ANTI ARRHYTHMIC DRUG THERAPY

Contents

• Electrophysiology of Heart

• Arrhythmia: Definition, Types, Mechanisms

• Antiarrhythmic drugs: Class I, II , III , IV

• Treatment of arrhythmia : Guidelines

Electrophysiology of Heart

Introduction

Normal conduction pathway

SA node Generates

action potential AV node

Delivers the impulse to

purkinje fibersPurkinje fibers

Conduct the impulse to the

ventricles

SAN

AVN

Impulse conductionNormal conduction pathway

Impulses originate regularly at a frequency of 60-100 beat/ min

Cardiac Action Potential

Divided into five phases (0,1,2,3,4) Phase 4 - Resting phase (resting membrane potential)

Associated with diastole portion of heart cycle Addition of current into cardiac muscle

(stimulation) causes Phase 0 –Opening of fast Na channels

Drives Na+ into cell, changing membrane potential Transient outward current due to movement of Cl- and

K+ Phase 1 – Initial rapid repolarization

Closure of the fast Na+ channels Phase 0 and 1 together correspond to the R and S

waves Keating MT, Sanguinetti MC: Molecular & Cellular Mechanisms of cardiac arrhythmia. Cell 2001;104;569

Cardiac Action Potential (contd) Phase 2 - Plateau phase

Sustained by the balance between the inward movement of Ca+ and outward movement of K +

Long duration compared to other nerve and muscle tissue

Corresponds to ST segment of the ECG Phase 3 – Repolarization

K+ channels remain open, Outward K+ movement, repolarization of cell Closure of K + channels when membrane

potential reaches certain level Corresponds to T wave on the ECG

-100

-80

-60

-40

-20

0

20

Phase 0

Phase 1

Phase 2

Phase 3

Phase 4

Na+ ca++

ATPase

mv Cardiac Action Potential

Resting membrane Potential

Na+m

Na+Na+Na+Na+Na+

hK+

ca++

K+K+K+

ca++ca++

(Plateau Phase)

K+K+K+ Na+

K+

Dep

ola

riza

tio

n

-100

-80

-60

-40

-20

0

20

Phase 0

Phase 1

Phase 2

Phase 3

Phase 4

Na+ ca++

ATPase

mv Cardiac Action Potential

R.M.P

Na+m

Na+Na+Na+Na+Na+

hK+

ca++

K+K+K+

ca++ca++

(Plateau Phase)

K+K+K+ Na+

K+

Dep

ola

riza

tio

nAP curve in pacemaker

Cells

Effective refractory period (ERP) Also called Absolute Refractory Period

(ARP) Period in which cells can’t be excited Takes place between phase 0 and 3

Duan D et al; Functtional role of ion channels in cardiac disease; Acta Pharmacol Sin 2005; 26;265

Arrhythmias

Variation in either the site or rate of cardiac impulse formation, and/or a variation in the sequence of cardiac impulse propagation

Causes: Arteriosclerosis Coronary artery Spasm Heart block Myocardial ischemiaHume RJ, Grant AO, Cardiac arrhythimia ; Katzung Basic & clinical pharmacology, Lange

Medical Publishers,12th ed,2012,pg227-250

Normal heartbeat & Arrhythmia

Normal rhythm

Arrhythmia

AV septum

Mechanisms of Arrhythmogenesis

1 -Abnormal Impulse Generation

Automatic rhythms

Triggered rhythms

Enhanced normal

automaticityEctopic focus

Delayed after daepolarizati

on

Early after depolarizati

on

↑AP from SA node

AP arises from sites other than SA node

Mechanisms of Arrhythmogenesis

2-Abnormal conduction

Conduction block

Reentry

1st degree

2nd degree

3rd degree

Circus moveme

nt

Reflection

When impulse is not conducted

from the atria to the ventricles

Mechanisms of Arrhythmogenesis

Mechanisms of bradycardias: Sinus bradycardia: D/t abnormally slow

automaticity Bradycardia due to AV block: Abnormal

conduction within the AV node or the distal AV conduction system

Mechanisms of tachycardias : - Accelerated automaticity. - Triggered activity - Re-entry (or circus movements)

