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Dr. Sanjib Das MD VII. Antiarrhythmic Drugs A. Learning objectives What ionic and electrophysiological changes are associated with normal cardiac rhythm? How might arrhythmias result from the effects of resting potentials on action potentials? What factors may precipitate or exacerbate arrhythmias? Explain how disturbances either in impulse formation (by a latent pacemaker or ectopic focus), or in impulse conduction (during reentry or "circus movement") result in arrhythmias. What are the major mechanisms of action of antiarrhythmic drugs? 1. Sodium channel blockers (Class I) Describe the [1] cardiac and extracardic effects, [2] toxic cardiac and extra cardiac effects, [3] pharmacokinetics, and [4] therapeutic uses for the following drugs: (a) quinidine (b) procainamide (c) disopyramide (d) lidocaine How do tocainide and mexiletine differ from lidocaine? How do flecainide, propafenone, and moricizine act, and what are they used for? 2. ß-Adrenergic blockers (Class II) -What are the antiarrhythmic properties of propranolol and other ß-adrenergic antagonists? -How does esmolol differ from sotalol? 3. Potassium channel blockers (Class III) -What are the cardiac and extracardic effects of bretylium? How is it administered and what is it used for? -What is sotalol used for? -Know that amiodarone also has Class I, II and IV actions 4. Calcium channel blockers (Class IV) -Describe the [1] cardiac and extracardic effects, [2] toxic cardiac and extra cardiac effects, [3] pharmacokinetics, and [4] therapeutic uses of verapamil. 5. Miscellaneous -What is the mechanism of antiarrhythmic action of adenosine and what is it used for? What are its toxic effects? -What are general principles of antiarrhythmic therapy? -What guidelines can be used to decide whether arrhythmias should be treated? Cardiac impulse generation & conduction Normal pacemaker is the sinoatrial (SA) node which generates 60-100 impulses/min From the SA node, impulses spread through the atria to enter the atrioventricular (AV) node where conduction slows to allow time for atrial contraction to propel blood into the ventricles Finally, impulses spread over the His-Purkinje fibers to spread to all parts of the ventricles SA node activity is regulated by reciprocal changes in: • Sympathetic stimulation through b-adrenergic receptors • Parasympathetic inhibition through muscarinic receptor • b-adrenergic activation increases heart rate, contractility, and ventricular pressure while muscarinic activation causes opposite changes and decreases everything Ionic Basis of Electrical Cardiac Impulses Transmembrane potential is determined by membrane concentrations of, and permeability to: Na+, K+, and Ca2+ K+ ion concentration being much higher inside the cell than outside, promotes the outward movement of K+ Conversely, Na+ ion concentration is much higher outside than inside Ion gradients are maintained by activity of Na+/K+ATPase At rest or during diastole, electrical charges are not flowing • The cell is negatively charged inside and positively charged outside so that the sarcolemma is polarized • Sodium does not enter, despite the substantial concentration gradient for Na+, because sodium channels are closed • K+ ions cross (because the sarcolemma is highly permeable to K+) leaving unbalanced negative charges that make the cell negative inside with a resting transmembrane potential of about -85 mV Cardiac Electrical Activity Cardiac action potential has 5 phases Ionic changes in pacemaker cells during phase 4 cause spontaneous depolarization Latent pacemaker activity resides in the SA node, AV node, and Purkinje fibers which have a phase 4 slope The steeper the phase 4 slope, the higher the automaticity which is highest in the SA node > AV node > Purkinje cells Differences in fast and slow response cell types PNa FAST SLOW PCa +20 0 -20 PCa -40 PK -60 -80 PNa Threshold potential PCa PK PK Slow depolarization Characteristics of Fast and Slow Response Cells in the Myocardium FAST RESPONSE SLOW RESPONSE Location: atria, ventricle, HisPurkinje Located: SA and AV node Rate of depolarization: fast Rate of depolarization: slow Conduction velocity: rapid Conduction velocity: slow Major ionic species involved in depolarization: Na+ Major ionic species involved in depolarization: Ca2+ Inhibitors of depolarization: Class I antiarrhythmic agents (quinidine) Inhibitors of depolarization: calciumentry blockers (verapamil, diltiazem) Recovery of excitability: prompt; ends with repolarization Recovery of excitability: delayed; outlasts repolarization Catecholamines (SNS): little effect on depolarization Catecholamines: enhance depolarization Acetylcholine (PS): no effect on depolarization Acetylcholine: significantly depresses depolarization Cardiac Impulses & the ECG Electrocardiograms (ECG) record electrical