Arrhythmia & Antiarrhythmic Drugs

Electrophysiology of the heart

Arrhythmia: definition, mechanisms, types

Drugs :class I, II, III, IV

Guide to treat some types of arrhythmia

1. Arrhythmia & Antiarrhythmic Drugs Slide no:1 Pharmacology Presented by S.Lakshmi Sravanthi 11AB1R0051 Vignan pharmacy college (Approved by AICTE , PCI & Affiliated to JNTU kakinada) Vadlamudi , Guntur (Dt)-522213

2. Electrophysiology of the heart Arrhythmia: definition, mechanisms, types Drugs :class I, II, III, IV Guide to treat some types of arrhythmia Date:26-07-2014 Pharmacology Slide no:2

3. Cardiac arrythmias results from alterations in the orderly sequence of depolarisation followed by repolarization in the heart. Cardiac arrythmias may result in alterations in heart rate or rhythm and arise from alterations in simple generation or conduction. CARDIAC ARRYTHMIAS Definition Date:26-07-2014 Pharmacololgy Slide no:3

4. ELECTROPHYSIOLOGY – CARDIAC RHYTHM Date:26-07-2014 Pharmacology Slide no:4

5. Conducting tissue SA node,AV node,bundle of his & purkije fibers. Contractile tissue Atria and ventricles. IMPULSE GENERATION AND CONDUCTION Date:26-07-2014 Pharmacology Slide no:5

6. Cardiac Action Potential Divided into five phases (0,1,2,3,4) Phase 0 – rapid depolarization Phase 1 – early repolarization Phase 2 – plateau phase Phase 3 – rapid repolarization Phase 4 – resting phase, diastolic depolarization Date:26-07-2014 Pharmacology Slide no:6

7. Action Potential Phase 0 Phase 4 Phase 3 Phase 2 Phase 1 - 90 mV 0 mV 30 mV Non nodal tissues Date:26-07-2014 Pharmacology Slide no:7

8. 0 1 2 3 4 Effective refractory period Absolute refractory period Relative refractory period 1 2 3 4 A RP RRP Date:26-07-2014 Pharmacology Slide no:8

9. Pacemaker AP Phase 4: pacemaker potential Na + influx and K + efflux and Ca ++ influx until the cell reaches threshold and then turns into phase 0 Phase 0: upstroke: Due to Ca ++ influx Phase 3: repolarization: Due to K + efflux Pacemaker cells (automatic cells) have unstable membrane potential so they can generate AP spontaneously Date:26-07-2014 Pharmacology Slide no:9

10. ECG showing wave segments Contraction of atria Contraction of ventricles Repolarization of ventricles Date:26-07-2014 Pharmacology Slide no:10

11. Arrhythmia Date:26-07-2014 Pharmacology Slide no:11

12. Depressed automaticity of SA node Enhanced automaticity of SA node Impulse from ectopic loci Ischemia, digitalis, catecholamine's, acidosis, hypokalaemia Less (-) resting membrane potential More (-) TP Abnormal impulse generation Date:26-07-2014 Pharmacology Slide no:12

13. Extra abnormal depolarisation Due to abnormal intracellular Ca 2+ regulation During or immediately after phase 3 After depolarisation may be categorized in to - Early after depolarisation - Delay after depolarisation Triggered Activity Date:26-07-2014 Pharmacology Slide no:13

14. After depolarizations EADs  prolonged APD Clinical arrhythmia : e.g., torsades de pointes due to: long QT syndrome genetic defects DADs  HR or [Ca 2+ ] i Clinical arrhythmia : e.g., Ca 2+ overload due to: digoxin or PDE inhibitor toxicity Date:26-07-2014 Pharmacology Slide no:14

15. Abnormal impulse conduction Date:26-07-2014 Pharmacology Slide no:15

16. Due to depression of impulse conduction at AV node & bundle of His, due to vagal influence or ischemia. Types : 1 st degree heart block – slowed conduction 2 nd degree block – some supraventricular complex not conducted 3 rd degree block – no supraventricular complex are conducted Conduction Block Date:26-07-2014 Pharmacology Slide no:16

