class i (na + channel blockers) 1a: procainamide, quinidine (no longer recommended)

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Arrhythmias and Antiarrhythmic Drugs. Class I (Na + channel blockers) 1A: procainamide, quinidine (no longer recommended) 1B: lidocaine 1C: flecainide, propafenone Class II (  -blockers) non-selective: propranolol selective: metoprolol Class III (K + channel blockers) - PowerPoint PPT Presentation

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  • Class I (Na+ channel blockers)1A: procainamide, quinidine (no longer recommended)1B: lidocaine1C: flecainide, propafenoneClass II (-blockers)non-selective: propranololselective: metoprololClass III (K+ channel blockers)amiodarone, sotalol, dofetilide, ibutilide, (azimilide)Class IV (Ca2+ channel blockers)verapamil, diltiazemOthers:adenosinedigoxinmagnesium sulfateArrhythmias and Antiarrhythmic DrugsAJ Davidoff 09Treatment Guidelines Medical Letters June 2007

  • What happens to QRS interval if conduction through heart is slowed?What happens to QT interval if APD is prolonged?What happens to PR interval if AV nodal conduction is prolonged?

  • ACh M2 ACh receptorsIK+ , ICa2+, IfNE 1-AR If ICa2+ (L-type)Sherwood Fig 9-24ACh = acetylcholineM-ACh = muscarinic AChNE = norepinephrine-AR = adrenergic receptorI = whole cell currentNodal cell firing rate control

  • Fast Action PotentialsFastNa+ current(INa)IKrIKsOutward K+ currents(delayed rectifiers)ITO = transient outward K+ currentITO

  • Nattel and Carlsson 2006 Nature Reviews; Drug Discovery 5:1034-1049ultra rapid K+ currentrapid K+ currentslow K+ currenttransient outward K+ currentfunny currentinward positive currentoutward positive currentNCX = sodium/calcium exchangerIKACh = ACh K+ currentICaL = L type Ca2+ currentINa = Na+ currentcurrent activationOptional informationPurkinje fiber

  • Most arrhythmias result from altered conduction and/or automaticityConduction abnormalities

    Typically arise from partial depolarization due to injury (e.g., over stretch, ischemia) or abnormal anatomy

    Partial or complete blockAccessory conduction pathwayse.g., Wolff-Parkinson-White (WPW) SyndromeRe-entryFibrillation (multi-re-entry loops)

  • Automaticity abnormalitiesOriginating from nodal cells or ectopic loci

    Depolarization-dependent automaticity: Changes in sinus node firing rate

    Prolonged action potential duration (APD)

    Early afterdepolarizations may lead to premature ventricular contractions (PVCs) or multiple extrasystoles

    Long QT syndrome may lead to Torsades de Pointes

  • In terms of cellular target and action potential (AP) duration, what strategy would you use for:

    Rapid nodal firing?

    Supraventricular tachycardias?

    Premature ventricular contractions (PVCs)?

    Ectopic ventricular arrhythmias?

    Ventricular tachycardias?Slow SA or AV nodal depolarizationsSlow atrial cell conductionSlow AV conductionSlow ventricular conductionProlong ventricular AP durationShorten ventricular AP duration

  • Strategies to convert fibrillation/tachycardiaFor acute atrial fibrillation or supraventricular tach.Target atrial muscle cells or AV nodal tissuehyperpolarize membrane conduction velocity AV nodeDrugs adenosineCa2+ channels-blockersdigoxin(nodal cell)

  • For V. fib. or V. tach.Target ventricular muscle cellsAP duration (APD) (refractory period) e.g., block K+ channels (now typically preferred over Class I drugs)conduction velocity (Vmax) e.g., block Na+ channels(Class I drugs)

  • For Maintenance(preventing re-occurrence)Slow AV nodal conduction or frequency of firingDrugs:digoxinCa2+ channel blockers-blockers

    Na+ channel blockers are contraindicated for:long-term therapypatients with structural defects (e.g., fibrosis, WPW)

  • Cellular models of arrhythmiasIncreased automaticity: sympathetic activity (e.g., NE or Epi) vagal activity (e.g., drug-induced, quinidine)Brenner Box 14-1TP = threshold potentialMDP = maximum diastolic potential

  • G&H Fig 10-1

  • Na+ channels inactivatedEctopic pacemaker activityOften due to partial ischemia, resulting in a more postive resting membrane potentialVmaxConduction

  • Sherwood Fig 4-7see also Katzung Fig 14-2Closed

    (ready to open)Resting potential(-90 mV)Open

    Threshold and activation potentials(-50 mV to +30mV)Closed

    (unable to open)Inactivation potentials(+30 mV to -90mV)

  • Normal conductionRe-entry loopUnidirectional blockIschemiaKatzung Fig 14-8Abnormal Impulse Conduction(hypothetical model)

  • A model for unidirectional blockAbnormal Impulse ConductionIschemic or fibrotic areas slow conductionIschemia partially depolarizes resting membrane potential, inactivates some Na+ channelsSlow rate of phase 0 (i.e., rapid depolarization phase) results in slow conduction through heartRe-entry loopsBoron Fig. 20-14

  • Afterdepolarizations(due to abnormal intracellular Ca2+ regulation)EADs prolonged APD

    Clinical arrhythmia: e.g., torsades de pointesdue to: long QT syndromegenetic defects (HERG)diseasedrug-inducedEADsDADsDelayedDADs HR or [Ca2+]i