changes occurring on the body surface as action potentials spread over the heart P wave forms as depolarization spreads from the SA node through both atria At the AV node, conduction slows considerably to produce the interval between P and Q waves (PR interval) Conduction through His-Purkinje fibers accelerates to produce the • Small Q wave on reaching the septum • QRS deflection spreading through the left ventricle Ventricular repolarization follows until the end of the T wave QRS duration = time required for ventricular activation QT interval = duration of ventricular action potential ECG recording is the most useful noninvasive method available for diagnosing arrhythmia and evaluating effects of antiarrhythmic drugs Cardiac Arrhythmias Are frequent clinical problems occurring in: • 25% of patients treated with digoxin • 50% of anesthetized patients • 80% of patients with acute myocardial infarction May be initiated or worsened by: • Ischemia, hypoxia, acidosis, or alkalosis • Electrolyte abnormalities • Autonomic imbalance due to catecholamine excess, scarred or diseased myocardial tissues, drug toxicity (i.e., digoxin or antiarrhythmic drugs) Classified according to anatomic origin as: • Supraventricular – originating in the SA node, atria, or AV node • Ventricular – originating in the ventricles Cause heart rates to become irregular, too fast, or too slow due to abnormalities in: • Site of impulse generation • Impulse rate or regularity • Impulse conduction Severity ranges from Mild & asymptomatic as in sinus bradycardia among athletes To hazardous & life-threatening as in ventricular fibrillation Treatment of arrhthmias: To terminate / prevent Pharmacologic Method : with Anti Arrhyhthmic drugs. Nonpharmacologic methods: -Pacemakers -Cardioversion -Catheter ablation and -Surgical methods . Common Arrhythmias A.Fibrillation Arrhythmias are often diagnosed based on ECG appearance. Atrial premature beats appearing as abnormal P waves are often asymptomatic. A. Flutter Atrial flutter or fibrillation is common in the elderly: • Flutter - rates of >300 bpm often occurring with AV block • Fibrillation – atrial beating is asynchronous and P waves are not recognizable Ventricular premature beats (VPBs) are discrete identifiable premature QRS complexes Ventricular tachycardia is a run of at least 4 consecutive VPBs Ventricular fibrillation shown by variations in size and frequency of ECG deflections, is lethal if it lasts for more than a few minutes ECG Interpretation of Arrhythmia To be scheduled on a Optional Lecture can be weekend? delivered on request In 2-3 sessions Case study-1 ID: A 48 year old Nevisian male teacher Ex smoker not known to have any medical illness presented to ER of Alexendra hospital with Hx of palpitation for 7 hrs duration. He has no hx of chest pain, dyspnea, orthopnea, PND, or syncopy , & no hx of hyperthyroidism O/E: pt was conscious & oriented. BP=115/75, HR=145/min irregular irregular CVS: normal S1+S2 , No murmur or L.L. edema Chest: clear Abdomen: soft & lax , with no organomegally No thyromegally Investigations: MANAGEMENT TO BE DISCUSSED AT THE END ECG: rapid AF CX-ray: NAD CBC: Hb:15, ESR:2, RBS: 108, CPK:81(normal) Troponin o.o4 (normal) PT: 11 FT3: 0.84 (N), FT4: 1.08(N) RFT, LFT, S.lytes: all were normal Case Study-2(m/c +ntation) A 56 years old man. Dx : Acute anterior wall MI ICU monitor multiple Ventricular Extrasystoles with Ventricular Tachycadia Serum electrolytes : K = 2.7 “ 3.5 - 5 mmol/l” Na = 136 “135-145 mmol/l” Cl = 98 “ 98 - 106 mmol/l” MANAGEMENT TO BE DISCUSSED AT THE END Case Study- 3 Mr X is 67 years old Canadian male patient experienced dizziness & SOB after walking to a nearby mal . He was brought to our ER for further evaluation. No chest pain, palpitation or syncope. He is a known case of diabetic type 2 since 10 months. On examination: BP 160/95, pulse rate 125/min (regular irregular), RR 16. Investigation: Urinalysis : glucose > 1000 Cardiac enzyme within normal. RFTs: sodium 129. LFTs: within normal CBC: within normal RBS: 289 FBS: 178 Lipid profile: cholestrol 180 TG: 263 ECG: sinus rhythm with multiple multifocal premature ventricular contraction. Chest x-ray: cardiomegaly & congested lung MANAGEMENT TO BE DISCUSSED AT THE END Mechanisms of Arrhythmogenesis Basic arrhythmogenic mechanisms generally result from: • Disturbances in automaticity (impulse formation) • Disturbances in impulse conduction • Or combinations of both Identifying the exact mechanism is clinically often difficult A.Disorders in automaticity or impulse formation • Automaticity is determined by the phase 4 slope which is : Inhibited by vagal stimulation, ß-adrenergic blockade, or CCAs Enhanced by ß-adrenergic stimulation, Ca2+, hypokalemia. • Arrhythmias from abnormal automaticity will occur whenever: SA node rates are too fast or too slow, or AV node and