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