Pharmacology of antiarrhytmic drugsDr. DATTEN BANGUN MSc,SpFKDr. HASANUL ARIFIN

Bagian Farmakologi dan Terapeutik,Fakultas KedokteranUniversitas Sumatera Utara

What is an Arrhythmia ?

Irregular rhythmAbnormal RateConduction abnormality

What causes an arrhythmia?Changes in automaticity of the PMEctopic foci causing abnormal APsReentry tachycardiasBlock of conduction pathwaysAbnormal conduction pathways (WPW)Electrolyte disturbances and DRUGSHypoxic/Ischaemic tissue can undergo spontaneous depolarisation and become an ectopic pacemaker

Normal heartbeat and atrial arrhythmiaNormal rhythmAtrial arrhythmiaAV septum

Definition of arrhythmiaCardiac arrhythmia is an abnormality of the heart rhythmBradycardia heart rate slow (100 beats/min)Clinical classification of arrhythmias= Heart rate (increased/decreased)= Heart rhythm (regular/irregular)= Site of origin (supraventricular / ventricular)= Complexes on ECG (narrow/broad)

Mechanisms of arrhythmia productionRe-entry (refractory tissue reactivated due to conduction block, causes abnormal continuous circuit. eg accessory pathways linking atria and ventricles in Wolff-Parkinson-White syndrome) Abnormal pacemaker activity in non-conducting/conducting tissue (eg ischaemia)Delayed after-depolarisation (automatic depolarisation of cardiac cell triggers ectopic beats, can be caused by drugs eg digoxin)

Electrophysiology - resting potentialA transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative with respect to outside the cell

Caused by unequal distribution of ions inside vs. outside cellNa+ higher outside than inside cellCa+ much higher K+ higher inside cell than outside

Maintenance by ion selective channels, active pumps and exchangers

Differences between nonpacemaker and pacemaker cell action potentialsPCs - Slow, continuous depolarization during restContinuously moves potential towards threshold for a new action potential (called a phase 4 depolarization)Spontaneousdepolarisation

Cardiac Action PotentialDivided into five phases (0,1,2,3,4)Phase 4 - resting phase (resting membrane potential)Phase cardiac cells remain in until stimulatedAssociated with diastole portion of heart cycle

Addition of current into cardiac muscle (stimulation) causes Phase 0 opening of fast Na channels and rapid depolarization Drives Na+ into cell (inward current), changing membrane potentialTransient outward current due to movement of Cl- and K+

Phase 1 initial rapid repolarizationClosure of the fast Na+ channelsPhase 0 and 1 together correspond to the R and S waves of the ECG

Cardiac Action Potential (cont)Phase 2 - plateau phasesustained by the balance between the inward movement of Ca+ and outward movement of K + Has a long duration compared to other nerve and muscle tissueNormally blocks any premature stimulator signals (other muscle tissue can accept additional stimulation and increase contractility in a summation effect)Corresponds to ST segment of the ECG.

Phase 3 repolarization K+ channels remain open, Allows K+ to build up outside the cell, causing the cell to repolarizeK + channels finally close when membrane potential reaches certain levelCorresponds to T wave on the ECG

ECG (EKG) showing wave segmentsContraction of atriaContraction of ventriclesRepolarization of ventricles

Cardiac Na+ channels

Therapeutic overviewNa+ channel blockade-adrenergic receptor blockadeProlong repolarizationCa2+ channel blockade

AdenosineDigitalis glycosides

Vaughan-Williams Classification

ClassMechanismExampleINa channel blockersMembrane StabilisersLignocaineIIBeta BlockersMetoprololIIIK channel blockersAmiodaroneIVCa channel blockersVerapamilOtherDigoxin. Adenosine.MgSO4. Atropine

Electrophysiological effects

Drug ClassExampleSodium Channel AffinityRate of DissociationClass IAQuinidineOpen > inactivatedSlowClass IB (Affect ischemic tissues)LidocaineInactivated > openRapidClass IC (Affect ventricular conduction) FlecainideOpen > inactivatedVery slow

Classification of antiarrhythmics(based on mechanisms of action)Class I blockers of fast Na+ channels Subclass IA Cause moderate Phase 0 depressionProlong repolarizationIncreased duration of action potentialIncludes Quinidine 1st antiarrhythmic used, treat both atrial and ventricular arrhythmias, increases refractory periodProcainamide - increases refractory period but side effectsDisopyramide extended duration of action, used only for treating ventricular arrthymias

Kinidin prototip dari klas I A Adalah d isomer dari kinin, memiliki semua sifat kinin seperti : - anitimalaria - antipiretik - oxitosik - skeletal muscle relaxantKinidin juga memiliki efek antikholinergik, yang jelasnyata pada awal terapi atau pada dosis rendah. Setelahtercapai konsentrasi terapi efek langsug(direct effect )yang bekerja . Kinidin juga memiliki efek MSA (membrane stabilizing activity) sifat anestesi lokal

Farmakokinetik: diserap per-oral komplit 80 % berikatan dengan plasma protein

Kontra Indikasi A.V Block C.H.F Hipotensi Hati hati : pemberian digitalis hiperkalemia miastenia gravis == why ?

