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1. PHARMACOLOGY OF ANTIARRYTHMIC DRUGS By Dr. Haileyesus Y. / IMR1/ moderator Dr. Tinbit / Emergency Medicine specialist/ 7/29/2021 antiarryhmic drugs, by H/eyesus 1

2. Outline introduction revision of arrhythmia and treatment options Classification of antiarrhythmic drugs Class I antiarrhythmic drugs Class II antiarrhythmic drugs Class III antiarrhythmic drugs Class IV antiarrhythmic drugs Other antiarrhythmic drugs 7/29/2021 antiarryhmic drugs, by H/eyesus 2

3. Introduction cardiac electrical activity 7/29/2021 antiarryhmic drugs, by H/eyesus 3

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6. Pacemaker action potential 7/29/2021 antiarryhmic drugs, by H/eyesus 6

7. ECG vs. action potential 7/29/2021 antiarryhmic drugs, by H/eyesus 7

8. Arrhythmia?? Definition ? Causes; HIS BEDS 7/29/2021 antiarryhmic drugs, by H/eyesus 8

9. Mechanism of arrhythmia formation Enhanced automaticity Re entry and Triggered activity 7/29/2021 antiarryhmic drugs, by H/eyesus 9

10. Classification of arrhythmia Depending on pathophysiology; arrhythmias of sinus origin Ectopic arrhythmias Re entry arrhythmias Conduction blocks Pre excitation syndromes 7/29/2021 antiarryhmic drugs, by H/eyesus 10

11. 2) Depending on a focus of occurrence; supraventricular and ventricular; PAC, PSVT, atrial flutter, atrial fibrillation, WPW syndrome, …. ventricular arrhythmias; ventricular tachycardia, ventricular fibrillation, TDP, PVC, ……. 7/29/2021 antiarryhmic drugs, by H/eyesus 11

12. Arrhythmia treatment Pharmacological Non pharmacologic; ICD external defibrillator, catheter ablation; radiofrequency vs. cryoablation CRT 7/29/2021 antiarryhmic drugs, by H/eyesus 12

13. Antiarrhythmic drugs Drugs used to treat abnormal rhythm By modulating autonomic function and cardiac ion channel Changes conduction velocity and refractory period Majority classified under Vaughan- Williams classification Some not classified 7/29/2021 antiarryhmic drugs, by H/eyesus 13

14. Vaughan- Williams classification Class I; class IA, IB and IC……….Na channel blockers Class II…………………………………….beta blocker Class III……………………………………….K channel blocker Class IV……………………………………..Ca channel blockers Others, not classified 7/29/2021 antiarryhmic drugs, by H/eyesus 14

15. Revised Vaughan- Williams classification 7/29/2021 antiarryhmic drugs, by H/eyesus 15

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18. How antiarrhythmic drugs affect an action potential and ECG 7/29/2021 antiarryhmic drugs, by H/eyesus 18

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20. Class I Mild to strong blockade of INa Increases excitability threshold Classified to subclass IA ……..moderate blockade IB……..mild blockade IC………strong blockade 7/29/2021 antiarryhmic drugs, by H/eyesus 20

21. Class IA Moderate blockade Procainamide, quinidine and disopyramide Usage limited b/c of side effects and proarrhythmic effects Quinidine may bring torsade de points Disopyramide, good for HOCMP but risks like hypotension CHF and anticholinergic effects like renal retention makes it difficult to use 7/29/2021 antiarryhmic drugs, by H/eyesus 21

22. Procainamide moderate blockade of INa and K channel so that decreases automaticity and conduction velocity prolongs refractory period and cardiac action potential NAPA, blocks K channels but lacks INa channel inhibition ….prolongs QT interval Indications; for life-threatening supraventricular and ventricular arrythmias Option not 1 st line for SVT and V- Tach’s Avoid in patients with prolonged QT interval and CHF 7/29/2021 antiarryhmic drugs, by H/eyesus 22

23. Dosing and administration Initial: 20–50 milligrams/min IV until the arrhythmia is suppressed, hypotension ensues, or the QRS complex is prolonged by 50% from its original duration (maximum dose: 17 milligrams/kg) Maintenance infusion rate: 1–4 milligrams/min OR 100 milligrams IV every 5 min until the arrhythmia is controlled or one of the above conditions is met 7/29/2021 antiarryhmic drugs, by H/eyesus 23

