ANTIARRHYTHMIC DRUGS

Dr. Kunal A. Chitnis1st Year Resident

TNMC, Mumbai

17th September 2010

SA Node fires at 60-100 beats/sec

Spreads through atria

Enters the AV Node(Delay of 0.15 sec)

Propagates through His Purkinje system

Depolarizes ventricles beginning from endocardial surface of apex to

epicardial surface of base

Normal Sinus Rhythm

Movement of ions across cell membrane

• Ions move across in response to electrical and concentration gradients

• Pass through specific ion channels or transporters

• The Equilibrium/Reversal potential is given by the

Nerst equation:

Eion= - 61Log(Ci/Ce)

• The Resting Membrane Potential of the cell is -95mV

• The cell maintain this transmembrane ionic gradient by

1. Active mechanisms like the Na+ pump and Na+/K+ ATPase (Electrogenic)

2. Fixed anionic charges within the cell

No Net movement

Net movement inside the cell

EK -94 ENa +65

Phase 0:RapidDepolarisation

(Na+ influx)

Phase 1:Early Repolarisation(Inward Na+ current

deactivated,Outflow of K+):

Transient Outward Current

Phase 2:Plateau Phase

(Slow inward Ca2+ Current balanced by outward delayed rectifier K+ Current)

Phase 3:Late Repolarisation

(Ca 2+current inactivates,K+ outflow)

Action Potential of Cardiac Muscle

Action Potential of SA Node

RMP not stable and full repolarisation at -60mV

Spontaneous Depolarisation occurs due to:

• Slow, inward Ca2+ currents• Slow, inward Na+ currents called “Funny Currents”

-50mV T-type Ca2+ channels

-40mV L-type Ca2+ channels

-35mV

Phase 3:Repolarisation

Action Potential in AV Node

• Very similar to SA Node

• Causes delay of conduction

• It gives time for atrial contraction and filling of the ventricles.

• Site of action of many antiarrhythmics

Regulation by autonomic toneParasympathetic/Vagus Nerve stimulation:

• Ach binds to M receptors, releasing G protein βγ subunits

• Activate Ach dependent K+ current

• ↓ slope of Phase 4

Sympathetic stimulation:

• Activation of β1 receptors

• Augmentation of L-type Ca2+ current and funny currents

• ↑ slope of Phase 4

Refractoriness

• Effective/Absolute Refractory period: During this period, depolarization on adjacent cardiac muscles does not produce a new depolarization.

• Protective mechanism and keeps the heart rate in check, prevents arrhythmias and coordinates muscle contraction

• During the plateau phase, max Na+ channels are in inactivated state, therefore refractory

• Upon repolarisation, recovery occurs from the inactivation state to closed state

• Only channels in closed state can be depolarised• It extends from phase 0 uptill sufficient recovery

of Na channels. • Changes in the ERP:

1. Altered recovery from inactivation

2. Action Potential Duration alteration

ERP of Fast responsive tissue

• Dependent on Na+ channels recovery

• Voltage dependent

ERP of Slow Responsive/ Nodal tissue

• Dependent on Ca2+ channels recovery

• Time dependent/ decremental response

Cardiac Arrhythmias

Arrhythmia means an Abnormal heart rhythm

Results from the abnormalities of:

Impulse generation (Rate or Site of origin)

Conduction Both

Classification of Arrhythmias1. Characteristics:

a. Flutter – very rapid but regular contractionsb. Tachycardia – increased ratec. Bradycardia – decreased rated. Fibrillation – disorganized contractile activity

2. Sites involved:

a. Ventricularb. Atrialc. SA Noded. AV Node

Supraventricular

Mechanisms of Cardiac Arrhythmias

(A) Enhanced Automaticity:

• In cells which normally display spontaneous diastolic depolarization (SA Node, AV Node, His-Purkinje System)

• Automatic behavior in sites that ordinarily lack pacemaker activity

A normal cardiac action potential may be interrupted or followed by an abnormal depolarization