Purkinje cells overcome or usurp the SA node • Latent pacemakers can become ‘ectopic’ pacemakers by usurpation Mechanisms of Arrhythmogenesis B. Disorders in impulse conduction • Conduction can be prolonged by blocking impulses at any point along the normal pathway • Reentry or “circus movement” is a common conduction abnormality in which a cardiac impulse reenters and excites the same pathway repeatedly • Three conditions required for reentry to occur: Conduction has to be blocked by an anatomic or physiologic obstacle creating a circuit around which the reentrant impulse can propagate The block must be unidirectional at some point in the circuit such that conduction is prevented in one direction but allowed to proceed in the opposite direction Conduction time around the circuit must exceed the effective refractory period Re-entry or Circus Movement: (conduction abnormality in which a cardiac impulse reenters and excites the same pathway repeatedly) Impulses are followed by a refractory period during which the tissue does not respond to stimulation When impulses travel down two branches they are extinguished at the meeting point Unidirectional block prevents in one direction but allows conduction to proceed in the opposite direction As the impulse travels through the intact branch upon reaching the blocked site it is conducted in retrograde fashion to initiate re-entry DIFFERENT TYPES OF RE-ENTRY ARRHYTHMIAS Abnormal Impulse Formation in Fast Response Fibers b. Afterdepolarizations: These are depolarizations that interrupt – -Phase 3 (early afterdepolarizations, EADs) or -phase 4 (delayed afterdepolarizations, DADs). DADs are triggered by abnormal calcium influx→manifest as fast heart rate and may be provoked by digitalis glycosides, catecholamines, and myocardial ischemia. EADs are manifested as slow heart rates and are responsible for prolonged QT-interval related arrhythmias. Mechanisms of Antiarrhythmic Drug Action All Antiarrhythmic drugs work with ion channels with or without involving ANS Antiarrhythmic drugs aim to: • Reduce ectopic pacemaker activity by reducing the phase 4 slope through blockade of sodium or calcium channels, and/or • Modify conduction or refractoriness in reentrant circuits by slowing conduction in reentrant arrhythmias Therapeutic doses usually affect abnormal tissues more (i.e., reduce impulse generation more in ectopic pacemakers than in the SA node, or slow conduction more in reentrant than in normal pathways) Toxic doses can affect even normal tissues (i.e., reduce impulse generation in the SA node, or slow conduction in normal pathways) and cause drug-induced arrhythmias like those occurring with digoxin Most antiarrhythmic drugs have a narrow margin of safety and adverse effects can occur even with therapeutic doses Doses required to suppress the arrhythmia without producing adverse effects have to be determined separately for each patient Classification of Antiarrhythmic Drugs Class I = block Na+ channels elevate threshold for excitation inhibit automaticity and conduction velocity prolong PR and QRS prevent recurrence of reentrant arrhythmias Many of these drugs also block K+ channels Further subdivided into: • IA – lengthen APD & ERP; moderate Na+ channel block (Open or Activated) plus K+ channel block Quinidine (1) , procainamide (2), disopyramide (13) • IB – shorten APD; (mild Na+ channel block ) Lidocaine (3), mexiletine (4) ,tocainide • IC – minimal effect on APD; marked Na+ channel block Flecainide (5) , propafenone, moricizine NBME Class II = b-adrenergic blockade decreases in heart rate and contractility Propranolol (6) , timolol, and other b-adrenergic antagonists Class III = block K+ channels to prolong APD and effective refractory period Amiodarone (7) , sotalol (8) , dofetilide, and ibutilide Class IV = CCAs like verapamil (9) , diltiazem (10) , or bepridil Miscellaneous antiarrhythmics: adenosine (11) , magnesium (12) , potassium NBME NBME In a nutshell To achieve clinical response by acting on -Fast response fibre :use Class I & III -Slow response(nodal tissues):Class II & IV Class IA - QUINIDINE Admininistered as gluconate, sulfate, or polygalacturonate salts Slows upstroke of the action potential, slows conduction, and prolongs QRS duration, PR interval, and QT interval on the ECG Used for maintaining sinus rhythm in atrial flutter or fibrillation but must be with prior digitalization to nullify the proarrythmic effect (next slide) • Used much less today but still highly tested on certification exams Two antiarrhythmic mechanisms: NBME • Mainly by blocking activated Na+ channels reduce automaticity especially on ectopic pacemakers • Also, blocks K+ channels to prolong APD and QT interval; longer APD reduces reentry frequency and tachycardia QUINIDINE – adverse effects Quinidine produces many adverse effects: Blocks a-adrenergic receptors to