Antiarrhythmic drugs


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Antiarrhythmic drugs

  1. 1. ANTIARRHYTHMIC DRUGSDr. Kunal A. Chitnis1st Year ResidentTNMC, Mumbai17th September 2010
  2. 2. SA Node fires at 60-100 beats/secSpreads through atriaEnters the AV Node(Delay of 0.15 sec)Propagates through His PurkinjesystemDepolarizes ventricles beginningfrom endocardial surface of apex toepicardial surface of baseNormal Sinus Rhythm
  3. 3. Movement of ions across cellmembrane• Ions move across in response to electrical andconcentration gradients• Pass through specific ion channels or transporters• The Equilibrium/Reversal potential is given by theNerst equation:Eion= - 61Log(Ci/Ce)
  4. 4. • The Resting Membrane Potential of thecell is -95mV• The cell maintain this transmembraneionic gradient by1. Active mechanisms like the Na+ pumpand Na+/K+ ATPase (Electrogenic)2. Fixed anionic charges within the cell
  5. 5. No NetmovementNet movementinside the cellEK -94 ENa +65
  6. 6. Phase 0:RapidDepolarisation(Na+ influx)Phase 1:Early Repolarisation(Inward Na+ currentdeactivated,Outflow of K+):Transient Outward CurrentPhase 2:Plateau Phase(Slow inward Ca2+ Current balanced byoutward delayed rectifier K+ Current)Phase 3:Late Repolarisation(Ca 2+current inactivates,K+ outflow)Action Potential of Cardiac Muscle
  7. 7. Action Potential of SA Node RMP not stable and fullrepolarisation at -60mV SpontaneousDepolarisation occurs dueto:• Slow, inward Ca2+ currents• Slow, inward Na+ currentscalled “Funny Currents”-50mV T-typeCa2+ channels-40mV L-typeCa2+ channels-35mVPhase 3:Repolarisation
  8. 8. Action Potential in AV Node• Very similar to SA Node• Causes delay ofconduction• It gives time for atrialcontraction and filling ofthe ventricles.• Site of action of manyantiarrhythmics
  9. 9. Regulation by autonomic toneParasympathetic/Vagus Nervestimulation:• Ach binds to M receptors, releasing Gprotein βγ subunits• Activate Ach dependent K+ current• ↓ slope of Phase 4Sympathetic stimulation:• Activation of β1 receptors• Augmentation of L-type Ca2+ currentand funny currents• ↑ slope of Phase 4
  10. 10. Refractoriness• Effective/Absolute Refractory period: During thisperiod, depolarization on adjacent cardiac muscles doesnot produce a new depolarization.• Protective mechanism and keeps the heart rate in check,prevents arrhythmias and coordinates musclecontraction
  11. 11. • During the plateau phase, max Na+ channels arein inactivated state, therefore refractory• Upon repolarisation, recovery occurs from theinactivation state to closed state• Only channels in closed state can be depolarised• It extends from phase 0 uptill sufficient recoveryof Na channels.• Changes in the ERP:1. Altered recovery from inactivation2. Action Potential Duration alteration
  12. 12. ERP of Fast responsivetissue• Dependent on Na+ channelsrecovery• Voltage dependentERP of Slow Responsive/Nodal tissue• Dependent on Ca2+ channelsrecovery• Time dependent/ decrementalresponse
  13. 13. CardiacArrhythmias
  14. 14. Arrhythmia means an Abnormal heartrhythmResults from the abnormalities of: Impulse generation (Rate or Site of origin) Conduction Both
  15. 15. Classification of Arrhythmias1. Characteristics:a. Flutter – very rapid but regular contractionsb. Tachycardia – increased ratec. Bradycardia – decreased rated. Fibrillation – disorganized contractile activity2. Sites involved:a. Ventricularb. Atrialc. SA Noded. AV NodeSupraventricular
