ANTI-ARRHYTHMICDRUGSDr. Rika Yuliwulandari, Ph.D24 dec 2012

ElectrophysiologyTerminology of arrhythmiaClassification of arrythmic agentsANTI ARRHYTHMIC DRUGS

ELECTROPHYSIOLOGY OF NORMAL CARDIAC RHYTHMTo understand how antiarrhythmic drugs work, need to understand electrophysiology of normal contraction of heartCaused by unequal distribution ofions inside vs. outside cellNa+ higher outside than inside cellCa+ much higher outside than insideK+ higher inside cell than outsideMaintenance by ion selective channels, active pumps and exchangersSA node-Atria-AV node-His Purkinya-Ventrikel

K++Na, Ca

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

FACTORS PRECIPITATING CARDIAC ARRHYTHMIAS:1. IschemiapH & electrolyte abnormalities80% 90% asstd with MI2. Excessive myocardial fiber stretch/ scarred/ diseased cardiac tissue 3. Excessive discharge or sensitivity to autonomic transmitters4. Excessive exposure to foreign chemicals & toxic substances20% - 50% ----- General Anesthesia10% - 20% ----- Digitalis toxicity

Two mechanisms: one or bothDisorders of impulse conductionDisorders of impulse formation

Impulses from the SA node pass down bifurcate pathway to activate the entire ventricular surfaceIn case of unidirectional block (myocardial injury, prolonged refractory period), impulse travels in retrograde direction and cause reexcitation and irregular beatDISORDERS OF IMPULSE CONDUCTION

DISORDERS OF IMPULSE FORMATIONNo signal from the pacemaker siteDevelopment of an ectopic pacemakerDevelopment of oscillatory afterdepolariztionsResult of drugs (digitalis, norepinephrine) used to treat other cardiopathologiesMay result inBradycardia (if have AV block)Tachycardia (if reentrant circuit occurs)

ARRHYTHMIAArrhythmia is any deviation from a normal heart beatFasterSlowerIrregularectopic Causes of arrhythmiasCardiac ischemia (AMI)Excessive discharge or sensitivity to autonomic transmittersExposure to toxic substances: Digitalis, anesthetic drugUnknown etiology

Epidemiologi Cardiac Arrhythmias: 25% treated with digitalis 50% anesthetized patients 80% patients with AMI reduced cardiac output drugs or nonpharmacologic:- Drugs: 4 classes and others- Nonpharmacologic: pacemaker, cardioversion, catheter ablation, surgery

Purpose of Antiarrhythmic Agent

ANTI-ARRHYTHMIC DRUGSMost antiarrhythmic drugs have major mechanism of action blocking of 1 or more cardiac ion current(s) Biggest problem antiarrhythmics can cause arrhythmia!Must be careful when determine dose, blood levels, and in follow-up when prescribing antiarrhythmics drugs

PHASES OF ACTION POTENTIALANTI ARRHYTHMIC DRUGSPhase 1- Limited depolarization/Partial repolarization- Inactivation of fast Na+ channels Na+ ion conc equalizes- K channels open --- K+ effluxPhase 2- Plateau Stage- Inactivation of Na+ channel- Ca channels open---Ca++ influx through slow Ca++ channels- K+ begins to leave cellPhase 3-- Rapid repolarization-- Na+ gates closed (resting)-- K+ efflux--Inactivation of slow Ca++ channelsPhase 4- Resting Membrane Potential- High K+ effluxPhase 0- Rapid depolarization- Fast Na+ Channels open rapid Na+ inward depolarizationS waveInitial QRSS-T segmentT waveEnd of T till next depolarization01234

ARRHYTHMIASupraventricular:

- Atrial Tachycardia- Paroxysmal TachycardiaMultifocal Atrial Tachycardia- Atrial Fibrillation- Atrial FlutterVentricular:

Wolff-Parkinson-White (pre-excitation syndrome)Ventricular TachycardiaVentricular FibrillationPremature Ventricular Contraction

