1. ANTIARRHYTHMIC DRUGS 1

2. INTRODUCTION The heart contains specialized cells that exhibit automaticity; that is, they can generate rhythmic action potentials in the absence of external stimuli This phenomenon of automaticity is carried out by the “pacemaker” cell that spreads the depolarization from the SA node → AV node → Bundle of His → Purkinje cells Dysfunction of impulse generation or conduction at any level in the heart can cause an abnormality in cardiac rhythm called Arrhythmia 2

3. Types OF Arrhythmia Altered Rate Premature beats Altered Conduction http://www.cvpharmacology.com/clinical%20topi cs/arrhythmias-2 http://www.cvpharmacology.com/clinical%20topi cs/arrhythmias-2 http://www.skillstat.com/tools/ecg-simulator 3

4. 4 Reentry For reentry to occur, certain conditions must be met that are related to the following: 1)the presence of a unidirectional block within a conducting pathway 2) critical timing 3) the length of the effective refractory period of the normal tissue

5. CONSEQUENCES OF ARRHYTHMIA Cause the heart to beat too slowly To beat too rapidly (vent tachycardia, atrial flutter To respond to impulses originating from sites other than the SA node To respond to impulses traveling along accessory pathways that lead to deviant depolarization 5

6. Action Potential in cardiac &His- Purkinje system 6 - 80 mV Resting Membrane Potential Plateau Phase (Opening of Ca-Na Channels and Decrease K permeability) Repolarization Phase (Opening of K Channels) Depolarization Phase (Opening of Fast Na Channels) + 20 mV 0.2 to 0.3 sec

7. PHASES OF AP in Fast fibers Phase 0 - depolarization - opening of Na channels( fast sodium current) Blocked by class I drugs phase 1 – Inactivation of Na channels, phase 2 – Plateau phase -- slow but prolonged opening of Ca channels balanced by late outward K⁺ current. Phase 3 – Final repolarization – closure of Ca channels and rapid K efflux. Blocked by class III drugs Phase 4 ---- return of membrane to resting potential by the activity of Na⁺/K⁺-ATPase 7

8. Three ion channel mechanisms contribute to the pacemaker potential – The first is a progressive reduction in potassium permeability. Second is presence of funny channels. Third is presence of T-type calcium channels (T transient).

9. ANS Regulation of Heart Rate SA & AV nodes are innervated by both PANS & SANS fibers activating M2 & b1 receptors respectively. Phase 4 slope increased by increase cAMP (b1 activation) & slowed by decrease cAMP (M2 activation). 9

10. CLASSES OF DRUGS CLASS I ANTIARRHYTHMIC DRUGS CLASS II ANTIARRHYTHMIC DRUGS CLASS III ANTIARRHYTHMIC DRUGS CLASS IV ANTIARRHYTHMIC DRUGS 10

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13. Class I – (Na CHANNEL BLOCKERS) 13

14. 14 Effects on depolarization Effects on repolarization Effects on automaticity Indirect vagal effects

15. Na+ Channel Blockers - Class IA Decrease Vmax(phase 0) via block of fast Na channels in the open or activated state Increase APD & Effective Refractory Period (ERP) 15

16. QUINIDINE Increase HR & AV conduction due to its muscarinic blockade Vasodilation due to blockade of alpha receptor → hypotension orally effective 16

17. THERAPEUTIC USES WIDE RANGE A-Fib, Ventricular tachyarrhythmias MAINTAIN NORMAL RHYTHM AFTER CARDIOVERSION 17

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19. Adverse effects nausea & vomiting, cinchonism (GI, tinnitus, ocular dysfunction, CNS excitation), syncope due to prolongation of QT interval (torsades), AV & SA block At toxic doses: ventricular tachycardia. Interactions: hyperkalemia increases its cardiotoxicity; enhances digoxin toxicity; Decrease effects of AChE inhibitors in myasthenia. 19

20. PROCAINAMIDE CLASS 1A DERIVATIVE OF LOCAL ANAESTHETIC PROCAINE ADVANTAGES LESS ANTIMUSCARINIC EFFECTS 20

21. Pharmacokinetics Well absorbed via oral route Short half-life Metabolized via N-acetyltransferase to N- acetyl procainamide (NAPA), an active metabolite NAPA is eliminated via the kidney 21

22. SIDE EFFECTS SLE LIKE SYNDROME, Hematotoxic CNS effect: DEPRESSION, HALLUCINATIONS, & PSYCHOSIS. CVS: TORSADES Toxic dose: ASYSTOLE, ventricular arrhythmia 22

