Anti arrhythmic Drugs

1. Anti arrhythmic Drugs Marwa A. Khairy , MD

2. TOPICS COVERED • Electrophysiology of the heart • Arrhythmia: definition, mechanisms, types • Drugs :class I, II, III, IV • Guide to treat some types of arrhythmia

3. Electrophysiology of the heart

4. This is the normal pathway for electricityto travel through the heart

5. This is the normal pathway for electricityto travel through the heart

6. This is the normal pathway for electricityto travel through the heart

7. This is the normal pathway for electricityto travel through the heart

8. Cardiac Action Potential • Resting membrane potential • Retention of many intracellular anions. • The resting cell membrane is almost 100 times more permeable to potassium than to sodium, • Na+K+ATPase pump. - 90mV Non-Pacemaker potential

9. Cardiac Action Potential Phase 0: fast upstroke Due to Na+ influx + 20mV N.B. The slope of phase 0 = conduction velocity Also the peak of phase 0 = Vmax Na Na Na - 90 mV • Non-Pacemaker potential

10. Resting Ready Open, Active M M M Open Closed threshold Gate Opens h h h Open Slowly Closed Depolarization tissue Na/K/ATPase pump active 3 Na out/2 K in helps repolarization -50 mv M gate closes -85 mv h gate opens Inactive refractory Open Repolarization Closed

11. Class IA Resting Ready Open, Active X X Class IC M M M Open Closed threshold Gate Opens h h h Open Slowly Closed Na channels Blockers Depolarization tissue Na/K/ATPase pump active 3 Na out/2 K in helps repolarization -50 mv M gate closes -85 mv h gate opens Class IB X Inactive refractory Open Repolarization Closed

12. Cardiac Action Potential + 20mV Phase 1: partial repolarization Due to rapid efflux of K+ - 90 mV • Non-Pacemaker potential

13. Cardiac Action Potential + 20mV Phase 2: plateau Due to Ca++ influx - 90 mV • Non-Pacemaker potential

14. Cardiac Action Potential + 20mV Phase 3: repolarization Due to K+ efflux - 90 mV • Non-Pacemaker potential

15. Cardiac Action Potential Phase 4: Resting Membrane Potential + 20mV - 90 mV • Non-Pacemaker potential

16. Cardiac Action Potential Phase 4: pacemaker potential Na influx and K efflux and Ca influx until the cell reaches threshold and then turns into phase 0 Pacemaker cells (automatic cells) have unstable membrane potential so they can generate AP spontaneously - 40mV - 60 mV • Pacemaker potential

17. Cardiac Action Potential Phase 0: upstroke: Due to Ca++ influx - 40mV Depolarization due to calcium NOT sodium! - 60 mV • Pacemaker potential

18. Cardiac Action Potential Phase 3: repolarization Due to K+ efflux - 40mV - 60 mV • Pacemaker potential

19. Cardiac Action Potential K+ Channels Open more Slow Ca++ Channels Open - 40mV Na+ Leak And less leaky to potassium - 60 mV • Pacemaker potential

20. Sympathetic and Parasympathetic • Sympathetic – speeds heart rate by  Ca++ & I-f channel flow • Parasympathetic – slows rate by  K+ efflux &  Ca++ influx

21. Cardiac Action Potential

22. Mechanism of Cardiac Contractile Cell Muscle Excitation, Contraction & Relaxation

23. Cardiac Action Potential Cardiac action potentials have long refractory periods (RP). No stimulus can produce another action potential during the effective refractory period.

24. Transmembrane action potential occurring in an automatic cardiac cell and the relationship of this action potential to events depicted on the electrocardiogram (ECG).

25. Arrhythmia: Definition, Mechanisms, Types

26. Arrhythemia Arrhythmia /dysrhythmia: abnormality in the site of origin of impulse, rate, or conduction If the arrhythmia arises from atria, SA node, or AV node it is called supraventricular arrhythmia If the arrhythmia arises from the ventricles it is called ventricular arrhythmia

27. Factors Precipitating Cardiac Arrhythmias 1. Ischemia • pH & electrolyte abnormalities • 80% – 90% asstd with MI 2. Excessive myocardial fiber stretch/ scarred/ diseased cardiac tissue 3. Excessive discharge or sensitivity to autonomic transmitters 4. Excessive exposure to foreign chemicals & toxic substances • 20% - 50% asstd with General Anesthesia • 10% - 20% asstd with Digitalis toxicity

