1. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chapter 49 Antidysrhythmic Drugs

2. 2 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Dysrhythmia  Dysrhythmia  An abnormality in the rhythm of the heartbeat (also known as arrhythmias)  Arises from impulse formation disturbances Tachydysrhythmias: SVT and ventricular Tachydysrhythmias: SVT and ventricular Bradydysrhythmias Bradydysrhythmias  Virtually all drugs that treat dysrhythmias can also cause dysrhythmias

3. 3 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Antidysrhythmic Drugs  Electrical properties of the heart  Generation of dysrhythmias  Classification of antidysrhythmic drugs  Prodysrhythmic effects of antidysrhythmic drugs  Overview of common dysrhythmias and their treatment

4. 4 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Electrical Properties of the Heart  Impulse conduction: pathways and timing  Sinoatrial (SA) node: pacemaker of heart  Atrioventricular (AV) node  His-Purkinje system

5. 5 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 49–1. Cardiac conduction pathways.

6. 6 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Cardiac Action Potentials  Fast potentials  Occur in fibers of the His-Purkinje system and in atrial and ventricular muscle  Five distinct phases Phase 0: depolarization Phase 0: depolarization Phase 1: (partial) repolarization Phase 1: (partial) repolarization Phase 2: plateau Phase 2: plateau Phase 3: repolarization Phase 3: repolarization Phase 4: stable potential Phase 4: stable potential

7. 7 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Cardiac Action Potentials  Slow potentials  Occur in cells of the SA node and AV node  Three features of special significance Phase 0: slow depolarization Phase 0: slow depolarization  Mediated by calcium influx Phases 1, 2, and 3 Phases 1, 2, and 3  Phase 1 absent  Phases 2 and 3 not significant Phase 4: depolarization Phase 4: depolarization

8. 8 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 49–2. Ion fluxes during cardiac action potentials and effects of antidysrhythmic drugs.

9. 9 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. The Electrocardiogram  Provides a graphic representation of cardiac electrical activity  Major components of an ECG  P wave Depolarization in the atria Depolarization in the atria  QRS complex Depolarization of the ventricles Depolarization of the ventricles  T wave Repolarization of the ventricles Repolarization of the ventricles  Three other components  PR interval  QT interval  ST segment

10. 10 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 49–3. The electrocardiogram.

11. 11 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Generation of Dysrhythmias  Two fundamental causes  Disturbances of automaticity  Disturbances of conduction  Atrioventricular block  Reentry (recirculating activation)

12. 12 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Classification of Antidysrhythmic Drugs  Vaughan Williams classification  Class I: sodium channel blockers  Class II: beta blockers  Class III: potassium channel blockers  Class IV: calcium channel blockers  Other: adenosine, digoxin, and ibutilide

13. 13 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Common Dysrhythmias and Their Treatment  Supraventricular  Impulse arises above the ventricle  Atrial fibrillation  Atrial flutter  Sustained supraventricular tachycardia (SVT)

14. 14 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Common Dysrhythmias and Their Treatment  Ventricular  Sustained ventricular tachycardia  Ventricular fibrillation  Ventricular premature beats  Digoxin-induced ventricular dysrhythmias  Torsades de pointes

15. 15 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Principles of Antidysrhythmic Drug Therapy  Balancing risks and benefits  Consider properties of dysrhythmias Sustained vs. nonsustained Sustained vs. nonsustained Asymptomatic vs. symptomatic Asymptomatic vs. symptomatic Supraventricular vs. ventricular Supraventricular vs. ventricular  Acute and long-term treatment phases  Minimizing risk

16. 16 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class I: Sodium Channel Blockers  Class IA agents  Class IB agents  Class IC agents

17. 17 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 49-4. Reentrant activation: mechanism and drug effects.

