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Arrhythmia & Antiarrhythmic Drugs

Electrophysiology of the heart

Arrhythmia: definition, mechanisms, types

Drugs :class I, II, III, IV

Guide to treat some types of arrhythmia

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Arrhythmia & Antiarrhythmic Drugs

  1. 1. Presented by S.Lakshmi Sravanthi 11AB1R0051 Vignan pharmacy college (Approved by AICTE , PCI & Affiliated to JNTU kakinada) Vadlamudi , Guntur (Dt)-522213 Pharmacology Slide no:1
  2. 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. 3. CARDIAC ARRYTHMIAS Definition  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. Date:26-07-2014 Pharmacololgy Slide no:3
  4. 4. ELECTROPHYSIOLOGY – CARDIAC RHYTHM Date:26-07-2014 Pharmacology Slide no:4
  5. 5. IMPULSE GENERATION AND CONDUCTION  Conducting tissue • SA node,AV node,bundle of his & purkije fibers. Contractile tissue • Atria and ventricles. Date:26-07-2014 Pharmacology Slide no:5
  6. 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. 7. Action Potential Phase 0 Phase 3 Phase 4 Phase 1 Phase 2 30 mV 0 mV - 90 mV Non nodal tissues Date:26-07-2014 Pharmacology Slide no:7
  8. 8. 0 1 2 3 4 • Effective refractory period • Absolute refractory period • Relative refractory period 1 0 2 3 4 ARP RRP Date:26-07-2014 Pharmacology Slide no:8
  9. 9. 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. 10. Contraction of atria Contraction of ventricles Repolarization of ventricles Date:26-07-2014 Pharmacology Slide no:10
  11. 11. Abnormal impulse generation Triggered activity Abnormal impulse conduction Date:26-07-2014 Pharmacology Slide no:11
  12. 12. Abnormal impulse generation  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 Date:26-07-2014 Pharmacology Slide no:12
  13. 13. Triggered Activity  Extra abnormal depolarisation - Due to abnormal intracellular Ca2+ regulation - During or immediately after phase 3 - After depolarisation may be categorized in to - Early after depolarisation - Delay after depolarisation Date:26-07-2014 Pharmacology Slide no:13
  14. 14. After depolarizations EADs  prolonged APD Clinical arrhythmia: e.g., torsades de pointes due to: long QT syndrome genetic defects DADs  HR or [Ca2+]i Clinical arrhythmia: e.g., Ca2+ overload due to: digoxin or PDE inhibitor toxicity Date:26-07-2014 Pharmacology Slide no:14
  15. 15. Conduction block Reentry phenomenon Accessory tract pathway Abnormal impulse conduction Date:26-07-2014 Pharmacology Slide no:15
  16. 16. Conduction Block  Due to depression of impulse conduction at AV node & bundle of His, due to vagal influence or ischemia.  Types :  1st degree heart block – slowed conduction  2nd degree block – some supraventricular complex not conducted  3rd degree block – no supraventricular complex are conducted Date:26-07-2014 Pharmacology Slide no:16
  17. 17. Re-entry phenomenon  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. Date:26-07-2014 Pharmacology Slide no:17
  18. 18. Date:26-07-2014 Pharmacology Slide no:18
  19. 19. Accessory pathway in the heart called Bundle of Kent Date:26-07-2014 Pharmacology Slide no:19
  20. 20. IMPORTANT CARDIAC ARRHYTHMIAS – premature beats  Due to abnormal automaticity or impulse arising from ectopic focus. – Sudden onset of AT 150-200/min  Due to circus movement type of Re-entry or accessory pathway – 200-300 / min  Due to re entry circuit in right atrium Date:26-07-2 014 Pharmacology Slide no:20
  21. 21. • 350-550/min • Due to electrophysiological inhomogenesity of atrial fibers. pharmacology Slide no:21 Date:26-07-2 014
