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Antiarrhythmic drugs

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pharmacotherapy of arrhythmias

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Antiarrhythmic drugs

  1. 1. Antiarrhythmic drugs
  2. 2. Antiarrhythmics ???? – In a textbook  Interesting but sedative. • Try it if you have insomnia –In the lecture  Confusion ?????????? • As always –In the exam hall  Panic! • Don’t worry rarely asked
  3. 3. • A-RHYTHM –IA • Defn- Arrhythmia is deviation of heart from normal RHYTHM. • RHYTHM 1) HR- 60-100 2) Should origin from SAN 3) Cardiac impulse should propagate through normal conduction pathway with normal velocity.
  4. 4. • CLASSIFICATION OF ARRHYTHMIAS
  5. 5. 100 60 Normal range 150 Simple tachyarrythmia 200 Paroxysmal TA 350 Atrial flutter . 500 Atrial fibrillation 40 Mild bradyarrhythmias 20 moderate BA Severe BA
  6. 6. ARRHYTHMIAS Sinus arrythmia Atrial arrhythmia Nodal arrhythmia (junctional) Ventricular arrhytmia SVT
  7. 7. Electrophysiology of cardiac tissue • Impulse generation and transmission • Myocardial action potential • Depolarization and repolarization waves as seen in ECG
  8. 8. Types of cardiac tissue (on the basis of impulse generation) • AUTOMATIC/ PACEMAKER/ CONDUCTING FIBRES (Ca++ driven tissues) Includes SA node, AV node, bundle of His, Purkinje fibres Capable of generating their own impulse Normally SA node acts as Pacemaker of heart • NON-AUTOMATIC MYOCARDIAL CONTRACTILE FIBRES (Na+ driven tissues) Cannot generate own impulse Includes atria and ventricles
  9. 9. Impulse generation and transmission
  10. 10. Myocardial action potential In automatic tissues In non-automatic tissues
  11. 11. Action potential in Non automatic myocardial contractile tissue
  12. 12. +30 mV 0 mV -80 mV -90 mV OUTSIDE MEMBRANE INSIDE Na+ 0 4 3 2 1 K+ Ca++ K+ Atp K+ Na+ K+ Ca++ Na+ K+ Na+ Phase zero depolarization Early repolarization Plateau phase Rapid Repolarization phase Phase 4 depolarization
  13. 13. Action potential in nodal tissues
  14. 14. +30 mV 0 mV -80 mV -90 mV OUTSIDE MEMBRANE INSIDE Na+ 0 4 3 2 1 K+ Ca++ K+ Atp K+ Na+ K+ Ca++ Na+ K+
  15. 15. Fast channel Vs slow channel AP Fast channel AP • Occurs in atria, ventricles, PF • Predominant ion in phase-0 is Na+ • Conduction velocity more • Selective channel blocker is tetradotoxin , LA Slow channel AP • Occurs in SA node, A-V node • Predominant ion in phase-0 is Ca2+ • Less • Selective channel blockers are calcium channel blockers
  16. 16. Common terms • Automaticity – Capacity of a cell to undergo spontaneous diastolic depolarization • Excitability – Ability of a cell to respond to external stimulus by depolariztion • Threshold potential – Level of intracellular negativity at which abrupt and complete depolarization occurs
  17. 17. Common terms • Conduction velocity of impulse – Determined primarily by slope of action potential and amplitude of phase-0, any reduction in slope leads to depression of conduction • Propagation of impulse – Depends on ERP & Conduction velocity
  18. 18. Refractory period
  19. 19. Depolarization & Repolarization waves seen in ECG
  20. 20. ECG is used as a rough guide to some cellular properties of cardiac tissue • P wave: atrial depolarization • PR-Interval reflects AV nodal conduction time • QRS DURATION reflects conduction time in ventricles • T-wave: ventricular repolarization • QT interval is a measure of ventricular APD
  21. 21. Mechanisms of cardiac arrythmia • Abnormal impulse generation: • Depressed automaticity • Enhanced automaticity • Triggered activity (after depolarization): • Delayed after depolarization • Early after depolarization • Abnormal impulse conduction: • Conduction block • Re-entry phenomenon • Accessory tract pathways
