Animal model for antiarrhythmic drug

1. UNDER THE GUIDANCE OF:
Dr. T. VEDAVATHIM.PHARM, PhD
PHARMACOLOGICAL SCREENING OF
ANTI-ARRHYTHMIC DRUG
PRESENTED BY:-
RAKESH KUMAR
M.PHARMACY (PHARMACOLOGY)
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2. CARDIAC ARRHYTHMIAS
Deviation from normal
• Origin/Conduction
• Rhythm
• Rate
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3. CLASSIFICATION OF ARRHYTMIAS
• Normal heart rate – 60-100 beats/min
Based on the heart rate:
• Tachyarrhythmia - rapid heart beat - >100/min
• Bradyarrhythmia – slow heart beat - <60/min
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4. SCREENING OF ANTI-ARRHYTHMICS
DRUG SCREENING:
Pre clinical testing of drugs in experimental
animals or in vitro for their biological and toxic
effects and potential clinical applications
The screening of anti-arrhythmics is done by two
different methods.
• In-vitro models
• In-vivo models
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5. IN VIVO MODELS
• Chemically induced arrhythmia
• Electrically induced arrhythmia
• Exercise induced ventricular fibrillation
• Mechanically induced arrhythmia
• Genetically induced arrhythmia
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6. CHEMICALLY INDUCED ARRHYTHMIA
• A large number of agents are capable of
inducing arrhythmias
• Administration of anesthetics like chloroform,
ether, halothane followed by a precipitating
stimulus such as adrenaline, ouabain alkaloids
cause arrhythmia
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7. PURPOSE AND RATIONALE:
Aconitine – acts persistently on sodium
channels and activates them – ventricular
arrhythmias
REQUIREMENTS:
Animals - Male Ivanovas rats (300-400g)
Anesthetic – Urethane
Standard drug – Procainamide i.v (5mg/kg)
Lidocaine i.v (5mg/kg)
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8. PROCEDURE
Animals – selected

Anesthetized


Test / std/control – administered
↓
Aconitine (5μg/kg +0.1N HNO₃) (administered through
saphenous vein)
↓
ECG – Recorded
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9. •
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EVALUATION
•Ventricular tachycardia
•Ventricular fibrillation
•Death
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10. • Electrical stimulations – flutters and
fibrillation
REQUIREMENTS :
• Animals – adult dogs (8-12kg)
• Anesthetic – sodium pentobarbital (35mg/kg)
ELECTRICALLY INDUCED ARHYTHMIAS
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11. PROCEDURE
Animal – selected
↓
Anesthetized
↓
Artificial respiration – Harvard respiratory pump
B.P – monitored
Body temperature – maintained by thermal blanket
↓
Chest cavity is opened
↓
Heart suspended in pericardial cradle
↓
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12. ↓
SA node – crushed
↓
For electric impulse – Ag-AgCl electrode embedded in a teflon
disc- sutured on left ventricle
↓
Test drug/ std/contol – femoral artery
↓
Constant current for 400ms is applied through electrode
↓
Recording elecrodes – surface of each ventricle
↓
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13. Recording elecrodes – surface of each ventricle
↓
ECG – monitored
↓
VFT is measured (minimal current intensity required to induce
sustained ventricular fibrillation)
When VF occurs – heart is defibrillated – recovered
EVALUATION
Ventricular Fibrillation Threshold
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14. EXERCISE INDUCED VENTRICULAR
FIBRILLATION
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REQUIREMENTS
Animals – Mongrel dogs (15 -19 kg)
Anesthetic – Sodium pentobarbitone (10mg/kg) i.v.

15. SURGICAL PREPARATION
Animals – selected
↓
Anesthetized
↓
Chest cavity – opened
↓
Heart suspended in pericardial cradle
↓
around left artery – Doppler flow inducer- to measure blood
pressure _
hydraulic occluder – place to occlude coronary
artery
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16. ↓
Pair of insulated silver coated wires – sutured on left and right
ventricles- measure HR
↓
Occlusion of LAD
↓
Myocardial infarction
↓
After 24 hrs- test drug/std/control - administered
During this experiment:
• Transdermal fentanyl patch (↓post operative discomfort)
• Bupivacaine HCl
• Antibiotic therapy(amoxicillin)
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17. 3-4 weeks after the production of MI
↓
Animals – run on a motor –driven treadmill
↓
Work load - ↑every 3 min for total of 18 mins
↓
During last minute-treadmill is stopped- left
artery- occluded for 2 mins
↓
After 10-20 sec of VF – defibrillation is achieved without
any delay by placing large metal plates across animal’s
chest
EVALUATION:
HR is measured
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18. MECHANICALLY INDUCED ARRHYTHMIA
Arrhythmias –induced directly by ischemia and
reperfusion
• Coronary artery ligation in anesthetized dog
results in:
↑ in HR
↑in heart contractility
↑ in BP
Ventricular arrhythmias
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19. REQUIREMENTS
Animals – Dogs (20-25Kg)
Anesthetic – Thiobutobarbital sodium (30mg/kg)
PROCEDURE:
Animals – selected
↓
Anesthetized
↓
Artificial respiration – positive pressure respirator
↓
Femoral artery – cannulated and connected to pressure transducer
↓
Chest cavity –opened
LAD is exposed
↓
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20. Silk suture is placed around LAD
↓
After 45 min(equilibration) – test/std/control-
administered through saphenous vein
↓
After 20 min- ligature of coronary artery is closed for 90
min
↓
Occlusion released – reperfusion period maintained for
30 min.
• All the parameters – recorded
• At the end – surviving animals are sacrificed by an
overdose of Pentobarbital sodium
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21. EVALUATION
• Mortality
• Hemodynamics
• Heart rate
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