Updates on antiarrhythmic drugs

Classification of antiarrhythmic drugs  Sicilian Gambit  channel blocking, receptor activation and ionic pump The Vaughan William’s Classification of AAD is based on their effects o

Updates on antiarrhythmic drugs

Dr TEO Wee Siong

MBBS (S’pore), M Med (Int Med), FAMS, MRCP (UK), FRCP (Edin), FACC, FHRS

President, APHRS

Mt Elizabeth Hospital, Singapore

Senior Advisor, Electrophysiology & Pacing

Department of Cardiology

National Heart Centre, Singapore

Antiarrhythmic Therapy

 General Medical measures

 electrolytes, sedation, acid base

 Pharmacotherapy

 Anti-arrhythmic drugs

 Drug treatment of etiologic factors – upstream therapy

 Electrical and Device therapy

 cardioversion, pacing, defibrillation

 Surgery

 antiarrhythmic surgery, revascularization

 Catheter Ablation

Depolarization

Rapid repolarization

Final repolarization Plateau

Resting potential Spontaneous

depolarization

Basic Cellular Electrophysiology

Basic Mechanism of Arrhythmias

Classification of antiarrhythmic drugs

 Sicilian Gambit

 channel blocking, receptor activation and ionic pump

The Vaughan William’s Classification of AAD is based

on their effects on the cardiac action potential (AP)

Class Action Drug

I Sodium Channel Blockade IA: Disopyramide

Quinidine Procainamide IB: Lidocaine

Mexiletine IC: Flecainide

Propafenone

III Potassium Channel Blockade Amiodarone

Sotalol

IV Calcium Channel Blockade Calcium Channel Blockers

Vaughn-Williams Classification of Antiarrhythmic Drug Actions

Cellular basis for action of antiarrhythmic drugs

Class 1 antiarrhythmic drugs

 Membrane stabilizers

 Main site of action

 blocks membrane Na channels

 inhibits fast inward Na current

 Results in

 reduction in velocity of action potential upstroke (phase 0)

 decrease in the max amplitude achieved (phase 1)

 prolong phase 3 repolarization of the action potential or the refractory period

 reduces conductivity, excitability and automaticity

 Continuous infusion 2-4 mg/min (20-80 mcg/kg/min)

 Oral Procainamide durules 1 gm tds

 Indicated for acute conversion of WCT, VT,

preexcited AF

 Side effects

 Hypotension

 Gastrointestinal – nausea, diarrhoea

 Drug induce SLE (allergic skin rash, arthralgia)

 Proarrhythmia – can result in incessant VT

Quinidine

• Type IA antiarrhythmic

• Indicated for atrial fibrillation and ventricular

tachycardias, Brugada syndrome

• Adverse effects

 Quinidine Syncope and Torsade de pointes

 Hypotension

 Cinchonism (headache, dizziness, tinnitus, deafness)

 Hypersensitivity reactions (hepatitis, thrombocytopenia)

 GIT (diarrhea, nausea, vomiting)

Cinchona succirubra

•Quinidine

•Chinine

Quinidine-Prolong QT- TdP

Class 1b

potential and QT interval

Clinical use Ventricular arrhythmias

Side effects CNS - confusion, tremors, fits

 Can use for AF, WPW, PVCs, Nonischemic VT, CPVT

 Generally used for patients WITHOUT structural heart disease

 ADVERSE EFFECTS

 Increase risk of Sudden Death when used in patients with ischemia and structural heart disease, LV dsyfunction (CAST Trial)

 Proarrhythmic effect – AFl with 1:1, VT

 Flecainide- Known for increasing pacing thresholds

 Propafenone – metallic taste, beta blocker side effect, constipation

In CAST I, encainide and flecainide treated pts had a 3.6 fold excessive risk of arrhythmic death compared with placebo treated pts

Class II - Beta blockers

Action Blocks AV node

Drugs Propranolol, Metoprolol, Bisoprolol, Nadolol

Clinical use Outflow tract PVCs, NSVT

Class III

channel tissue without significant effect on conduction and depolarization

Sotalol

 Nonselective β- adrenergic receptor antagonist with type III antiarrhythmic activity

 Clinically used for the treatment of :

For treatment of supra & ventricular arrhythmias in pediatric age

group

 Adverse reaction

• Torsade de pointes - Do not initiate if QT > 450 ms

Amiodarone

 Type III antiarrhythmic agent

 Contains alpha- & beta-receptor blocking

properties as well as sodium-, potassium-, &

calcium- channel blocking properties

 Clinical use of amiodarone:

 Recurrent & refractory ventricular & supraventricular arrhythmias

 Arrhythmias associated with WPW syndrome

 Maintaining sinus rhythm in patients with AF

SCD-HeFT NYHA Class III

Amiodarone – higher mortality

CTAF- Kaplan-Meier estimates of patients

remaining free of recurrence of AF

Roy D et al New Engl J Med 2000;342:913-920

Amiodarone - side effects

Intravenous Hypotension

Oral

Photosensitivity and dermatitis

Digoxin

• Action:

• Vagolytic effects slow heart rate and conduction through

Adenosine

 Half life very short 0.6-1.5 seconds

 Given as rapid IV push (6 mg over 1-2 sec) , flush with saline

 If no effect after 1-2 min, give 12 mg; may repeat 12 mg dose once

 Main disadvantage is the cost

 Unwanted effects are transient The duration of effect is less than 60 s

 Side effects- flushing, bronchospasm, chest pain, transient AV block

 Contraindicated in pts with asthma, pts taking dipyridamole or

theophylline

Magnesium

or 2-4 gm over 20-60 mins

Newer Antiarrhythmic drugs

Dronedarone vs amiodarone

Connolly S

Dronedarone – Adverse reactions

Ranolazine

 Ranolazine is a drug that exerts antianginal and antiischemic effects

without impacting heart rate or bp

 At therapeutic levels, ranolazine inhibits the late phase of the inward sodium channel (late INa) in ischemic cardiac myocytes, reducing

intracellular sodium concentrations This channel inhibition results in a reduction in calcium influx via Na+-Ca2+ exchange, translating into

decreased oxygen consumption

 At higher concentrations, ranolazine inhibits the rapid delayed rectifier potassium current (IKr) thus increasing the ventricular action potential duration and prolonging the QT interval

 For atrial arrhythmias, ranolazine is synergistic with Dronedarone and further suppresses AF without increasing proarrhythmia hazard

Scirica B European Society of Cardiology Congress 2007; September

Bradycardia <45 beat per minute,

complete heart block, or pause >2.5 sec

Harmony Trial –

Ranolazine and Dronedarone

Reiffel J et al Circ Arrhythm Electrophysiol 2015;8:1048-1056

Fragakis N et al Am J Cardiol 2012;110:673-7

Antiarrhythmic drugs - role

 Major role in acute treatment of arrhythmias

 However may require cardioversion if

hemodynamically unstable or drugs fail

 Long term role more limited

Acute Antiarrhythmic drug treatment

PSVT Adenosine, Verapamil, Amiodarone

Rate control AF Verapamil, Diltiazem, Digoxin,

Amiodarone

AF conversion Class IC drugs-Flecainide, Propafenone

VT Lignocaine, Amiodarone

Use of antiarrhythmic drugs

Class IA Class 1C Sotalol

Amiodarone Lignocaine