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Electrophysiology of the heart Arrhythmia: definition, mechanisms, types Drugs :class I, II, III, IV, others Guide to treat some types of arrhythmia Normal conduction pathway: 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 Other types of conduction that occurs between myocardial cells: When a cell is depolarized adjacent cell depolarizes along 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 Non-pacemaker action potential Phase 1: partial repolarization Due to rapid efflux of K+ Phase 0: fast upstroke Due to Na+ influx Phase 2: plateu Due to Ca++ 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 Pacemaker Action Potential Phase 0: upstroke: Due to Ca++ influx 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 Phase 3: repolarization: Due to K+ efflux 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 If the arrhythmia arises from atria, SA node, or AV node it is called supraventricular arrhythmia Causes of arrhythmia arteriosclerosis Coronary artery spasm If the arrhythmia arises from the ventricles it is called ventricular arrhythmia Heart block Myocardial ischemia 1- Abnormal impulse generation Altered normal Automatic rhythms Rate of impulse generation Site of impulse generation(Ectopic focus) AP arises from sites other than SA node ↑AP from SA node Triggered rhythms Delayed Early afterdepolarization afterdepolarization 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 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) DAD –AP occurs once 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 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 2-Abnormal conduction Conduction block 1st degree 2nd degree Reentry 3rd degree Anatomical determine Funtional determine 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) 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 Abnormal anatomic conduction Here is an accessory pathway in the heart called Bundle of Kent •Present only in small populations •Lead to reexcitation WolfParkinson-White Syndrome (WPW) In case of abnormal generation: Decrease of phase 4 slope (in pacemaker cells) Before drug after phase4 In case of abnormal conduction: ↓conduction velocity (remember phase 0) Raises the threshold ↑ERP (so the cell won’t be reexcited again) Tachydysrhythmias Regular Irregular Narrow complex Wide complex Narrow complex Wide complex Sinus Tachycardia Atrial Tachycardia Atrial Flutter AVNRT/AVRT Ventricular tachycardia Pacer-mediated tachycardia SVT with pre-existing BBB SVT with rate-dependent BBB MAT Atrial Fibrillation Atrial Flutter with variable block Torsade des Pointes Ventricular fibrillation 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 •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 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 K+ channel blocker 1. ↑action potential duration (APD) or effective refractory period (ERP). 2. Delay repolarization. Inhibit reentry tachycardia Ca++ channel blocker Slowing the rate of rise in phase 4 of SA node & conduction velocity ↓conduction velocity in SA and AV node III IV Class I Have moderate K+ channel blockade IA They act on open Na+ channels or inactivated only IB IC They ↓ conduction velocity in non-nodal tissues (atria, ventricles, and purkinje fibers) 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 Class IA Quinidine Procainamide Dysopyramide Slowing of the rate of rise in phase 0 ↓conduction velocity ↓of Vmax of the cardiac action potential prolong muscle action potential & ventricular (ERP) ↓ the slope of Phase 4 spontaneous depolarization (SA node) Decreased pacemaker activity They make the slope more horizontal Intermidiate interection with sodium channel blocker Pharmacokinetics: quinidine procainamide Good oral bioavailability 80% protein binding Metabolized in the liver (P4 50) active metabolite (50 % has anti arrythmic effect) Good oral bioavailability 15 % protein binding . Concentrate @heart & other tissue > plasma loadingIV 12mg/kg,0.3mg/kg/min maintenance 2-5 mg/min Dysopyramide Oral administration Extensive protein binding 50 % excreted unchanged in urine 20 % to dealkylated metabolite (1/10 antiarrythmic effect ) Dose 150mg qid up to 1gm/day Oral 0.2-0.6 gm 2-4x a day Procainamide metabolized into N-acetylprocainamide (NAPA) (active class III)major metabolite which is cleared by the kidney (avoid in renal failure) 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) Quinidine myocardial depression Hypotension( a adrenoreceptor blockade) Torsades de pointes arrhythmia because it ↑ ERP (QT interval) Shortens A-V nodal refractoriness (↑AV conduction) by antimuscarinic like effect ↑digoxin concentration by : 1- displace from tissue binding sites 2- ↓renal clearance SA dysfunction & AV block esp pt with sick sinus syndrome Procainamide Reduce CO &Hypotensive-rapid IV Cardiac conduction abnormalityAsystole or ventricular arrhythmia Hypersensitivity : fever, agranulocytosis Systemic lupus erythromatosus (SLE)-like symptoms: arthralgia, fever, pleuralpericardial inflammation. Symptoms are dose and time dependent Common in patients with slow hepatic acetylation Notes: Torsades de pointes: twisting of the point . Type of tachycardia that gives special characteristics on ECG At large doses of quinidine cinchonism occurs: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 QTVentricular reentry arrythmia, VF, TDP Class IB lidocaine mexiletine tocainide 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 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) Death 