Reaches threshold & causes secondary upstrokes

2 Major forms:

1. Early Afterdepolarization2. Late Afterdepolarization

(B) Afterdepolarization and Triggered Automaticity

1. Early Afterdepolarization

•Phase 3 of repolarization interrupted

•Result from inhibition of Delayed Rectifier K+ Current

•Marked prolongation of Action Potential

•Slow heart rate, ↓ Extracellular K+, Drugs prolonging APD

2. Late Afterdepolarizations

•Secondary deflection after attaining RMP

•Intracellular Ca2+ overload

•Adrenergic stress, digitalis intoxication, ischemia-reperfusion

(C) Re-entrant Arrhythmia

Defined as circulation of an activation wave around an inexitable object

3 requirements for Re-entrant Arrhythmia:

1. Obstacle to conduction

2. Unidirectional block

3. CT>ERP

Unidirectional Block

Establishment of Re-entrant circuit

Requirement to treat an arrhythmia:

1. ↓ CO:• Slow contractions (bradyarrhythmias)• Fast contractions (tachyarrhythmias)• Asynchronous contractions (V Tach, V Fib)

2. Convert to serious Arrhythmias:• Afl → VTach, V Tach → VF

3. Thrombus formation:• AF→ Stasis in Atrium→ Thrombus formation→ Embolism

Management Of Arrhythmias

Management

• Acute Management• Prophylaxis

• Non Pharmacological• Pharmacological

Non Pharmacological• Acute1. Vagal Maneuvers

2. DC Cardioversion

• Prophylaxis1. Radiofrequency Ablation

2. Implantable Defibrillator

• Pacing (Temporary/ Permanent)

Pharmacological Approach

Drugs may be antiarrhythmic by:

• Suppressing the initiator mechanism• Altering the re-entrant circuit

1. Terminate an ongoing arrhythmia

2. Prevent an arrhythmia

Drugs may ↓ automatic rhythms by altering:

A. ↓ Phase 4 slope

B. ↑ Threshold potential

C. ↑ Max diastolic potential

D. ↑ Action Potential Duration

Vaughan Williams Classification

Phase 4

Phase 0

Phase 1

Phase 2

Phase 3

0 mV

-80mV

II

IIII

IV

Class I: block Na+ channels Ia (quinidine, procainamide, disopyramide) (1-10s)Ib (lignocaine) (<1s)Ic (flecainide) (>10s)

Class II: ß-adrenoceptor antagonists (atenolol, sotalol)

Class III: block K+ channels (amiodarone, dofetilide,sotalol)

Class IV: Ca2+ channel antagonists (verapamil, diltiazem)

Class I: Na+ Channel Blockers

• IA: Ʈrecovery moderate (1-10sec)

Prolong APD

• IB: Ʈrecovery fast (<1sec)

Shorten APD

• IC: Ʈrecovery slow(>10sec)

Minimal effect on APD

Trecovery is time required to complete approximately 63% of an exponentially determined process to complete

Effect of Na+ channel block on ERP:

The point at which sufficient no. (25%) of Na+ channels recovered from inactivation is prolonged.

↑ ERP thus blocking early extrasystoles

At times, post repolarization refractoriness.

Drug

State Dependent Block of Na+ channels

• Na+ channel blockers binds to channels in open &/or inactivated state, poorly/ not at all to resting state

• Dissociate during diastole • Results in phasic changes in extent of block during AP

Effect of increased heart rate on the Na+ channel block

↑ Na+ channel block as time spent in diastole ↓→↑ERP

Drugs having ↓ Rate of Recovery

Slow dissociation Rate→ ↑ Na+ Channel block→ ↑ ERP

Effect of RMP on Na+ channel Block

• At RMP of -85mV: block is rapidly reversed during diastole

• As RMP↑ : more no. of channels remain in inactivated state→↑ block

• Marked drug binding, conduction block & loss of excitability. Thus sick tissue is selectively inhibited

Ectopic Pacemaker

↓ Upstroke

↑ Threshold↓ Slope phase 4

Block INa

Vm

(mV)

-80mV

0mV

Effect on Re-entrant Arrhythmia

Effect of Class I drugs:

1. ↓ Vmax: Extinguishing of propagating re-entrant wavefront

2. ↑ERP: CT<ERP

Ia Ib IcModerate Na+ channel blockade

Mild Na+ channel blockade

Marked Na+ channel blockade

Slow rate of rise of Phase 0

Limited effect on Phase 0

Markedly reduces rate of rise of phase 0

Prolong refractoriness by blocking several types of K+ channels

Little effect on refractoriness as there is minimal effect on K+ channels

Prolong refractoriness by blocking delayed rectifier K+ channels

Lengthen APD & repolarization

Shorten APD & repolarization

No effect on APD & repolarization

Prolong PR, QRS & QT

QT unaltered or slightly shortened

Markedly prolong PR & QRS

Procainamide (Class Ia)

• Blocks open Na+ channels & Non specific blockade of K+ channels • Ganglion blocking properties, thus can cause hypotension on iv use

• Risk of excessive prolongation of QT interval & torsades de pointes

• Drug induced Lupus Syndrome

• N-acetylprocainamide (NAPA) an active metabolite has class III activity

• NAPA causes APD prolongation but no drug induced lupus

• Fast acetylators: QT prolongation common Slow acetylators: Drug induced Lupus common

• Effective in most atrial & ventricular arrhythmias

Quinidine (Class Ia)

• Diastereomer of antimalarial quinine

• Similar to procainamide

• Cardiac antimuscarinic (vagolytic)

• Risk of torsades due to QT prolongation

• Nausea, diarrhoea, vomiting, cinchonism (headache, dizziness & tinnitus)

Disopyramide (Class Ia)

• Cardiac antimuscarinic effects more marked than quinidine (blurred vision, dry mouth, urinary retention)

• Risk of torsades

• Maintain sinus rhythm in AF/Afl

• To prevent VTach/VF

Lidocaine (Class Ib)

• Highly effective in arrhythmias associated with AMI

• Blocks activated & inactivated Na+ channels with rapid kinetics

• The inactivated channel block ensures greater effects on cells with long action potentials like purkinje fibres & ventricular cells

• Selective depression in depolarized &/or rapidly driven cells

• S/E Seizures, tremors, dysarthria, altered consciouness, nystagmus

• Action terminated by rapid redistribution (t1/2 8mins) & hepatic metabolism(t1/2120mins)

• Given only i.v.

• Termination of ventricular arrhythmias, prevention VF after cardioversion

Mexiletine (Class Ib)

• Orally acting congener of Lidocaine

• Electrophysiological & antiarrhythmic actions similar to Lidocaine

• Other uses: Relieving pain due to diabetic neuropathy & nerve injury

Flecainde (Class Ic)

• Potent blocker of Na+ & K+ channels with slow unblocking kinetics

• Blocks K+ channels but does not prolong APD & QT interval

• Maintain sinus rhythm in supraventricular arrhythmias

Cardiac Arrhythmia Suppression Test (CAST Trial):When Flecainide & other Class Ic given prophylactically to patients convalescing from Myocardial Infarction it increased mortality by 21/2 fold. Therefore the trial had to be prematurely terminated

Propafenone (Class Ic)

• Properties similar to flecainide

• Weak β blocking activity

• Used for supraventricular arrhythmias

Moricizine (Class Ic)

• Phenothiazine analogue

• Chronic treatment of ventricular arrhythmias

CAST II Increased mortality shortly after a myocardial

infarction & did not improve survival during long term therapy

Class II: β Adrenoreceptor Blocking Drugs

β Adrenergic Stimulation β Blockers

↑ magnitude of Ca2+ current & slows its inactivation

↓ Intracellular Ca2+ overload

↑ Pacemaker current→↑ heart rate ↓Pacemaker current→↓ heart rate

↑ DAD & EAD mediated arrhythmias Inhibits after-depolarization mediated automaticity

Epinephrine induces hypokalemia (β2 action)

Propranolol blocks this action

Other Actions:• ↑ AV Nodal conduction time & prolong its

refractoriness (↑PR interval)

Useful in re-entrant arrhythmias involving AV node & controlling ventricular response in Afl/AF

• Controlling arrhythmias associated with physical or emotional stress

(blocking β mediated actions of catecholamines)