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24. DISOPYRAMIDE CLASS I A NEGATIVE IONOTROPIC ANTI MUSCARINIC EFFECT – GREATER SIDE EFFECTS ANTICHOLINERGIC EFFECTS NOT FIRST LINE DRUG. USED AS AN ALTERNATIVE TO OTHER CLASS 1A DRUGS CI: in patients with heart failure 24

25. Na+ Channel Blockers - Class IB Decrease Vmax – block fast Na+ channels in the inactivated state - preference for tissues partly depolarized (ischemic or hypoxic tissues) Decrease APD( blockade of slow Na⁺ window current in the plateau) (SHORTENS PHASE 3 REPOLARISATION) 25

26. ROUTE – I.V. EXTENSIVE FIRST PASS METABOLISM preclude oral use. USES : arrhythmias during an MI, & DOC (Drug Of Choice) for arrhythmias following attempted cardioversion. MC : VENTRICULAR ARRHYTHMIAS Digoxin toxicity 26

27. Lidocaine Adverse effects: CNS toxicity culminating in seizures. Least cardiotoxic of conventional antiarrhythmics. 27

28. OTHER CLASS 1 B MEXILETINE TREATMENT OF VEN. ARRHY. MOSTLY WITH PAST H/O OF MI. Side effects: Epigastric burning: nausea (common) Neurologic side effects: – diplopia, vertigo, slurred speech, tremor 28

29. CLASS 1B TOCAINIDE - VTA SIDE EFFECTS fatal bone marrow aplasia pulmonary fibrosis. RARELY USED 29

30. Na+ Channel Blockers - Class IC Decrease Vmax - block fast Na+ channels in all states No effect on APD 30

31. CLASS 1 C - FLECAINIDE Na channel blocker at all states SLOWS PHASE O NEGATIVE IONOTROPIC EFFECT CI : HEART FAILURE-CAN INDUCE V TAC (proarrhythmic) SIDE EFFECTS : DIZZINESS, BLURRED VISION USES : reserved for management of life-threatening arrhythmias or refractory VA 31

32. CLASS II ( BETA BLOCKERS) Decrease SA & AV nodal activity Decrease slope of phase 4 (diastolic currents) of AP in pacemakers prevent b1 adrenoceptors activation which would normally increase cAMP 32

33. Propranolol (non-selective) & cardioselective drugs – acebutolol, metoprolol esmolol 33

34. Rx uses: prophylaxis post-MI & in SVTs & Atrial arrhythmias; esmolol (IV) is used in acute SVTs. 34

35. Class III (K+ Channel Blockers) Increase APD & ERP especially in Purkinje & ventricular tissues Decrease IK (delayed rectifier current) slowing phase 3 of AP. 35

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37. CLASS III ( K CHANNEL BLOCKERS) AMIODARONE Dofetilide SOTALOL PROLONGS PHASE 3 REPOLARIZATION BLOCKS K OUTLFOW, ↑ APD & ERP All class III drugs prolong QT-interval except Amiodarone 37

38. SOTALOL β₁ blocker but acts as a K⁺ channel blocker USES: Treatment of life threatening arrhythmia SUPPRESS ECTOPIC BEATS DECREASES rate of sudden death following an acute MI & IN PTS with SUSTAINTED VENT. TACHYCARDIA. 38

39. AMIODARONE Both antianginal & antiarrhythmic activity. Shows actions of class I, II, III, IV. Does not prolong the QT-interval Use: in treatment of severe refractory Supraventricular and VTA. SE: GI intolerance, photosensitivity, ataxia, blue skin discoloration, tremor, dizziness, liver toxicity, pul. Fibrosis hepatotoxicity, hypo/hyperthyroidism. 39

40. CLASS IV (Ca Channel blockers) Verapamil Diltiazem Decrease the influx of Ca²⁺ – decrease the rate of phase 0 depolarization and phase 4 spontaneous depolarization Decrease conduction velocity 40

41. USES Used in treatment of atria than ventricular arrhythmia SVTs of nodal arrhythmias They also have effect on the vascular smooth muscle and the heart. So can be used in treatment of hypertension also. CI: in pts with depressed heart function 41

42. SE: GI distress: CONSTIPATION dizziness flushing Hypotension AV block Interaction: Verapamil displaces digoxin from binding sites 42

43. Other drugs: ADENOSINE 1.Activates adenosine receptor 2.Gi-coupled decreasing cAMP Decrease SA and AV nodal activity USES: Used mainly for the abolishing paroxysmal Supraventricular tachycardia( IV route ) AV nodal arrhythmia 43

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45. Possible side effects - flushing, sedation & dyspnea, bronchospasm Antagonized by theophylline. 45

46. DIGOXIN Prolongs ERP Diminishes conduction velocity in purkinje fibers. Can be used in atrial fib and flutter. Toxic dose: results in ventricular tachycardia 46

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