ANTI-ARRHYTHMICS

CARDIAC ELECTROPHYSIOLOGY

NORMAL CONDUCTION PATHWAY

ACTION POTENTIAL OF THE HEART

The slope of phase 0 = conduction velocity

Also the peak of phase 0 = Vmax

PACEMAKER ACTION POTENTIAL

EFFECTIVE REFRACTORY PERIOD (ERP)

It is also called as absolute refractory period (ARP) In this period the cell cannot be excited It takes place between phase 0 and 3

ARRHYTHMIA/DYSRHYTHMIA Abnormality in the site of origin of impulse, rate or conduction

Automaticity: ability of a cell to depolarize spontaneously

Fastest and steepest phase 4 in SA node

Conductance: phase 0 ARRHYTHMOGENIC MECHANISMS

Disorders in impulse formation or disorders in conduction

Disturbances of impulse formation a) Enhanced/ectopic pacemaker activity determined by ↑ slope of phase 4 b) Triggered activity: the next action potential (“after-depolarizations”) occurs before

phase 4 crosses the threshold potential

After potential in Phase 2 or 3 After potential in Phase 4

Disturbances of impulse conduction a) Re-entry: due to circus movement b) Wolff-Parkinson-White syndrome

ACTION OF DRUGS

Re-entry Wolff-Parkinson-White syndrome

IMPORTANT CARDIAC ARRHYTHMIAS

Extrasystoles (ES): AES, VES, nodal ES

Atrial flutter: Atrial rate: 200-350/min with 2:1 to 4:1 block

Atrial fibrillation: Atrial rate: 350-550/min Asynchronous activation of atrial fibers

Ventricular tachycardia: 4 or more consecutive extrasystoles

Ventricular fibrillation: irregular, rapid, uncoordinated contraction of ventricular fibers Loss of pumping function Leads to sudden cardiac death

Torsades de pointes: twisting of the points

Polymorphic ventricular tachycardia

Paroxysmal supraventricular tachycardia (PSVT): atrial tachycardia with 1:1 conduction (150-200) – due to re-entry or after depolarization

AV block: 1st, 2nd or 3rd degree (complete) TYPES OF ARRHYTHMIAS

Bradyarrhythmias

Tachyarrhythmias POSSIBLE MECHANISMS OF DRUG ACTION

Decrease conduction velocity (block Na+ or Ca+ channels)

Change the duration of the effective refractory period (block K+ channels)

Suppress abnormal automaticity (block Ca2+ channels or block β receptors) CLASSIFICATION Proposed by Vaughan Williams and Singh in 1969

Class Basic mechanism Drugs

I IA IB IC

Sodium channel blockers

Moderate

Weak

Strong

Quinidine, Procainamide

Lignocaine, Mexiletine

Propafenone, Flecainide

II Beta blockers Propranolol, Esmolol, Metoprolol

III Potassium channel blockers Amiodarone, Bretylium

IV Calcium channel blockers Verapamil, Diltiazem

* Biggest problem – anti-arrhythmics can cause arrhythmia!!!

CLASS I DRUGS – Na+ CHANNEL BLOCKERS

CLASS IA DRUGS

Effects on depolarization: Blockade Na+ channels: Activated (phase 0) > inactivated Slows the rate of rise of Phase 0 and decrease conduction of impulse

Effects on repolarization: prolonged repolarisation ↑ ERP

Slow the rate of rise of phase 0 of the action potential

Useful in atrial and ventricular arrhythmias CLASS IB DRUGS

Blockade Na+ channels: Inactivated (phase 2) > activated

Rapidly associate and dissociate from Na+ channels shorten the phase 3 repolarisation, hence decrease the ERP as well as APD

Effective in ventricle arrhythmias and in partially depolarised tissue (ischaemia) as in myocardial infarction more inactivated channels are available

Lignocaine is given I.V. as loading and maintenance dose I.V. due to high first pass metabolism LD and MD dose due to high volume of distribution and short duration of action