26 Ventricular Arrest 24 22 Respiratory arrest 20 Cardiac Arrhythmia 18 Coma 16 Myocardial depression 14 Loss of conciousness CNS excitation 12 Convulsion 10 Muscle twitching 8 Visual disturbances 6 Lightheadness, tinnitus, circumoral & tongue numbness 4 2 Positive inotropy, anticonvulsant, antiarrythmic 0 Plasma lidocaine concentration µg/ml Class IC flecainide propafenone Markedly slow Phase 0 fast depolarization Markedly slow conduction in 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. Clinical use Pharmacokinetics Refractory ventricular Rapid and complete absorbed arrhythmias. after oral: bioavailability-90% particularly potent suppressant of premature 40-50% protein binding ventricular contractions (beats) Vd: 5-10 L/kg Dosage : Orally :100 – 200 mg bd IV :2 mg/kg up to 150 mg Metabolized in liver 25% excreted unchanged by the kidneys Elimination half life: 7-15 h Elimination decrease in ; over 10-30 mins Infusion : CCF , renal failure 1.5 mg/kg/h for 1 hour, Drugs interaction Then 0.1 – 0.25 mg/kg/h Flecainide increase the plasma concentrations of digoxin and Therapeutic plasma con. : propanolol 0.2-1.0 ug/ml 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 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 Mechanism of action Negative inotropic and chronotropic action. Clinical Uses Treatment of increased sympathetic activity-induced arrhythmias such as stress- and exercise-induced arrhythmias Prolong AV conduction (delay)- prolong PR interval Diminish phase 4 depolarization suppressing automaticity(of ectopic focus) Atrial flutter and fibrillation. AV nodal tachycardia. Reduce mortality in postmyocardial infarction patients Protection against sudden cardiac death 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 perioperative 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 Oral dose: Adverse effects Bradycardia,hypotension, ( Chronic suppression of ventricular dysrhythmia) myocardial suppression and bronchospasm, acccentuate CCF IV: 1 mg per minute, cross placenta readily. Fetal total dose3 to 6mg bradycardia, hypoglycaemia, (emergency suppression hyperbilirubinaemia and of cardiac dysrythmia) intrauterine growth retardation (IUGR) are concerns. Propranolol Most reports have not shown was proved to reduce the incidence of sudden significant adverse fetal effects arrhythmatic death & reinfact after myocardial but beta-blockers are probably infarction best avoided in known IUGR 10 to 80mg every 6-8 hr 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 Class III sotalol amiodarone ibutilide 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 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 Ibutilide Used in atrial fibrillation or flutter Only drug in class three that possess pure K+ blockade Slow repolarization Prolong cardiac action potensials IV administration May lead to torsade de pointes by enhance influx Na, blocked K channel 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 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 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 fibrosis which 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 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 Verapamil 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 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 CI- Sick sinus syndrome. heart block, poor left ventricular failure 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 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 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 carriermediated 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 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 Mode of action Co-factor for membrane enzyme Na+/K+ ATPase Lack of magnesium may lead to intracellular K+ depletion Slow the conduction Dose: 1-2 g (2-4 ml of 50% solution) dilute in 50 ml D5 over 1h ( poorly absorbed from gut) trough AV node and Mg is excreted by kidneys prolong the refractory and accumulate in renal period in atria & ventricles– similar class 111 failure Clinical use Adverse effect Torsade de pointes Hypotension Ventricular arrhythmias ass with digitalis toxicity Multifocal atrial tachycardia 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 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 Treatment of digoxin toxicity Stop digoxin adm. Gastric lavage, actvated charchoal Correct precipitating factor – K+ SVT – propanolol AV blockade – pacing, atropine, isoprenaline Ventricular arrhythmias – phenytoin, lignocaine, pacing Digoxin – specific Fab a/body fragments class ECG QT Conduction velocity Refractory period IA ++ ↓ ↑ IB 0 no ↓ IC + ↓ no II 0 ↓In SAN and AVN ↑ in SAN and AVN III ++ No ↑ IV 0 ↓ in SAN and AVN ↑ in SAN and AVN 1st: Reduce thrombus formation by using anticoagulant warfarin 2nd: Prevent the arrhythmia from converting to ventricular arrhythmia: First choice: class II drugs: •After MI or surgery •Avoid in case of heart failure Second choice: class IV digoxin •Only in heart failure of left ventricular dysfunction Address precipitating factors : hyperthyroidism, heart failure & etc 3rd: Conversion of the arrhythmia into normal sinus rhythm: Class III: IV ibutilide, IV/oral amiodarone, or oral sotalol Class IA: ( no longer recommended except vagally mediated AF coz More effective drug available , extra cardiac side effect & proarrythmia effect) Use direct current in case Oral quinidine + digoxin (or any drug from the 2nd step) of unstable hemodynamic patient Class IC: Oral propaphenone or IV/oral flecainide