Pharmacological screening of anti arrhythmic drugs 3

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Pharmacological screening of anti arrhythmic drugs 3

  1. 2. BY: NASREEN SULTANA M-PHARM (PHARMACOLOGY) 10T21S0111 . UNDER THE GUIDANCE OF: Dr. T. VEDAVATHI M.PHARM, PhD
  2. 3. CARDIAC ARRHYTHMIAS <ul><li>DEFINITION: </li></ul><ul><li>Deviation from normal </li></ul><ul><li>Origin/Conduction </li></ul><ul><li>Rhythm </li></ul><ul><li>Rate </li></ul><ul><li>Mainly occurs in patient who have acute M.I. , taking Digitalis or in anaesthetized patients. </li></ul>
  3. 4. NORMAL ELECTRICAL ACTIVITY OF HEART
  4. 5. CARDIAC ACTION POTENTIAL
  5. 6. ECG
  6. 7. CLASSIFICATION OF ARRHYTMIAS <ul><li>Normal heart rate – 60-100 beats/min. </li></ul><ul><li>Based on the heart rate : </li></ul><ul><li>Tachyarrhythmia - rapid heart beat – >100/min </li></ul><ul><li>Bradyarrhythmia – slow heart beat-<60/min </li></ul>
  7. 8. TACHYARRHYTHMIAS <ul><li>Caused by 2 mechanisms: </li></ul><ul><li>Increased automaticity </li></ul><ul><li>Re-entry </li></ul><ul><li>Depending on ectopic focus tachyarrhythmias </li></ul><ul><li>are classified as </li></ul><ul><li>Atrial tachyarrhythmias </li></ul><ul><li>Ventricular tachyarrhythmias </li></ul>
  8. 9. ATRIAL TACHYARRYTHMIAS <ul><li>Atrial tachycardia: abnormal P wave </li></ul><ul><li>Atrial flutters: the heart rate (atrial) is approximately 300/min </li></ul><ul><li>Atrial fibrillation: irregularly spaced QRS complex with absent P waves. </li></ul>
  9. 10. VENTRICULAR ARRHYTHMIAS <ul><li>Ventricular tachycardia: abnormal QRS complex and heart rate- >120beats/min . </li></ul><ul><li>Torsade de pointes: QT prolongation . </li></ul><ul><li>Ventricular fibrillation: </li></ul><ul><li>VF produces rapid, uncoordinated, movement of the ventricles which produces no pulse. The ECG shows chaotic, bizarre, irregular ventricular complexes. </li></ul>
  10. 11. ANTI-ARRHYTHMIC DRUGS
  11. 12. NEW DRUGS <ul><li>Conventional anti arrhythmic drugs - ↑risk of proarrhythmias. </li></ul><ul><li>Dronedrone - analogue of amiodrone (MULTAQ)-> LESS TOXIC. </li></ul><ul><li>Vernalakant - atrial selective (↓proarrhythmic risk) </li></ul><ul><li>Ranolazine – anti-anginal </li></ul><ul><li>atrial selective </li></ul>
  12. 13. HERBAL DRUGS <ul><li>Haw thorn – strengthens heart muscle </li></ul><ul><li>improves blood circulation. </li></ul><ul><li>Magnesium – relaxes and calms the heart. </li></ul><ul><li>Angelica </li></ul><ul><li>Astragalus – heart tonic </li></ul><ul><li>Barberry – heart tonic </li></ul>
  13. 14. SCREENING OF ANTI-ARRHYTHMICS <ul><li>DRUG SCREENING: </li></ul><ul><li>Pre clinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications </li></ul><ul><li>The screening of anti-arrhythmics is done by two different methods. </li></ul><ul><li>In-vitro models </li></ul><ul><li>In-vivo models </li></ul>
  14. 15. IN-VITRO MODELS <ul><li>LAGENDROFF TECHNIQUE: </li></ul>
