Antiarrhythmic drugs
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    Antiarrhythmic drugs Antiarrhythmic drugs Presentation Transcript

    • HEART ashfaq
    • Pumping blood Details??
    • Rate & Rhythm Contraction
    • Contraction •Chambers ( coordination) Recall
    • • Contraction with – Rhythm & Rate – Coordinated • (alternate Contraction (systole) & (Diastole) How comes ???
    • Specialsed Conducting System
    • The Conducting System of the Heart
    •  Pacemaker Activity (automaticity)  Absence of fast Na+ current in SA & AV node  Ca++ current initiates action potential.  Long action potential (Plateau) & Refractory period  Influx of Ca+ during Plateau
    • Normal Cardiac Rhythm
    • Parts of a Normal Typical ECG 0.1- 0.22 < 0.12 < 0.10 0.44 – 0.46
    • Ionic Basis of Membrane Electrical Activity
    • During Cardiac Cycle: Ions ( Na+, K+, Ca+ & Cl- ) moves across cell membranes in response to their concentration gradients only when their channels open. Ionic movement produces currents responsible for the cardiac action potential.
    • Diastolic channel currents Inward Na+ Current
    • m (activation) gate: their opening for Na+ ions leads to depolarization from threshold to action potential voltage. h (inactvation) gate: closure occurs after this brief opening of m gates
    • - 85 influx eflux Absolute Refractory Period Relative R.P. E after depolarization D Threshold Phase 0: Depolarization; Rapid Sodium Influx; Resting voltage has become positive. Phase 1: Early Repolarization; brief K+ & Cl- eflux Phase 2: Plateu phase; Ca++ influx Phase 3: Rapid repolarization; K+ & Cl- eflux Phase 4 ( automaticity ): Ratio of Na+/K+ permeability; cellular electrolyte balance is slowly restored. Slow Diastolic Depolarization; Until the threshold potential is reached. Early & Delayed - after depolarization may occur during relative refractory period before the phase 4, due to myocardial damage, so leading to arrhythmias. Early & Delayed depolarizations interrupt Phase 3
    • T-type Ca++ opens K+ closed Na+ unchanged L-type Ca++ K+ opens
    • Myocardial Action Potential I b = background inward sodium current, If = ‘funny current’, I cat= transient or ‘T’ type calcium current, opening of channels leads to threshold I cal = slow responding ‘ L’ type calcium channels, I k = delayed rectifier potassium current, Threshold Ical Slow Responding Fibers; Ca++ role; as at -55 mV Na+ channels close SA Node & AV Node or Damaged fibers
    • I k1= inward rectifier current, I Na= Fast responding inward sodium current, ( Na channels closes at -55 to -70 mv at which however Ca channel opens ) so in ischemic damage, fast responding fibers are changed into slow responding fibers I to = transient outward potassium current, I cal = ‘L’ type calcium channel, I k = delayed rectifier potassium current, Upstroke -85 resting potential O - Fast Responding Fibers; Na+ Role
    • the only conduction pathway Body Surface Manifestations of the Depolarization and Repolarization Waves of the heart. The only conduction pathway delay of 0.15 sec. at to allow blood to enter from atria to Ventricles AV node
    • Normal Sinus Rhythm P waves preceding each QRS complex
    • Normal 12 leads Electrocardiogram
    • The Main Factors affecting Heart Rate Gender ANS activity ( Sympathetic/Parasympathetic) Age Circulating Hormones ( Adrenaline, Thyroxin) Physical Activity Temperature Baroreceptors Reflex Emotional States
    • Arryhthmia Dysrhythmia
    • Cardiac Arrhythmia is an abnormality in: Rate, Rhythm, Site of origin & the conduction of cardiac impulse.
    • Arrhythmias occur in: Myocardial Infarction ( >80% ) Anesthetized Patients ( Up To 50% ) Digitalized Patients ( Up To 25% ) (All Antiarrythmics are Arrhythmogenic )
    • Arrhythmias are caused by: • abnormal pacemaker activity or • abnormal impulse propagation & conduction • Shift of pacemaker function from SA to other part of the Heart • Block transmission in the Heart • Abnormal pathway in the heart • Spontaneous generation of Impulses in the heart There is a normal relationship between “refractory period and conduction velocity”. Any change in this relationship may lead to arrhythmias
    • Factors Affecting Rhythm: Automaticity, Conduction & its Velocity, Excitability, Responsiveness, Refractoriness & ERP.