• Clinical trials suggest that they significantly reduce incidence of re-

infarction & sudden death after an MI ↓ Size of infarct & arhhythmiasIncrease energy required to defibrillate the

heart↓ chances of subsequent MI

• Includes Propranolol, Esmolol, Timolol, Metoprolol, Atenolol, Bisoprolol

Selected β Adrenergic Receptor blockersPropranolol:• Exert Na+ channel blocking (membrane stabilizing)

effects at high concentrations• Clinical significance is unknown

Acebutolol:• Suppresses ventricular ectopics

Esmolol:• β1 selective metabolized by RBC esterases• t1/2 9 mins

• Rate control of rapidly conducted AF

Class III: K+ Channel Blockers

Prolong action potential by blocking K+ currents usually Ikr

Enhance inward current also through Na+ channels

Prolong Repolarization→ QT Prolongation

Thereby ↓ Automaticity & inhibit Re-entry (↑ ERP)

Other actions: ↓ Defibrillation energy requirement, ↑ contractility & inhibition of VF owing to ischemia

Vm

(mV)

-80mV

0mV

↑ APD

Ectopic Pacemaker

Block IK

Reverse Use Dependence:

Action potential prolongation is least marked at fast rates & most marked at slow rates Thus risk of torsades

Toxicity:These drugs have a risk of torsades as they prolong cardiac action potentialMore common in women

Amiodarone

• Blocks variety of channels: IKr , IKs , IKto , IKir

• Also blocks inactivated Na channels, ↓Ca current, adrenergic blocker

• Thus Class I,II,III,IV effects

•↓abnormal automaticity, prolongs APD, ↓ conduction velocity

PK:

• Oral bioavailability 30%

• Distributed in lipids

• Undergoes hepatic metabolism by CYP3A4 to desethyl-amiodarone (active metabolite)

• Effect maintained over 1-3 months after discontinuation

Adverse effects:

• Hypotention • Torsades• Pulmonary fibrosis (CXR, PFT)• Corneal microdeposits• Hypo/hyper thyroidism• Peripheral neuropathy, proximal weakness• Photosensitivity• Hepatic dysfunction

Uses

• Oral→ chronic arrhythmias, iv→acute life threatening arrhythmias

• Prevention of Recurrent VTach/VF

• Maintain sinus rhythm in AF

• Acute termination of VTach/VF

• Wolf-Parkinson-White syndrome

Dronedarone

• Structural analogue of amiodarone without iodine

• Blocks IKr, IKs, ICa, INa & β receptors

• No thyroid & pulmonary toxicity

• Maintain sinus rhythm in paroxysmal/persistent AF/Afl

Dofelitide

• Potent & Pure IKr blocker

• Slow rate of recovery

• PK: 100% bioavailability, excreted unchanged by kidneys

• S/E: torsades viz dose dependent

• Used to maintain sinus rhythm in AF/Afl

Ibutilide

• IKr blocker & activates INa

• Rapid iv infusion used for immediate conversion of Afl/AF to sinus rhythm

• Efficacy Afl>AF

• PK: undergoes extensive 1st pass metabolism. Thus not used orally. t1/2 6hrs

• S/E: torsades

Sotalol

• IKr blocker and non selective β receptor blocker • Class II,III actions

• ↑ APD, ↓ automaticity, slows AV Nodal conduction & prolong AV Nodal refractoriness

• Prolongs QT interval

• S/E: EAD’s & torsades

• PK: 100% bioavailable, excreted unchanged in urine • Uses: Ventricular arrhythmias, maintenance of sinus rhythm AF, used in pediatric age-group

Vernakalant (RSD1235)

• Investigational multichannel ion blocker

• Blocks IKr, IKur, IKAch, Ito

Thus prolong atrial repolarization & ERP. Less action potential prolongaton in ventricle

• Rate dependent Na channel block (Recovery is fast)

• Slows conduction of AV node

• S/E: dysgeusia, cough, paraesthesia, hypotension

• PK: metabolized in liver by CYP2D6, t1/2 2hrs • Use: Converting recent onset AF to sinus rhythm

Class IV: Ca2+ Channel Blocking Drugs

• Block L-Type Ca 2+ channels in slow- response tissues & depress Phase 3 & 4

• Slows SA Node by its direct action

• AV Node conduction time & effective refractive period increased (Prolongs PR interval)

• Important effect on upper & middle parts of AV Node

• Shorten plateau of action potential & reduce force of contraction

• Suppress both Early & Late Depolarization

• May have a particular value in blocking one limb of re-entry circuit

His Bundle

Normal ERP

PrematureAtrial Beat

Atrium“Dispersion of Refractoriness”