Prokainamid : efek hampir = kinidin dengan perbedaan - sumber - antimuskarinik

Classification of antiarrhythmics(based on mechanisms of action)Subclass IBWeak Phase 0 depressionShortened depolarizationDecreased action potential durationIncludesLidocane (also acts as local anesthetic) blocks Na+ channels mostly in ventricular cells, also good for digitalis-associated arrhythmiasMexiletine - oral lidocaine derivative, similar activityPhenytoin anticonvulsant that also works as antiarrhythmic similar to lidocane

Lignocaine (Lidocaine) Class Ib (blocks Na+ channels, reduces AP duration)Ventricular arrhythmias (acute Rx)IV infusion only (2 hour half life, high first pass metabolism)Hepatic metabolism (inhibited by cimetidine, propranolol)SE mainly CNS - drowsiness, disorientation, convulsions, hypotension

Classification of antiarrhythmics(based on mechanisms of action)Subclass ICStrong Phase 0 depressionNo effect of depolarizationNo effect on action potential duration

IncludesFlecainide (initially developed as a local anesthetic)Slows conduction in all parts of heart, Also inhibits abnormal automaticity

PropafenoneAlso slows conductionWeak blockerAlso some Ca2+ channel blockade

FlecainideClass Ic (block Na+ channels, no change to AP)Slows conduction in all cardiac cellsAcute Rx /prophylaxisSupraventricular tachycardiasParoxysmal atrial fibrillationVentricular tachycardiasOral/IVLong acting (T1/2 14 hours)Hepatic metabolism, urinary elimination

FlecainideCAST (Cardiac Arrhythmia Suppression Trial) 1989 increased mortality post MI (VF arrest)Side-effects: = cardiac failure,= ventricular-arrhythmias,blurred vision, abdominal discomfort, nausea, paraesthesia, dizzyness, tremor, metallic taste

Classification of antiarrhythmics(based on mechanisms of action)Class II adrenergic blockersBased on two major actions1) blockade of myocardial adrenergic receptors2) Direct membrane-stabilizing effects related to Na+ channel blockade

IncludesPropranolol causes both myocardial adrenergic blockade and membrane-stabilizing effectsSlows SA node and ectopic pacemakingCan block arrhythmias induced by exercise or apprehensionOther adrenergic blockers have similar therapeutic effect Metoprolol Nadolol Atenolol Acebutolol Pindolo StalolTimolol Esmolol

Classification of antiarrhythmics(based on mechanisms of action)Class III K+ channel blockers Developed because some patients negatively sensitive to Na channel blockers (they died!)Cause delay in repolarization and prolonged refractory periodIncludesAmiodarone prolongs action potential by delaying K+ efflux but many other effects characteristic of other classesIbutilide slows inward movement of Na+ in addition to delaying K + influx.Bretylium first developed to treat hypertension but found to also suppress ventricular fibrillation associated with myocardial infarctionDofetilide - prolongs action potential by delaying K+ efflux with no other effects

AmiodaroneClass III - increases refractory period and APMajor effect acutely is depression of AV nodeAcute Rx/prophylaxisAtrial and ventricular arrhythmiasOral or IV (central line)Loading and maintenance dosesT1/2 ; 54 daysLarge volume of distributionAccumulatesHepatic metabolism- biliary and intestinal excretion

Amiodarone adverse effectsPhotosensitive rashesGrey/blue discolouration of skinThyroid abnormalities 2%Pulmonary fibrosisCorneal depositsCNS/GI disturbancePro-arrhythmic effects (torsade de pointes)Heart blockNightmares 25%Interacts with digoxin, warfarin (reduces clearance)

Classification of antiarrhythmics(based on mechanisms of action)Class IV Ca2+ channel blockers slow rate of AV-conduction in patients with atrial fibrillation

IncludesVerapamil blocks Na+ channels in addition to Ca2+; also slows SA node in tachycardiaDiltiazem