Mechanisms of Arrhythmogenesis ACCELERATED AUYOMATICITY D/t increase in rate of diastolic

depolarization or changing threshold potential

Can occur in virtually all cardiac tissues and may initiate arrhythmias

Thought to produce sinus tachycardia, escape rhythms and accelerated AV nodal (junctional) rhythms

Mechanisms of Arrhythmogenesis TRIGGERED ACTIVITY Myocardial damage → oscillations of

transmembrane potential → 'after depolarizations’ → threshold potential → Arrhythmia

Can be exaggerated by pacing, catecholamines, electrolyte disturbances, and some medications

Examples : Digoxin toxicity → causes Atrial tachycardias Ventricular arrhythmia in the long QT syndrome

Mechanisms of Arrhythmogenesis

RE-ENTRY (OR CIRCUS MOVEMENT) Occurs when 'ring' of cardiac tissue surrounds

inexcitable core Tachycardia initiated if an ectopic beat finds one

limb refractory (α) resulting in unidirectional block and the other limb excitable

Circus movement will be maintained If: Time to conduct around the ring > Recovery

times (refractory periods) of the tissue within the ring

Majority of regular paroxysmal tachycardias are produced by this mechanism

Reentry Arrhythmias

Normal

Re-enterant

Tachycardia

Mechanisms of Arrhythmogenesis

ABNORMAL ANATOMIC CONDUCTION Bundle of

Kent

•Present only in small populations•Lead to reexcitation Wolf-Parkinson-White Syndrome (WPW)

Types of Arrhythmia

Sinus Tachycardia:

High sinus rate of 100-180 beats/min

Occurs during exercise or other conditions that lead to increased SA nodal firing rate

Atrial Tachycardia:

Series of 3 or more consecutive atrial premature beats occurring at a frequency >100/min

Paroxysmal Atrial Tachycardia (PAT):

Tachycardia which begins and ends in acute manner

Types of Arrhythmia

Atrial Flutter: Sinus rate of 250-350 beats/min.

Atrial Fibrillation: Uncoordinated atrial depolarizations.

AV blocks Conduction block within the AV node ,

occasionally in the bundle of His → impairs impulse conduction from the atria to the ventricles.

Types of Arrhythmia

Ventricular Premature Beats (VPBs): Ectopic ventricular foci; characterized by

widened QRS. Ventricular Tachycardia (VT):

High ventricular rate caused by abnormal ventricular automaticity or by intraventricular reentry

Can be sustained or non-sustained (paroxysmal);

Characterized by widened QRS; rates of 100 to 200 beats/min; life-threatening.

Types of Arrhythmia

Ventricular Flutter:

Ventricular depolarizations >200/min.

Ventricular Fibrillation:

Uncoordinated ventricular depolarizations

Management of Arrhythmia

Management of Arrhythmia

Pharmacological therapy (Antiarrhythmic Drugs)

Cardioversion

Pacemaker therapy

Surgical therapy e.g. aneurysmal excision

Interventional therapy “ablation”

Antiarrhythmic Drugs

Pharmacologic rationale & Goal The ultimate goal of antiarrhythmic

drug therapy: Restore normal sinus rhythm and

conduction Prevent more serious and possibly lethal

arrhythmias from occurring. Antiarrhythmic drugs are used to:

Decrease conduction velocity Change the duration of the effective

refractory period (ERP) Suppress abnormal automaticity

Shrivatsa U, Wadhani M, Singh AB; Mechanisms of antiarrhythmic drug action & their clinical relevance for controlling disorders of cardiac rhythm; Curr Cardiol Rep 2002;4;401

Classification of Antiarrhythmic Drugs

Classified a/c to Vaughan William into four classes

Class Mechanism Action Notes

INa+

channel blocker

Change the slope of phase 0

Can abolish tachyarrhythmia

caused by reentry circuit

II β blocker ↓heart rate and conduction velocity

Can indirectly alter K and Ca conductance

III K+ channel blocker

1. ↑action potential duration (APD) or

effective refractory period (ERP).