  22. 22. – 4 or more consecutive ventricular extrasystoles  Due to either discharge from ectopic focus or reentry circuits  Polymorphic VT with rapid asynchronous complex, twisting along the baseline on ECG with long QT interval  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. 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. 24. Pharmacological goals  The ultimate goal of antiarrhythmic drug therapy: o Restore normal sinus rhythm and conduction o Prevent more serious and possibly lethal arrhythmias from occurring.  Antiarrhythmic drugs are used to: o Decrease conduction velocity o Change the duration of the effective refractory period (ERP) o Suppress abnormal automaticity Date:26-07-2 014 Pharmacology Slide no:24
  25. 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. 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 1. ↑action potential duration (APD) or effective refractory period (ERP). 2. 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. 27. Class I IA IB IC They ↓ automaticity in non-nodal tissues (atria, ventricles, and purkinje fibers) Have moderate K+ channel blockade They act on open Na+ channels or inactivated only Date:26-07-2 014 Pharmacology Slide no:27
  28. 28. IA Quinidine Procainamide Disopyramide Moricizine  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. 29. QUINIDINE  Antimalarial, antipyretic, skeletal muscle relaxant and atropine like action. Mechanism of 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. Date:26-07-2 014 Pharmacology Slide no:29
  30. 30.  Diarrhoea  “Cinchonism” – tinnitus, vertigo, headache, nausea & blurred vision.  200-400 mg orally tds C/I AV block QT prolongation - Torsades de pointes Digoxin, enzyme inducer Myasthenia gravis A/E Date:26-07-2 014 Pharmacology Slide no:30
  31. 31. Uses • Ventricular tachyarrythmias • Used in the termination of ventricular tachycardia Drug interactions • 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 Date:26-07-2 014 Pharmacology Slide no:31
  32. 32. PROCAINAMIDE  Procaine derivative, quinidine like action Mechanism of action  Procainamide binds to open and inactivated Na+ channels and prevents sodium influx, slowing the rapid upstroke during phase 0  Hypotension  Hypersensitivity reaction A/E Date:26-07-2 014 Pharmacology Slide no:32
  33. 33.  Premature atrial contractions  Paroxysmal atrial tachycardia Dose:1-1.5g rate of 20-50mg/min • Procainamide hypersensitivity • Bronchial asthma • Cimitidine inhibits the metabolism of procainamide Uses C/I Drug Interactions Date:26-07-2 014 Pharmacology Slide no:33
  34. 34. DISOPYRAMIDE Mechanism of action  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 A/E Date:26-07-2 014 Pharmacology Slide no:34
  35. 35. • ventricular tachycardia • AF & AFI - CHF Disopyramide Uses C/I Drug Interactions  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. Date:26-07-2 014 Pharmacology Slide no:35
  36. 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. 37.  They shorten Phase 3 repolarization  ↓ the duration of the cardiac action potential  Prolong phase 4 IB Lidocaine Mexiletine Phenytoin Date:26-07-2 014 Pharmacology Slide no:37
  38. 38. LIDOCAINE the duration of action potential decreases  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. 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. Drug interactions • Proponolol increases its toxicity. • The myocardial depressant effect of lidocaine is enhanced by phenytoin administration. Date:26-07-2 014 Pharmacology Slide no:39
  40. 40. PHENYTOIN  Phenytoin was originally introduced for the control of convulsive disorders but now also been shown to be effective in the treatment of cardiac arrythmias. Uses  Anaesthesia  Open heart surgery  Digitalized induced and ventricular arrythmia in children Date:26-07-2 014 Pharmacology Slide no:40
  41. 41. A/E C/I  Respiratory arrest Severe bradycardia  Hypotension Severe heart failure AF & AFI Drug Interactions  Plasma phenytoin concentrations are increased in the presence of chloramphenicol, disulfiram, and isoniazid, since the later drugs inhibit the hepatic metabolism of phenytoin Date:26-07-2 014 Pharmacology Slide no:41
  42. 42. MEXELETINE Mechanism of action  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. Date:26-07-2 014 Pharmacology Slide no:42