28. Mechanisms of Arrhythmogenesis Abnormal heart pulse formation • Sinus pulse • Ectopic pulse • Triggered activity Abnormal heart pulse conduction • Reentry • Conduct block

29. Mechanisms of Arrhythmogenesis Triggered activity • Early afterdepolarizationsassociated with QT prolongation (torsades de pointes) • Delayed afterdepolarizationsassociated with Ca2+ overload (e.g. digoxin)

30. The “Re-Entry” Mechanism of Ectopic Beats & Rhythms • Most common mechanism • Requires two separate paths of conduction • Requires an area of slow conduction • Requires unidirectional block

31. Re-entry Circuits as Ectopic Foci and Arrhythmia Generators • Atrio-Ventricular Nodal Re-entry • supraventricular tachycardia • Ventricular Re-entry • ventricular tachycardia • Atrial Re-entry • atrial tachycardia • atrial fibrillation • atrial flutter • Atrio-Ventricular Re-entry • Wolf Parkinson White • supraventricular tachycardia

32. Antiarrhythmic drugs

33. Pharmacologic Rationale & Goals The ultimate goal of antiarrhythmic drug therapy: • Restore normal sinus rhythm and conduction • Prevent more serious and possibly lethal arrhythmias from occurring. Antiarrhythmic drugs are used to: • Suppressing automaticity in pacemaker • Prolonging the effective refractory period • Facilitating impulse conduction along normal conduction pathways

34. Classification of Antiarrhythmic Drugs Class I: Sodium channel blockers (membrane-stabilizing agents) 1 a:Block Na+channel and prolong action potential 1 b: Block Na+channel and shorten action potential1 c:Block Na + channel with no effect on action potential Class II: β- blockers Class III: Potassium channel blockers (main effect is to prolong the action potential) Class IV: Slow (L-type) calcium channel blockers

35. CLASS IA • Procainamide, • Quinidine, • Disopyramide Block Na channels Intermediate (< 5 s) binding Kinetics prolong AP duration, amplitude of AP, Vmax They make the slope more horizontal

36. CLASS IB • Lidocaine • Mexiletine • Phenytoin • Tocainide Block Na channels Fast onset/offset binding kinetics (< 500 ms) shortened AP duration, no change Vmax

37. CLASS IC • Flecainide, • Propafenone, • Moricizine Block Na channels Slow binding kinetics (10–20 s) slow conduction but minimal prolongation of refractoriness. Vmax

38. CLASS II • Propranolol • Atenolol • Metoprolol • Timolol, • Esmolol Blockade of β-adrenoceptor

39. CLASS III • Amiodarone • Sotalol, • Bretylium • Dofetilide • Ibutilide Block K channels

40. CLASS IV • Verapamil • Diltiazem Block slow Ca2+ channel

41. Modification of the Sicilian Gambit Drug Classification System modification of the Sicilian Gambit drug classification system

42. Proarrhythmia effect of antiarrhythmia agents • Ia, Ic class:Prolong QT interval, will cause VT or VF in coronary artery disease and heart failure patients • III class: Like Ia, Ic class agents • II, IV class:Bradycardia

43. Class I

44. Procainamide • Mechanism of Action • INa (primary) and IKr (secondary)blockade. • Slowed conduction velocity and pacemaker activity. • Prolonged action potential duration and refractory period. prolong AP duration, amplitude of AP, Vmax

45. Procainamide Clinical Applications • Most atrial and ventricular arrhythmias • Drug of second choice for most sustained ventricular arrhythmias associated with acute myocardial infarction

46. Procainamide Pharmacokinetics • Oral and parenteral; oral slow-release forms available Duration: 2–3 h • eliminated by hepatic metabolism to (NAPA) and renal elimination • NAPA implicated in torsades de pointes in patients with renal failure

47. Procainamide Toxicities, Interactions • Increased arrhythmias, hypotension, lupus-like syndrome Dose • For stable wide-QRS tachycardia • IV dose: 20-50 mg/min slowly until • Arrhythmia suppressed, hypotension ensues, QRS duration increases 50%, or maximum dose 17 mg/kg given • Maintenance infusion: 1-4 mg/min • Avoid if prolonged QT or CHF

48. Quinidine • Similar to procainamide but more toxic (cinchonism, torsades); rarely used in arrhythmias

49. Disopyramide • Similar to procainamide but significant antimuscarinic effects; may precipitate heart failure; not commonly used

50. Lidocaine Mechanism of Action • Sodium channel (INa) blockade • Blocks activated and inactivated channels with fast kinetics • Does not prolong and may shorten action potential