2. Delay repolarization.

Inhibit reentry tachycardia

IVCa++

channel blocker

Slowing the rate of rise in phase 4 of SA node(slide

12)

↓conduction velocity in SA and AV node

Classification of Antiarrhythmic Drugs

Phase 0

Phase 1

Phase 2

Phase 3

Phase 4

R.M.P

(Plateau Phase)

Class I:

Na + channel blockers.

- Pacemaker potential

--

-

Class III:K + channel blockers

-Class IV:

Ca ++ channel blockers

Class II:Beta blockers

Classification of Anti-Arrhythmic Drugs

Treatment of tachyarrhythmias:

Class I drugs (Membrane stabilizing drugs) :

Mechanism: Class I drugs block fast Na+ channels, thereby

Reducing the rate of phase 0 depolarization Prolonging the effective refractory periodIncreasing the threshold of excitability Reducing phase 4 depolarization

These drugs also have local anesthetic properties

Woosely RL. Antiarrhythmic drugs. Hurst’s The Heart (Ed. Fuster V, Alexander RW, O’Rourke RA, et al.) 10th edition.2001;1:899–924

Class IA

1. Quinidine Alkaloid – cinchona , dextro isomer of quinine. Blocks sodium channel & potassium channel

also Anti-muscarinic and Alpha blocking action Administered orally & is rapidly absorbed from

gastrointestinal tract Hydroxylated in the liver t1/2 of approximately 5—12 hours, longer in

hepatic or renal disease & in heart failure Bitter and irritant Inhibitor of CYP P450 system.

1. Quinidine

↑↑ plasma conc of digoxin by displacing it from tissue binding sites & decreasing its renal & biliary clearance.

Uses: Atrial fibrillation Ventricular tachycardia

Adverse effects : GIT : Diarrhea, nausea, vomiting and

cinchonism Thrombocytopenia Precipitate torsade de pointes by

prolonging QT interval

1. Quinidine

Drug interactions Increases digoxin plasma levels &risk of

digitalis toxicity t1/2 reduced by agents that induce drug-

metabolizing enzymes (phenobarbital, phenytoin)

May enhance the activity of coumarin anticoagulants & other drugs metabolized by hepatic microsomal enzymes

Cardiotoxic effects exacerbated by hyperkalemia

2. Procainamide

Like quinidine, but Safer to use intravenously Produces fewer adverse GI effects

Acetylated in liver to N-acetylprocainamide (NAPA)

Eliminated by the kidney (t ½ -3 – 5 hrs) More likely than quinidine to produce

severe or irreversible heart failure Adverse effects

SLE like syndrome consisting of arthralgia and arthritis specially in slow acetylators

3. Disopyramide

Prominent anti-cholinergic activity Eliminated by the kidney (t ½ - 4 – 10 hrs) Approved only for ventricular arrhythmia &

Atrial fibrilllation (not a first line) Adverse Events:

Proarrhythmic Urinary retention, Blurred vision, Dry

mouth ( Parasympatholytic) Mild negative ionotrophy

Class IB

1. Lidocaine: Least cardiotoxic : (t ½ - 1.5 - 2 hrs) Block inactivated Na channels : preferred

for partially depolarized cells in ischemic area

High first pass metabolism – not given orally

Used in: Ventricular arrhythmia Digoxin induced arrhythmia

Main toxicity:Neurological – drowsiness, nystagmus &

seizures

2. Mexiletine and Tocainide

Similar in action to lidocaine Can be administered orally T ½ - Mexiletine – 10-12 hrs - Tocanide – 11-23 hrs Used for long-term treatment of

ventricular arrhythmias associated with previous Myocardial Infarction

Adverse events: Mexiletine : Ataxia, dizziness, tremors Tocainide : Blood dyscrasias, pulmonary

fibrosis, GI and neurological symptoms

Moricizine

Phenothiazine

Has properties of class IB, IA, and IC antiarrhythmics,

Use should be limited to life-threatening ventricular arrhythmias

Class IC

Class of potent Na channel blocker

Drugs of this class have negative inotropic effect

High pro-arrhythmogenic potential – sudden death

Class IC

1.Flecainide Orally active antiarrhythmic Metabolized by microsomal enzymes (t ½ -