    Clinical arrhythmia: e.g., Ca2+ overloaddue to: digoxin or phosphodiesterase (PDE) inhibitor toxicityBrenner Box 14-1

  • Boron Fig. 20-15If afterdepolarization is large can trigger PVCIf sustained, can trigger run of extra systoles

  • Nature of Antiarrhythmic DrugsAll have potential of being pro-arrhythmic: Toxicity may depress automaticity or depress conduction velocity Many are metabolized by cytochrome P450 enzymes(induced/inhibited, poor metabolizers) Most have a low TI(especially Na+ channel blockers)

    Most show use- (or frequency-) dependent blockhigher affinity for membranes depolarizing frequentlyAdvantage, because drugs may be selective for abnormally fast rhythmsGenerally classified based on primary mechanism of action

  • Brody Table 14-3Class INa+ channel blockersuse-dependent blockNa+ channels inactivatedresting/closed

  • VmaxAPDQuinidine (oral)prototype Class IArarely used anymore

    Procainamide (oral or IV)less (-) on vagusClass 1A Block Na+ channels and K+ channelsNo longer drugs of choiceIndications: (alternative DOC)Atrial fibrillation or flutterSVTVentricular fib or tachycardiaToxicity includes:Prolongs APD too muchAntimuscarinic effects(may inhibit vagus n.)Brenner Fig 4-2

  • Class 1B Block inactivated Na+ channelsIndications:Ventricular tachycardia V. re-entrant loops? (PVCs)during surgeryNo effect on atrial cells (with short APD)Toxicity:Relatively safe (hemodynamically)but efficacy is relatively lowRapidly binds to depolarized membranes(e.g., during ischemia) Rapidly dissociates from resting cellsVmaxAPDLidocaine (IV only)

  • Flecainide mortality after acute MI(CAST; cardiac arrhythmia suppression trial) VmaxAPDClass 1C Block open, closed and inactivated Na+ channelsIndications: (alternative drug of choice)Sustained ventricular tachycardiaParoxysmal A. fib or SVTonly with no signs of structural heart disease (e.g., ischemia, hypertrophy)Very slow off rates, not selective for fast rhythmsToxicity:Slows conduction (Vmax) too muchCan cause re-entrant loops(especially v. arrhythmias)FlecainidePropafenone (also ~-blocker)

  • Class II (-blockers)Some may be cardioprotective after acute MIPropranolol (non-selective)Metoprolol (1 selective)Brenner Fig 4-4Block -AR on nodal and muscle cells:HRA-V conduction(may contractility)Slow rate of depolarization of phase 4 (pacemaker potential)

    Indicated for:Acute/chronic A. Fib and FlutterLong term SVT

    IV or PO

  • Class IV (Ca2+ channel blockers: cardioselective)Inhibit L-type Ca2+ channelsEffectively raise threshold potential to fire an APUse-dependent block, therefore more effective with fast HRHR, A-V conduction velocity, (may contractility)

    Indicated for:Acute/chronic A. Fib and FlutterAcute/chronic SVTVerapamil (more effect on A-V conduction)Dihydropyridines (DHPs) have little antiarrhythmic activityDiltiazem (more effect on SA nodal cells)

  • Block delayed rectifier channel (IKr)(as well as other channels)APDClass III (K+ channel blockers)Amiodarone (DOC)also Na+, Ca2+ channel blockerand -blockerSotalolalso -blocker (non-selective)Indicated for SVT, A. fib, V. fib and V. tachPure Class III blockersDofetilide (PO only)Ibutilide (IV only)Azimilide (blocks IKr and IKs)risk of torsades de pointes (not with amiodarone)

  • Others Antiarrhythmic DrugsDigoxinInhibits Na/K ATPase Slows A-V conduction (through increasing vagal tone)Increases refractory period

    Indicated for:A. Fib with fast ventricular rate* (and CHF)

    Toxicity:complete heart block (narrow TI)may precipitate Ca2+ overload (e.g., torsades)*approaches are now focusing on controling heart rate (with warfarin), rather than rhythm (G. Wyse, AHA website updated 5/08). Thus digoxin is used much less frequently now.

  • Digoxin:

    Cardiac effects: Increases intracellular [Na+], increases in Ca2+ (via NCX)more Ca2+ to trigger SR Ca2+ release,increases contraction (positive inotropic effects, discussed in heart failure lecture)

    Decreases intracellular [K+], depolarizes membrane potentialpartially inactivates Na+ channels in fast fibers,reduces excitability, slows conduction

    High affinity to vagus nerve (particularly at the AV node), increases vagal toneslows AV nodal conduction

    Binds to, and inhibits Na+/K+ ATPase pumps in other tissues (non-cardiac toxicities include visual distrubances -yellow hues), with highest affinity to cardiac and vagal nerve.

  • AdenosineOpens K+ channels hyperpolarizes membrane(also blocks Ca2+ channels)Selective for coronary arteries and atrial muscle cells (not ventricular myocytes)Slows SA nodal firingSlows A-V conduction

    Very short T1/2 (seconds)Indicated for cardioconversionMagnesiumInhibits Ca2+ influx through L-type Ca2+ channelsIndicated for:Drug-induced torsadesDigoxin-induced ventricular arrhythmias

  • Triggered activity due too much intracellular Ca2+[Ca2+]i Na/Ca exchange [Na+]i (3Na+(in): 1Ca2+(out))(depolarize membrane)Open L-type Ca2+ channelsMg2+(for tors