  15. 16. PROCEDURE <ul><li>Animal – Guinea pig (300-500g) </li></ul><ul><li>Animal – selected </li></ul><ul><li> </li></ul><ul><li>Sacrificed (stunning) </li></ul><ul><li> </li></ul><ul><li>heart – removed – placed in Ringer’s solution (37⁰C) </li></ul><ul><li> </li></ul><ul><li>Aorta – located and cut – cannulated with Ringer’s solution (perfused at 40 mm Hg) </li></ul><ul><li> </li></ul><ul><li>Ligature – placed around LAD </li></ul>
  16. 17. <ul><li>Ligature – placed around LAD </li></ul><ul><li> </li></ul><ul><li>Test /std/control - administered. </li></ul><ul><li> </li></ul><ul><li>Occluded for 10 minutes </li></ul><ul><li> </li></ul><ul><li>reperfusion </li></ul><ul><li> </li></ul><ul><li>ECG electrode – pulsatile stimulation, induction of arrhythmia </li></ul><ul><li> </li></ul><ul><li>Heart rate and contractile force –measured </li></ul>
  17. 18. <ul><li>EVALUATION: </li></ul><ul><li>Heart rate (chronometer) </li></ul><ul><li>Contractile force (force transducer) </li></ul><ul><li>Incidence and duration of ventricular fibrillation or ventricular tachycardia is recorded in the control as well as test group. </li></ul>
  18. 19. IN VIVO MODELS <ul><li>In vivo models used to screen anti arrhythmic drugs can be divided into five groups: </li></ul><ul><li>Chemically induced arrhythmia </li></ul><ul><li>Electrically induced arrhythmia </li></ul><ul><li>Exercise induced ventricular fibrillation </li></ul><ul><li>Mechanically induced arrhythmia </li></ul><ul><li>Genetically induced arrhythmia </li></ul>
  19. 20. CHEMICALLY INDUCED ARRHYTHMIA <ul><li>A large number of agents are capable of inducing arrhythmias. </li></ul><ul><li>Administration of anesthetics like chloroform, ether, halothane (sensitizing agents) followed by a precipitating stimulus such as adrenaline, ouabain alkaloids cause arrhythmia. </li></ul>
  20. 21. <ul><li>PURPOSE AND RATIONALE: </li></ul><ul><li>Aconitine – acts persistently on sodium channels and activates them – ventricular arrhythmias. </li></ul><ul><li>REQUIREMENTS: </li></ul><ul><li>Animals - Male Ivanovas rats (300-400g) </li></ul><ul><li>Anesthetic – Urethane </li></ul><ul><li>Standard drug – Procainamide i.v (5mg/kg) </li></ul><ul><li>Lidocaine i.v (5mg/kg) </li></ul>
  21. 22. PROCEDURE: <ul><li>Animals – selected </li></ul><ul><li> </li></ul><ul><li>Anesthetized </li></ul><ul><li> </li></ul><ul><li>Test / std/control – administered </li></ul><ul><li>↓ </li></ul><ul><li>Aconitine (5 μ g/kg +0.1N HNO₃) (administered through saphenous vein) </li></ul><ul><li>↓ </li></ul><ul><li>ECG – Recorded (lead II) </li></ul>
  22. 23. <ul><li>EVALUATION: </li></ul><ul><li>Anti-arrhythmic effect of test is measured by the amount of Aconitine/100g animal. </li></ul><ul><li>Includes: </li></ul><ul><li>Ventricular extra systoles </li></ul><ul><li>Ventricular tachycardia </li></ul><ul><li>Ventricular fibrillation </li></ul><ul><li>Death </li></ul>
  23. 24. ELECTRICALLY INDUCED ARHYTHMIAS
  24. 25. <ul><li>PURPOSE AND RATIONALE: </li></ul><ul><li>Electrical stimulations – flutters and fibrillation. </li></ul><ul><li>REQUIREMENTS : </li></ul><ul><li>Animals – adult dogs (8-12kg) </li></ul><ul><li>Anesthetic – sodium pentobarbital (35mg/kg) </li></ul>
