Pharmacological screening of anti arrhythmic drugs 3
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Transcript of Pharmacological screening of anti arrhythmic drugs 3
BY: NASREEN SULTANAM-PHARM (PHARMACOLOGY)10T21S0111.
UNDER THE GUIDANCE OF:Dr. T. VEDAVATHIM.PHARM, PhD
CARDIAC ARRHYTHMIASCARDIAC ARRHYTHMIAS
DEFINITION: Deviation from normal
• Origin/Conduction• Rhythm• Rate
Mainly occurs in patient who have acute M.I., taking Digitalis or in anaesthetized patients.
NORMAL ELECTRICAL ACTIVITY OF HEART
CARDIAC ACTION POTENTIAL
ECG
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
TACHYARRHYTHMIAS
Caused by 2 mechanisms:• Increased automaticity• Re-entryDepending on ectopic focus tachyarrhythmiasare classified as • Atrial tachyarrhythmias• Ventricular tachyarrhythmias
ATRIAL TACHYARRYTHMIAS
• Atrial tachycardia: abnormal P wave• Atrial flutters: the heart rate (atrial) is
approximately 300/min• Atrial fibrillation: irregularly spaced QRS
complex with absent P waves.
VENTRICULAR ARRHYTHMIAS
• Ventricular tachycardia: abnormal QRS complex and heart rate- >120beats/min.
• Torsade de pointes: QT prolongation.• Ventricular fibrillation: VF produces rapid, uncoordinated, movement
of the ventricles which produces no pulse. The ECG shows chaotic, bizarre, irregular ventricular complexes.
ANTI-ARRHYTHMIC DRUGS
NEW DRUGS• Conventional anti arrhythmic drugs - ↑risk of
proarrhythmias.• Dronedrone - analogue of amiodrone
(MULTAQ)→ LESS TOXIC.• Vernalakant - atrial selective (↓proarrhythmic
risk)• Ranolazine – anti-anginal atrial selective
HERBAL DRUGS
• Haw thorn – strengthens heart muscle improves blood circulation.• Magnesium – relaxes and calms the heart.• Angelica • Astragalus – heart tonic• Barberry – heart tonic
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
IN-VITRO MODELS
• LAGENDROFF TECHNIQUE:
PROCEDURE Animal – Guinea pig (300-500g)
Animal – selected
Sacrificed (stunning)
heart – removed – placed in Ringer’s solution (37⁰C)
Aorta – located and cut – cannulated with Ringer’s solution (perfused at 40 mm Hg)
Ligature – placed around LAD
Ligature – placed around LAD
Test /std/control - administered.
Occluded for 10 minutes
reperfusion
ECG electrode – pulsatile stimulation, induction of arrhythmia
Heart rate and contractile force –measured
EVALUATION:• Heart rate (chronometer)• Contractile force (force transducer)• Incidence and duration of ventricular
fibrillation or ventricular tachycardia is recorded in the control as well as test group.
IN VIVO MODELS
In vivo models used to screen anti arrhythmic drugs can be divided into five groups:
• Chemically induced arrhythmia• Electrically induced arrhythmia• Exercise induced ventricular fibrillation• Mechanically induced arrhythmia• Genetically induced arrhythmia
CHEMICALLY INDUCED ARRHYTHMIA
• A large number of agents are capable of inducing arrhythmias.
• Administration of anesthetics like chloroform, ether, halothane (sensitizing agents) followed by a precipitating stimulus such as adrenaline, ouabain alkaloids cause arrhythmia.
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)
PROCEDURE:Animals – selected
Anesthetized
Test / std/control – administered
↓Aconitine (5μg/kg +0.1N HNO₃) (administered through
saphenous vein) ↓
ECG – Recorded (lead II)
EVALUATION: • Anti-arrhythmic effect of test is measured by
the amount of Aconitine/100g animal.• Includes:• Ventricular extra systoles• Ventricular tachycardia• Ventricular fibrillation• Death
ELECTRICALLY INDUCED ARHYTHMIAS
PURPOSE AND RATIONALE: • Electrical stimulations – flutters and
fibrillation. REQUIREMENTS :• Animals – adult dogs (8-12kg)• Anesthetic – sodium pentobarbital (35mg/kg)
PROCEDUREAnimal – 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↓
PERICARDIALCRADLE
Heart suspended in pericardial cradle
↓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↓
Recording elecrodes – surface of each ventricle
↓ECG (Lead II) – monitored
↓VFT is measured (minimal current intensity required to induce
sustained ventricular fibrillation)When VF occurs – heart is defibrillated – recovered.
EVALUATION:VFT - determined
EXERCISE INDUCED VENTRICULAR FIBRILLATION
• PURPOSE AND RATIONALE: Tests combining coronary constriction with physical exercise
may resemble most closely the situation in coronary patients
• REQUIREMENTS:
Animals – Mongrel dogs (15 -19 kg)Anesthetic – Sodium pentobarbitone (10mg/kg) i.v.
SURGICAL PREPARATION: Animals – selected
↓Anesthetized
↓Chest cavity – opened
↓Heart suspended in pericardial cradle
↓around left circumflex artery – Doppler flow inducer- to
measure blood pressure - hydraulic occluder - to occlude coronary artery are placed
↓
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)
EXERCISE-PLUS-ISCHEMIA TEST
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 circum flex
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
MECHANICALLY INDUCED ARRHYTHMIA
• PURPOSE AND RATIONALE: Arrhythmias –induced directly by ischemia and
reperfusion• Coronary artery ligation in anesthetized dog
results in:↑ in HR↑in heart contractility↑ in BPVentricular arrhythmias
REQUIREMENTSAnimals – 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↓
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.
EVALUATION
• Mortality• Hemodynamics• ArrhythmiaVentricular fibrillation% animals with VF.
CONCLUSION
Species differences do exist with respect to factors that
determine arrhythmogenesis and no animal model will accurately mimic the human suffering of arrhythmia.
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.
REFERENCES• 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.
• Gupta.S.K: Drug Screening Methods (Pre Clinical Evaluation of New Drug): Second Edition: Jaypee, New Delhi, 2009, Chapter-18, Antiarrhythmics, pg-285-296.
Websites:• Circ.ahajournals.org• Oxfordjournals.org• Onlinejacc.org• Japphysiology.org