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Antiarrhythmic drugs

Antiarrhythmic drugs. Tuan norizan bt. Tuan mahmud Pakar anaestesiology , hsnz. LECTURE’S OUTLINE:. Electrophysiology of the heart Arrhythmia: definition, mechanisms, types Drugs :class I, II, III, IV, others Guide to treat some types of arrhythmia. Physiology of the normal heart.

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Antiarrhythmic drugs

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  1. Antiarrhythmic drugs Tuan norizanbt. Tuan mahmud Pakaranaestesiology, hsnz

  2. LECTURE’S OUTLINE: Electrophysiology of the heart Arrhythmia: definition, mechanisms, types Drugs :class I, II, III, IV, others Guide to treat some types of arrhythmia

  3. Physiology of the normal heart Normal conduction pathway: Other types of conduction that occurs between myocardial cells: When a cell is depolarized  adjacent cell depolarizes along 1- SA node generates action potential and delivers it to the atria and the AV node 2- The AV node delivers the impulse to purkinje fibers 3- purkinje fibers conduct the impulse to the ventricles

  4. Action potential of the heart: In the atria, and ventricles the AP curve consists of 5 phases In the SA node , AV node and purkinje AP curve consists of 3 phases

  5. Non-pacemaker action potential Phase 1: partial repolarization Due to rapid efflux of K+ Phase 2: plateu Due to Ca++ influx Phase 0: fast upstroke Due to Na+ influx Phase 3: repolarization Due to K+ efflux Phase 4: resting membrane potential N.B. The slope of phase 0 = conduction velocity Also the peak of phase 0 = Vmax

  6. Pacemaker Action Potential Phase 0: upstroke: Due to Ca++ influx Phase 3: repolarization: Due to K+ efflux Phase 4: pacemaker potential Na influx and K efflux and Ca influx until the cell reaches threshold and then turns into phase 0 Pacemaker cells (automatic cells) have unstable membrane potential so they can generate AP spontaneously

  7. Effective refractory period (ERP) • It is also called absolute refractory period (ARP) : • In this period the cell can’t be excited • Takes place between phase 0 and 3

  8. Arrhythmia Arrhythmia /dysrhythmia: abnormality in the site of origin of impulse, rate, or conduction If the arrhythmia arises from atria, SA node, or AV node it is called supraventricular arrhythmia If the arrhythmia arises from the ventricles it is called ventricular arrhythmia

  9. Mechanisms of Arrhythmogenesis Delayed afterdepolarization Early afterdepolarization AP arises from sites other than SA node ↑AP from SA node

  10. Enhanced automaticity • Refers to the accelerated generation of an action potential by either normal pacemaker tissue (enhanced normal automaticity) or by abnormal tissue within the myocardium (abnormal automaticity). • The discharge rate of normal or abnormal pacemakers may be accelerated by drugs, various forms of cardiac disease, reduction in extracellular potassium, or alterations of autonomic nervous system tone

  11. Triggered activity arrhythmias that arise as a result of afterdepolarizations (abnormal depolarizations that interrupt phase 2, phase 3, or phase 4 ) which on depends of the prior impulse (or series of impulses) • AED –AP occurs during repolarization • Causes • Congenital defective of K channel • Prolong QT syndrome • Abn Na Channel- fast recovery to resting state • K channel blockers drug • Hypokalemia eg: use of diuretic • Bradycardia prolong Action potential duration • DAD –AP occurs once repolarization complete • caused by intracellular Ca / Na overload • Adrenergic stimulation (Ca & Na overload) • Digitalis (- Na K APTase, red Na effux, >NA intra cellular, + Na Ca exchanger , • Miocardia Ischaemia/ infaction( reduce O2, reduce ATP production, reduce Na K ATPase activity

  12. 1-This pathway is blocked This is when the impulse is not conducted from the atria to the ventricles 3-So the cells here will be reexcited (first by the original pathway and the other from the retrograde) 2-The impulse from this pathway travels in a retrograde fashion (backward)