17. Due to abnormality of conduction , an impulse may recirculate in the heart and causes repetitive activation without the need for any new impulse to be generated. These are called reentrant arrythmias. Circus movement type: A premature impulse temporarily blocked in one direction by refractory tissue, makes a one-way transit around an obstacle finds the original spot in an advanced state of recovery and rexicites it, setting up recurrent activation of adjacent myocardium. Re-entry phenomenon Date:26-07-2014 Pharmacology Slide no:17

18. Date:26-07-2014 Pharmacology Slide no:18

19. Accessory tract pathway Accessory pathway in the heart called Bundle of Kent Date:26-07-2014 Pharmacology Slide no:19

20. Important cardiac arrhythmias Extra systole – premature beats Due to abnormal automaticity or impulse arising from ectopic focus. PSVT – Sudden onset of AT 150-200/min Due to circus movement type of Re-entry or accessory pathway AFL – 200-300 / min Due to re entry circuit in right atrium Date:26-07-2 014 Pharmacology Slide no:20

21. Atrial fibrillation 350-550/min Due to electrophysiological inhomogenesity of atrial fibers. Date:26-07-2 014 pharmacology Slide no:21

22. VT – 4 or more consecutive ventricular extrasystoles Due to either discharge from ectopic focus or reentry circuits Torsades de points Polymorphic VT with rapid asynchronous complex, twisting along the baseline on ECG with long QT interval VF Grossly irregular, rapid & fractionated action of ventrcles – resulting in incoordinated contraction of ventricles with loss of pumping function. Date:26-07-2 014 Pharmacology Slide no:22

23. Possible mechanisms of antiarrhythmic drugs 1. Suppressing the Automaticity ↓ Rate of phase 0 ↓ Slope of phase 0 Duration ERP ↑ TP less negative Resting membrane potential more negative 2. Abolishing reentry Slow conduction ↑ ERP Date:26-07-2 014 Pharmacology Slide no:23

24. 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: Decrease conduction velocity Change the duration of the effective refractory period (ERP) Suppress abnormal automaticity Pharmacological goals Date:26-07-2 014 Pharmacology Slide no:24

25. Vaughan-Williams Classification CLASS MECHANISM I Na + channel blocker II β blocker III K + channel blocker IV Ca ++ channel blocker Date:26-07-2 014 Pharmacology Slide no:25

26. class mechanism action notes I Na + channel blocker Change the slope of phase 0 Can abolish tachyarrhythmia caused by reentry circuit II β blocker ↓ heart rate and conduction velocity Can indirectly alter K and Ca conductance III K + channel blocker ↑ action potential duration (APD) or effective refractory period (ERP). Delay repolarization. Inhibit reentry tachycardia IV Ca ++ channel blocker Slowing the rate of rise in phase 4 of SA node. ↓ conduction velocity in SA and AV node Anti arrythmic drugs Date:26-07-2 014 Pharmacology Slide no:26

27. They ↓ automaticity in non-nodal tissues (atria, ventricles, and purkinje fibers ) They act on open Na + channels or inactivated only Use dependence Have moderate K + channel blockade Date:26-07-2 014 Pharmacology Slide no:27

28. Slowing the rate of rise in phase 0 They prolong action potential & ERP ↓ the slope of Phase 4 spontaneous depolarization ↑ QRS & QT interval Date:26-07-2 014 Pharmacology Slide no:28

29. Antimalarial, antipyretic, skeletal muscle relaxant and atropine like action. Quinidine binds to open and inactivated sodium channels and prevents sodium influx, slowing the rapid upstroke during phase o. It also decreases the slope of phase 4 spontaneous depolarization and inhibits potassium channels. QUINIDINE Mechanism of action Date:26-07-2 014 Pharmacology Slide no:29