24. Adverse effects most common is hypotension , conduction abnormalities and rash severe adverse effects like TDP, V- fib and paradoxical increase in HR in atrial fib and flutter, hepatotoxicity, CHF Cinchonism ……quinidine drug induced lupus…….procainamide TDP ……all class IA groups 7/29/2021 antiarryhmic drugs, by H/eyesus 24

25. Class IB Weak blockade with fast dissociation Lidocaine and mexiletine Used preferably in post MI Lidocaine …class IB antiarrhythmic with local anesthetic effect Indication, 2 nd option for pulseless v-tach and v-fib Adverse effects dose dependent …. risk of hemodynamic effect and CNS symptoms like dizziness somnolence , seizure and speech disturbance 7/29/2021 antiarryhmic drugs, by H/eyesus 25

26. dosing of lidocaine For ventricular arrythmia; Loading dose: 50–100 milligrams (0.7–1.4 milligrams/kg) IV over 2–3 min. May repeat in 5 min (up to 300 milligrams in any 1-h period) Maintenance: 1–4 milligrams/min IV (0.014–0.057 milligrams/kg/mi For V fibrillation; Initial dose: 1–1.5 milligrams/kg IV If VF/pulseless VT persists, additional doses of 0.5–0.75 milligrams/kg IV every 5–10 min (maximum total dose: 3 milligrams/kg) 7/29/2021 antiarryhmic drugs, by H/eyesus 26

27. Class IC Strong blockade of INa channel with marked QRS prolongation but not QT prolongation Acts only on open INa with high degree refractoriness and conduction delay b/c of blockade and dissociation behavior Higher proarrhythmic effect Most studies shows increased mortality when used in case of underlying heart disease Propafenone and flecainide 7/29/2021 antiarryhmic drugs, by H/eyesus 27

28. Propafenone Class IC agent with beta blocker effect Selective for cell with high rate of conduction Indicated for conversion of acute < 7 days AF 450 mg po for < 70 and 600 mg po for > 70 kg Adverse effects include hypotension, bradycardia, bronchospasm, atrial flutter with 1:1 AV conduction and and ventricular arrythmias. Avoid in CAD and significant structural heart disease Use cautiously in case of asthma and liver disease 7/29/2021 antiarryhmic drugs, by H/eyesus 28

29. Flecainide Effect more seen at his Purkinje system and ventricular myocardium Indicated for conversion of acute < 7 days AF Dose 200 mg and 300 mg for < 70 and > 70 kg respectively Adverse effects; hypotension, atrial flutter with 1:1 AV conduction and ventricular arrythmias. Avoid in case of CAD and significant structural heart disease, CHF and hypokalemia 7/29/2021 antiarryhmic drugs, by H/eyesus 29

30. Class II ( beta blockers) as a group has beta blocking property so inhibits sympathetic effect Differs in intrinsic sympathomimetic effect, alpha blocking effect and pharmacokinetics Used for arrythmias/ SVT, ventricular arrythmias, recurrent AF/, HTN, Thyroid ds and heart failure Selective vs non selective……dose dependent 7/29/2021 antiarryhmic drugs, by H/eyesus 30

31. Esmolol short acting with rapid onset Beta1 selective blockade Negative inotropic and chronotropic effect…..decreases HR Only parenteral formulation with rapid onset and short duration of action / 10- 30 min DOA/ Dosing is 500 mic/kg bolus can be repeated Q4 minutes until 3 doses Infuse with 50 mic g/kg/min escalate Q 4 minutes until 200 mic g/kg/min 7/29/2021 antiarryhmic drugs, by H/eyesus 31

32. Metoprolol Antihypertensive effect by Selective inhibition of B1, Renin inhibition Inhibiting sympathetic outflow and Decreasing cardiac output 7/29/2021 antiarryhmic drugs, by H/eyesus 32

33. Labetalol Non selective beta antagonist and alpha 1 antagonist Affects beta receptor more than alpha Use to treat hypertension at pregnancy and hypertensive emergency Dosing 20 mg IV Q 2 min / 40- 80 mg over 10 min/ not to exceed 300 mg IV daily Po 100 mg po BID escalate Q 2-3 day max 2400 mg in divided dose 7/29/2021 antiarryhmic drugs, by H/eyesus 33

34. Adverse effects of beta blockers bradycardia Conduction block Hypotension Bronchospasm Pulmonary edema CHF Reflex hypertension especially in case of esmolol with rapid discontinuation 7/29/2021 antiarryhmic drugs, by H/eyesus 34