VerapamilClass IV (calcium channel blocker)Prolongs conduction and refractoriness in AV node, slows rate of conduction of SA nodeUsed IV/oralSUPRAVENTRICULAR NOT VENTRICULAR ARRHYTHMIAS (cardiovascular collapse)Do not use IV verapamil with - blocker (heart block)T1/2 6-8 hours

Verapamil- adverse effectsHeart failureConstipationBradycardiaNausea

AdenosinePurine nucleosideActs on A1 adenosine receptorsOpens Ach sensitive K channelsInhibits Ca in current Suppresses Ca dependent AP (Nodal)Increases K out current HyperpolarisationInhibits AVN > SANIncreases AVN refractory period

ADENOSINEInterrupts re-entry and aberrant pathways through AVN Diagnosis and TreamentDrug for narrow complex PSVTSVT reliant on AV node pathwayNOT atrial flutter or fibrillation or VTContraindications:VT Hypotension and deteriorationHigh degree AV blockPoison or drug induced tachycardiaBronchospasm but short DOA

ADENOSINECarotid massage and vagal maneuvers firstRapid IV push 6mg 12 mg 12 mgFlush with 20ml N/SRecord rhythm stripFLUSHINGCHEST PAINASYSTOLE/BRADYVENTRICULAR ECTOPY

Adenosine- adverse effectsFeeling of impending doom!Flushing, dyspnoea, chest pain, transient arrhythmiasContraindicated in asthma, heart block

DigoxinNot in Vaughan Williams class

Cardiac glycoside (digitalis, foxglove)

Act on Na/K-ATPase of cell membrane (inhibits Na+/K+ pump, increases intracellular Na+ and calcium)/ increases vagal activity

Increase cardiac contraction and slows AV conduction by increasing AV node refractory period

DigoxinAtrial fibrillation or flutter (controls ventricular rate)Acute Rx/prophylaxisOral/IVLoading and maintenance dosesT1/2 36 hoursExcreted by kidneysNarrow therapeutic indexTherapeutic drug monitoringReduce dose in elderly/renal impairment

Digoxin adverse effectsArrhythmias, heart block, anorexia, nausea, diarrhoea, xanthopsia, gynaecomastia, confusion, agitation

Adverse-effects potentiated by hypokalaemia and hypomagnesaemia

Overdose Digibind (digoxin binding antibody fragments), phenytoin for ventricular arrhythmias, pacing, atropine

Anti-bradycardia agents-adrenic receptor activatorM-cholinergic receptor blockerNon-specific activator

- atropin(M-cholinergic receptor blocker)

- stimulator (-adrenic receptor activator)

- pacemaker (pacu jantung )Dalam keadaan denyut jantung amatmelambat ( bradikardia ):

PacemakersSurgical implantation of electrical leads attached to a pulse generatorOver 175,000 implanted per year1.Leads are inserted via subclavicle vein and advanced to the chambers on the vena cava (right) side of the heart2. 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 clavicle4. 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

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

Not all drugs fit this classification

In clinical practice treatment of arrhythmias is determined by the type of arrhythmia (SVT, VT) and clinical condition of the patient

Anti-arrhythmic drugs are efficacious but may have serious adverse effectsNot all arrhythmias are treated with drug therapy alone

Take-Home MessageAnti-arrhythmics are also pro-arrhythmicsDangerous side effectsIf patient is unstable rather cardiovertEnlist expert helpStick to drugs you knowLimited choice in SA anyway

*Re-entry is when tisue that is usually refractory is reactivated. Occurs if there is a ring of tissue that does not conduct normally. Usually the two paths of action potentials meet and die out, but if they do not meet then a circuit is set up.Abnormal pacemaker activity can occur if myocardial cells are damaged eg ischaemic heart disease also via catecholamine overactivityDelayed after-depolarisation occurs when in cardiac tissue that usually has to wait for the initiation of an action potential from pacemaker tissue, the cardiac cell automatically depolarises. This leads to a repetitive discharge (triggers ectopic beats -R on T phenomenon) (related to extent of inward Ca current) caused by cardiac glycosides eg digoxin

Re-entry (partial conduction block eg accessory pathways linking atria and ventricles eg Wolff-Parkinson-White syndrome) halted by drugs that prolong the refractory period

*Links AA drugs to a MOANot all drugs are included Some commonly usedSome drugs overlap classes - Sotalol

*Digoxin-specific binding (Fab) fragment, antibody to digoxin, neutralises digoxin in the plasma*