  16. 16. Mechanisms of Cardiac Arrhythmias(A) Enhanced Automaticity:• In cells which normally display spontaneousdiastolic depolarization (SA Node, AV Node, His-Purkinje System)• Automatic behavior in sites that ordinarily lackpacemaker activity
  17. 17. A normal cardiac action potential may beinterrupted or followed by an abnormaldepolarizationReaches threshold & causes secondary upstrokes2 Major forms:1. Early Afterdepolarization2. Late Afterdepolarization(B) Afterdepolarization and TriggeredAutomaticity
  18. 18. 1. EarlyAfterdepolarization•Phase 3 of repolarizationinterrupted•Result from inhibition of DelayedRectifier K+ Current•Marked prolongation of ActionPotential•Slow heart rate, ↓ Extracellular K+,Drugs prolonging APD
  19. 19. 2. LateAfterdepolarizations•Secondary deflection afterattaining RMP•Intracellular Ca2+ overload•Adrenergic stress, digitalisintoxication, ischemia-reperfusion
  20. 20. (C) Re-entrant ArrhythmiaDefined as circulation of anactivation wave around aninexitable object3 requirements for Re-entrantArrhythmia:1. Obstacle to conduction2. Unidirectional block3. CT>ERP
  21. 21. UnidirectionalBlockEstablishment of Re-entrant circuit
  22. 22. 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 → VF3. Thrombus formation:• AF→ Stasis in Atrium→ Thrombus formation→ Embolism
  23. 23. Management OfArrhythmias
  24. 24. Management• Acute Management• Prophylaxis• Non Pharmacological• Pharmacological
  25. 25. Non Pharmacological• Acute1. Vagal Maneuvers2. DC Cardioversion• Prophylaxis1. Radiofrequency Ablation2. Implantable Defibrillator• Pacing (Temporary/ Permanent)
  26. 26. Pharmacological ApproachDrugs may be antiarrhythmic by:• Suppressing the initiator mechanism• Altering the re-entrant circuit1. Terminate an ongoing arrhythmia2. Prevent an arrhythmia
  27. 27. Drugs may ↓ automatic rhythms by altering:A. ↓ Phase 4 slopeB. ↑ Threshold potentialC. ↑ Max diastolic potentialD. ↑ Action Potential Duration
  28. 28. Vaughan Williams ClassificationPhase 4Phase 0Phase 1Phase 2Phase 30 mV-80mVIIIIIIIVClass I: block Na+ channelsIa (quinidine, procainamide,disopyramide) (1-10s)Ib (lignocaine) (<1s)Ic (flecainide) (>10s)Class II: ß-adrenoceptorantagonists (atenolol, sotalol)Class III: block K+ channels(amiodarone, dofetilide,sotalol)Class IV: Ca2+ channelantagonists (verapamil, diltiazem)
  29. 29. 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 APDTrecovery is time required to completeapproximately 63% of an exponentiallydetermined process to complete
  30. 30. Effect of Na+ channelblock on ERP:The point at which sufficientno. (25%) of Na+ channelsrecovered from inactivation isprolonged.↑ ERP thus blocking earlyextrasystolesAt times, post repolarizationrefractoriness.Drug
  31. 31. State Dependent Block of Na+ channels• Na+ channel blockersbinds to channels in open&/or inactivated state,poorly/ not at all to restingstate• Dissociate duringdiastole• Results in phasicchanges in extent of blockduring AP
  32. 32. Effect of increased heart rate on theNa+ channel block↑ Na+ channel block as time spent in diastole ↓→↑ERP
  33. 33. Drugs having ↓ Rate of RecoverySlow dissociation Rate→ ↑ Na+ Channel block→ ↑ ERP
  34. 34. Effect of RMP on Na+ channel Block• At RMP of -85mV: blockis rapidly reversed duringdiastole• As RMP↑ : more no. ofchannels remain ininactivated state→↑ block• Marked drug binding,conduction block & loss ofexcitability. Thus sicktissue is selectivelyinhibited
  35. 35. EctopicPacemaker↓ Upstroke↑ Threshold↓ Slope phase 4Block INaVm(mV)-80mV0mV