  13. Reentry tachyarhytmia • Reexcitation of cardiac tissue by return of the same cardiac impulse using a circuitous pathway • Due to imbalance of conduction and refractories • Mech of PVCVT and VFSVT,AF,flutter

  14. Abnormal anatomic conduction Here is an accessory pathway in the heart called Bundle of Kent • Present only in small populations • Lead to reexcitation Wolf-Parkinson-White Syndrome (WPW)

  15. Action of drugs In case of abnormal generation: In case of abnormal conduction: Decrease of phase 4 slope (in pacemaker cells) ↓conduction velocity (remember phase 0) ↑ERP (so the cell won’t be reexcited again) Before drug Raises the threshold after phase4

  16. Classification

  17. Pharmacologic Rationale & Goals • 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

  18. Antyarrhythmic drugs • Most antiarrhythmic drugs are pro-arrhythmic (promote arrhythmia) • They are classified according to Vaughan William into four classes according to their effects on the cardiac action potential

  19. Class I drugs Have moderate K+ channel blockade They ↓ conduction velocity in non-nodal tissues (atria, ventricles, and purkinje fibers) They act on open Na+ channels or inactivated only So they are used when many Na+ channels are opened or inactivated (in tachycardia only) because in normal rhythm the channels will be at rest state so the drugs won’t work

  20. Slowing of the rate of rise in phase 0  ↓conduction velocity • ↓of Vmaxof the cardiac action potential • prolong muscle action potential & ventricular (ERP) • ↓ the slope of Phase 4 spontaneous depolarization (SA node) Decreased pacemaker activity mechanism of action They make the slope more horizontal

  21. Class IA Drugs • Intermidiate interection with sodium channel blocker Pharmacokinetics: Procainamide metabolized into N-acetylprocainamide (NAPA) (active class III)-major metabolite which is cleared by the kidney (avoid in renal failure)

  22. Class IA – Clinical Uses • Supraventricular and ventricular arrhythmias • Quinidine –prevent recurrent supraventricular tachydysrhythmias & suppress ventricular premature contraction • Oral quinidine/procainamide are used with class III drugs in refractory ventricular tachycardia patients with implantable defibrillator • IV procainamide used • for hemodynamically stable ventricular tachycardia • for acute conversion of atrial fibrillation including Wolff-Parkinson-White Syndrome (WPWS)

  23. Class IA Drugs Toxicity • Systemic lupus erythromatosus (SLE)-like symptoms: arthralgia, fever, pleural-pericardial inflammation. • Symptoms are dose and time dependent • Common in patients with slow hepatic acetylation

  24. Notes: Torsades de pointes: twisting of the point . Type of tachycardia that gives special characteristics on ECG At large doses of quinidinecinchonismoccurs:blurred vision, tinnitus, headache, psychosis and gastrointestinal upset Quinidine has anti vagal action accelerate AVN conduction Digoxin is administered before quinidine to prevent the conversion of atrial fibrillation or flutter into paradoxical ventricular tachycardia Adverse effect of Disopyramide- -Negetive inotropic effect , CI in Cardiac failure or AV block -Urinary retension,dry mouth,blurred vision & precipitated glaucoma (anticholinergic activity) -Sinus Node depression& Prolong QTVentricular reentry arrythmia, VF, TDP

  25. Class IB Drugs • They shorten Phase 3 repolarization • ↓ the duration of the cardiac action potential • Suppress arrhythmias caused by abnormal automaticity • Show rapid association & dissociation (weak effect) with Na+ channels with appreciable degree of use-dependence • Min change on conduction velocity

  26. Agents of Class IB Lidocaine • Used IV because of extensive 1st pass metabolism • Clearence is related to hepatic blood flow, liver fx,microsomal activity-prolong in liver dis, heart failure, elderly • Propanolol , cimetidine, halothane  dec hepatic clearence of lignocaine Mexiletine • Oral analogs of lidocaine • Used for chronic treatment of ventricular arrhythmias associated with previous myocardial infarction Adverse effects: 1- neurological effects 2- negative inotropic activity • Uses • They are used in the treatment of ventricular arrhythmias arising during myocardial ischemia or due to digoxin toxicity • They have little effect on atrial or AV junction arrhythmias (because they have min effect on conduction velocity)