30. Diarrhoea “Cinchonism” – tinnitus, vertigo, headache, nausea & blurred vision. 200-400 mg orally tds A/E Date:26-07-2 014 Pharmacology Slide no:30

31. Ventricular tachyarrythmias Used in the termination of ventricular tachycardia Quinidine can interact the plasma concentration of digoxin, which may in turn lead to signs and symptoms of digitalis toxicity. Cimitidine increases hepatic metabolism of quinidine Uses Drug interactions Date:26-07-2 014 Pharmacology Slide no:31

32. Procaine derivative, quinidine like action Procainamide binds to open and inactivated Na+ channels and prevents sodium influx, slowing the rapid upstroke during phase 0 Hypotension Hypersensitivity reaction PROCAINAMIDE Mechanism of action A/E Date:26-07-2 014 Pharmacology Slide no:32

33. Paroxysmal atrial tachycardia Premature atrial contractions Dose:1-1.5g rate of 20-50mg/min Procainamide hypersensitivity Bronchial asthma Cimitidine inhibits the metabolism of procainamide Uses Drug Interactions C/I Date:26-07-2 014 Pharmacology Slide no:33

34. DISOPYRAMIDE Disopyramide produces a negative ionotropic effects that is greater than weak effect exerted by quinidine and procainamide, and unlike the latter drugs, disopyramide causes peripheral vasoconstriction. Myocardial depression Urinary retention Constipation Mechanism of action A/E Date:26-07-2 014 Pharmacology Slide no:34

35. Disopyramide ventricular tachycardia AF & AFI - CHF In the presence of phenytoin, the metabolism of disopyramide is increased and the accumulation of its metabolite is also increased, there by increasing the probability of anticholinergic properties. Uses C/I Drug Interactions Date:26-07-2 014 Pharmacology Slide no:35

36. A/E Nausea Dizziness A-V block Uses Ventricular tachycardia C/I A-V block Drug hypersensitivity MORICIZINE Drug interactions No significant interactions Mechanism of action Moricizine reduces the maximal upstroke of phase 0 and shortens the cardiac transmembrane action potential. The phenomenon may explain the efficacy of moricizine in suppressing rapid ecotopic activity. Date:26-07-2 014 Pharmacology Slide no:36

37. They shorten Phase 3 repolarization ↓ the duration of the cardiac action potential Prolong phase 4 Date:26-07-2 014 Pharmacology Slide no:37

38. the duration of action potential decreases LIDOCAINE It shorten phase 3 repolarization and decreases the duration of action potential Drowsiness Slurred speech Confusion and convulsions VA Digitalis toxicity A/E Uses Mechanism of action Date:26-07-2 014 Pharmacology Slide no:38

39. C/I Lidocaine is contraindicated in the presence of second and third degree heart block, since it may increase the degree of block and can abolish the idioventricular Pacemaker responsible for maintaining the cardiac rhythm. Proponolol increases its toxicity. The myocardial depressant effect of lidocaine is enhanced by phenytoin administration. Drug interactions Date:26-07-2 014 Pharmacology Slide no:39

40. Phenytoin was originally introduced for the control of convulsive disorders but now also been shown to be effective in the treatment of cardiac arrythmias. Anaesthesia Open heart surgery Digitalized induced and ventricular arrythmia in children PHENYTOIN Uses Date:26-07-2 014 Pharmacology Slide no:40

41. Respiratory arrest Severe bradycardia Hypotension Severe heart failure AF & AFI Plasma phenytoin concentrations are increased in the presence of chloramphenicol, disulfiram, and isoniazid, since the later drugs inhibit the hepatic metabolism of phenytoin A/E C/I Drug Interactions Date:26-07-2 014 Pharmacology Slide no:41

42. It is a local anaesthatic and an active antiarrythmic by the oral route; chemically and pharmacologically similar to lidocaine. It reduces automaticity in PF, both by decreasing phase 4 slow and by increasing threshold voltage. By reducing the rate of 0 phase depolarization in ischemic PF it may convert one-way block to two-way block. MEXELETINE Mechanism of action Date:26-07-2 014 Pharmacology Slide no:42