CLASSIFICATION OF ANTI-ARRHYTHMIC

Class I(Na channel blockerClass IIBeta blockerClass IIIK channel blockerClass IVCa channel blockerOtherDysopyramide (IA)EsmololAmiodaronDiltiazemAdenosinPhlecainid (IC)MetoprololBretilliumVerapamilDigoxinLidocain (IB)PindololSotalolAtropinMexilletin (IB)PropanololElectrolyte supplementPracainamid (IA)Propafenon (IC)Quinidin (IA)Tocainid (IB)

Prototype of Class 1A drugsBinds to Na channel and prevent the activation of the channel ----- refractor period, conduction rate, pacemaker rate, conduction & excitabilityAffect on ischemic heart > normal heart Class IA binds to depolarized membraneClass IA binds to low pH membranePharmacokinetics:Oral rapid GI absorption , t max: 60-90Quinidine gluconas: slower absorption, t max: 3-4 hrs80% plasma protein binding 20% excreted unchanged in the urine enhanced by acidityt = 6 hoursParenteral hypotension, pain in inj site, creatine kinaseDosage: 0.2 to 0.6 gm 2-4X a dayCLASS I: NA CHANNEL BLOCKERCLASS IA: QUINIDINE

Toxicity:Antimuscarinic actions inh. vagal effectsQuinidine syncope (lightheadedness, fainting)Arrhythmia or asystoleDepress contractility & BPWidening QRS durationDiarrhea, nausea, vomitingCinchonism (dizziness, tinnitus)Rare: rashes, fever, hepatitis, thrombocytopenia,etcDrug Interaction:Increases digoxin plasma levels

Therapeutic Uses:Atrial flutter & fibrillationVentricular tachycardiaSide effect :Slight cinconism: tinnitues, deafness, blurry, GI tr symptomHeavier Se: headache, diplopia, fotofobia, flushing, delirium, psichosisGeneral SE:>2g/ml widening of QRS complex and Q-T interval (can be used for tx monitoring) ---- if QRS >50%, dose High dose: Blockage SA, AV, Ventricular arrhytmia, asistoleTakikardia ventrikel polimorfik (torsades de pointes) fatalIf QT widen at low dose of Quinid ---- tend to get torsades de pointes arrhytmia ----- find other drug

Antiarrhythmia class IA, ProcainamideDerivative of local anesthetic: ProcaineMoa = QuinidinePharmacokinetics:Oral: absorbtion good, for long term txIv: rarely used, cause hypotentionMetabolism: acetylated in liver --- N-acetyl procainamide (NAPA) (class III action) ----eliminated via kidneySe: high dose ---- EKG changes like Quinidine (widen Q-T interval)Long term effect: 25-30% of px develop antibodi antinuklear within 2 years SLE reversible

Toxicity:

- Cause new arrhythmias- LE-like syndrome- Pleuritis, pericarditis, parenchymal pulmonary disease- ANA- nausea, DHA, rash, fever, hepatitis, agranulocytosis

Stronger antimuscarinic effects than quinidine slows AV conductionPharmacokinetics: oral administration- extensive protein binding- t = 6 to 8 hrsDosage: 150 mg TID up to 1 g/dayTherapeutic Use: Ventricular arrhythmiasToxicity:- Negative inotropic action (Heart fail without prior myocardial dysfunction)- Urinary retention, dry mouth, blurred vision, constipation, worsening glaucomaCLASS IA: DISOPYRAMIDE

Only for serious ventricular arrhythmiasBroad spectrum of action on the heartVery effective Na+ channel blocker but low affinity for activated channelsLengthens AP by blocking also K+ channelsWeak Ca++ channel blockerNoncompetitive inhibitor of adrenoceptorsPowerful inhibitor of abnormal automaticitySlows sinus rate & AV conductionMarkedly prolongs the QT intervalProlongs QRS duration atrial, AV nodal & ventricular refractory periodsAntianginal effects due to noncompetetive & blocking property and block Ca++ influx Perivascular dilatation - blocking property and Ca++ channel-inhibiting effects

CLASS IA: AMIODARONE

Lidocaine, Phenitoin, Tocainide, MexiletineLidocaine: Prototype of Class IBWork on Na+ channelsPotent abnormal cardiac activity suppressorOnly ivPharmacokinetics: - Extensive first-pass hepatic metabolism- t = 1 to 2 hrsDosages: loading- 150 to 200 mg, maintenance- 2-4 mgDrug Interaction: propranolol, cimetidine clearanceTherapeutic Use: DOC for suppression of recurrences of ventricular tachycardia & fibrillation after AMI.