Normal ERP

βIschemic Area Long ERP

PSVT: •140-220 min -1• sudden onset• palpitations,dizziness

AV Node Re-entry

Ischemic Area

Verapamil/ Diltiazem

Normal ERP

Long ERP

β

Long ERP

ERP>CT

Effect of ClassIV Drugs on AV Nodal Reentrant Arrhythmia

• Parental verapamil & diltiazem approved for rapid conversion of PSVT to sinus rhythm & temporary control of rapid ventricular rate in AF/Afl

• C/I in WPW syndrome

• Oral verapamil in conjugation with digoxin to control ventricular rate in chronic AF/AFl

Verapamil

• Blocks both activated & inactivated Ca2+ channels

• Given orally with a t1/2 8hrs

• extended release formulation available

• If used with digoxin, then dose is reduced

• S/E constipation, lassitude, peripheral edema

Diltiazem

• Similar in efficacy to verapamil

• Undergoes a high first pass metabolism

• Relatively more smooth muscle relaxing action

Miscellaneous

Adenosine

• Naturally occurring nucleoside

• Acts on specific G protein-coupled adenosine receptors

• Activates IKAch channels in SA node, AV node & Atrium Shortens APD, hyperpolarization & ↓ automaticity

• Inhibits effects of ↑ cAMP with sympathetic stimulation

↓ Ca currents

↑AV Nodal refractoriness & inhibit DAD’s

Vm

(mV)

-80mV

0mV

↓ APD

Hyperpolarization

Adenosine

PK:

• Carrier mediated uptake & metabolism by deaminase in most cells

• t1/2 few seconds

• Given as iv bolus

• Theophylline & caffeine→ block adenosine receptors

Adverse effects:

• flushing, shortness of breath, chest burn

Use:

• DOC for acute termination of re-entrant supraventricular arrhythmia

•Rare cases of DAD mediated VTach

Digitalis

• Acts by blocking Na+/K+ATPase→ +ve Inotropic effect • Antiarrhythmic actions exerted by AV Nodal Refractoriness by: Vagotonic actions→ inhibit Ca2+ currents in AV node

• Activation of IKAch in atrium: hyperpolarization & shortening of APD in atria

• ↑ Phase 4 slope→ ↑ Rate of automaticity in ectopic pacemakers

• ECG: PR prolongation, ST segment depession

• Adverse Effects:

Non cardiac: Nausea, disturbance of cognition, yellow vision

Cardiac: Digitalis induced arrhythmias

• PK: Digoxin- 20-30% protein bound, slow distribution to effector sites, loading dose given, t1/2 36hrs, renal elimination

Digitoxin- hepatic metabolism, highly protein bound, t1/2 7daysToxicity results with amiodarone & quindine (↓ clearance) Thus dose has to be decreased

• Used in terminating re-entrant arrhythmia involving AV Node & controlling ventricular rate in AF

Magnesium

• Its mechanism of action is unknown but may influence Na+/K+ATPase, Na+ channels, certain K+ channels & Ca2+ channels • Digitalis induced arrhythmias if hypomagnesemia present • Torsade de pointes even if serum Mg2+ is normal • Given 1g over 20mins

Bradyarrhythmias

Resting heart rate of <60/min

Classified as Atrial/AV Nodal/Ventricular

Management:

• Acute→ iv atropine

• Permanent→ Pacemakers

Toxicities

Class IConduction slowing can account for toxicity

Afl 300/min

Slowing of conduction with Na+ channel blocker

AV Node permits greater no of impulses

(Drop in Afl 300/min with 2:1 or 4:1 AV conduction to 220/min with 1:1 conduction HR 220beats/min)

• Re-entrant VTach after MI can ↑ frequency & severity arrhythmic episodes

• Slowed conduction allows the re-entrant wave front to persist within tachycardia circuit

• Difficult to treat

• Na+ infusion may be beneficial

Class II

• Bradycardia & exacerbation of CCF in patients with low ejection fraction

Class Ia & Class III

• Excessive QT prolongation & torsades de pointes

• ‘‘Twisting of points”

• Rapid, polymorphic ventricular tachycardia •Twist of the QRS complex around the isoelectric baseline

• Fall in arterial blood pressure

• Can degenerate into Ventricular fibrillation

Treatment:

• Withdrawal of offending drug •Magnesium sulphate

•Phenytoin

•Isoproterenol infusion/Pacing

•Defibrillation

Digitalis Induced Arrhythmias

• Can cause virtually any arrhythmia• DAD related tachycardia with impairment of SAN & AVN• Atrial tachycardia with AV block is classic• Ventricular bigeminy• Bidirectional ventricular tachycardia• AV junctional tachycardia• Various degrees of AV block• Sever intoxication: Severe bradycardia with hyperkalemia

Treatment

• Sinus bradycardia & AV block: Atropine

• Digitalis induced tachycardia responds to Mg2+

• Antidigoxin (DIGIBIND) binds to digoxin & digitoxin thereby enhancing their renal excretion

• SA & Node AV Node dysfunction may require temporary pacing

TRIALS

• Cardiac Arrhythmia Suppression Trial (CAST)

• Cardiac Arrhythmia Pilot Study (CAPS)

• Antiarrhythmics Versus Implantable Defibrillators (AVID)

• Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM)

Therapeutic Drug Monitoring

• Important as these drugs have narrow therapeutic index

• Class IA & Digoxin- Most important for drug monitoring

• Amiodarone- TDM has limited role

• TDM less important for Class II, III & IV drugs

• TDM no value for Lignocaine & Procainamide due to Active metabolites (GX, MEGX & NAPA)

Evaluation of Antiarrhythmic Drug Action

Ex-Vivo Models:

• Guinea pig muscle strips

In-Vivo Models:

• Atrial Arrhythmias

1. Atrial Rapid Pacing Model

2. Afl with Anatomical Obstacle Model

• Ventricular Arrhythmias

1. Digitalis-induced Ventricular Arrhythmia

2. Halothane adrenaline Arrhythmia

3. Canine two stage coronary ligation Arrhythmia

4. Programmed electrical stimulation induced re-entry Arrhythmia

5. Coronary artery occlusion/reperfusion Arrhythmia

• Genetic Models:

1. Homozygous null connexin 40 vulnerability to atrial arrhythmias

2. Transgenic mouse model→ Over expresses a constitutively active form of TGF-b1

Clinical Evaluation:

Two designs commonly used:

1. Evaluating antiarrhythmic agents in pts with ICDOutcome parameter – number of defibrillator discharge

2. Evaluating antiarrhythmic agents in target populationMortality rates could be assessedLarge sample size required

Newer Advances

ZP123-Rotigaptide • Prevents uncoupling of connexin 43 mediated gap junction communication during acute metabolic stress• Selective for atrial electrophysiology• ↓ AF vulnerability in MR

Tedisamil • Class III antiarrhythmic• Blocks Ito, IKATP, IKr, IKs, IKur

• Prolongs APD atria>ventricles• Could be used for AF, Afl

Azimilide • Class III antiarrhythmic• Blocks IKr & IKs

• Converts and maintains sinus rhythm in patients with atrial arrhythmias• Reduces frequency and severity of ventricular arrhythmias in patients with implanted cardioverter-defibrillators

AVE0118 • Blocks IKur & Ito

• Prolongs atria ERP• May be useful in atrial arrhythmis

AZD 7009• Inhibition of IKr, Ito, IKur and INa, a mixed ion channel blockade• Promising drug for converting AF to sinus rhythm• Phase II trial

AP-792 • Cardioselective Ca2+ channel blocker • Suppresses the ventricular arrhythmias Encainide (MJ9067)• Probably has effects on Phase 2• Can be effective in suppressing ventricular ectopics

BRL32872

• Blocks IKr & L-type Ca2+ channels• Prolongs APD• May possibly prevent torsades de pointes

Piboserod• Functional 5-HT4 receptor antagonist• Could be used for AF

Nifekalant• Class III antiarrhythmic• Blocks IKr

• Approved in Japan• Ventricular tachycardia

Conclusion

• Precipitating factors (ischemia, electrolyte imbalance, drugs) should be eliminated

• Drugs acting on particular mechanism of arrhythmia should be used

• Some arrhythmias should not be treated

• Risk benefit ratio assessed (drug provoked arrhythmias)

• Patient specific contraindications (disopyramide→CCF, amiodarone→pulmonary disease)