  27. Death Toxicity 26 24 22 20 18 16 14 12 10 8 6 4 2 0 Ventricular Arrest Respiratory arrest Cardiac Arrhythmia Coma Myocardial depression Loss of conciousness Convulsion Muscle twitching CNS excitation Visual disturbances Lightheadness, tinnitus, circumoral & tongue numbness Positive inotropy, anticonvulsant, antiarrythmic Plasma lidocaine concentration µg/ml

  28. Class IC Drugs • Markedly slow Phase 0fast depolarization • Markedly slow conductionin the myocardial tissue • They possess slow rate of association and dissociation (strong effect) with sodium channels • Have only minor effects on the duration of action potential and refractoriness • Reduce automaticity by increasing the threshold potential rather than decreasing the slope of Phase 4 spontaneous depolarization.

  29. Flecainide • Clinical use • Refractory ventricular arrhythmias. • particularly potent suppressant of premature ventricular contractions (beats) • Dosage : • Orally :100 – 200 mg bd • IV :2 mg/kg up to 150 mg over 10-30 mins Infusion : 1.5 mg/kg/h for 1 hour, Then 0.1 – 0.25 mg/kg/h • Therapeutic plasma con. : 0.2-1.0 ug/ml • Pharmacokinetics • Rapid and complete absorbed after oral: bioavailability-90% • 40-50% protein binding • Vd: 5-10 L/kg • Metabolized in liver • 25% excreted unchanged by the kidneys • Elimination half life: 7-15 h • Elimination decrease in ; • CCF , renal failure • Drugs interaction • Flecainide increase the plasma concentrations of digoxin and propanolol

  30. Toxicity and Cautions for Class IC Drugs: • Potentially serious proarrhythmogenic effect causing: • severe worsening of a preexisting arrhythmia (ventricular arrhythmia aggravated in 5-12 % patient) • In patients with frequent premature ventricular contraction (PVC) following MI, flecainide increased mortality compared to placebo. • CNS effect comman- diziness, visual disturbance, GIT upset Notice: Class 1C drugs are particularly of low safety and have shown even increase mortality when used chronically after MI

  31. Compare between class IA, IB, and IC drugs as regards effect on Na+ channel & ERP • Sodium channel blockade:   IC > IA > IB • Increasing the ERP:IA>IC>IB (lowered) Because of K+ blockade

  32. Class II ANTIARRHYTHMIC DRUGS (β-adrenergic blockers) Mechanism of action • Negative inotropic and chronotropic action. • Prolong AV conduction (delay)- prolong PR interval • Diminish phase 4 depolarization  suppressing automaticity(of ectopic focus) Clinical Uses • Treatment of increased sympathetic activity-induced arrhythmias such as stress- and exercise-induced arrhythmias • Atrial flutter and fibrillation. • AV nodal tachycardia. Reduce mortality in post-myocardial infarction patients Protection against sudden cardiac death

  33. EsmololRelative cardioselective B-blocker with rapid onset and offset • Pharmacokinetic • Protein bound – 60% • Rapid metabolized by red blood cell esterase to inactive acid metabolism and methyl alcohol • Half-life 10 minute • Clinical use • Short term management of tachycardia and hypertension in peri-operative period, acute SVT • No intrinsic sympathomimetic activity or membrane stabilizing properties • Adverse effect • Cardiac • precipitate heart failure • Non cardiac • act B2- adrenoreceptor antagonism at high dose – caution in asthmatics • Irritant to veins and extravasations - tissue necrosis

  34. Propanolol(non cardioselective) • Oral dose: • 10 to 80mg every 6-8 hr ( Chronic suppression of ventricular dysrhythmia) • IV: • 1 mg per minute, total dose3 to 6mg (emergency suppression of cardiac dysrythmia) Adverse effects • Bradycardia,hypotension, myocardial suppression and bronchospasm, acccentuate CCF • cross placenta readily. Fetal bradycardia, hypoglycaemia, hyperbilirubinaemia and intrauterine growth retardation (IUGR) are concerns. • Most reports have not shown significant adverse fetal effects but beta-blockers are probably best avoided in known IUGR Propranolol was proved to reduce the incidence of sudden arrhythmatic death & reinfact after myocardial infarction