Antiarrhythmia agent Class IB

Toxicity:Worsen impaired conductionExacerbates ventricular arrhythmiasHypotension in HFNeurologic: paresthesias, tremor, nausea, lightheadedness, hearing disturbances, slurred speech, convulsions

Similar to lidocaineOral route - resistant to first-pass hepatic metabolism Usage: ventricular arrhythmiast = 8 to 20 hrsDosage:Mexiletene 600 to 1200 mg/dayTocainide 800 to 2400 mg/daySide effect: tremors, blurred vision, lethargy, nausea, rash, fever, agranulocytosisCLASS IB: TOCAINIDE & MEXILETENE

Anti-convulsant with anti-arrhythmic propertiesSuppresses ectopic pacemaker activityUseful in digitalis-induced arrhythmiaExtensive, saturable first-pass hepatic metabolismHighly protein boundToxicity: ataxia, nystagmus, mental confusion, serious dermatological & BM reactions, hypotension, gingival hyperplasiaD/I: Quinidine, Mexiletene, Digitoxin, Estrogen, Theophyllin, Vitamin DOther CLASS IB: PHENYTOIN

Fleicainide, Encainide, ProphenonPotent blocker of Na+ & K+ channelsNo antimuscarinic effectsUsed in patients with supraventricular arrhythmias Hepatic metabolism & renal eliminationDosage: 100 to 200 mg bidIndication: ventricular arrhythmia ---- malignant arrhythmia, CHF, biphasic blockSe: proarrhythmia in 8-15% px with malignant ventricular arrhythmia, blurred vision in high doseCLASS IC: FLECAINIDE

Action = flecainide(+) weak -blocking activity ---- slows conduction in all cardiac tissuest = 5 to 7 hrs.Dosage: 450 900 mg TIDUsage: supraventricular arrhythmias, broad spectrum antiarrhythmic agentsSE: metallic taste, constipation, arrhythmia exacerbationCLASS IC: PROPAFENONE

Antiarrhythmic phenothiazine derivative Used in ventricular arrhythmiasPotent Na+ channel blockerDosage: 200 to 300 mg orally tidSE: dizziness, nauseaCLASS IC: MORICIZINE

Moa:Block receptor 1 Block catecholamine endogenIncrease K+ inward, block Na+ channel & decrease membrane responseMost effective in px with increased sympathetic activity (stress pre anesthetic/surgery, MI, CHF, Hyperthyroidism)Effect: AV nodal conduction time ( PR interval), Prolong AV nodal refractorinesUsage: reentrant arrhythmias, controlling ventricular response in AF & A.fib., Depresses phase 4 slows recovery of cells, slows conduction & decrease automaticity, Reduces HR, decrease IC Ca2+ overload & inhibit after depolarization automaticity, Prevent recurrent infarction & sudden death in patients recovering from AMImembrane stabilizing effectExert Na+ channel blocking effect at high dosesAcebutolol, metoprolol, propranolol, labetalol, pindololintrinsic sympathetic activityLess antiarrhythmic effectAcebutolol, celiprolol, carteolol, labetalol, pindololTherapeutic indications: Supraventricular & ventricular arrhythmias, hypertension

CLASS II: BETA ADRENOCEPTOR BLOCKERS

Propranolol: block 1 & 2 Selective 1 blockerAcebutolol : as effective as quinidine in suppressing ventricular ectopic beatsEsmolol: short acting hence used primarily for intra-operative & ther acute arrhythmiasSotalol : Block K+ channel as well as beta blocker T1/2 long (20 hrs), 1 ddhas K+ channel blocking actions (class III)Nonselective beta-blocker that also slows repolarization & prolongs AP durationUsed in supraventricular & ventricular arrhythmias in pediatric age groupRenal excretionDosage: 80 320 mg bidToxicity: torsades de pointes , beta-blockade symptoms