  25. 26. PROCEDURE <ul><li>Animal – selected </li></ul><ul><li>↓ </li></ul><ul><li>Anesthetized </li></ul><ul><li>↓ </li></ul><ul><li>Artificial respiration – Harvard respiratory pump </li></ul><ul><li>B.P – monitored </li></ul><ul><li>Body temperature – maintained by thermal blanket </li></ul><ul><li>↓ </li></ul><ul><li>Chest cavity is opened </li></ul><ul><li>↓ </li></ul><ul><li>Heart suspended in pericardial cradle </li></ul><ul><li>↓ </li></ul>
  26. 27. PERICARDIALCRADLE
  27. 28. <ul><li>Heart suspended in pericardial cradle </li></ul><ul><li>↓ </li></ul><ul><li>SA node – crushed </li></ul><ul><li>↓ </li></ul><ul><li>For electric impulse – Ag-AgCl electrode embedded in a teflon disc- sutured on left ventricle </li></ul><ul><li>↓ </li></ul><ul><li>Test drug/ std/contol – femoral artery </li></ul><ul><li>↓ </li></ul><ul><li>Constant current for 400ms is applied through electrode </li></ul><ul><li>↓ </li></ul><ul><li>Recording elecrodes – surface of each ventricle </li></ul><ul><li>↓ </li></ul>
  28. 29. <ul><li>Recording elecrodes – surface of each ventricle </li></ul><ul><li>↓ </li></ul><ul><li>ECG (Lead II) – monitored </li></ul><ul><li>↓ </li></ul><ul><li>VFT is measured (minimal current intensity required to induce sustained ventricular fibrillation) </li></ul><ul><li>When VF occurs – heart is defibrillated – recovered. </li></ul><ul><li>EVALUATION: </li></ul><ul><li>VFT - determined </li></ul>
  29. 30. EXERCISE INDUCED VENTRICULAR FIBRILLATION <ul><li>PURPOSE AND RATIONALE: </li></ul><ul><li>Tests combining coronary constriction with physical exercise may resemble most closely the situation in coronary patients </li></ul>
  30. 31. <ul><li>REQUIREMENTS: </li></ul><ul><li>Animals – Mongrel dogs (15 -19 kg) </li></ul><ul><li>Anesthetic – Sodium pentobarbitone (10mg/kg) i.v. </li></ul><ul><li>SURGICAL PREPARATION: </li></ul><ul><li>Animals – selected </li></ul><ul><li>↓ </li></ul><ul><li>Anesthetized </li></ul><ul><li>↓ </li></ul><ul><li>Chest cavity – opened </li></ul><ul><li>↓ </li></ul><ul><li>Heart suspended in pericardial cradle </li></ul><ul><li>↓ </li></ul><ul><li>around left circumflex artery – Doppler flow inducer- to measure blood pressure </li></ul><ul><li>- hydraulic occluder - to occlude coronary artery are placed </li></ul>
  31. 32. <ul><li>↓ </li></ul><ul><li>Pair of insulated silver coated wires – sutured on left and right ventricles- measure HR </li></ul><ul><li>↓ </li></ul><ul><li>Occlusion of LAD </li></ul><ul><li>↓ </li></ul><ul><li>Myocardial infarction </li></ul><ul><li>↓ </li></ul><ul><li>After 24 hrs- test drug/std/control - administered </li></ul><ul><li>During this experiment: </li></ul><ul><li>Transdermal fentanyl patch (↓post operative discomfort) </li></ul><ul><li>Bupivacaine HCl </li></ul><ul><li>Antibiotic therapy(amoxicillin) </li></ul>
  32. 33. EXERCISE-PLUS-ISCHEMIA TEST