  35. Class III ANTIARRHYTHMIC DRUGSK+ blockers • Prolongation of phase 3 repolarization without altering phase 0 upstroke or the resting membrane potential • prolong both the duration of the action potential and ERP

  36. Clinical Uses: • Wide spectrum activity against refractory supraventricular and ventricular tachyarrhythmia • Pulseless ventricular tachycardia and fibrillation resistant to defibrillation • Effective for suppression of tachyarrhythmia a/w WPWS

  37. Sotalol (Sotacor) • non selective B adrenergic blockade • prolongs the duration of action potential and refractoriness in all cardiac tissues (by action of K+ blockade) – class 111 action • suppresses Phase 4 spontaneous depolarization • possibly producing severe sinus bradycardia (by β blockade action) • β-adrenergic blockade combined with prolonged action potential duration may be of special efficacy in prevention of sustained ventricular tachycardia • Most dangerous S/ E: • the polymorphic torsades de pointes ventricular tachycardia because it increases ERP, prolong QT interval

  38. Ibutilide • Used in atrial fibrillation or flutter • Only drug in class three that possess pure K+ blockade • Slow repolarization by enhance influx Na, blocked • Prolong cardiac action potensials K channel • IV administration • May lead to torsade de pointes

  39. Amiodarone (Cordarone) • A Benzoflurance derivative, resembles thyrosine • Amiodarone is a drug of multiple actions ,complex comprising class I, II, III, and IV actions • Dominant effect: Prolongation of action potential duration and refractoriness • It slows cardiac conduction, works as Ca2+ channel blocker, and as a weak β-adrenergic blocker Dose and administration • VF/VT unresponsive to CPR, shock and vasopressor • IV: 300 mg (5mg/kg) bolus • Life threatening arrhythmias • Max dose: 2.2 g IV over 24H • Rapid Infusion 150 mg over 10 minutes , Slow infusion: 360 mg over 6H, Maintenance Infusion: 540 mg over 18H • Therapeutic blood level: 1.0 – 3.5 mcg/ml

  40. Pharmacokinetics • Poorly absorbed from gut,oral bioav. 50-70% • Highly protein-bound >95% • Vd 2-70 l/kg • Elimination half-life 20-100 days • Hepatic metabolism produces desmethylamiodarone – antiarrhythmic activity • Not removed by hemodialysis • Drug interaction • effect of other highly protein bound drugs (phenytoin, warfarin) are increase – dose should adjust • Plasma level of digoxin may rise when amiodarone added

  41. Toxicity • Common with patient chronic treatment • Most common include GI intolerance, tremors, ataxia, dizziness, and hyper-or hypothyrodism (2-4 %) • Cardiac – bradycardia and hypotension. Prolonged QT interval (inc ventricular tachyarrrythmia including Torsade de points) • Corneal microdeposits may be accompanied with disturbed night vision • Others: liver toxicity, photosensitivity & rash (10 %) , gray facial discoloration, neuropathy, prox muscle weakness, and weight loss • The most dangerous side effect is pulmonary fibrosiswhich occurs in 2-5% of the patients • can be irreversible and life threatening -unusual at doses used for atrial fibrillation (200 mg/day) • 10% fatal, most reversible

  42. Class IV ANTIARRHYTHMIC DRUGS (Calcium Channel Blockers) • Calcium channel blockers decrease inward Ca2+ currents resulting in a decrease of phase 4 spontaneous depolarization (SA node) • They slow conductance in Ca2+ current-dependent tissues like AV node. • Examples: verapamil & diltiazem • Because they act on the heart only and not on blood vessels. • Dihydropyridine family are not used because they only act on blood vessels