Specific beta blocker agents:

Bretillium, dophetillid, amiodaroneSotalol beta blocker, + class III effectMoa: blocking K+ channelDrugs that prolong effective refractory period by prolonging action potentialProlong AP by blocking K+ channels in cardiac muscle ( inward current through Na+ & Ca++ channels)Quinidine & Amiodarone prolong AP durationBretylium & Sotalol prolong AP duration & refractory periodIbutilide & Dofetilide pure class III agentsReverse use-dependenceIndication: Ventricular arrhythmia & atrial arrhythmia

CLASS III: POTASSIUM CHANNEL BLOCKERS

Antihypertensive, increase refractory periode, interferes with neuronal release of catecholamines, Lengthens ventricular AP duration & effective refractory period, (+) inotropic actionIntravenous administrationDosage: 5 mg/kgUsage: ventricular fibrillation, when lidocaine & cardioversion have failed (In emergency setting/resuscitation) SE: postural hypotension, ventricular arrhythmia, nausea & vomiting

BRETYLIUM

Slows repolarizationProlong cardiac action potentialsMech of action: inward Na+ current, blocking Ikr- channel or bothroutes: Oral, IV (1 mg over 10min)Clin. Uses: atrial flutter, atrial fibrillationToxicity: Torsades de pointes

CLASS III: POTASSIUM CHANNEL BLOCKERSIBUTILIDE

A potential Ikr- blockerDosage: 250-500 ug bidClin. Uses: Atrial flutter & fibrillationRenal excretionToxicity: Torsade de pointes

DOFETILIDE

Blocks both activated & inactivated calcium channelsProlongs AV nodal conduction & effective refractory periodSuppress both early & delayed afterdepolarizationsMay antagonize slow responses in severely depolarized tissuesPeripheral vasodilatationOral administration 20% bioavailabilityt = 7 hrsLiver metabolismDosage: IV: 5-10 mg every 4-6 hrs or infusion of 0.4 ug/kg/minOral: 120-640 mg daily, divided in 3-4 dosesUses: SVT, AF, atrial fib, ventricular arrhythmiasToxicity: AV block, can cause sinus arrest, constipation, nervousness, peripheral edema

CLASS IV: CALCIUM CHANNEL BLOCKERSVERAPAMIL

Similar efficacy to verapamil in supraventricular arrhythmias & rate control in atrial fibrillationBepridil - AP & QT prolonging action ventricular arrhythmias but may cause torsade de pointes- Rarely used primarily to control refractory anginaDILTIAZEM & BEPRIDIL

Indirectly alters autonomic outflow by increasing parasympathetic tone & decreasing sympathetic tone Results in decreased conduction time & increased refractory period in the AV node OTHER ANTI-ARRHYTHMIC AGENTS:DIGITALISA nucleoside that occurs naturally in the bodyt 10 secondsMOA: enhances K+ conductance & inhibits cAMP-induced Ca++ influx results in marked hyperpolarization & suppression of Ca++-dependent APIV bolus: directly inhibits AV nodal conduction & AV nodal refractory periodADENOSINE

DOC for prompt conversion of paroxysmal SVT to sinus rhythm due to its high efficacy & very short duration of actionDosage: 6-12 mg IV bolusD/I: theophylline, caffeine adenosine receptor blockersDipyridamole adenosine uptake inhibitorToxicity: flushing, SOB or chest burning, atrial fibrillation, headache, hypotension, nausea, paresthesiaADENOSINE

Effective in patients with recurrent episodes of torsades de pointes (MgSO4 1 to 2 g IV) & in digitalis-induced arrhythmiaMOA: unknown influence Na+/K+ ATPase, Na+ channels, certain K+ and Ca++ channelsMAGNESIUMTherapy directed toward normalizing K+ gradients & pools in the bodyEffects of increasing serum K+:1. resting potential depolarizing action2. membrane potential stabilizing actionHypokalemia:- risk of early & delayed afterdepolarization- ectopic pacemaker activity esp if (+) digitalisHyperkalemia:- Depression of ectopic pacemakers- Slowing of conduction

POTASSIUM

BASIC MECHANISM OF ANTI-ARRHYTHMICAPD, action potential duration; ERP, effective refractory period; SA, sinoatrial node; AV, atrioventricular node.