cause vasodilation, marked hypotension, and reflex tachycardia Blocks muscarinic receptors (relative sympathetic domination) - can overcome its direct myocardial effects to result in faster atrioventricular conduction; in patients with atrial fibrillation or flutter the vagal inhibition can accelerate AV node conduction to increase ventricular rate and cause paradoxical ventricular tachycardia- Arrhythmogenic/ NBME Proaarrhythmic effect Gastrointestinal adverse effects consisting of diarrhea, nausea, vomiting may cause cinchonism (headache, dizziness, tinnitus) Increases plasma digoxin (displaces from tissue binding sites) and precipitate digoxin toxicity – A real situation often seen and to be taken care off. NBME Hyperkalemia increase chances of arrhythmia by prolonging depolarization time (due to slow down of ungated potassium channel activity) NBME Syncope (recurrent lightheadedness and fainting) may occur due to torsade de pointes Torsade de pointes NBME Atypical ventricular tachycardia manifested on the ECG by wide and narrow (twisting of the points) QRS complexes Caused by changes in Na+or K+ channels lengthens phase 2 of the action potential prolong QT interval and APD Occurs when the potassium channel gene (HERG) is blocked by antiarrhythmic drugs (e.g., quinidine, sotalol) or electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia) Usually end spontaneously but can sometimes progress to ventricular fibrillation death In a nutshell Any drug/condition that has strong antimuscuranic property or directly blocks Potassium channel & prolong depolarization of tissue can cause torsade de pointes e.g-Few Antihistaminics -All TCAs -Quinidine -Meperidine -Sotalol -Hypokalemia -Hypomagnesemia -Hypocalcemia Class IA - PROCAINAMIDE A procaine analogue with electrophysiologic effects like those of quinidine, but has weaker antimuscarinic activity 1. Ganglion-blocking activity may cause vasodilation and hypotension but these effects are less pronounced than those of quinidine (because of no alpha blocking effect 2.) 1+2 →less ANS induced A/E Most troublesome adverse effect with long-term therapy is a lupus-like syndrome with NBME rash, arthralgia, arthritis, pericarditis, and renal lupus .(in slow acetylators) Other adverse effects include nausea and diarrhea (10%), rash, fever, hepatitis (> 5%), and agranulocytosis (0.2 %) [immunological etiology] Eliminated by hepatic metabolism and renal excretion Short half-life of 3-4 hrs necessitates oral dosing with a sustained-release preparation every 6 hours Better tolerated than quinidine when given IV, but not as useful for long-term oral treatment due to its short half-life and adverse effects Procainamide does not elevate digoxin levels Given orally or parenterally for atrial and ventricular arrhythmias Class IA Antiarrhythmics - DISOPYRAMIDE Cardiac effects very similar to, but more antimuscarinic than quinidine or procainamide Intensity of antimuscarinic activity in descending order is: • Disopyramide > quinidine > procainamide Antiarrhythmic profile and electrophysiologic effects resemble those of quinidine and procainamide Approved for treatment of ventricular arrhythmias Not a first-line antiarrhythmic because its negative inotropic action may induce CHF even without previous history of myocardial dysfunction Adverse effects caused by its pronounced anticholinergic activity include: • Urinary retention (usually in males with enlarged prostate) • Dry mouth, blurred vision, constipation • Worsening of preexisting glaucoma Comparison of Class IA Antiarrhythmics NBME SIMILARITY All block Na+ and K+ channels, and can induce torsade de pointes DIFFERENCES Quinidine Antimuscarinic actions Procainamide Disopyramide ++ + +++ Lupus-like syndrome - ++ - Plasma digoxin, + - - thrombocytopenia, a-adrenergic block Class IB Antiarrhythmics - LIDOCAINE Blocks both activated and inactivated sodium channels (mainly) in Purkinje fibers and ventricular cells to: • Elevate excitation threshold and reduce automaticity • Suppress electrical activity of depolarized arrhythmogenic tissues NBME (ischemic or digitalized ) with minimal effects on polarized normal or atrial tissues In ischemic tissue, cells are partly depolarized because they lack the amount of ATP needed to operate the Na+ pump. As a result, these cells spend more time in the inactivated state than do cells in non-ischemic tissue. ↓APD is due to blokade of slow Sodium window current (slow leakage of sodium during 1,2 & 3 phase of AP) in ischemic fibres →THUS BRINGS APD BACK TO NORMAL-Pseudo-arrhythmogenic (actually Antiarrhythmic) effect. Must be given intravenously: orally ineffective as only 3% appears in plasma because of extensive first-pass hepatic metabolism Most effective against arrhythmias associated with depolarization as in ischemia or digoxin toxicity but relatively ineffective against