  43. Verapamil Mechanism of action • Prevents influx of Ca through slow (L) channel in SA and AV node – reduce their automaticity • They prolong ERP of AV node  ↓conduction of impulses from the atria to the ventricles • Coronary artery dilatation • Clinical Uses • More effective in treatment of atrial than ventricular arrhythmias. • Treatment of supra-ventricular tachycardia preventing the occurrence of ventricular arrhythmias • Treatment of atrial flutter and fibrillation • Dose • 5 – 10 mg IV bolus over 1-3 min • Infusion 5 mcg/kg

  44. Phamacokinetic • Orally and IV • 90% absorbed from gut, oral bioav.25% d/t high first-pass metabolism • 90% bound to plasma protein • Metabolized in liver • Excreted in urine • Vd 3-5 l/kg • Elimination half-life 3-7 hrs Adverse effect • Cardiac • SVT with WPW syndrome • verapamil precipitate VT • Pt with poor LV function • precipitate cardiac failure • With agent that slow AV conduction (digoxin,B-blocker, halothane) • precipitate serious bradycardia and AV block • Increase serum level of digoxin • Non cardiac • cerebral artery dilatation, constipation CI- Sick sinus syndrome. heart block, poor left ventricular failure

  45. MISCELLANEOUS ANTIARRHYTHMIC DRUGS Adenosine • Endogenous nucleoside • slows conduction of cardiac impulses through the AVN and accessory pathways • uses • Effective for stable narrow complex SVT • Effective in terminating those due to reentry involving AV node or sinus node • Regular and monomorphic wide-complex • Not effective in AF, flutter or VT

  46. Mechanism of action • Its stimulates cardiac adenosine 1 receptors to increase K+ currents • shorten the action potential duration • hyperpolarize cardiac cell membranes. • In addition, Adenosine decrease cAMP concentration • Phamacokinetic • Its short-lived cardiac effects • Elimination half time : 10 seconds by carrier-mediated cellular uptake • Dosage • IV : 6mg iv rapid bolus (over 1-3 second followed by NS bolus) , followed by a dose of 12mg if necessary • Drug interaction • Inhibit by theophylline • Potentiated by adenosine uptake inhibitors such as dipyridamole

  47. Side effects • Facial flushing , Headache • Dyspnea, Chest discomfort • Nausea • Transient atrioventricular heart block, asystole • Rare – bronchospasm • Pharmacologic effects of adenosine are antagonized by methyxanthines (theophylline, caffeine) and potentiated by dipyridamole • Contraindication • 2nd or 3rd degree heart block & Sick sinus syndrome

  48. Magnesium • Mode of action • Co-factor for membrane enzyme Na+/K+ ATPase • Lack of magnesium may lead to intracellular K+ depletion • Slow the conduction trough AV node and prolong the refractory period in atria & ventricles– similar class 111 • Clinical use • Torsade de pointes • Ventricular arrhythmias ass with digitalis toxicity • Multifocal atrial tachycardia • Dose: • 1-2 g (2-4 ml of 50% solution) dilute in 50 ml D5 over 1h ( poorly absorbed from gut) • Mg is excreted by kidneys and accumulate in renal failure • Adverse effect • Hypotension

  49. Digoxin • Mode of action • Direct – • bind and inhibit cardiac Na+/K+ ATPase  increase intracellular Na+ and decrease intracellular K+ • Raised intracellular Na+ increased exchanged with extracellular Ca2+ resulting increase availability of intracellular Ca2+  positive inotopic effect, increasing excitability and force of contraction • Indirect- • release of Ach at cardiac muscarinic receptors – slow conduction and prolong refractory period in AV node and bundle of HIS

  50. Clinical use • Treatment of atrial fibrilation or flutter • Dose • Loading dose 1 – 1.5 mg, divided dose over 24h • Maintenance dose 125 – 500 mcg/day • Therapeutic range 1-2 mcg/l • Adverse effect • Cardiac • PVC, bigemini, all form of AV block • ECG – prolonged PR interval, ST segment depression, T wave flattening and short QT interval • Non cardiac • Anorexia, nausea and vomiting, diarrhoe and lethargy, • visual disturbance, headache and gynecosmatia • Toxicity – plasma conc >2.5 mcg/l

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