  36. 36. Effect on Re-entrant ArrhythmiaEffect of Class I drugs:1. ↓ Vmax: Extinguishingof propagating re-entrant wavefront2. ↑ERP: CT<ERP
  37. 37. Ia Ib IcModerate Na+ channelblockadeMild Na+ channelblockadeMarked Na+ channelblockadeSlow rate of rise ofPhase 0Limited effect onPhase 0Markedly reduces rateof rise of phase 0Prolong refractorinessby blocking severaltypes of K+ channelsLittle effect onrefractoriness as thereis minimal effect on K+channelsProlong refractorinessby blocking delayedrectifier K+ channelsLengthen APD &repolarizationShorten APD &repolarizationNo effect on APD &repolarizationProlong PR, QRS &QTQT unaltered orslightly shortenedMarkedly prolong PR& QRS
  38. 38. Procainamide (Class Ia)• Blocks open Na+ channels & Non specific blockade of K+channels• Ganglion blocking properties, thus can cause hypotension on ivuse• Risk of excessive prolongation of QT interval & torsades depointes• Drug induced Lupus Syndrome• N-acetylprocainamide (NAPA) an active metabolite has class IIIactivity
  39. 39. • NAPA causes APD prolongation but no drug inducedlupus• Fast acetylators: QT prolongation commonSlow acetylators: Drug induced Lupus common• Effective in most atrial & ventricular arrhythmias
  40. 40. 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)
  41. 41. Disopyramide (Class Ia)• Cardiac antimuscarinic effects more markedthan quinidine (blurred vision, dry mouth, urinaryretention)• Risk of torsades• Maintain sinus rhythm in AF/Afl• To prevent VTach/VF
  42. 42. Lidocaine (Class Ib)• Highly effective in arrhythmias associated with AMI• Blocks activated & inactivated Na+ channels with rapidkinetics• The inactivated channel block ensures greater effects oncells with long action potentials like purkinje fibres &ventricular cells• Selective depression in depolarized &/or rapidly drivencells
  43. 43. • 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 VFafter cardioversion
  44. 44. Mexiletine (Class Ib)• Orally acting congener of Lidocaine• Electrophysiological & antiarrhythmic actionssimilar to Lidocaine• Other uses: Relieving pain due to diabeticneuropathy & nerve injury
  45. 45. Flecainde (Class Ic)• Potent blocker of Na+ & K+ channels with slowunblocking kinetics• Blocks K+ channels but does not prolong APD & QTinterval• Maintain sinus rhythm in supraventriculararrhythmiasCardiac Arrhythmia Suppression Test (CAST Trial):When Flecainide & other Class Ic givenprophylactically to patients convalescing fromMyocardial Infarction it increased mortality by 21/2 fold.Therefore the trial had to be prematurely terminated
  46. 46. Propafenone (Class Ic)• Properties similar to flecainide• Weak β blocking activity• Used for supraventricular arrhythmias
  47. 47. Moricizine (Class Ic)• Phenothiazine analogue• Chronic treatment of ventricular arrhythmiasCAST II Increased mortality shortly after a myocardialinfarction & did not improve survival during longterm therapy
  48. 48. Class II: β AdrenoreceptorBlocking Drugs
  49. 49. β Adrenergic Stimulation β Blockers↑ magnitude of Ca2+ current & slowsits inactivation↓ Intracellular Ca2+ overload↑ Pacemaker current→↑ heart rate ↓Pacemaker current→↓ heart rate↑ DAD & EAD mediated arrhythmias Inhibits after-depolarization mediatedautomaticityEpinephrine induces hypokalemia (β2action)Propranolol blocks this action
  50. 50. Other Actions:• ↑ AV Nodal conduction time & prolong itsrefractoriness (↑PR interval)Useful in re-entrant arrhythmias involving AV node& controlling ventricular response in Afl/AF• Controlling arrhythmias associated with physicalor emotional stress(blocking β mediated actions of catecholamines)