normally polarized tissues as in atrial flutter or fibrillation ( Preferrential binding) Has no effect on normal impulse conduction as it does not affect K+ channels Class IB Antiarrhythmics - LIDOCAINE Is the least cardiotoxic of currently used sodium blockers; exacerbates ventricular arrhythmias in < 10% of patients (good!!!) but, it may precipitate SA node standstill or worsen impaired conduction in 1% of patients with myocardial infarction In patients with preexisting heart failure, large doses cause hypotension by depressing myocardial contractility Most common adverse effects are neurologic: paresthesias, NBME tremor, nausea, lightheadedness, hearing disturbances, slurred speech, and convulsions Seizures occur most commonly after rapid IV administration in elderly patients Used mainly for acute termination of ventricular arrhythmias post MI and to prevent ventricular fibrillation after cardioversion & during open heart surgery. NBME Class IB Antiarrhythmics - MEXILETINE Lidocaine analog resistant to first-pass hepatic metabolism and is effective orally Electrophysiologic and antiarrhythmic actions like those of lidocaine Elimination half-life of 8-20 hrs allows oral administration 2-3 times daily Adverse effects of therapeutic doses are predominantly neurologic including tremor, blurred vision, lethargy, and nausea Useful for treatment of ventricular arrhythmias Also used for relief of chronic pain especially that due to diabetic neuropathy and nerve injury NBME Class IC Antiarrhythmics All are given orally, but have been found to increase mortality from cardiac arrest or arrhythmic sudden death in patients with recent myocardial infarction Practically blocks sodium channels of all states NBME FLECAINIDE • Blocks Na+ and K+ channels without antimuscarinic effects • Used for maintaining sinus rhythm in supraventricular arrhythmias • Very effective for suppressing premature ventricular contractions • May exacerbate arrhythmias in patients with preexisting ventricular tachyarrhythmias or myocardial infarction PROPAFENONE • Blocks Na+ channels and structurally similar to propranolol with weak ßblocking activity • Same uses as flecainide • Has a metallic taste • May exacerbate arrhythmias and cause constipation MORICIZINE • Antiarrhythmic phenothiazine derivative for ventricular arrhythmias • Potent sodium channel blocker that does not prolong APD • May exacerbate arrhythmias; adverse effects are nausea and vomiting Class II Antiarrhythmics: ß-adrenergic blockers NBME ↓Slope of Phase 4→↓SA & AV nodal activity Propranolol and metoprolol are most frequently used for: • Treatment of supraventricular and ventricular arrhythmias caused by sympathetic stimulation tachycardia • To prevent ventricular fibrillation Esmolol is a short-acting drug used primarily for acute arrhythmias occurring during surgery Beneficial effects are due to Diminished sympathetic activation of heart and blood vessels Reduced cardiac activity and reduced vasoconstriction Hypotension and bradycardia Diminished cardiac workload Reduced myocardial oxygen demand • Prevents recurrent infarction and sudden death in patients with acute myocardial infarction NBME Harmful effects = negative inotropic effects may induce or worsen CHF in patients with acute myocardial infarction or decompensated heart failure; CNS penetration may cause insomnia and depression Class III Antiarrhythmics: Amiodarone Given orally or IV for treatment of serious or life-threatening ventricular arrhythmias Also effective for: • Preventing recurrent ventricular arrhythmias • Treatment of supraventricular arrhythmias like atrial fibrillation • Adjuvant treatment to decrease uncomfortable discharges of implanted cardioverter-defibrillators Decreases re-entry by blocking IKr+ (potassium rectifier current) to prolong AP duration and QT interval (Class III activity) Also decreases rate of firing in pacemaker cells by blocking inactivated Na+ NBME channels (Class I activity) Also blocks a- and b-adrenergic receptors and Ca2+ channels and thus inhibit AV node conduction to produce bradycardia (Class II & IV activity) Relatively high efficacy with low incidence of torsade de pointes despite prolonged QT Amiodarone Pharmacokinetics Variably absorbed with 35-65% bioavailability Undergoes hepatic metabolism with the major metabolite, desethylamiodarone, being bioactive Complex elimination half-life with rapid component of 3-10 days (50% of the drug) followed by a slower component lasting for several weeks.