Antiarrhythmic DrugsAntiarrhythmic Drugs

Department of PharmacologyDepartment of Pharmacology

NEIGRIHMS, ShillongNEIGRIHMS, Shillong

ContentContent

Physiology of normal cardiac rhythmPhysiology of normal cardiac rhythm Definition and mechanisms of arrhythmiasDefinition and mechanisms of arrhythmias Classification of drugs to treat arrhythmiasClassification of drugs to treat arrhythmias Important anti-arrhythmic drugs Important anti-arrhythmic drugs

(mechanism and pharmacological (mechanism and pharmacological characteristics)characteristics)

Arrhythmias in clinical practiceArrhythmias in clinical practice

Cardiac PhysiologyCardiac Physiology

Recall: to function efficiently, heart needs Recall: to function efficiently, heart needs to contract sequentially (atria, then to contract sequentially (atria, then ventricles) and in synchronicityventricles) and in synchronicity

Relaxation must occur between Relaxation must occur between contractions (not true for other types of contractions (not true for other types of muscle [exhibit tetany muscle [exhibit tetany contract and hold contract and hold contraction for certain length of time]contraction for certain length of time]

Coordination of heartbeat is a result of a Coordination of heartbeat is a result of a complex, coordinated sequence of changes complex, coordinated sequence of changes in membrane potentials and electrical in membrane potentials and electrical discharges in various heart tissuesdischarges in various heart tissues

Cardiac Physiology – Cardiac Physiology – Myocardial CellsMyocardial Cells

2 types2 types – Pacemaker and non – Pacemaker and non pacemakerpacemaker

Pacemaker and conducting Pacemaker and conducting cellscells – SAN, AVN, Bundle of – SAN, AVN, Bundle of His and Purkinje`s fibresHis and Purkinje`s fibres

Non pacemakerNon pacemaker – Working – Working Myocardial Cell (WMC) or CMCMyocardial Cell (WMC) or CMC

Sinus rhythm means rhythm Sinus rhythm means rhythm originates in SANoriginates in SAN

Sinus tachycardia means Sinus tachycardia means tachycardia but rhythm tachycardia but rhythm originates in SAN – fever, originates in SAN – fever, exercise etc.exercise etc.

Tachycardia = heart rate Tachycardia = heart rate > > 100 per minute100 per minute

Bradycardia = heart rate < 60 Bradycardia = heart rate < 60 per min.per min.

Cardiac Electrophysiology Cardiac Electrophysiology

A transmembrane electrical gradient (potential) is A transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative maintained, with the interior of the cell negative with respect to outside the cellwith respect to outside the cell

Caused by unequal distribution of ions inside vs. Caused by unequal distribution of ions inside vs. outside celloutside cell Na+ higher outside than inside cellNa+ higher outside than inside cell Ca+ much higher “ “ “ “ Ca+ much higher “ “ “ “ K+ higher inside cell than outsideK+ higher inside cell than outside

Maintenance by ion selective channels, active Maintenance by ion selective channels, active pumps and exchangerspumps and exchangers

Cardiac Action Potential - Cardiac Action Potential - WMCsWMCs

Cardiac Action Potential Cardiac Action Potential

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

Phase cardiac cells remain in until stimulatedPhase cardiac cells remain in until stimulated Associated with diastole portion of heart cycle Associated with diastole portion of heart cycle

Addition of current into cardiac muscle (stimulation) causes Addition of current into cardiac muscle (stimulation) causes Phase 0Phase 0 – opening of fast Na channels and rapid – opening of fast Na channels and rapid

depolarization depolarization Drives NaDrives Na++ into cell (inward current), changing membrane into cell (inward current), changing membrane

potentialpotential Transient outward current due to movement of ClTransient outward current due to movement of Cl-- and K and K++

Phase 1Phase 1 – initial rapid repolarization – initial rapid repolarization Closure of the fast NaClosure of the fast Na++ channels channels Phase 0 and 1 together correspond to the R and S waves Phase 0 and 1 together correspond to the R and S waves

of the ECGof the ECG

Cardiac Na+ channelsCardiac Na+ channels

Cardiac Action Potential – Cardiac Action Potential – contd.contd. Phase 2 - plateau phasePhase 2 - plateau phase

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

Has a long duration compared to other nerve and muscle tissueHas a long duration compared to other nerve and muscle tissue Normally blocks any premature stimulator signals (other muscle Normally blocks any premature stimulator signals (other muscle

tissue can accept additional stimulation and increase tissue can accept additional stimulation and increase contractility in a summation effect)contractility in a summation effect)

Corresponds to ST segment of the ECG.Corresponds to ST segment of the ECG.