  51. 51. • Clinical trials suggest that theysignificantly reduce incidence of re-infarction & sudden death after an MI↓ Size of infarct & arhhythmiasIncrease energy required to defibrillate theheart↓ chances of subsequent MI• Includes Propranolol, Esmolol, Timolol,Metoprolol, Atenolol, Bisoprolol
  52. 52. Selected β Adrenergic Receptor blockersPropranolol:• Exert Na+ channel blocking (membrane stabilizing)effects at high concentrations• Clinical significance is unknownAcebutolol:• Suppresses ventricular ectopicsEsmolol:• β1 selective metabolized by RBC esterases• t1/2 9 mins• Rate control of rapidly conducted AF
  53. 53. Class III: K+ ChannelBlockers
  54. 54.  Prolong action potential by blocking K+ currentsusually Ikr Enhance inward current also through Na+channels Prolong Repolarization→ QT Prolongation Thereby ↓ Automaticity & inhibit Re-entry(↑ ERP) Other actions: ↓ Defibrillation energyrequirement, ↑ contractility & inhibition of VF owingto ischemia
  55. 55. Vm(mV)-80mV0mV↑ APDEctopicPacemakerBlock IK
  56. 56. Reverse Use Dependence:Action potential prolongation is least markedat fast rates & most marked at slow ratesThus risk of torsadesToxicity:These drugs have a risk of torsades as theyprolong cardiac action potentialMore common in women
  57. 57. 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
  58. 58. PK:• Oral bioavailability 30%• Distributed in lipids• Undergoes hepatic metabolism by CYP3A4 todesethyl-amiodarone (active metabolite)• Effect maintained over 1-3 months afterdiscontinuation
  59. 59. Adverse effects:• Hypotention• Torsades• Pulmonary fibrosis (CXR, PFT)• Corneal microdeposits• Hypo/hyper thyroidism• Peripheral neuropathy, proximal weakness• Photosensitivity• Hepatic dysfunction
  60. 60. Uses• Oral→ chronic arrhythmias, iv→acute lifethreatening arrhythmias• Prevention of Recurrent VTach/VF• Maintain sinus rhythm in AF• Acute termination of VTach/VF• Wolf-Parkinson-White syndrome
  61. 61. Dronedarone• Structural analogue of amiodarone without iodine• Blocks IKr, IKs, ICa, INa & β receptors• No thyroid & pulmonary toxicity• Maintain sinus rhythm in paroxysmal/persistentAF/Afl
  62. 62. Dofelitide• Potent & Pure IKr blocker• Slow rate of recovery• PK: 100% bioavailability, excreted unchanged bykidneys• S/E: torsades viz dose dependent• Used to maintain sinus rhythm in AF/Afl
  63. 63. Ibutilide• IKr blocker & activates INa• Rapid iv infusion used for immediate conversion ofAfl/AF to sinus rhythm• Efficacy Afl>AF• PK: undergoes extensive 1st pass metabolism.Thus not used orally. t1/2 6hrs• S/E: torsades
  64. 64. 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
  65. 65. • PK: 100% bioavailable, excreted unchanged inurine• Uses:Ventricular arrhythmias, maintenance of sinusrhythm AF, used in pediatric age-group
  66. 66. Vernakalant (RSD1235)• Investigational multichannel ion blocker• Blocks IKr, IKur, IKAch, ItoThus prolong atrial repolarization & ERP.Less action potential prolongaton in ventricle• Rate dependent Na channel block (Recovery isfast)• Slows conduction of AV node
  67. 67. • S/E: dysgeusia, cough, paraesthesia,hypotension• PK: metabolized in liver by CYP2D6, t1/2 2hrs• Use: Converting recent onset AF to sinus rhythm
  68. 68. Class IV: Ca2+ ChannelBlocking Drugs
  69. 69. • 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 & effectiverefractive period increased (Prolongs PRinterval)• Important effect on upper & middle parts ofAV Node