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36. Class III Inhibits inward potassium current……prolongs refractory period….myocardium resistant to reentrant circuits prolongs QT interval ….risk for TDP Includes amiodarone, dronedarone ibutulide , sotalol, dofetilide and vernaklant 7/29/2021 antiarryhmic drugs, by H/eyesus 36

37. Amiodarone Posses all four antiarrhythmic properties 7/29/2021 antiarryhmic drugs, by H/eyesus 37

38. Highly effective, broad spectrum antiarrhythmic drugs used for acute and chronic conversion of supraventricular and ventricular arrhythmia Highly lipophilic and distributed to the tissue Half life and duration of action approximates 50 days Metabolized by liver and excreted thorough biliary tract 7/29/2021 antiarryhmic drugs, by H/eyesus 38

39. I ndications 7/29/2021 antiarryhmic drugs, by H/eyesus 39

40. Dosing and administration 7/29/2021 antiarryhmic drugs, by H/eyesus 40

41. Higher dose and infusion rate higher risk of hypotension, bradycardia and phlebitis Infuse with 5%DW not with NS No renal dose adjustment but hepatic 7/29/2021 antiarryhmic drugs, by H/eyesus 41

42. pharmacokinetics 7/29/2021 antiarryhmic drugs, by H/eyesus 42

43. Adverse effects of amiodarone liver, thyroid, lung and ocular toxicities Long QT interval but TDP not common even in patients with underlying heart disease Inhibits liver enzymes……drug drug interaction Augments bradycardia and and QT prolongation with other drugs Dose reduction necessary for digoxin warfarin , procainamide simvastatin, levastatin and flecainide Drug interaction may persist for months 7/29/2021 antiarryhmic drugs, by H/eyesus 43

44. Adverse effects 7/29/2021 antiarryhmic drugs, by H/eyesus 44

45. Dronedarone Derivative of amiodarone non iodinated which is less lipophilic with less side effect Mainly class III antiarrhythmic but has MOA of 4 types of antiarrhythmic drugs indicated for hospitalization benefit in case of sinus rhythm with hx of persistent or paroxysmal AF Less efficacious than amiodarone for maintaining sinus rhythm Dose; 400 mg po BID with but not with grape fruit 7/29/2021 antiarryhmic drugs, by H/eyesus 45

46. less lung toxicity and no thyroid toxicity relative to amiodarone Hepatic toxicity New CHF, bradycardia, long QTc, AV block, sick sinus syndrome contraindicated in case of severe CHF and permanent AF If AF developed while on dronedarone either cardiovert or stop dronedarone 7/29/2021 antiarryhmic drugs, by H/eyesus 46

47. Summary for indications of class III antiarrhythmic 7/29/2021 antiarryhmic drugs, by H/eyesus 47

48. CLASS IV ANTIARRHYTHMICS: CALCIUM CHANNEL BLOCKERS inhibit L-type calcium channels, resulting in slowing of atrioventricular nodal conduction and an increase in the refractory period of nodal tissue. In the myocardium, calcium channels primarily affect the action potential plateau and modulate the strength of muscle contraction. divided into two categories Dihydropyridine; vascular selective…antihypertensives non dihydropyridine; have greater cardioselectivity and are used for paroxysmal supraventricular tachycardia and rate control in atrial fibrillation, 7/29/2021 antiarryhmic drugs, by H/eyesus 48

49. DILTIAZEM/VERAPAMIL slow atrioventricular nodal conduction, increase the atrioventricular node’s refractory period decrease automaticity, and prolong the PR interval. Verapamil is more potent than diltiazem …..used frequently to abort SVT 7/29/2021 antiarryhmic drugs, by H/eyesus 49

50. Indication; PSVT and AF To abort PSVT commonly use verapamil which is as effective as adenosine Diltiazem for rapid ventricular rate at Both agents are contraindicated for wide-complex tachyarrhythmia's Other contraindications include sick sinus syndrome, second- or third-degree atrioventricular block, severe hypotension, cardiogenic shock, administration concomitantly or within a few hours of IV β-blockers . 7/29/2021 antiarryhmic drugs, by H/eyesus 50