(overall t1/2 is 80days)→Loading dose required infront of such a long 4-5 t1/2 Measurable tissue levels occur even after a year.Long half life of AmIodarone is +ce of Iodine which is not easily excreble out of the body. Has many drug interactions as it is a substrate for hepatic metabolism by CYP3A4: • Tissue levels are increased by drugs that inhibit this enzyme (e.g., H2 NBME NBME NBME blocker cimetidine) • Tissue levels are decreased by drugs that induce this enzyme (e.g., anti-TB rifampin) • Inhibits other liver cytochome metabolizing enzymes to elevate levels of NBME other drugs like digoxin or warfarin Amiodarone Toxicity Because of its wide variety of actions, many adverse effects can result including: • Peripheral vasodilation especially with IV administration • Asymptomatic bradycardia and AV block in patients with SA or AV node disease • Most important adverse effects are respiratory difficulties leading to fatal NBME pulmonary fibrosis which occurs in 1% of patients. (inflammatory reaction as a bodily defensive mechanism to remove iodine)[Other drugs cause Pulmonary fibrosis and relavent PFTs are important ] • Abnormal liver function and hepatitis (as a consequence of inflammatory reaction against iodine) Fatty change resembling alcoholic hepatitis Liver fibrosis • Skin reaction of Iodine with starches resulting in photodermatitis and grayish-blue skin discoloration in sun-exposed areas (Smurf skin) • Corneal microdeposits, reduced visual acuity, and optic neuritis progressing to blindness NBME Amiodarone Toxicity Because of its wide variety of actions, many adverse effects can result including: • Neurologic effects as paresthesias, tremor, ataxia, and headaches • Thyroid dysfunction, both hypo- and hyperthyroidism (iodine induced), caused by peripheral blockade of converting T4 to T3. • Gastrointestinal symptoms Has a long half-life and toxicity may persist long after it is discontinued Because amiodarone can affect virtually every organ system, treatment with it must be reevaluated whenever new symptoms occur NBME Class III Antiarrhythmics: Sotalol Non-selective ß-adrenergic blocker that also prolongs APD and has antiarrhythmic properties Formulated as a racemic mixture of d- and l-isomers • All ß-adrenergic activity resides in the l-isomer • AP prolongation is shared by both isomers May cause prolonged repolarization resulting in torsade de pointes Well absorbed orally with 100% bioavailability Half-life about 12 hours and excreted unchanged by kidneys 6% incidence of torsade de pointes at highest daily dose Used for: • Treatment of life-threatening ventricular arrhythmias • Maintaining sinus rhythm in atrial fibrillation • Treatment of supraventricular and ventricular arrhythmias in pediatrics Class III Antiarrhythmics: DOFETILIDE and IBUTILIDE Block the rapid component of the delayed rectifier potassium current IKr to slow cardiac repolarization Ibutilide (IV only) • An intravenous Class III antiarrhythmic agent recommended for rapid conversion of atrial fibrillation or atrial flutter to normal sinus rhythm. Dofetilide (orally) Used for the conversion and maintenance of normal sinus rhythm in atrial fibrillation/flutter in highly symptomatic patients Common adverse effects are prolonged QT interval and torsade de pointes Class IV Antiarrhythmics: CCAs Bepridil, diltiazem, verapamil Orally active drugs that block L-type Ca2+ channels in myocardium and vascular smooth muscles Nifedipine is not used as an antiarrhythmic as it is likely to cause reflex tachycardia due to pronounced vasodilation By contrast, verapamil and diltiazem depress the SA and AV nodes directly to: • Decrease contractility • Reduce SA node automaticity • Slow AV node conduction Oral CCAs are used for: • Acute and chronic management of PSVT • Control of ventricular rate in atrial flutter or atrial fibrillation Verapamil is more effective than digoxin MISCELLANEOUS ANTIARRHYTHMICS ADENOSINE Nucleoside normally formed by dephosphorylation of ATP then metabolized by adenosine deaminase to form inosine Acts on two types of adenosine receptors: A1 in myocardium negative inotropic, chronotropic, and dromotropic • A2 in endothelium and vascular smooth muscles coronary vasodilation • NBME Enhances potassium conductance and inhibits Ca2+ influx prolonged AV node refractory period and slowed conduction Current drug of choice, by rapid intravenous injection, for converting paroxysmal supraventricular tachycardia to sinus rhythm because it is highly (90-95%) efficient with a very short action NBME Adverse effects are flushing, shortness of breath or chest burning, headache, hypotension, nausea, and paresthesia NBME MISCELLANEOUS ANTIARRHYTHMICS MAGNESIUM Magnesium chloride or sulfate [parenteral] Mechanism of antiarrhythmic action unknown, but has been used to prevent torsades de pointes and for digoxininduced arrhythmias NBME POTASSIUM Hypokalemia can produce ectopic pacemaker activity especially during digoxin treatment Antiarrhythmic effect results by increasing K+ ions hyperpolarization lowered phase 4 slope decreased automaticity NBME Management of Atrial fibrillation Consists of rate control and anticoagulation with warfarin (goal INR of 2–3) • • Rate control is defined as ventricular