18. 18 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class IA Agents  Quinidine  Effects on the heart Blocks sodium channels Blocks sodium channels Slows impulse conduction Slows impulse conduction Delays repolarization Delays repolarization Blocks vagal input to the heart Blocks vagal input to the heart  Effects on ECG Widens the QRS complex Widens the QRS complex Prolongs the QT interval Prolongs the QT interval  Therapeutic uses Used against supraventricular and ventricular dysrhythmias Used against supraventricular and ventricular dysrhythmias

19. 19 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class IA Agents  Quinidine (cont’d)  Adverse effects Diarrhea Diarrhea Cinchonism Cinchonism Cardiotoxicity Cardiotoxicity Arterial embolism Arterial embolism Alpha-adrenergic blockade, resulting in hypotension Alpha-adrenergic blockade, resulting in hypotension Hypersensitivity reactions Hypersensitivity reactions  Drug interactions Digoxin Digoxin

20. 20 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Class IA Agents  Procainamide (Procanbid)  Similar to quinidine  Only weakly anticholinergic  Adverse effects: symptoms of systemic lupus erythematosus  Disopyramide (Norpace)  Similar to quinidine  Prominent side effects have limited its use

21. 21 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class IB Agents  Lidocaine (Xylocaine)  Effects on the heart and ECG Blocks cardiac sodium channels Blocks cardiac sodium channels  Slows conduction in the atria, ventricles, and His-Purkinje system Reduces automaticity in the ventricles and His-Purkinje system Reduces automaticity in the ventricles and His-Purkinje system Accelerates repolarization Accelerates repolarization  Adverse effects CNS effects CNS effects Drowsiness Drowsiness Confusion Confusion Paresthesias Paresthesias

22. 22 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class IB Agents  Other class IB agents  Phenytoin Antiseizure medication also used to treat digoxin-induced dysrhythmias Antiseizure medication also used to treat digoxin-induced dysrhythmias  Mexiletine Oral analog of lidocaine Oral analog of lidocaine Used for symptomatic ventricular dysrhythmias Used for symptomatic ventricular dysrhythmias

23. 23 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class IC Agents  Block cardiac sodium channels  Delay ventricular repolarization  All class IC agents can exacerbate existing dysrhythmias and create new ones  Two class IC agents  Flecainide  Propafenone

24. 24 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class II: Beta Blockers  Beta-adrenergic blocking agents  Only four approved for treating dysrhythmias 1.Propranolol 2.Acebutolol 3.Esmolol 4.Sotalol

25. 25 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class II: Beta Blockers  Propranolol (Inderal): nonselective beta- adrenergic antagonist  Effects on the heart and ECG Decreased automaticity of the SA node Decreased automaticity of the SA node Decreased velocity of conduction through the AV node Decreased velocity of conduction through the AV node Decreased myocardial contractility Decreased myocardial contractility  Therapeutic use Dysrhythmias caused by excessive sympathetic stimulation Dysrhythmias caused by excessive sympathetic stimulation Supraventricular tachydysrhythmias Supraventricular tachydysrhythmias  Suppression of excessive discharge  Slowing of ventricular rate

26. 26 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class II: Beta Blockers  Propranolol (Inderal) (cont’d)  Adverse effects Heart block Heart block Heart failure Heart failure AV block AV block Sinus arrest Sinus arrest Hypotension Hypotension Bronchospasm (in asthma patients) Bronchospasm (in asthma patients)  Other class II: beta blockers  Acebutolol (Sectral)  Esmolol (Brevibloc)

27. 27 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class III: Potassium Channel Blockers  Amiodarone (Cordarone, Pacerone)  Therapeutic use For life-threatening ventricular dysrhythmias only For life-threatening ventricular dysrhythmias only Recurrent ventricular fibrillation Recurrent ventricular fibrillation Recurrent hemodynamically unstable ventricular tachycardia Recurrent hemodynamically unstable ventricular tachycardia

28. 28 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class III: Potassium Channel Blockers  Amiodarone (Cordarone, Pacerone) (cont’d)  Effects on the heart and ECG Reduced automaticity in the SA node Reduced automaticity in the SA node Reduced contractility Reduced contractility Reduced conduction velocity Reduced conduction velocity QRS widening QRS widening Prolongation of the PR and QT intervals Prolongation of the PR and QT intervals

29. 29 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class III: Potassium Channel Blockers  Amiodarone (Cordarone, Pacerone) (cont’d)  Adverse effects Protracted half-life Protracted half-life Pulmonary toxicity Pulmonary toxicity Cardiotoxicity Cardiotoxicity Toxicity in pregnancy and breast-feeding Toxicity in pregnancy and breast-feeding Corneal microdeposits Corneal microdeposits Optic neuropathy Optic neuropathy