51. Diltiazem loading 0.25mg/kg over 2 min if no adequate repeat .35/kg /min then continuous infusion of 5-15mg/ hr. until rate control where can be switched to oral Verapamil 2.5 mg – 5 mg iv over 2 minute, repeat 5-10 mg iv after 15 – 30 min, total dose not to exceed 20 – 30 mg Side effects; well tolerated when compared to other antiarrhythmics bradyarrhythmia, asystole, fatigue, headache, hypotension, atrioventricular block, peripheral edema, syncope, and dizziness. 7/29/2021 antiarryhmic drugs, by H/eyesus 51

52. OTHER ANTIARRHYTHMIC MEDICATIONS Digoxin cardiac glycoside with + ve inotropic, chronotropic and dromotropic effect…..due to inhibition of Na-K ATPase Has narrow therapeutic index 0.5 2 ng/ml pharmacokinetics affected with CHF, hypokalemia and renal failure and thyroid disease Has numerous drug interaction 7/29/2021 antiarryhmic drugs, by H/eyesus 52

53. indicated for rate control in AF….not 1 st line For symptomatic HF patients while on optimal medical therapy Contraindications; ventricular arrythmia , WPW syndrome electrolyte abnormalities, AV block, renal impairment. Dose; 0.25-0.5 mg iv Q 30 min-2hr up to 1.5 mg max, maintenance dose 0.125- 0.375 mg po daily Adjusting dose necessary depending on age renal function and concomitant drugs and comorbidities 7/29/2021 antiarryhmic drugs, by H/eyesus 53

54. Adverse effects Mostly GI symptoms Rash, eosinophilia, thrombocytopenia, gynecomastia, arrythmias like bradyarrhythmia's , blocks / AV or SA/ even ventricular arrythmias Digoxin toxicity symptoms; mental status changes, visual disturbances, delirium, and seizures. 7/29/2021 antiarryhmic drugs, by H/eyesus 54

55. ATROPINE Blocks effects of acetylcholine at smooth muscles so that increases cardiac output Indications ; 1 st line for symptomatic bradycardia, but not for asystole or PEA use with caution in patients with coronary heart disease, congestive heart failure, tachycardia, and hypertension. 7/29/2021 antiarryhmic drugs, by H/eyesus 55

56. Dosing; 0.5 milligram IV every 3–5 min (maximum total dose: 3 milligrams or 0.04 milligram/kg) Doses < 0.5 or slow injection associated with paradoxical Adverse effects; tachyarrhythmia, constipation, xerostomia, blurred vision, and photophobia. 7/29/2021 antiarryhmic drugs, by H/eyesus 56

57. ADENOSINE endogenous nucleoside binds adenosine receptors and inhibits adenylate cyclase ….. decreases flow of calcium ions in the atrioventricular node. decreases SA depolarization by activation of acetylcholine-sensitive potassium currents. These effects result in hyperpolarization and automaticity in cardiac nodal tissue. Adenosine is a first-line for narrow-complex SVT, and also used as diagnostic tool. 7/29/2021 antiarryhmic drugs, by H/eyesus 57

58. Indications ; supraventricular tachycardia with or without reentry pathways, after failure of vagal maneuvers . Dosing; for PSVT, 6 milligrams IV If ineffective after 1–2 min, may give second dose of 12 milligrams IV. Adverse effects; transient asystole (treatment goal), chest discomfort/pressure, headache, flushing, and nausea even bronchospasm and AF may happen but transient 7/29/2021 antiarryhmic drugs, by H/eyesus 58

59. MAGNESIUM SULFATE IV magnesium sulphate exerts antiarrhythmic effect in TDP Antiarrhythmic effect mediated by inhibiting Ca current which is responsible for pathologic early after depolarization…with resulting cardiac dyssynchronization slows sinoatrial node activity, prolongs myocardial conduction time, stabilizes excitable membranes Indication; torsade de pointes, polymorphic ventricular tachycardia associated with a prolonged QT interval, and cardiac arrest when ventricular fibrillation/pulseless ventricular tachycardia is associated with torsade de pointes. 7/29/2021 antiarryhmic drugs, by H/eyesus 59

60. Dosing 1 to 2 grams IV is diluted in normal saline or 5% dextrose in water and administered as a rapid bolus. Rapid IV administration of magnesium sulfate is associated with vasodilation, flushing, and hypotension. 7/29/2021 antiarryhmic drugs, by H/eyesus 60

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62. THANK YOU FOR YOUR PATIENCE . 7/29/2021 antiarryhmic drugs, by H/eyesus 62