  22. 22. a) Enhanced automaticity Automatic behavior in sites ordinarily lacking pacemaker activity CAUSES: Ischaemia/digitalis/catecholamines/acidosis/ hypokalemia/stretching of cardiac cells Nonpacemaker nodal tissues: membrane potential comes to -60mv Increased slope of phase 4 depolarisation Become ECTOPIC PACEMAKERS.(AV nodal rhythm, idioventricular rhythm, ectopic beats)
  23. 23. Less negative RMP More negative TP Ectopic pacemaker activity encouraged by
  24. 24. b) Trigerred automaticity +30 mV 0 mV -80 mV -90 mV
  25. 25. b) Trigerred automaticity +30 mV 0 mV -80 mV -90 mV Intracellular cal. Overload (Ischemia reperfusion, adr.stress, digitalis intoxication or heart failure)
  26. 26. c. Abnormal impulse conduction • Conduction block – First degree block – Second degree block – Third degree block • Re-entry phenomenon • Accessory tract pathways
  27. 27. INEXCITABLE TISSUE Re-entry 1 2
  28. 28. Re-entry
  29. 29. Counterclockwise right atrial reentry LA is passively activated
  30. 30. Requirements for re-entry circuit • Presence of anatomically defined circuit • Region of unidirectional block • Re-entry impulse with slow conduction
  31. 31. Anatomical: Wolff- Parkinson-White syndrome Functional: Fibrillation Accessory tract pathways
  32. 32. WPW: Initiation of SVT Supraventricular tachycardia • initiated by a closely coupled premature atrial complex (PAC) • blocks in the accessory pathway • but conducts through the AV node • retrograde conduction via accessory pathway • inverted P wave produced by retrograde conduction visible in the inferior ECG leads
  33. 33. Regulation by autonomic tone Parasympathetic/Vagus Nerve stimulation: • Ach binds to M2 receptors • Activate Ach dependent outward K+ conductance (thus hyperpolarisation) • ↓ phase 4 AP Sympathetic stimulation: • Activation of β1 receptors • Augmentation of L-type Ca2+ current • Phase 4 AP more steeper
  34. 34. +30 mV 0 mV -80 mV -90 mV OUTSIDE MEMBRANE INSIDE Na+ 0 4 3 2 1 K+ Ca++ K+ Atp K+ Na+ K+ Ca++ Na+ Na+ Ca++ K+ RATE SLOPE Effective Refractory Period RMP THRESHOLD POTENTIAL Possible MOA of antiarrythmic agents
  35. 35. Classification of Anti-Arrhythmic Drugs (Vaughan-Williams-Singh..1969) Phase 4 Phase 0 Phase 1 Phase 2 Phase 3 0 mV - 80m V II I III IV Class I: block Na+ channels Ia (quinidine, procainamide, disopyramide) (1-10s) Ib (lignocaine) (<1s) Ic (flecainide) (>10s) Class II: ß-adrenoceptor antagonists (atenolol, sotalol) Class III: prolong action potential and prolong refractory period (amiodarone, dofetilide, sotalol) Class IV: Ca2+ channel antagonists (verapamil, diltiazem)
  36. 36. Classification based on clinical use • Drugs used for supraventricular arrhythmia`s – Adenosine, verapamil, diltiazem • Drugs used for ventricular arrhythmias – Lignocaine, mexelitine, bretylium • Drugs used for supraventricular as well as ventricular arrhythmias – Amiodarone, - blockers, disopyramide, procainamide
  37. 37. Na+ channel blocker • Bind to and block Na+ channels (and K+ also) • Act on initial rapid depolarisation (slowing effect) • Local Anaesthetic (higher concentration): block nerve conduction • Do not alter resting membrane potential (Membrane Stabilisers) • At times, post repolarization refractoriness. • Bind preferentially to the open channel state • USE DEPENDENCE : The more the channel is in use, the more drug is bound