Phase 3 – repolarization Phase 3 – repolarization K+ channels remain open, K+ channels remain open, Allows K+ to build up outside the cell, causing the cell to Allows K+ to build up outside the cell, causing the cell to

repolarizerepolarize K + channels finally close when membrane potential reaches K + channels finally close when membrane potential reaches

certain levelcertain level Corresponds to T wave on the ECGCorresponds to T wave on the ECG

Cardiac Action Potential – Cardiac Action Potential – Pacemaker CellsPacemaker Cells

• PCs - Slow, continuous depolarization during restSlow depolarization during 0 phase• Continuously moves potential towards threshold for a new action potential (called a phase 4 depolarization)•Funny current (If)

Cardiac Electrophysiology – Cardiac Electrophysiology – contd.contd.

ECG (EKG) showing wave segments

Contraction of atria

Contraction of ventricles

Repolarization of ventricles

The Normal EKGThe Normal EKG

P

Q

R

S

T

Right Arm

Left Leg

QTPR

0.12-0.2 s approx. 0.44 s

Atrial muscledepolarization

Ventricular muscledepolarization

Ventricular musclerepolarization

Cardiac arrhythmiasCardiac arrhythmias

Cardiac ArrhythmiasCardiac Arrhythmias

Cardiac dysrhythmia (arrhythmia)Cardiac dysrhythmia (arrhythmia) Large and heterogeneous group of conditions in which Large and heterogeneous group of conditions in which

there is abnormal electrical activity in the heartthere is abnormal electrical activity in the heart The hearts too fast or too slow, and may be regular or The hearts too fast or too slow, and may be regular or

irregularirregular Results in rate and/or timing of contraction of heart muscle Results in rate and/or timing of contraction of heart muscle

that is insufficient to maintain normal cardiac output (CO)that is insufficient to maintain normal cardiac output (CO) Result from disorders of impulse formation, Result from disorders of impulse formation,

conduction, or both conduction, or both Causes of arrhythmiasCauses of arrhythmias

Cardiac ischemiaCardiac ischemia Excessive discharge or sensitivity to autonomic transmittersExcessive discharge or sensitivity to autonomic transmitters Exposure to toxic substancesExposure to toxic substances Unknown etiologyUnknown etiology

Cardiac Arrhythmias – Clinical Cardiac Arrhythmias – Clinical ClassificationClassification

Heart rate (increased / decreased)Heart rate (increased / decreased) TachycardiaTachycardia – heart rate fast (>100 beats/min) – heart rate fast (>100 beats/min) BradycardiaBradycardia – heart rate slow (<60 beats/min) – heart rate slow (<60 beats/min)

Heart rhythm (regular/irregular)Heart rhythm (regular/irregular) Site of origin (supraventricular / ventricular)Site of origin (supraventricular / ventricular) Complexes on ECG (narrow/broad)Complexes on ECG (narrow/broad)

PR interval, QRS complex, ST segment or QT PR interval, QRS complex, ST segment or QT complex etc complex etc

Normal Vs Atrial ArrhythmiaNormal Vs Atrial Arrhythmia

Normal RhythmNormal Rhythm Atrial RhythmAtrial Rhythm

Ventricular ArrhythmiaVentricular Arrhythmia

Ventricular arrhythmias are Ventricular arrhythmias are common in most people and common in most people and are usually not a problem are usually not a problem but…but…

VA’s are most common cause VA’s are most common cause of sudden deathof sudden death

Majority of sudden death Majority of sudden death occurs in people with neither occurs in people with neither a previously known heart a previously known heart disease nor history of VA’sdisease nor history of VA’s

Medications which decrease Medications which decrease incidence of VA’s do not incidence of VA’s do not decrease (and may increase) decrease (and may increase) the risk of sudden deaththe risk of sudden death treatment may be worse then treatment may be worse then the disease!the disease!