  43. 43. A/E C/I  Tremor  Hypotension  Bradycardia • Cardiogenic shock • Second or third-degree heart block Uses Drug Interactions • 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. Date:26-07-2 014 Pharmacology Slide no:43
  44. 44. IC flecainide Encainide Propafenone moricizine  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. 45. FLECAINIDE & ENCAINIDE Mechanism of action  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 Date:26-07-2 014 Pharmacology Slide no:45
  46. 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. 47. PROPAFENONE  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. Date:26-07-2 014 Pharmacology Slide no:47
  48. 48. MORICIZINE  Has all three subclass properties  Less proarrhythmogenic effect  Used in ventricular arrhythmias  200-400mg orally at 8hourly Date:26-07-2 014 Pharmacology Slide no:48
  49. 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. 50. Hypoglycemia (infants) Asthma Branchospasm C/I Asthma Bradycardia Severe CHF 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. 51.  Acebutolol is a cardioselective β1-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. Acebutolol A/E Bradycardia GI upset Uses • VA • Angina pectoris C/I Cardiogenic shock Severe bradycardia ACEBUTOLOL Date:26-07-2 014 Pharmacology Slide no:51
  52. 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. 53. USES Sympathetically mediated arrhythmia Sinus tachycardia Supraventricular arrhythmia – AF / PSVT Ventricular arrhythmia – QT Date:26-07-2 014 pharmacology Slide no:53
  54. 54. • K+ channel blockers • AP / ERP without affecting phase 0 / 4 • Prolong QT & PR Date:26-07-2 014 pharmacology Slide no:54 Class III Amiodarone Bretylium Sotalol
  55. 55. Amiodarone Iodine – containing Block K+ Na+ , Ca++ & β HR & AV nodal conduction  Arrhythmic death in post MI Uses =VF, VT & AF QT prolongation LD-150mg slow IV MD-1mg/min for 6hrs A/E – heart block, pulmonary, hepatitis, dermatitis, corneal deposits & thyroidism Interaction – digoxin, diltiazem & quinidine Date:26-07-2 014 pharmacology Slide no:55
  56. 56. Bretylium Antihypertensive Uses-VF & VT C/I – digitalis induced, shock A/E – postural hypotension Date:26-07-2 014 pharmacology Slide no:56
  57. 57. Sotalol Like – Amiodarone  Non cardioselective blocker  Has both class II & class III actions  Oral dose 80mg twice daily  Proarrhythmic effect  C/I - hypokalaemia  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. 58. NEWER CLASS III Dronedarone Vernakalant Azimilide Tedisamil Without iodine, short t1/2, 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. 59. Verapamil Diltiazem  Mechanism Class IV • 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. 60. Date:26-07-2 014 pharmacology Slide no:60
  61. 61. Verapamil  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 Diltiazem  Mixed action  Oral dose 30-90mg 6hourly Date:26-07-2 014 pharmacology Slide no:61
  62. 62. WHICH OTHER DRUGS…… Adenosine Naturally occurring nucleoside Adenosine receptors – open GP-K+ & inhibits nodal conduction Used in Reentry circuit, PSVTs & SVT Ultra short t1/2 (10-20 sec) A/E – facial flushing, short breath, bronchospasm, metallic taste Dipyridamole  it’s action 3mg IV bolus Date:26-07-2 014 pharmacology Slide no:62
  63. 63. Magnesium Na+/K+ATPase, Na+, K+ & Ca++ VT, digitalis-induced & torsades de point Potassium Normal –  conduction,  ERP &  automaticity Hypokalaemia – EAD & DAD Date:26-07-2 014 pharmacology Slide no:63
  65. 65. Drugs that prolong QT interval Antiarrhythimcs Quinidine Procainamide Disopyramide Propafenone Amiodarone Antimicrobials Quinine Mefloquine Artemisinin Sparfloxacin & gatifloxacin Antihistaminics Terfenadine Astemizole Ebastine Antidepressants Amitryptylline Antipsychotics Thioridazine Risperidone Prokinetics Cisapride Date:26-07-2 014 pharmacology Slide no:65
  66. 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