30. 30 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class III: Potassium Channel Blockers  Amiodarone (Cordarone, Pacerone) (cont’d)  Drug interactions (increases levels) Quinidine Quinidine Diltiazem Diltiazem Cyclosporine Cyclosporine Digoxin Digoxin Procainamide Procainamide Diltiazem Diltiazem Phenytoin Phenytoin Warfarin Warfarin Lovastatin, simvastatin, atorvastatin Lovastatin, simvastatin, atorvastatin

31. 31 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class III: Potassium Channel Blockers  Amiodarone levels can be increased by grapefruit juice and by inhibitors of CYP3A4. Toxicity can result  Amiodarone levels can be reduced by cholestyramine (which decreases amiodarone absorption) and by agents that induce CYP3A4 (eg, St. John’s wort, rifampin)

32. 32 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class III: Potassium Channel Blockers  The risk of severe dysrhythmias is increased by diuretics (because they can reduce levels of potassium and magnesium) and by drugs that prolong the QT interval, of which there are many (see Chapter 7)  Combining amiodarone with a beta blocker, verapamil, or diltiazem can lead to excessive slowing of heart rate

33. 33 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class III: Potassium Channel Blockers  Dronedarone (Multaq)  Derivative of amiodarone approved in 2009  Effects on the heart and ECG  Pharmacokinetics  Adverse effects Common side effects Common side effects Cardiac effects in severe heart failure Cardiac effects in severe heart failure Liver toxicity Liver toxicity Toxicity in pregnancy and breast-feeding Toxicity in pregnancy and breast-feeding  Drug interactions Multiple—many involve CYP3A4 Multiple—many involve CYP3A4

34. 34 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class III: Potassium Channel Blockers  Sotalol (Betapace)  Combined class II and class III properties  Beta blocker that also delays repolarization  Dofetilide (Tikosyn)  Oral class III antidysrhythmic  Predisposes patient to torsades de pointes  Ibutilide (Covert)  Class III agent  IV agent used to terminate atrial flutter/fibrillation

35. 35 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class IV: Calcium Channel Blockers  Verapamil (Calan, Isoptin, Verelan) and diltiazem (Cardizem)  Reduce SA nodal automaticity  Delay AV nodal conduction  Reduce myocardial contractility  Therapeutic uses Slow ventricular rate (atrial fibrillation or atrial flutter) Slow ventricular rate (atrial fibrillation or atrial flutter) Terminate SVT caused by an AV nodal reentrant circuit Terminate SVT caused by an AV nodal reentrant circuit

36. 36 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Class IV: Calcium Channel Blockers  Verapamil (Calan, Isoptin, Verelan) and diltiazem (Cardizem) (cont’d)  Adverse effects Bradycardia Bradycardia Hypotension Hypotension AV block AV block Heart failure Heart failure Peripheral edema Peripheral edema Constipation Constipation Can elevate digoxin levels Can elevate digoxin levels Increased risk when combined with a beta blocker Increased risk when combined with a beta blocker

37. 37 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Antidysrhythmic Drugs  Adenosine (Adenocard)  Effects on the heart and ECG Decreases automaticity in the SA node Decreases automaticity in the SA node Slows conduction through the AV node Slows conduction through the AV node Prolongation of PR interval Prolongation of PR interval  Therapeutic use: termination of paroxysmal SVT

38. 38 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Antidysrhythmic Drugs  Adenosine (Adenocard) (cont’d)  Adverse effects Sinus bradycardia Sinus bradycardia Dyspnea Dyspnea Hypotension Hypotension Facial flushing Facial flushing Chest discomfort Chest discomfort  Drug interactions Methylxanthines Methylxanthines Dipyridamole Dipyridamole

39. 39 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Antidysrhythmic Drugs  Digoxin (Lanoxin)  Primary indication is heart failure  Also used to treat supraventricular dysrhythmias (inactive against ventricular dysrhythmias) Suppresses dysrhythmias by decreasing conduction through AV node and automaticity in the SA node Suppresses dysrhythmias by decreasing conduction through AV node and automaticity in the SA node QT interval may be shortened QT interval may be shortened  Adverse effect: cardiotoxicity Risk increased by hypokalemia Risk increased by hypokalemia

40. 40 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Nondrug Treatment of Dysrhythmias  Implantable cardioverter-defibrillators  Radiofrequency catheter ablation