Bovine Coronary Artery: Spiral strips from bovine coronary artery can
be used for assaying relaxing activity of test compounds. This activity is compared to
relaxation caused by PGI2.

Isolated Rabbit Aorta Preparation: Contraction of aortic rings is induced by adding
potassium chloride or norepinephrine .Test drugs with calcium channel blocking
activity have a relaxing effect on isolated rabbit aorta preparation.

Heart Lung Preparations : This model mimics systemic circulation, lungs maintain
their ability to oxygenate & preload & afterload may be adjusted. Useful to evaluate
hemodynamic effects of drugs. Wistar Rats are used.


Plastic Casts from Coronary Vascular Bed: Prolonged administration of coronary
dilator drugs has been shown to increase the number and size of collaterals of dogs
and pigs after coronary occlusion. Filling the arterial coronary bed with a plastic
provides the possibility to make the collaterals visible and to quantify them.



IN Vivo Models
Isoproterenol Induced Myocardial Necrosis in Rats: Myocardial Necrosis can be
induced using Isoproterenol. Histological, Biochemical markers are compared Test
and Standard group.
Acute Ischemia by Injection of Microspheres in Dogs: Severe left ventricular failure
is induced by repeated injections of 50 m plastic microspheres into the left main
coronary artery of anesthetized dogs. The test can be used to evaluate the influence
of drugs on myocardial performance during acute ischemic left ventricular failure in
dogs.
Occlusion of Coronary Artery in Anesthetized Dogs and Pigs: Compounds
potentially reducing infarct-size are tested by studying the size of the infarct after
proximal occlusion of the left anterior descending coronary artery dogs.
Stenosis Induced Coronary Thrombosis Model: Clamping induces thrombosis in
coronary artery . Stenosis of the artery alters the cyclical variations in the coronary
blood flow. Drugs with coronary vasodilator action may improve the flow pattern in
the stenosed artery.

Electrical stimulation induced coronary thrombosis: Electrical stimulation induces
thrombosis in coronary artery .An alteration in coronary blood flow with transient
platelet aggregation at the site of coronary constriction is assessed using this model.

Influence on Myocardial Preconditioning.: Myocardial precondition (brief duration
of ischemia & reperfusion) can reduce the damage produced by prolonged ischemia
& reperfusion. Certain drugs like ACE inhibitors have protective on cardiac myocytes
by altering preconditioning response. This effect can be evaluated.


Clinical Evaluation:
Patient Selection
Inclusion & Exclusion Criteria:
Efficacy Endpoints:
Exercise based variables (Exercise capacity, Time to the onset of angina, Time to ST
segment depression). Measure of Anginal Pain (Canadian Clasification Society (CCS)
Angina Grading Scale,Concomitant use of short acting nitrates). Health-Related
Quality of Life (HRQoL),Morbidity and mortality
Exercise Testing : Treadmill Test
Study Design:
Safety Aspects










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