rate of 50–100 bpm with usual daily activities and not exceeding 120 bpm except with moderate to strenuous activity Recommended treatments NBME Conventional rate control agents in young adults (1) β-Blockers (2) Calcium channel blockers (3) Digoxin • Rate control agents in patients with heart failure, coronary artery disease, or ongoing ischemia Never calcium channel (1) β-Blockers blockers with heart failure (2) Digoxin • Amiodarone or others agents are useful: (1) When rate control with preferred agents fail (2) When cardioversion is anticipated GENERAL CHARACTERISTICS OF ANTIARRHYTHMIC THERAPY Two types of benefits, both difficult to establish, are reductions in: [1] Arrhythmic symptoms like palpitations, syncope, or cardiac arrest [2] Long-term mortality in asymptomatic patients All antiarrhythmic drugs have a narrow margin of safety and the ratio between therapeutic versus toxic doses varies widely from one patient to another; doses that are therapeutically effective in some patients may be either ineffective or toxic in others. The heart condition causing the arrhythmia strongly influences the antiarrhythmic drug response; patients with defective impulse conduction are greater risk for developing complete AV block during treatment with quinidine than those whose impulse conduction is normal. GENERAL CHARACTERISTICS OF ANTIARRHYTHMIC THERAPY Increased mortality from cardiac arrest or sudden death in patients with recent myocardial infarction has occurred with almost all antiarrhythmic drugs, and only ß-blockers have been shown to reduce mortality. Initial treatment with any antiarrhythmic drug should first determine the effective therapeutic dose for each patient, and then maintain that dose for as long as necessary without producing adverse effects Some antiarrhythmic drugs have specific contraindications like: • Prostatism for disopyramide (causes urinary retention due to marked anticholinergic activity), • Chronic arthritis for procainamide (causes lupus-like syndrome) • Advanced lung disease for amiodarone (causes pulmonary fibrosis). Do not use digoxin, verapamil, or beta-blockers if atrial fibrillation is associated with a known or suspected accessory pathway such as Woolf-White-Parkinson (WPW) syndrome. Extra Credit Quiz Section Case study-1 ID: A 48 year old Nevisian male teacher Ex smoker not known to have any medical illness presented to ER of Alexendra hospital with Hx of palpitation for 7 hrs duration. He has no hx of chest pain, dyspnea, orthopnea, PND, or syncopy , & no hx of hyperthyroidism O/E: pt was conscious & oriented. BP=115/75, HR=145/min irregular irregular CVS: normal S1+S2 , No murmur or L.L. edema Chest: clear Abdomen: soft & lax , with no organomegally No thyromegally Investigations: MANAGEMENT TO BE DISCUSSED AT THE END ECG: rapid AF CX-ray: NAD CBC: Hb:15, ESR:2, RBS: 108, CPK:81(normal) Troponin o.o4 (normal) PT: 11 FT3: 0.84 (N), FT4: 1.08(N) RFT, LFT, S.lytes: all were normal Case Study-2(m/c +ntation) A 56 years old man. Dx : Acute anterior wall MI ICU monitor multiple Ventricular Extrasystoles with Ventricular Tachycadia Serum electrolytes : K = 2.7 “ 3.5 - 5 mmol/l” Na = 136 “135-145 mmol/l” Cl = 98 “ 98 - 106 mmol/l” MANAGEMENT TO BE DISCUSSED AT THE END Case Study- 3 Mr X is 67 years old Canadian male patient experienced dizziness & SOB after walking to a nearby mal . He was brought to our ER for further evaluation. No chest pain, palpitation or syncope. He is a known case of diabetic type 2 since 10 months. On examination: BP 160/95, pulse rate 125/min (regular irregular), RR 16. Investigation: Urinalysis : glucose > 1000 Cardiac enzyme within normal. RFTs: sodium 129. LFTs: within normal CBC: within normal RBS: 289 FBS: 178 Lipid profile: cholestrol 180 TG: 263 ECG: sinus rhythm with multiple multifocal premature ventricular contraction. Chest x-ray: cardiomegaly & congested lung MANAGEMENT TO BE DISCUSSED AT THE END Treatment Objectives (in general) To control the heart rate To restore sinus rhythm To control ventricular rate To prevent or treat associated complications To treat the underlying condition e.g. thyrotoxicosis To prevent thromboembolism Non Pharmacological T/t – Reassure the patient – Avoid excessive intake of alcohol, coffee or tea (if these are possible precipitating factors) – Massage of the carotid sinus on one side for a few seconds. – This may terminate an attack of paroxysmal supraventricular tachycardia. – If the duration is less than 48 hours, patients may need immediate – cardioversion Pharmacological T/t Atrial fibrillation Digoxin, oral,250 micrograms 12 hourly over 24-48 hours, Maintenance dose,250 micrograms daily Alternative treatment or in combination with Digoxin Atenolol, oral, (avoid in heart failure) 50-100 mg daily Or Bisoprolol, oral,1.25-10 mg daily Antiplatelet and anticoagulant therapy Aspirin, oral,75-300 