Cardiac Arrhythmias - MechanismCardiac Arrhythmias - Mechanism

1.1. Enhanced or ectopic pacemaker activityEnhanced or ectopic pacemaker activity Catecholamine over activityCatecholamine over activity Injury current in damaged myocardial cells, Injury current in damaged myocardial cells,

e.g. Myocardial ischemiae.g. Myocardial ischemia2.2. Oscillatory After-depolarizationOscillatory After-depolarization

EAD: depolarization at phase 3 interrupted EAD: depolarization at phase 3 interrupted and MP oscillatesand MP oscillates

DAD: Related to Ca++ current. After DAD: Related to Ca++ current. After attaining RMP premature action potential attaining RMP premature action potential develops, e.g. digitalis toxicitydevelops, e.g. digitalis toxicity

3.3. Reentry PhenomenonReentry Phenomenon

After depolarization – EAD and After depolarization – EAD and DADDAD

Cardiac Arrhythmias - Reentry Cardiac Arrhythmias - Reentry PhenomenonPhenomenon

Probably the cause of most arrhythmiasProbably the cause of most arrhythmias Common abnormality of conduction also called Common abnormality of conduction also called

“circus movement”“circus movement” One impulse reenters and excites areas of heart One impulse reenters and excites areas of heart

more than oncemore than once Path of re-entering impulses may be Path of re-entering impulses may be

small areas of heart (near AV node) small areas of heart (near AV node) Large (atrial or ventricular wall) – atrial and ventricular Large (atrial or ventricular wall) – atrial and ventricular

fibrillationfibrillation Anatomically determined (WPW syndrome) – reentry Anatomically determined (WPW syndrome) – reentry

circuit consists of atrial tissue, AV node, ventricular wall circuit consists of atrial tissue, AV node, ventricular wall and accessory ventricular connection (a bypass tract)and accessory ventricular connection (a bypass tract)

Reentry Phenomenon – Reentry Phenomenon – Functional reentryFunctional reentry

Reentry Phenomenon – Reentry Phenomenon – Accessory pathway (WPW Accessory pathway (WPW

syndrome)syndrome)

Arrhythmia ConditionsArrhythmia Conditions

Extrasystole:Extrasystole: abnormal automaticity/after depolarization abnormal automaticity/after depolarization Paroxysmal Supraventricular Tachycardia:Paroxysmal Supraventricular Tachycardia: 150-200/minute 150-200/minute

(1:1), reentry phenomenon (AV node) (1:1), reentry phenomenon (AV node) Atrial Flutter:Atrial Flutter: 200-350/minute (2:1), reentrant circuit in right 200-350/minute (2:1), reentrant circuit in right

atriumatrium Atrial Fibrillation:Atrial Fibrillation: 350-550/min, electrophysiological 350-550/min, electrophysiological

inhomogenicity of atrial muscles (bag of worms)inhomogenicity of atrial muscles (bag of worms) Ventricular tachycardia:Ventricular tachycardia: 4 or more consecutive extrasystole of 4 or more consecutive extrasystole of

ventriclesventricles Ventricular Fibrillation:Ventricular Fibrillation: rapid irregular contractions – fatal (MI, rapid irregular contractions – fatal (MI,

electrocution)electrocution) Torsades de pointes:Torsades de pointes: polymorphic ventricular tachycardia, polymorphic ventricular tachycardia,

rapid asynchronous complexes, rise and fall in baseline of rapid asynchronous complexes, rise and fall in baseline of ECG ECG

Atrio-ventricular Block (A-V Block):Atrio-ventricular Block (A-V Block): vagal influence or vagal influence or ischaemia - 1st, 2ischaemia - 1st, 2ndnd and 3 and 3rdrd degree degree

Antiarrhythmic DrugsAntiarrhythmic Drugs

Biggest problemBiggest problem – antiarrhythmics can cause – antiarrhythmics can cause arrhythmia!arrhythmia! Example: Treatment of a non-life threatening Example: Treatment of a non-life threatening

tachycardia may cause fatal ventricular arrhythmiatachycardia may cause fatal ventricular arrhythmia Must be vigilant in determining dosing, blood levels, and Must be vigilant in determining dosing, blood levels, and

in follow-up when prescribing antiarrhythmicsin follow-up when prescribing antiarrhythmics Mechanism of action:Mechanism of action:

Sodium channel blockadeSodium channel blockade Blockade of sympathetic autonomic effectsBlockade of sympathetic autonomic effects Blockade of Effective Refractory Period (ERP) – increase Blockade of Effective Refractory Period (ERP) – increase

ERP/APD ratioERP/APD ratio Calcium Channel BlockadeCalcium Channel Blockade

Antiarrhythmic DrugsAntiarrhythmic Drugs

Vaugham-Williams classification:

• Class I – Na+ Channel Blockers• Class II - Beta-adrenergic Blockers• Class III – Prolong Repolarization• Class IV – Calcium Channel Blocker

Class I - antiarrhythmicsClass I - antiarrhythmics

Class IA Class IB Class IC

Class I antiarrhythmics are further classified to IA, IB and IC

QuinidineProcainamideDisopyramide

LidocainePhenytoin

FlecainidePropafenone

Subclass – I A

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

Shorten action potential Limited effect on rate of rise of phase 0 Shorten repolarization Shorten QT Raise fibrillation threshold in ventricular

tissues Mild-moderate sodium channel blockade Little effect on refractoriness since there is

essentially no blockade of potassium channels E.g, lignocaine, mexilitine, phenytoin,

propafenone

Subclass - IBSubclass - IB

Subclass – IC

No effect on length of action potential Markedly reduces rate of rise of phase 0 Little effect on repolarization Markedly prolongs PR and QRS Refractory period of AV node is increased Marked Na+ channel blockade Prolong refractoriness by blocking outward-

rectifying potassium channels Used in life threatening ventricular fibrillation

since they have highest affinity to Na+ channels E.g, flecainide

Antiarrhythmic Drugs - Antiarrhythmic Drugs - QuinidineQuinidine Dextroisomer of Quinine: N+ channel blocking and antivagal Dextroisomer of Quinine: N+ channel blocking and antivagal

actionaction Actions: Actions:

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

contractility, vomiting and diarrhoea etc contractility, vomiting and diarrhoea etc Kinetics: well absorbed orally, half life – 10 HrsKinetics: well absorbed orally, half life – 10 Hrs Uses: Uses:

Broad spectrum antiarrhythmic Broad spectrum antiarrhythmic Atrial fibrillation and flutter, AF after direct current cardioversion to Atrial fibrillation and flutter, AF after direct current cardioversion to

maintain sinus rhythm, prevention of PSVT and prevention of maintain sinus rhythm, prevention of PSVT and prevention of ventricular tachycardiaventricular tachycardia

Adverse effects: Not used now for adverse effects like Adverse effects: Not used now for adverse effects like Proarrhythmia (torsades de pointes), sudden cardiac arrest, Proarrhythmia (torsades de pointes), sudden cardiac arrest, cinchonism etc.cinchonism etc.

Antiarrhythmic Drugs - Antiarrhythmic Drugs - ProcainamideProcainamide

Procaine derivative (amide) 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

Antiarrhythmic – 0.5 to 1 gm oral followed by 0.25-0.50 mg every 2 Hrs

Uses: Mainly for monomorphic VTs and to prevent recurrences

Antiarrhythmic Drugs - Antiarrhythmic Drugs - LidocaineLidocaine

Popular antiarrhythmic and also local anaesthetic Actions:

Suppression of automaticity in ectopic foci Slowing of O phase and shortening of phase 3 of CMC and PF No action on SAN and AVN Reduction in APD in ventricular myocardium Suppression of reentry – ventricular

Kinetics: Ineffective orally, given IV lasts for 10-20 minutes. Therefore given as IV bolus 50-100 mg followed by 20-40 mg every 10-20 minutes

Adverse effects: Neurological – drowsiness, paresthesia, blurred vision, nystagmus and fits etc.

Uses: 1st line of drug in Arrhythmia following acute MI and cardiac surgery Prevention of ventricular tachycardia Digitalis toxicity

Class II Antiarrhythmics

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

Drugs used are beta-blockers:Propranolol, Sotalol, Esmolol and Acebutlol

Class II – contd.