  38. 38. Ia Ib Ic Moderate Na channel blockade Mild Na channel blockade Marked Na channel blockade Slow rate of rise of Phase 0 Limited effect on Phase 0 Markedly reduces rate of rise of phase 0 Prolong refractoriness by blocking several types of K channels Little effect on refractoriness as there is minimal effect on K channels Prolong refractoriness by blocking delayed rectifier K channels Lengthen APD & repolarization Shorten APD & repolarization No effect on APD & repolarization Prolong PR, QRS QT unaltered or slightly shortened Markedly prolong PR & QRS
  39. 39. Class I: Na+ Channel Blockers • IA: Ʈrecovery moderate (1-10sec) Prolong APD • IB: Ʈrecovery fast (<1sec) Shorten APD in some heart tissues • IC: Ʈrecovery slow(>10sec) Minimal effect on APD
  40. 40. Class IA
  41. 41. Quinidine • Historically first antiarrhythmic drug used. • In 18th century, the bark of the cinchona plant was used to treat "rebellious palpitations“ pharmacological effects threshold for excitability automaticity prolongs AP
  42. 42. Quinidine • Clinical Pharmacokinetics • well absorbed • 80% bound to plasma proteins (albumin) • extensive hepatic oxidative metabolism • 3-hydroxyquinidine, • is nearly as potent as quinidine in blocking cardiac Na+ channels and prolonging cardiac action potentials.
  43. 43. Quinidine • Uses • to maintain sinus rhythm in patients with atrial flutter or atrial fibrillation • to prevent recurrence of ventricular tachycardia or VF
  44. 44. Quinidine Adverse Effects- Non cardiac • Diarrhea, thrombocytopenia, • cinchonism & skin rashes. cardiac marked QT-interval prolongation &torsades de pointes (2-8% ) hypotension tachycardia
  45. 45. Drug interactions • Metabolized by CYP450 • Increases digoxin levels • Cardiac depression with beta blockers • Inhibits CYP2D6
  46. 46. Disopyramide • Exerts electrophysiologic effects very similar to those of quinidine. • Better tolerated than quinidine • exert prominent anticholinergic actions • Negative ionotropic action. • A/E- • precipitation of glaucoma, • constipation, dry mouth, • urinary retention
  47. 47. Procainamide • Lesser vagolytic action , depression of contractility & fall in BP • Metabolized by acetylation to N-acetyl procainamide which can block K+ channels • Doesn’t alter plasma digoxin levels • Cardiac adverse effects like quinidine • Can cause SLE not recommended > 6 months • Use: Monomorphic VT, WPW Syndrome
  48. 48. Ia Ib Ic Moderate Na channel blockade Mild Na channel blockade Marked Na channel blockade Slow rate of rise of Phase 0 Limited effect on Phase 0 Markedly reduces rate of rise of phase 0 Prolong refractoriness by blocking several types of K channels Little effect on refractoriness as there is minimal effect on K channels Prolong refractoriness by blocking delayed rectifier K channels Lengthen APD & repolarization Shorten APD & repolarization No effect on APD & repolarization Prolong PR, QRS QT unaltered or slightly shortened Markedly prolong PR & QRS
  49. 49. Class IB drugs Lignocaine, phenytoin, mexiletine Block sodium channels also shorten repolarization
  50. 50. Class Ib
  51. 51. Lignocaine • Blocks inactivated sodium channels more than open state • Relatively selective for partially depolarized cells • Selectively acts on diseased myocardium • Rapid onset & shorter duration of action • Useful only in ventricular arrhythmias , Digitalis induced ventricular arrnhythmias
  52. 52. • Lidocaine is not useful in atrial arrhythmias??? • atrial action potentials are so short that the Na+ channel is in the inactivated state only briefly compared with diastolic (recovery) times, which are relatively long