  33. 34. <ul><li>3-4 weeks after the production of MI </li></ul><ul><li>↓ </li></ul><ul><li>Animals – run on a motor –driven treadmill </li></ul><ul><li>↓ </li></ul><ul><li>Work load - ↑every 3 min for total of 18 mins </li></ul><ul><li>↓ </li></ul><ul><li>During last minute-treadmill is stopped- left circum flex artery- occluded for 2 mins </li></ul><ul><li>↓ </li></ul><ul><li>After 10-20 sec of VF – defibrillation is achieved without any delay by placing large metal plates across animal’s chest. </li></ul><ul><li>EVALUATION: </li></ul><ul><li>HR is measured </li></ul>
  34. 35. MECHANICALLY INDUCED ARRHYTHMIA <ul><li>PURPOSE AND RATIONALE: </li></ul><ul><li>Arrhythmias –induced directly by ischemia and reperfusion </li></ul><ul><li>Coronary artery ligation in anesthetized dog results in: </li></ul><ul><li>↑ in HR </li></ul><ul><li>↑ in heart contractility </li></ul><ul><li>↑ in BP </li></ul><ul><li>Ventricular arrhythmias </li></ul>
  35. 36. REQUIREMENTS <ul><li>Animals – Dogs (20-25Kg) </li></ul><ul><li>Anesthetic – Thiobutobarbital sodium (30mg/kg) </li></ul><ul><li>PROCEDURE: </li></ul><ul><li>Animals – selected </li></ul><ul><li>↓ </li></ul><ul><li>Anesthetized </li></ul><ul><li>↓ </li></ul><ul><li>Artificial respiration – positive pressure respirator </li></ul><ul><li>↓ </li></ul><ul><li>Femoral artery – cannulated and connected to pressure transducer </li></ul><ul><li>↓ </li></ul><ul><li>Chest cavity –opened </li></ul><ul><li>LAD is exposed </li></ul><ul><li>↓ </li></ul>
  36. 37. <ul><li>Silk suture is placed around LAD </li></ul><ul><li>↓ </li></ul><ul><li>After 45 min(equilibration) – test/std/control- administered through saphenous vein </li></ul><ul><li>↓ </li></ul><ul><li>After 20 min- ligature of coronary artery is closed for 90 min </li></ul><ul><li>↓ </li></ul><ul><li>Occlusion released – reperfusion period maintained for 30 min. </li></ul><ul><li>All the parameters – recorded </li></ul><ul><li>At the end – surviving animals are sacrificed by an overdose of Pentobarbital sodium. </li></ul>
  37. 38. EVALUATION <ul><li>Mortality </li></ul><ul><li>Hemodynamics </li></ul><ul><li>Arrhythmia </li></ul><ul><li>Ventricular fibrillation </li></ul><ul><li>% animals with VF. </li></ul>
  38. 39. CONCLUSION <ul><li>Species differences do exist with respect to factors that determine arrhythmogenesis and no animal model will accurately mimic the human suffering of arrhythmia. </li></ul><ul><li>Nevertheless, the knowledge gathered from animal studies undoubtedly has been instrumental in devising diagnostic and therapeutic strategies both in supraventricular and ventricular arrhythmias. In the future, new knowledge will be obtained from experiments performed at many levels. </li></ul>
  39. 40. REFERENCES <ul><li>Vogel.G.H: Drug Discovery and Evaluation (Pharmacological Assays): Second Edition: McGraw- Hill, New York, 2002, Chapter-Cardiovascular activity, A.5, Anti-arrhythmic activity, Page 209-227.   </li></ul><ul><li>Gupta.S.K: Drug Screening Methods (Pre Clinical Evaluation of New Drug): Second Edition: Jaypee, New Delhi, 2009, Chapter-18, Antiarrhythmics, pg-285-296. </li></ul><ul><li>Websites: </li></ul><ul><li>Circ.ahajournals.org </li></ul><ul><li>Oxfordjournals.org </li></ul><ul><li>Onlinejacc.org </li></ul><ul><li>Japphysiology.org </li></ul>

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