PHARMACOLOGY OF ANTI- ARRYTHMIC DRUGS

By: Prasanna kumar 11T21S0112

Guide: Dr. VIJAY R CHIDRAWAR

M.pharm Phd.

CONTENTS

Electric Conducting System of Heart Cardiac Action Potential Normal ECG Classificatioln of Arrythmias Pharmacology of Anti-Arrythmic Drugs Newer Drugs Summary

ELECTRICAL CONDUCTING SYSTEM

1. SA node

2. AV node
3. Bundle of His

4.Left and Right

bundle branches 5. Left and Right anterior fascicles

CARDIAC ACTION POTENTIAL

Phase 0 Rapid depolarisation (Na +

entry)

30 mV 0 mV

Phase 1 Phase 2

Phase 1- Inactivation of sodium channels

Phase 2 (Plateau) Inward movement

of Ca2+ and outward movement of K+

Phase 3

Phase 0
Phase 4

Phase 3- Rapid repolarisation Phase 4 resting membrane potential - 90 mV

VARIOUS SEGMENTS IN ECG

P Wave- potential

generated when atria

depolarise before contraction begins

QRS complex potential generated when ventricles

depolarize before
contraction T wave Potential

generated as the
ventricels recover from the state of

depolarisation.

MECHANISM OF ARRHYTHMIAS

Delayed after- depolarisation is caused by an inward current assocaite with abnormally raised intracellular Ca2+ which triggers ectopic beats. Re- entry is resulting from partial conduction block facilitated when parts of the myocardium are depolarised as a result of diesease. Ectopoic pacemeaker activity which is enocuraged by sympathetic activity. Heart block results from disesae in the conducting system, especially the AV node.

ATRIAL FIBRILATION

Atrial fibrillation is an extremely (400 to 600 atrial beats per minute) and disorganized atrial activation ECG of patient with Atrial fibrillation shows no P waves from the atria or only a fine, high-frequency, very low voltage wavy record. The QRS-T complexes are normal , but their timing is irregular

CLASSIFICATION OF ARRHYTHMIAS
1. Tachy Arrhythmias: a) Supraventricular tachycardia Atrial fibrillation or atrial flutter Paroxymal supraventricular tachycardia Automatic atrial tachycardia b) ventricular arrhymias: premature ventricular complexes(pvcs) ventricular tachycardia torsade depointes ventricular fibrilation 2. Brady arrhythiamas: Sinus brady cardia Heart block

ATRIAL FLUTTER

This arrhythmia is characterized by rapid (270 to 330 atrial beats per minute) but regular atrial activation The slower and regular electrical activity results in a regular ventricular response .

ECG of patient with Atrial flutter shows strong P waves because of contraction of semicoordinate masses of muscle.

PAROXYSMAL TACHYCARDIA

Life-threatening symptoms (syncope, hemodynamic collapse) are associated with extremely rapid rate (e.g., >200 beats per minute) and atrial fibrillation associated with an accessory AV pathway. ECG of PSVT commonly shows a rapid, narrow-QRS-complex tachycardia, regular in rhythm, that starts and stops abruptly. Atrial activity, although present, is difficult to ascertain on surface ECG because P waves are buried within the QRS complex or T wave.

PREMATURE VENTRICULAR COMPLEXS(PVCS)

PVCs are very common ventricular rhythm disturbances that occur in patients with or without heart disease. Experimental models have shown that premature ventricular depolarizations may be elicited by abnormal automaticity, triggered activity, or re-entry mechanism. Patients with some forms of PVCs are at higher risk for sudden death than if they did not have these minor rhythm disturbances

VENTRICULAR TACHYCARDIA

Ventricular tachycardia is a wide-QRS-complex tachycardia that may occur acutely as a result of metabolic abnormalities, ischemia, or drug toxicity or recur chronically as a paroxysmal form An acute episode of ventricular tachycardia may be precipitated by severe electrolyte abnormalities (hypokalemia), hypoxemia, digitalis toxicity or heart failure. On ECG inspection, ventricular tachycardia may appear as either repetitive monomorphic or polymorphic ventricular complexes.

TORSADE DE POINTES

It is a rapid form of polymorphic ventricular tachycardia that is associated with evidence of delayed ventricular repolarization (long QT interval or prominent U waves) on surface ECGs Acquired forms of TdP are associated with electrolyte disturbances , subarachnoid hemorrhage, myocarditis, liquid protein diets, arsenic poisoning, hypothyroidism, or most commonly, drug therapy.

VENTRICULAR FIBRILLATION

By definition, VF results in hemodynamic collapse, syncope, and cardiac arrest. Ventricular fibrillation is electrical anarchy of the ventricle resulting in no cardiac output and cardiovascular collapse

Patients who have sudden cardiac death .

SINUS BRADYCARDIA

Sinus bradyarrhythmias (heart rate <60 beats per minute) is a common finding, especially in young, athletically active individuals. Thus the patient may experience paroxysmal episodes of dizziness or syncope because of sinus arrest

ATRIOVENTRICULAR BLOCK
AV block usually is categorized into three different types based on surface ECG findings. First-degree AV block is 1:1AVconduction with a prolonged PR interval. Second-degree AV block is divided into two forms: Mobitz I AV block (Wenkebach periodicity) is less than 1:1 AV conduction with progressively lengthening PR intervals Mobitz II AV block is intermittently dropped ventricular beats in a random fashion without progressive PR-interval Third-degree AV block is complete heart block where AV conduction is totally absent (AV dissociation).