  70. 70. • Shorten plateau of action potential &reduce force of contraction• Suppress both Early & Late Depolarization• May have a particular value in blockingone limb of re-entry circuit
  71. 71. His BundleNormal ERPPrematureAtrial BeatAtrium“Dispersion ofRefractoriness”Normal ERPβIschemic AreaLong ERPPSVT:•140-220 min -1• sudden onset• palpitations,dizzinessAV Node Re-entry
  72. 72. Ischemic AreaVerapamil/DiltiazemNormal ERPLong ERPβLong ERPERP>CTEffect of ClassIV Drugs on AV NodalReentrant Arrhythmia
  73. 73. • Parental verapamil & diltiazem approved forrapid 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 tocontrol ventricular rate in chronic AF/AFl
  74. 74. 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
  75. 75. Diltiazem• Similar in efficacy to verapamil• Undergoes a high first pass metabolism• Relatively more smooth muscle relaxing action
  76. 76. Miscellaneous
  77. 77. Adenosine• Naturally occurring nucleoside• Acts on specific G protein-coupled adenosine receptors• Activates IKAch channels in SA node, AV node & AtriumShortens APD, hyperpolarization & ↓ automaticity• Inhibits effects of ↑ cAMP with sympathetic stimulation↓ Ca currents↑AV Nodal refractoriness & inhibit DAD‟s
  78. 78. Vm(mV)-80mV0mV↓ APDHyperpolarizationAdenosine
  79. 79. PK:• Carrier mediated uptake & metabolism bydeaminase in most cells• t1/2 few seconds• Given as iv bolus• Theophylline & caffeine→ block adenosinereceptors
  80. 80. Adverse effects:• flushing, shortness of breath, chest burnUse:• DOC for acute termination of re-entrantsupraventricular arrhythmia•Rare cases of DAD mediated VTach
  81. 81. Digitalis• Acts by blocking Na+/K+ATPase→ +ve Inotropic effect• Antiarrhythmic actions exerted by AV Nodal Refractorinessby:Vagotonic actions→ inhibit Ca2+ currents in AV node• Activation of IKAch in atrium: hyperpolarization & shorteningof APD in atria• ↑ Phase 4 slope→ ↑ Rate of automaticity in ectopicpacemakers
  82. 82. • 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, slowdistribution to effector sites, loading dose given,t1/2 36hrs, renal elimination
  83. 83. Digitoxin- hepatic metabolism, highly proteinbound, t1/2 7daysToxicity results with amiodarone & quindine(↓ clearance) Thus dose has to be decreased• Used in terminating re-entrant arrhythmiainvolving AV Node & controlling ventricularrate in AF
  84. 84. Magnesium• Its mechanism of action is unknown but mayinfluence Na+/K+ATPase, Na+ channels, certainK+ channels & Ca2+ channels• Digitalis induced arrhythmias ifhypomagnesemia present• Torsade de pointes even if serum Mg2+ isnormal• Given 1g over 20mins
  85. 85. BradyarrhythmiasResting heart rate of <60/minClassified as Atrial/AV Nodal/VentricularManagement:• Acute→ iv atropine• Permanent→ Pacemakers
  86. 86. Toxicities
  87. 87. Class IConduction slowing can account for toxicityAfl 300/minSlowing of conduction with Na+ channel blockerAV Node permits greater no of impulses(Drop in Afl 300/min with 2:1 or 4:1 AV conductionto 220/min with 1:1 conduction HR 220beats/min)
  88. 88. • Re-entrant VTach after MI can ↑ frequency &severity arrhythmic episodes• Slowed conduction allows the re-entrant wavefront to persist within tachycardia circuit• Difficult to treat• Na+ infusion may be beneficial
  89. 89. Class II• Bradycardia & exacerbation of CCF in patientswith low ejection fractionClass Ia & Class III• Excessive QT prolongation & torsades depointes• „„Twisting of points”