Indication: Acute ventricular arrhythmias following myocardial infarction and cardiac surgery

Pharmacokinetics of lignocaine: Inactive orally Distributes rapidly Duration of action: 10-20 minutes Metabolism depends on hepatic blood flow

Adverse effects of lignocaine: drowsiness, slurred speech, paresthesia, agitation, confusion, convulsion, least cardiotoxic (it has no effect on normal myocardium)

CLASS IC DRUGS Effects on depolarization:

Blockade Na+ channels: Activated (phase 0) > inactivated

Dissociates slowly

Have effect on normal myocardium (cause arrhythmias)

Markedly decrease the rate of phase 0 depolarisation in Purkinje and ventricular myocardial fibres

SUMMARY

Sodium channel blockade: IC > IA > IB

Increasing the ERP: IA > IC > IB (↓) ANS REGULATION OF HEART RATE

SNS: β1 receptors: ↑cAMP

PNS: M2 receptors: ↓ cAMP

↑cAMP: ↑ Ca2+ influx ↑ automaticity and conduction in pacemaker cells ↑ K+ efflux Shorten APD

CLASS II DRUGS – β BLOCKERS

SA node: ↓ automaticity Use: Exercise induced arrhythmias, arrhythmias in hyperthyroidism

AV node: ↑ERP Use: to control supraventricular arrhythmias

Prevent re-infarction and sudden cardiac death in post myocardial infarction patients

Uses of esmolol Short acting β blocker Used I.V. in acute arrhythmias

CLASS III DRUGS – K+ CHANNEL BLOCKERS

Block K+ channels

Prolong repolarization

Prolong duration of AP without altering phase 0

Prolong ERP Amiodarone is used commonly

Additional mechanism of action: Blocks inactivated Na+ channels Blocks Ca2+ channels and beta receptors

Hence has a broader spectrum of action

Used in supraventricular and ventricular arrhythmias Adverse effects of amiodarone:

↓BP, bradycardia

Nausea, GI upset

Photosensitization and skin pigmentation

Corneal deposits

Pulmonary alveolitis, fibrosis

Peripheral neuropathy

Liver damage

Abnormality in thyroid status (amiodarone is an iodine containing drug hence causes altered thyroid function)

Less arrhythmogenic CLASS IV DRUGS – Ca2+ CHANNEL BLOCKERS

Inhibit L-type Ca2+ channels

Depress depolarization (phase 0) in automatic fibers decrease conduction in AV node

Decrease in phase 4 spontaneous depolarization decrease automaticity in SA node

Uses of verapamil: Supraventricular arrhythmias PSVT (as first line drug) To control ventricular rate in AF and AFl

ADENOSINE

Naturally occurring nucleoside

Actions: Decreases conduction velocity Prolongs refractory period Mechanism of action: Stimulates adenosine receptors (A1 receptors) opens K+

channels hyperpolarisation in SA and AV nodes and atrium prolongs refractory period, ↓ conduction

Acute supraventricular arrhythmias and PSVT

Pharmacokinetics: t1/2 = 10 seconds taken by RBCs and endothelial cells

Adverse effects: flushing, bronchospasm

Drugs for PSVT Drugs for AV block

Diltiazem

Verapamil

Propranolol

Esmolol

Digoxin

Atropine

Adrenaline

Isoprenaline

Condition Drug Comments

Sinus tachycardia Class II, IV Other underlying causes may

need treatment

Atrial fibrillation/flutter Class IA, IC, II, III, IV, Digitalis Ventricular rate control is

important goal; anti-coagulation is required

Paroxysmal supraventricular tachycardia

Class IA, IC, II, III, IV, Adenosine –

AV block Atropine –

Ventricular tachycardia Class I, II, III –

Premature ventricular complexes

Class II, IV, Magnesium sulphate PVCs are often benign and do

not require treatment

Digitalis toxicity Class IB, Magnesium sulphate –