43. Tremor Hypotension Bradycardia Cardiogenic shock Second or third-degree heart block VA Congenital long QT syndrome When mexiletine is administered with phenytoin or rifampin, since these drugs stimulate the hepatic metabolism of mexiletine, reducing its plasma concentration. A/E C/I Uses Drug Interactions Date:26-07-2 014 Pharmacology Slide no:43

44. markedly slow Phase 0 depolarization slow conduction in the myocardial tissue minor effects on the duration of action potential and ERP reduce automaticity by increasing threshold potential rather than decreasing slope of Phase 4 depolarization. Date:26-07-2 014 Pharmacology Slide no:44

45. Flecainide suppresses phase 0 upstroke in purkinje and myocardial fibers. This causes marked slowing of conduction in all cardiac tissues, with a minor effect on the duration of the action potential and refractoriness. Automaticity is reduced by an increase in the threshold potential rather than a decrease in the slope of phase 4 depolarization FLECAINIDE & ENCAINIDE Mechanism of action Date:26-07-2 014 Pharmacology Slide no:45

46. Proarrhythmogenic efffect on patients with coronary artery disease Use - ventricular arrhythmia A/E – torsades de point, visual disturbances & headache Digoxin toxicity C/I - cardiogenic shock Date:26-07-2 014 Pharmacology Slide no:46

47. Structural similarities with propranolol C/I – Heart failure A/E – proarrhythmogenic effect, metallic taste & constipation 150-200mg at 8 hourly Uses – VT & supra ventricular arrhythmias . PROPAFENONE Date:26-07-2 014 Pharmacology Slide no:47

48. Has all three subclass properties Less proarrhythmogenic effect Used in ventricular arrhythmias 200-400mg orally at 8hourly MORICIZINE Date:26-07-2 014 Pharmacology Slide no:48

49. Class II drugs – Propranolol, Metoprolol, Esmolol, Acebutolol Depress phase 4 depolarization depress automaticity prolong AV conduction ↑ ERP Prolong PR interval  HR  contractility Date:26-07-2 014 Pharmacology Slide no:49

50. Hypoglycemia (infants) Asthma Branchospasm Asthma Bradycardia Severe CHF C/I PROPANOLOL Mechanism of action Propanolol decreases the slope of phase 4 depolarization and other ectopic foci. Prolong the ERP of A-V node . Uses AF Digitalis-induced arrythmias A/E Date:26-07-2 014 Pharmacology Slide no:50

51. Acebutolol is a cardioselective β 1-adrenoreceptor blocking agent that also has some minor membrane stabilizing effect on the action potential. Mechanism of action Acebutolol reduces blood pressure in patients with essential hypotension primarily through its negative ionotropic and chronotropic effects. Uses VA Angina pectoris ACEBUTOLOL Date:26-07-2 014 Pharmacology Slide no:51

52. ESOMOLOL Esomolol is a short-acting i.v administered β1-selective adrenoreceptor blocking agent. It doesn’t posses membrane-stabilizing activity. A/E Hypotension Nausea Headache Dyspnea Uses Supraventricular tachyarrythmias C/I Asthma Sinus bradycardia A-V block Severe CHF Date:26-07-2 014 pharmacology Slide no:52

53. Uses Date:26-07-2 014 pharmacology Slide no:53

54. K+ channel blockers  AP / ERP without affecting phase 0 / 4 Prolong QT & PR Date:26-07-2 014 pharmacology Slide no:54

55. Date:26-07-2 014 pharmacology Slide no:55

56. Date:26-07-2 014 pharmacology Slide no:56

57. Non cardioselective blocker Has both class II & class III actions Oral dose 80mg twice daily Proarrhythmic effect C/I - hypokalaemia Like – A miodarone  Arrhythmic death in post MI Uses =VF, VT & AF A/E= fatigue, Headache, chest pain Drug interactions Drug with inherent QT- Interval prolonging activity may enhance the class 3 effects of sotalol. Date:26-07-2 014 pharmacology Slide no:57