  90. 90. • Rapid, polymorphic ventricular tachycardia•Twist of the QRS complex around theisoelectric baseline• Fall in arterial blood pressure• Can degenerate into Ventricular fibrillation
  91. 91. Treatment:• Withdrawal of offending drug•Magnesium sulphate•Phenytoin•Isoproterenol infusion/Pacing•Defibrillation
  92. 92. Digitalis Induced Arrhythmias• Can cause virtually any arrhythmia• DAD related tachycardia with impairment ofSAN & 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 withhyperkalemia
  93. 93. 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 requiretemporary pacing
  94. 94. TRIALS• Cardiac Arrhythmia Suppression Trial (CAST)• Cardiac Arrhythmia Pilot Study (CAPS)• Antiarrhythmics Versus Implantable Defibrillators (AVID)• Atrial Fibrillation Follow-Up Investigation of RhythmManagement (AFFIRM)
  95. 95. 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 toActive metabolites (GX, MEGX & NAPA)
  96. 96. Evaluation of Antiarrhythmic Drug Action Ex-Vivo Models:• Guinea pig muscle stripsIn-Vivo Models:• Atrial Arrhythmias1. Atrial Rapid Pacing Model2. Afl with Anatomical Obstacle Model
  97. 97. • Ventricular Arrhythmias1. Digitalis-induced Ventricular Arrhythmia2. Halothane adrenaline Arrhythmia3. Canine two stage coronary ligation Arrhythmia4. Programmed electrical stimulation induced re-entry Arrhythmia5. Coronary artery occlusion/reperfusion Arrhythmia• Genetic Models:1. Homozygous null connexin 40 vulnerability to atrialarrhythmias2. Transgenic mouse model→ Over expresses a constitutivelyactive form of TGF-b1
  98. 98. Clinical Evaluation:Two designs commonly used:1. Evaluating antiarrhythmic agents in pts with ICDOutcome parameter – number of defibrillator discharge2. Evaluating antiarrhythmic agents in target populationMortality rates could be assessedLarge sample size required
  99. 99. Newer Advances
  100. 100. ZP123-Rotigaptide• Prevents uncoupling of connexin 43 mediated gapjunction communication during acute metabolic stress• Selective for atrial electrophysiology• ↓ AF vulnerability in MRTedisamil• Class III antiarrhythmic• Blocks Ito, IKATP, IKr, IKs, IKur• Prolongs APD atria>ventricles• Could be used for AF, Afl
  101. 101. Azimilide• Class III antiarrhythmic• Blocks IKr & IKs• Converts and maintains sinus rhythm in patients withatrial arrhythmias• Reduces frequency and severity of ventriculararrhythmias in patients with implanted cardioverter-defibrillatorsAVE0118• Blocks IKur & Ito• Prolongs atria ERP• May be useful in atrial arrhythmis
  102. 102. AZD 7009• Inhibition of IKr, Ito, IKur and INa, a mixed ion channelblockade• Promising drug for converting AF to sinus rhythm• Phase II trialAP-792• Cardioselective Ca2+ channel blocker• Suppresses the ventricular arrhythmiasEncainide (MJ9067)• Probably has effects on Phase 2• Can be effective in suppressing ventricular ectopics
  103. 103. BRL32872• Blocks IKr & L-type Ca2+ channels• Prolongs APD• May possibly prevent torsades de pointesPiboserod• Functional 5-HT4 receptor antagonist• Could be used for AFNifekalant• Class III antiarrhythmic• Blocks IKr• Approved in Japan• Ventricular tachycardia
  104. 104. Conclusion• Precipitating factors (ischemia, electrolyte imbalance,drugs) should be eliminated• Drugs acting on particular mechanism of arrhythmiashould be used• Some arrhythmias should not be treated• Risk benefit ratio assessed (drug provokedarrhythmias)• Patient specific contraindications (disopyramide→CCF,amiodarone→pulmonary disease)
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