mg daily Or Unfractionated Heparin, IV, 5,000-10,000 units Or Low molecular weight Heparin e.g. Enoxaparin, subcutaneously, 1 mg/kg daily (100 units/kg) every 12 hours, and then refer patients to a specialist. Case 1: A 48 year old Nevician male teacher with Atrial Fibrillation Management: Patient initially admitted to the medical ward & started on Digoxin, but then it was holded & transported to CC & started on Amiodarone IV infusion (300mg IV over 1h then 1200mg over 24 hrs) & also he was started on IV Heparin The pt then converted to sinus rhythm after 24 hrs of starting Amiodarone Pt then started on Amiodarone orally 200mg Tid Next day he was transferred to medical ward on where he had sinus rhythm continously there after. He didn’t develop any AF since he was converted to Sinus Rhythm. Echo was done & it was normal. He was discharged in a good & stable condition with F/V appointment in cardiology OPD after 1 month Discharge medication: 1- ASA 81mg Po OD 2- amiodarone 200mg PO Tid X 5days then 200mg PO OD X 1 month NB: drug of choice for AF is Digoxin then Amiodarone Case 2: A 56 years old man diagnosed as Acute anterior wall treated in the ICCU developed multiple Ventricular Extrasystoles with Ventricular Tachycadia How would you manage this pt. ? Case 3: Mr X is 67 years old Canadian male diabetic patient developed Premature Ventricular Complexes. Treatment: Amiodarone 400 mg 2 tablets BID, then 1 tablet TID, then 1 tablet BID, then 1 tablet OD. Glibendamide 2.5 mg PO BID for controlling DM. Now answer following Qs before you practice MCQs What are the major mechanisms of action of antiarrhythmic drugs? 1. Sodium channel blockers (Class I) Describe the [1] cardiac and extracardic effects, [2] toxic cardiac and extra cardiac effects, [3] pharmacokinetics, and [4] therapeutic uses for the following drugs: (a) quinidine (b) procainamide (c) disopyramide (d) lidocaine How do tocainide and mexiletine differ from lidocaine? How do flecainide, propafenone, and moricizine act, and what are they used for? 2. ß-Adrenergic blockers (Class II) -What are the antiarrhythmic properties of propranolol and other ß-adrenergic antagonists? -How does esmolol differ from sotalol? 3. Potassium channel blockers (Class III) -What are the cardiac and extracardic effects of bretylium? How is it administered and what is it used for? -What is sotalol used for? -Know that amiodarone also has Class I, II and IV actions 4. Calcium channel blockers (Class IV) -Describe the [1] cardiac and extracardic effects, [2] toxic cardiac and extra cardiac effects, [3] pharmacokinetics, and [4] therapeutic uses of verapamil. 5. Miscellaneous -What is the mechanism of antiarrhythmic action of adenosine and what is it used for? What are its toxic effects? -What are general principles of antiarrhythmic therapy? -What guidelines can be used to decide whether arrhythmias should be treated? In a 55-year-old man who has an irregularly irregular heart rate of 154 bpm and irregular QRS complexes on the ECG, which of the following is given intravenously but ineffective if given orally? A) Moricizine B) Quinidine C) Lidocaine D) Procainamide E) Nifedipine ANS = C High first-pass effect with lidocaine; metabolic clearance In a 45-year-old white man who has atrial flutter and benign prostatic hyperplasia, which of the following indicates the correct rank order of drugs most likely to cause urinary retention when used for antiarrhythmic therapy? A) Disopyramide > procainamide > quinidine B) Disopyramide > quinidine > procainamide C) Procainamide > disopyramide > quinidine D) Procainamide > quinidine > disopyramide E) Quinidine > disopyramide > procainamide Ans = B Remember this order of anticholinergic activity Antiarrhythmic drugs Sodium channel blockers (Class I) β-adrenergic blockers (Class II) Quinidine (Ia) Procainamide (Ia) Acebutolol Esmolol Metoprolol Propranolol Lidocaine (Ib) Tocainide (Ib) Mexiletine (Ib) Potassium channel blockers (Class III) Calcium channel blockers (Class IV) Amiodarone Sotalol Dofetilide Ibutilide Verapamil Diltiazem Miscellaneous Adenosine PSVT Magnesium Toresade Potassium Digoxin toxicity Ia = prolong duration of AP Ib = reduces duration of AP Ic = no change in AP duration Ia & III = cause toresades de pointe Which of the following would be most preferred to treat a 57-year-old, who smokes and has severe chronic obstructive pulmonary disease, requiring Advanced Cardiac Life Support for ventricular fibrillation? A. Adenosine B. Amiodarone C. Esmolol D. Lidocaine E. Quinidine Answer: D Normally amiodarone would be considered drug of choice; but not with lung disease Which of the following is the drug of choice to treat a 55-year-old asthmatic woman with paroxysmal supraventricular tachycardia (PSVT)? A. Adenosine B. Esmolol C. Methoxamine D. Procainamide E. Sotalol Answer: A Adensosine drug of choice for PSVTs