  53. 53. Pharmacokinetics • High first pass metabolism • Metabolism dependent on hepatic blood flow • T ½ = 8 min – distributive, 2 hrs – elimination • Propranolol decreases half life of lignocaine • Dose= 50-100 mg bolus followed by 20-40 mg every 10-20 min i.v
  54. 54. Adverse effects • Relatively safe in recommended doses • Drowsiness, disorientation, muscle twitchings • Rarely convulsions, blurred vision, nystagmus • Least cardiotoxic antiarrhythmic
  55. 55. • Local anaesthetic • Inactive orally • Given IV for antiarrhythmic action • Na+ channel blockade which occurs • Only in inactive state of Na+ channels • CNS side effects in high doses • Action lasts only for 15 min • Inhibits purkinje fibres and ventricles but • No action on AVN and SAN so • Effective in Ventricular arrhythmias only
  56. 56. Mexiletine • Oral analogue of lignocaine • No first pass metabolism in liver • Use: – chronic treatment of ventricular arrhythmias associated with previous MI – Unlabelled use in diabetic neuropathy • Tremor is early sign of mexiletine toxicity • Hypotension, bradycardia, widened QRS , dizziness, nystagmus may occur
  57. 57. Tocainide • Structurally similar to lignocaine but can be administered orally • Serious non cardiac side effects like pulmonary fibrosis, agranulocytosis, thrombocytopenia limit its use
  58. 58. Class I C drugs Encainide, Flecainide, Propafenone Have minimal effect on repolarization Are most potent sodium channel blockers • Risk of cardiac arrest , sudden death so not used commonly • May be used in severe ventricular arrhythmias
  59. 59. Class Ic
  60. 60. Propafenone class 1c • Structural similarity with propranolol & has - blocking action • Undergoes variable first pass metabolism • Reserve drug for ventricular arrhythmias, re- entrant tachycardia involving accesory pathway • Adverse effects: metallic taste, constipation and is proarrhythmic
  61. 61. Flecainde (Class Ic) • Potent blocker of Na & K channels with slow unblocking kinetics • Blocks K channels but does not prolong APD & QT interval • Maintain sinus rhythm in supraventricular arrhythmias • Cardiac Arrhythmia Suppression Test (CAST Trial): When Flecainide & other Class Ic given prophylactically to patients convalescing from Myocardial Infarction it increased mortality by 2½ fold. Therefore the trial had to be prematurely terminated
  62. 62. Class II: Beta blockers • -receptor stimulation: • ↑ automaticity, • ↑ AV conduction velocity, • ↓ refractory period • -adrenergic blockers competitively block catecholamine induced stimulation of cardiac - receptors
  63. 63. Beta blockers • Depress phase 4 depolarization of pacemaker cells, • Slow sinus as well as AV nodal conduction : – ↓ HR, ↑ PR • ↑ ERP, prolong AP Duration by ↓ AV conduction • Reduce myocardial oxygen demand • Well tolerated, Safer
  64. 64. β Adrenergic Stimulation β Blockers ↑ magnitude of Ca2+ current & slows its inactivation ↓ Intracellular Ca2+ overload ↑ Pacemaker current→↑ heart rate ↓Pacemaker current→↓ heart rate ↑ DAD & EAD mediated arrhythmias Inhibits after-depolarization mediated automaticity Epinephrine induces hypokalemia (β2 action) Propranolol blocks this action
  65. 65. Use in arrhythmia • Control supraventricular arrhythmias • Atrial flutter, fibrillation, PSVT • Treat tachyarrhythmias caused by adrenergic • Hyperthyroidism Pheochromocytoma, during anaesthesia with halothane • Digitalis induced tachyarrythmias • Prophylactic in post-MI • Ventricular arrhythmias in prolonged QT syndrome +
  66. 66. Esmolol • β1 selective agent • Very short elimination t1/2 :9 mins • Metabolized by RBC esterases • Rate control of rapidly conducted AF • Use: • Arrythmia associated with anaesthesia • Supraventricular tachycardia
