Evaluation of Anti-Anginal Agents.

Dr. Jayesh U Patil 3rd 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. Betablockers 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

Reference:
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