58. Newer class III Without iodine, short t 1/2 , AF Oral 400mg twice daily Na + & K + , atrial ERP, AF Block both rapid & slow k+ channel Date:26-07-2 014 pharmacology Slide no:58

59. Mechanism Block L-type calcium channels.  Rate of phase 4 in SA / AV node Slow conduction – prolong ERP Phase 0 upstroke  Date:26-07-2 014 pharmacology Slide no:59

60. Date:26-07-2 014 pharmacology Slide no:60

61. Stronger action on heart than smooth muscle Used in supraventricular arrhythmia 80-120mg three times a day A/E – ankle oedema, constipation C/I – AV block, LVF, hypotention & WPW It  digoxin toxicity Mixed action Oral dose 30-90mg 6hourly Verapamil Diltiazem Date:26-07-2 014 pharmacology Slide no:61

62. Which other drugs…… Naturally occurring nucleoside Adenosine receptors – open GP-K + & inhibits nodal conduction Used in Reentry circuit, PSVTs & SVT Ultra short t 1/2 (10-20 sec) A/E – facial flushing, short breath, bronchospasm, metallic taste Dipyridamole  it’s action 3mg IV bolus Adenosine Date:26-07-2 014 pharmacology Slide no: 62

63. Magnesium Na + /K + ATPase, Na + , K + & Ca ++ VT, digitalis-induced & torsades de point Normal –  conduction,  ERP &  automaticity Hypokalaemia – EAD & DAD Potassium Date:26-07-2 014 pharmacology Slide no:63

64. ARRHYTHMIAS ACUTE THERAPY CHRONIC THERAPY FIRST CHOICE ALTERNATIVES FIRST CHOICE ALTERNATIVES 1 AF/AFL ESMOLOL VERAPAMILE DIGOXIN PROPRANOLOL 2 PSVT ADENOSINE ESMOLOL DILTIZEM VERAPAMIL DIGOXIN VERAPAMILE PROPRANOLOL PROPAFENONE 3 VT LIDOCAINE CARDIOVERSION PROCAINAMIDE MEXILETINE AMIODARONE AMIODARONE DOFETILIDE MEXILETINE PROPRANOLOL PROPAFENONE 4 TORSADES DE POINT PACING ISOPRENALINE MAGNESIUM PROPRANOLOL PACING 5 VF ELECTRICAL DEFIBRILLATION LIDOCAINE AMIODARONE AMIODARONE PROCAINAMIDE DOFETILIDE 6 WPW CARDIOVERSION AMIODARONE PROPAFENONE PROCAINAMIDE AMIODARONE PROPRANOLOL QUINIDINE PROPAFENONE Date:26-07-2 014 pharmacology Slide no:64

65. Antiarrhythimcs Quinidine Procainamide Disopyramide Propafenone Amiodarone Antimicrobials Quinine Mefloquine Artemisinin Sparfloxacin & gatifloxacin Antihistaminics Terfenadine Astemizole Ebastine Antidepressants Amitryptylline Antipsychotics Thioridazine Risperidone Prokinetics Cisapride Drugs that prolong QT interval Date:26-07-2 014 pharmacology Slide no:65

66. REFERENCES Pharmacology - IV edition , Pg.no:196-207 - Lippincotts Illustrated reviews Clinical pharmacology - IX edition , Pg.no:497-519 - P.N.Bennett - M.J.Brown Essentials of medical pharmacology – K .D. Tripathi Pg.no:508-520 Pharmacology – Rang/ dale - fifth edition , Pg no:277-280 Modern pharmacology with clinical Applications. - Sixth edition - Charles R.Ciaig. Robert E. Stitzel Date:26-07-2 014 pharmacology Slide no:66

67. THANK YOU