Block beta-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

AV conductions also needs sympathetic activity – Beta blockers prevent these activity

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 Propranolol is used to treat sympathetically mediated

arrhythmias - phaeochromocytoma and halothane anaesthesia

Class III Antiarrhythmics 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

Class III - 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 vasodiltorKinetics: 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)

Uses: Most tachyarrhythmic conditions – ventricular and

supraventricular Recurrent VT and VF WPW syndrome

Amiodarone

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

Class IV - Antiarrhythmics

Relatively selective AV nodal L-type calcium channel blockers – slow sinus rhythm, prolong PR interval, no effect on QRS complex

(Verapamil, diltiazem and bepridil)

Sinus Bradycardia – SA node and PF AV block – no rentry Negative ionotropic effect – interference with Ca++ mediated

contraction 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 – contd.

Uses: Verapamil PSVT:

For termination of attack – 5 mg IV over 2-3 minutes (reflex bradycardia)

For prevention of attack 60-120 mg orally tds

Reduce ventricular rate in Atrial fibrillation (AF)

Miscellaneous Agents

Compounds whose actions do not fit the standard four classes – digoxine, adenosine and alinilide (a chloride channel blocker)

Adenosine: Endogenously produced important chemical

mediator used in PSVT MOA:

Activation of Ach sensitive K+ channel - membrane hyper polarization of SA node (G-protein coupled adenosine receptor) – depression of SA node and also slowing of AV conduction and shortening of action potential in atrium

Also indirectly reduces CA++ current in AV node – depression of reentry in PSVT

Adenosine – contd.

Very short half life – 20-30 sec. - Uptake by RBCs and endothelial cells

Administered intravenously 6 mg given as a rapid intravenous bolus

(administered over a 1-2 second period) If the first dose does not result in elimination of

the supraventricular tachycardia within 1-2 minutes - 12 mg should be given as a rapid intravenous bolus

ADR: chest tightness, dyspnoea, fall in BP and flushing etc.

SummarySummary

Anti-arrhythmic drugs are classified by their effect on the Anti-arrhythmic drugs are classified by their effect on the cardiac action potentialcardiac action potential

An ideal antiarrhythmic drug should target ectopic An ideal antiarrhythmic drug should target ectopic pacemakers and rapidly depolarizing tissues to a greater pacemakers and rapidly depolarizing tissues to a greater extent than normal tissues of the heartextent than normal tissues of the heart

Many of the Na and Ca channel blockers have this property Many of the Na and Ca channel blockers have this property because they preferentially block sodium and calcium because they preferentially block sodium and calcium channels in the depolarized tissueschannels in the depolarized tissues

Most of the drugs exhibit mixed actionMost of the drugs exhibit mixed action In clinical practice treatment of arrhythmias is determined In clinical practice treatment of arrhythmias is determined

by the type of arrhythmia (SVT, VT) and clinical condition of by the type of arrhythmia (SVT, VT) and clinical condition of the patientthe patient

Anti-arrhythmic drugs are efficacious but may have serious Anti-arrhythmic drugs are efficacious but may have serious adverse effectsadverse effects

Not all arrhythmias are treated with drug therapy aloneNot all arrhythmias are treated with drug therapy alone

Non-pharmacological Non-pharmacological treatmenttreatment

AcuteAcute Vagal manoeuvresVagal manoeuvres DC cardioversionDC cardioversion

ProphylaxisProphylaxis Radiofrequency ablationRadiofrequency ablation Implantable defibrillatorImplantable defibrillator

Pacing (external, temporary, Pacing (external, temporary, permanent)permanent)

PacemakersPacemakers

Surgical implantation of electrical leads attached to a pulse generator

1) Leads are inserted via subclavian vein and advanced to the chambers on the vena cava (right) side of the heart

2) Two leads used, one for right atrium, other for right ventricle3) Pulse generator containing microcircuitry and battery are

attached to leads and placed into a “pocket” under the skin near the clavicle

4) Pulse generator sends signal down leads in programmed sequence to contract atria, then ventricles

Pulse generator can sense electrical activity generated by the heart and only deliver electrical impulses when needed.

Pacemakers can only speed up a heart experiencing bradycardia, they cannot alter a condition of tachycardia

The PacemakerThe Pacemaker

Thank YouThank You

Watch the VideoWatch the Video