  67. 67. Class III drugs ↑APD & ↑RP by blocking the K+ channels
  68. 68. Vm (mV) -80mV 0mV ↑ APD Block IK
  69. 69. Amiodarone • Iodine containing long acting drug • Mechanism of action: (Multiple actions) –Prolongs APD by blocking K+ channels –blocks inactivated sodium channels –β blocking action , Blocks Ca2+ channels –↓ Conduction, ↓ectopic automaticity
  70. 70. • Pharmacokinetics: –Variable absorption 35-65% –Slow onset 2days to several weeks –Duration of action : weeks to months • Dose –Loading dose: 150 mg over 10min –Then 1 mg/min for 6 hrs –Then maintenance infusion of 0.5 mg/min for 24 hr Amiodarone
  71. 71. Amiodarone • Uses: – Can be used for both supraventricular and ventricular tachycardia • Adverse effects: – Cardiac: heart block , QT prolongation, bradycardia, cardiac failure, hypotension – Pulmonary: pneumonitis leading to pulmonary fibrosis – Bluish discoloration of skin, corneal microdeposits – GIT disturbances, hepatotoxicity – Blocks peripheral conversion of T4to T3 can cause hypothyroidism or hyperthyroidism
  72. 72. • Antiarrhythmic • Multiple actions • Iodine containing • Orally used mainly • Duration of action is very long (t ½ = 3-8 weeks) • APD & ERP increases • Resistant AF, V tach, Recurrent VF are indications • On prolonged use- pulmonary fibrosis • Neuropathy may occur • Eye : corneal microdeposits may occur
  73. 73. • Bretylium: – Adrenergic neuron blocker used in resistant ventricular arrhythmias • Sotalol: – Beta blocker • Dofetilide, Ibutilide : – Selective K+ channel blocker, less adverse events – use in AF to convert or maintain sinus rhythm – May cause QT prolongation
  74. 74. Newer class III drugs • Dronedarone • Vernakalant • Azimilide • Tedisamil
  75. 75. Calcium channel blockers (Class IV) • Inhibit the inward movement of calcium ↓ contractility, automaticity , and AV conduction. • Verapamil & diltiazem
  76. 76. Verapamil • Uses: – Terminate PSVT – control ventricular rate in atrial flutter or fibrillation • Drug interactions: – Displaces digoxin from binding sites – ↓ renal clearance of digoxin
  77. 77. Other antiarrhythmics • Adenosine : – Purine nucleoside having short and rapid action – IV suppresses automaticity, AV conduction and dilates coronaries – Drug of choice for PSVT – Adverse events: • Nausea, dyspnoea, flushing, headache
  78. 78. Vm (mV) -80mV 0mV ↓ APD Hyperpolarization Adenosine
  79. 79. Adenosine • Acts on specific G protein-coupled adenosine receptors • Activates AcH sensitive K+ channels channels in SA node, AV node & Atrium • Shortens APD, hyperpolarization & ↓ automaticity • Inhibits effects of ↑ cAMP with sympathetic stimulation • ↓ Ca currents • ↑AV Nodal refractoriness & inhibit DAD’s
  80. 80. • Atropine: Used in sinus bradycardia • Digitalis: Atrial fibrillation and atrial flutter • Magnesium SO4: digitalis induced arrhythmias Other antiarrhythmics
  81. 81. Magnesium • Its mechanism of action is unknown but may influence Na+/K+ATPase, Na+ channels, certain K+ channels & Ca2+ channels • Use: Digitalis induced arrhythmias if hypomagnesemia present, refractory ventricular tachyarrythmias, Torsade de pointes even if serum Mg2+ is normal • Given 1g over 20mins
  82. 82. Drugs of choices S. No Arrhythmia Drug 1 Sinus tachycardia Propranolol 2 Atrial extrasystole Propranolol, 3 AF/Flutter Esmolol, verapamil ,digoxin 4 PSVT Adenosine ,esmolol 5 Ventricular Tachycardia Lignocaine , procainamide , Amiodarone 6 Ventricular fibrillation Lignocaine, amiodarone 7 A-V block Atropine , isoprenaline

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