20 hrs) Used for ventricular tachyarrhythmias &

maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation and/or atrial flutter & WPW

C/I in pts with structural heart disease Adverse events :

Heart failure, dizziness, headache , Blurred vision

2. Propafenone

Spectrum of action similar to that of quinidine Possesses β-adrenoceptor antagonist activity Metabolized by hepatic microsomal enzymes T ½ - 2 – 10 hrs Approved for treatment of supraventricular

arrhythmias and suppression of life-threatening ventricular arrhythmias

C/I in structural heart disease Adverse events:

Nausea, Vomitting, altered taste

Class II

They Are β-adrenoceptor antagonists, including propranolol

Act by reducing sympathetic stimulation Inhibit phase 4 depolarization Depress automaticity Prolong AV conduction Decrease

Heart rate Contractility

Class II

Major drugs Propranolol, a nonselective β-adrenoceptor antagonist

Acebutolol & esmolol, more selective β1-adrenoceptor antagonists

Used to treat ventricular arrhythmias

Propranolol, metoprolol, nadolol, and timolol frequently used to prevent recurrent MI

Class II

Absorption and elimination: Propranolol: oral, iv Esmolol: iv only (very short acting T½, 9

min) Cardiac effects

APD and refractory period in AV node to slow AV conduction velocity

decrease phase 4 depolarization (catecholamine dependent)

Class II

Uses: Treating sinus and catecholamine

dependent tachyarrhythmias Converting reentrant arrhythmias in AV Protecting the ventricles from high atrial

rates Side effects:

Bronchospasm Hypotension  Don’t use in partial AV block or

ventricular failure

Class III

Class III drugs: Prolong action potential duration Prolong effective refractory period

Act by: interfering with outward K+

currents or slow inward Na+ currents

Class III

1. Amiodarone

Structurally related to thyroxine. Net effect:

Increases refractoriness Depresses sinus node automaticity Slows conduction.

Long half-life (14—100 days) ↑ risk of toxicity Plasma conc not well correlated with its effects After parenteral administration:

Electrophysiologic effects →within hours Effects on abnormal rhythms may not be seen

for several days

1. Amiodarone

Antiarrhythmic effects may last for weeks or months after the drug is discontinued

Uses: Refractory life-threatening ventricular arrhythmias in preference to lidocaine

T/t of atrial and/or ventricular arrhythmias

Adverse effects Pulmonary fibrosis Skin pigmentation Corneal deposits Interferes with the thyroid function

2. Ibutilide

Administered by intravenous infusion Pure Ikr channel blocker

Also activates inward Na+ current Net result in APD Causes QT Uses :

Conversion of atrial fibrillation and flutter       Side effects :

Torsades de pointes

3. Sotalol

Prolongs the cardiac action potential Increases the duration of the refractory period Has nonselective β-adrenoceptor antagonist

activity Uses:

Atrial arrhythmias or life-threatening ventricular arrhythmias

Treatment of sustained ventricular tachycardia Adverse effects:

Proarrhythmic actions, dyspnea, and dizziness

4. Dofetilide

Administered orally APD and refractory period Potent inhibitor of K+-channels Used in T/t of atrial fibrillation or atrial

flutter Adverse effects:

Serious arrhythmias, Torsades de pointes

5.Bretylium Also has some direct antiarrhythmic

action. Has properties of class II drugs Used for T/t of Ventricular arrhythmia

after lidocaine failure

Class IV

Mechanism

Class IV drugs selectively block L-type calcium channels.

These drugs prolong nodal conduction and effective refractory period and have predominate actions in nodal tissues

Class IV

Verapamil

Phenylalkylamine that blocks both activated and inactivated slow calcium channels.

Tissues that depend on L-type calcium channels are most affected

Has equipotent activity on the AV and SA nodes and in cardiac and vascular muscle tissues

Useful in: Supraventricular tachycardia Atrial flutter and fibrillation

Verapamil

Adverse effects:

Negative inotropic action that limits its use in damaged hearts;

Can lead to AV block when given in large doses or in patients with partial blockage.