ANTI ARRYTHMIC DRUGS

Class I: block sodium channels Ia (quinidine, procainamide, disopyramide) AP Ib (lignocaine) AP Ic (flecainide) AP

Phase 1

Class II: -adrenoceptor antagonists (atenolol, sotalol) Class III: prolong action potential and prolong refractory period (suppress re-entrant rhythms) (amiodarone, sotalol) Class IV: Calcium channel blockers. Impair impulse propagation in nodal and damaged areas (verapamil, Diltiazem)

IV
0 mV Phase 0 Phase 2

III

-80mV

Phase 4

II

ANTI ARRYTHMIC DRUGS SUBCLASS I A

o

Lengthen action potential Slow rate of rise of phase 0 Prolong repolarization Prolong refractoriness by blocking several types of potassium channel

Prolong PR, QRS, QT

Moderate-marked sodium channel blockade in Open state E.g, quinidine, procainamide, disopyramide

ANTI ARRHYTHMIC DRUGS- QUINIDINE

Dextroisomer of Quinine: N+ channel blocking and antivagal action Actions:

Inhibition of Na channel slanted O phase and Decreases phase 4 Net result is delay in conductivity and increase in refractoriness Other actions include alpha blockade, decreased skeletal muscle contractility, vomiting and diarrhoea etc

Kinetics: well absorbed orally, half life 10 Hrs

Uses:

Broad spectrum antiarrhythmic Atrial fibrillation and flutter, AF after direct current cardioversion to maintain sinus rhythm, prevention of PSVT and prevention of VT

Adverse effects: Proarrhythmia (torsades de pointes), sudden cardiac arrest, cinchonism etc.

PROCAINAMIDE

Procaine derivative (amide) has Identical action with quinidine except:

Minimal antivagal action Lesser suppression of ectopic automaticity Lesser depression of automaticity and AV conduction No alpha blocking action

Kinetics:

Absorbed orally and bioavailability is 80% Metabolized in liver to N-acetyl-procainamide (NAPA) blocks K channel and

prolongs repolarization
Dosage 250 mg tabs and 1gm/ml injections

Uses: Mainly for monomorphic VTs and to prevent recurrences

CLASS II

They act indirectly on Electrophysiology by blocking beta-adrenergic receptor, prolong PR interval, but no effects on QRS or QT interval

Block -1 receptor in heart and decreases heart rate

Adrenline causes ventricular extrasystole and fibrillation by increasing the slope of phase 4 depolarization Also increases spontaneous firing of SA node

Blocks AV conduction

Uses:

Reduce mortality after MI Arrhythmias associated with increased sympathetic activity sinus tachycardia, atrial extrasystoles provoked by emotion and exercise

Less effective in PSVT than adenosine and verapamil

CLASS III

Class III drugs K channel blockers prolong repolarization (increase refractoriness) by blocking outward potassium conductance Prolongation of Cardiac action potential Also have interaction with the ANS Diverse Pharmacology which is poorly understood

Drugs Ibutilide, dofetilide, sotalol (II + III action), amiodarone and bretylium Bretylium is used only in life threatening arrhythmias

AMIODARONE
MOA: Long acting and highly lipophillic Weak class I, II (beta- blocker) and class IV actions Depresses automaticity of SA and AVN Also non-competitive alpha and beta blocking property Also direct coronray and peripheral vasodiltor Kinetics: Incompletely and slowly absorbed daily oral dose is give for several days for actions tto develop, t1/2 = 3-8 weeks Dose: 400-600 mg/day p.o for many days followed by 100-200 mg/day as maintenance (100-300 mg slow IV)

AMIODARONE
Uses: Most tachyarrhythmic conditions ventricular and supraventricular

Recurrent VT and VF

WPW syndrome Adverse effects: Photosensitization Peripheral neuropathy Myocardial depression bradycardia Pulmonary alveolitis and fibrosis Cornel micro deposits hypothyroidism

CLASS IV

Relatively selective AV nodal L-type calcium channel blockers slow sinus rhythm, prolong PR interval, no effect on QRS complex Negative ionotropic effect interference with Ca++ mediated contraction

DRUGS: (Verapamil, diltiazem and bepridil)

MOA: Block L-type channels Phase 4 depolarization of SA and PF reduced Reduce slow inward current and force of contraction Also slow conduction of AV node due to calcium channel blockade

CLASS IV

Uses: (Verapamil) PSVT: Reduce ventricular rate in Atrial fibrillation (AF)

ADR :

Negative ionotropic effect AV block Hypotension, Ventricular Fibrillation

NEWER DRUGS

Dronedarone: It is a benzofuran derivative of amiodarone. It acts by blocking K+ currents. Tecadenoson: It is an Adenosine receptor blocker. It terminates PSVT Tedlisamil: Blockade of multiple K+ channels. It lengthens monophasic Action Potential and Refractory Period Azimilide: Exerts its effects by blocking K+ currents

SUMMARY

Anti-arrhythmic drugs are classified by their effect on the cardiac action potential An ideal antiarrhythmic drug should target ectopic pacemakers and rapidly depolarizing tissues to a greater extent than normal tissues of the heart Many of the Na and Ca channel blockers have this property because they preferentially block sodium and calcium channels in the depolarized tissues Most of the drugs exhibit mixed action In clinical practice treatment of arrhythmias is determined by the type of arrhythmia (SVT, VT) and clinical condition of the patient Anti-arrhythmic drugs are efficacious but may have serious adverse effects Not all arrhythmias are treated with drug therapy alone

THANK YOU