ClassDrug ClassificationBasic MechanismINa channel blockerReduce phase 0 slope and peak of action potential.IAMODERATE- Quinidine 1st antiarrhythmic used, treat both atrial and ventricular arrhythmias, increases refractory period- Procainamide - increases refractory period but side effects- Disopyramide extended duration of action, used only for treating ventricular arrthymiasModerate reduction in phase 0 slopeProlong repolarizationIncrease APDIncrease ERP.IBWEAK- Lidocane (also acts as local anesthetic) blocks Na+ channels mostly in ventricular cells, also good for digitalis-associated arrhythmias- Mexiletine - oral lidocaine derivative, similar activity- Phenytoin anticonvulsant that also works as antiarrhythmic similar to lidocaneSmall reduction in phase 0 slopeShortened depolarizationReduce APDDecrease ERP.IC STRONGFlecainide (initially developed as a local anesthetic)Slows conduction in all parts of heart, Also inhibits abnormal automaticity

PropafenoneAlso slows conductionWeak blockerAlso some Ca2+ channel blockadeStrong reduction in phase 0 slopeNo effect on APD or ERP.

BASIC MECHANISM OF ANTI-ARRHYTHMIC

IIBeta blockerPropranolol Causes both myocardial adrenergic blockade and membrane-stabilizing effectsSlows SA node and ectopic pacemakingCan block arrhythmias induced by exerciseOther adrenergic blockers have similar therapeutic effect :Metoprolol, Nadolol, Atenolol, AcebutololPindolol, Satolol, Timolol, EsmololBlock sympathetic activity ( adrenergic rec)Stabilize cell membraneIncrease P-R intervalIIIPotassium channel blockerAmiodarone prolongs action potential by delaying K+ effluxIbutilide slows Na inward movement and 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 Developed because some patients negatively sensitive to Na channel blockers (they died!)Delay repolarization (phase 3)Increase APD and ERP

ClassDrug ClassificationBasic Mechanism

BASIC MECHANISM OF ANTI-ARRHYTHMIC

IVCalcium-channel blockadeVerapamil - blocks Na+ channels and Ca2+; - Slows SA node in tachycardiaDiltiazemBepridilBlock L-type calcium-channelsMost effective at SA and AV nodesReduce rate and conduction.Slow rate of AV-conduction in patients with atrial fibrillationOthersAdenosineElectrolyte supplement: - Magnesium - PotassiumAtropinInhibits AV conduction & increases AV refractory period

Na+/K+ ATPase, Na+, K+, Ca++ channelsNormalize K+ gradientsMuscarinic receptor agonist

ClassDrug ClassificationBasic Mechanism

INDICATION

ConditionDrugSinus tachycardiaClass II, IVAtrial fibrillation/flutterClass IA, IC, II, III, IV digitalisParoxysmal supraventricular tachycardiaClass IA, IC, II, III, IV adenosineAV blockatropineVentricular tachycardiaClass I, II, IIIPremature ventricular complexesClass II, IV magnesium sulfateDigitalis toxicityClass IB magnesium sulfate

QT interval: repolarization time, action potential duration in individual cells in the ventricel*Ectopic: not a sinus node*There is substantial cell-cell variability in the shape and duration of individual action potential*siteDepolarisasi: jaringan rusak cenderung terdepolarisai krn kebocoran K+, kebanyakan antiaritmia kelas I lbh terikat pd jaringan terdepolarisasi

Jaringan iskemik lbh asam: kebanyakan antiaritmia kelas I lbh terikat pd membran dg pH rendah

*Jg for IV treatment of malaria

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