Can precipitate sinus arrest in diseased patients

Causes peripheral vasodilation.

Miscellaneous Antiarrhythmic Drugs Adenosine

Acts through specific purinergic (P1) receptors. Causes an increase in potassium efflux and

decreases calcium influx. This hyperpolarizes cardiac cells and decreases

the calcium-dependent portion of the action potential.

Drug of choice for the treatment of paroxysmal supraventricular tachycardia, including those associated with Wolff-Parkinson-White syndrome

Digoxin

Mode of action: Na-K ATPase inhibition Positive inotrope Vagotonic

T ½ - Premature (61hrs), Neonate (35hrs), Infant (18hrs), Child (37hrs), Adult (35-48hrs )

Uses: Supraventricular Tachycardia

Digoxin

Interactions: Coumadin- ↑ PT ↑ Digoxin level Quinidine, amiodarone, verapamil ↓ renal function/renal tubular excretion

(Spironolactone) Worse with ↓ K+, ↓ Ca++

Digoxin Toxicity

Proarrhythmic Causes nausea/vomiting, lethargy,

visual changes Metabolic

Hyper K+, Ca++

Hypo K+, Mg++

Hypoxemia Hypothyroidism

Investigational Drugs

Analogs of Amiodarone are being developed such as: ATI-2001 Dronedarone SR-33589

Dronedarone: Resonable safety profile Well characterized pharmacokinetic &

pharmacodynamic profile Effective in doses lower than 2000 mg/dayWolbrette D et al ; Dronedarone for the treatment of atrial fibrillation and atrial flutter: Approval and efficacy ; Vasc Health Risk Manage 2010;6;517

Investigational Drugs

Azimilide : Potassium-channel blocking properties Prolongs cardiac AP & refractory periods Found to be effective in patients with

symptomatic tachyarrhythmias and ICDs therapies in recent studies

Other drugs, such as Ambasilide, are also in clinical development

Chromanol 293B is in preclinical testing

Reynolds RM, Josephson ME. Sustained ventricular tachycardiain ischemic cardiomyopathy : current management. ACC Current Journal Review 2005;14:63-71

Treatment of bradyarrhythmias

Atropine Blocks the effects of acetylcholine. Elevates sinus rate and AV nodal and

sinoatrial (SA) conduction velocity, & decreases refractory period

Used to treat bradyarrhythmias that accompany MI

Adverse effects: Dry mouth, mydriasis, and cycloplegia; May induce arrhythmias.

Treatment of bradyarrhythmias Isoproterenol

Stimulates β-adrenoceptors Increases heart rate and contractility. Uses: Maintain adequate heart rate and

cardiac output in patients with AV block Adverse effects:

Tachycardia, Anginal attacks Headaches, Dizziness Flushing, and tremors

T/t of Atrial Flutter/Fibrillation1. Reduce thrombus formation by using

anticoagulant warfarin2. Prevent the arrhythmia from converting to

ventricular arrhythmia First choice: class II drugs:

After MI or surgery Avoid in case of heart failure

Second choice: class IV drugs Third choice: digoxin

Only in heart failure of left ventricular dysfunction

T/t of Atrial Flutter/Fibrillation3. Conversion of the arrhythmia into normal

sinus rhythm Class III: IV ibutilide, IV/oral amiodarone, or oral sotalol Class IA: Oral quinidine + digoxin (or any drug from the

2nd step) Class IC: Oral propaphenone or IV/oral flecainide Use direct current in case of unstable

hemodynamic patient Fuster V et al; ACC/AHA/ESC Guidelines for the management of patients with atrial fibrillation. Circulation 2006;114;700

T/t of Ventricular Arrhythmia Premature ventricular beat (PVB) First choice: class II

IV followed by oral

Early after MI

Second choice: amiodarone

Avoid using class IC after MI ↑ mortality

T/t of Ventricular Tachycardia First choice: Lidocaine IV

Repeat injection if needed

Second choice: procainamide IV

Adjust the dose in case of renal failure

Third choice: class III drugs

Especially amiodarone and sotalol

Grant AO, Recent advances in the treatment of arrhythmia. Circ J 2003;67;651

Thank You