    • Factors Precipitating Arrhythmias 1. Ischemia: Myocardial Infarction, Coronary Vessels Disease, 2. Hypoxia : Chronic Cor-pulmonale, Shock, Severe Anemia, 3. Acidosis : Pneumonia, Ketoacidosis, Lactic Acodosis, 4. Alkalosis: Respiratory, Metabolic ( K+/Cl- Depletion ), 5. Electrolyte Abnormalities: Hypokalemia, Hypocalcemia, 6. Excessive Catecholamines: Sympathetic Stimulation, Exercise, Hypertension, Thyrotoxicosis, Pheochromocyto ma, 7. Autonomic Influences: Vasovagal Induced and Postprandial Arrhythmias, Caffeine, Smoking, Recreational Drug Use, Alcohol Abuse, 8. Drug Toxicities: Digoxin, Amiodarone, Β – Blockers, 9. Diseases of Cardiac Fibers: Cardiomyopathy, Fibrosis of His Purkinje System, Post - Cardiac Surgery,
    • Mechanism of Arrhythmias
    • • A). Disturbances of Impulse Formation: 1. Changes in Automaticity: 2. Triggered Activity: • B). Disturbances of Impulse Conduction; 1. Abnormal Regulation of the Heart Beat by sympathetic, vagal activity or re-entry • C). Molecular & Genetic Basis of Arrhythmias
    • A). Disturbances of Impulse Formation: a). Increase or decrease in pacemaker rate: due to increased or decreased depolarization of Pace Maker Cells; slope 4: if decreased i.e., more negative leads to slow normal pace maker rate, e.g., Vagal discharge, β-receptor Blockers b). Latent Pace Makers: ( Some Purkinje Fibers; Quiescent Atrial & Ventricular Cells ) they show normally slow phase 4 depolarization and are more prone to acceleration thus may show repetitive pace maker activity esp. in hypokalemia D 1. Changes in Automaticity:
    • a). Afterdepolarizations: EADs, DADs ( early or delayed after depolarization ) 2. Triggered Activity:
    • Early After Depolarization's: are usually produced & exacerbated at slow heart rates and contribute to the development of long QT – related arrhythmias. Delayed After Depolarization's: occur when intracellular calcium is increased and are exacerbated by fast heart rates and usually responsible for arrhythmias related to digitalis / catecholamine & to myocardial ischemia
    • a. Increased slope of phase 4 depolarization as in hypokalemia, β stimulation, etc. leads to early completion of diastolic depolarization, ↑Pace Making b. Reduced Threshold Potential --- early completion of diastolic depolarization. “Triggered Activity”: stimulating during relative refractory period so getting action potential earlier than normal. E. Early after depolarization, arises almost from the plateau. D. Delayed after depolarization, arises from the resting potential. a b accelerated automaticity e.g., in sympathetic stimulation Threshold Normal or Reduced Pace Maker Depolarization= Durations of Action Potential & Diastolic Interval )
    • Four Basic Mechanisms CAUSING Disturbed rhythm • Delayed after Depolarization • Re-Entry • Ectopic pace maker • Heart Block
    • B). Disturbances of Impulse Conduction; Abnormal Regulation of the Heart Beat 1). In A / B: Effects of sympathetic stimulation & Nor epinephrine. Sympathetic stimulation increases the heart rate by increasing the slope of the pacemaker potential
    • 2). In C / D: depressed conduction due to increased vagal activity (AV nodal block, bundle branch block) C D Vagal stimulation decreases the atrial force of contraction by marked shortening of action potential; also increased K+ permeability & reduced Ca++ current both contribute to block AV conduction
    • 3). Re - entry (circus movement tachycardia): if an ectopic beat finds one limb refractory Impulse passes down both limbs at equal speed Retrograde Impulse will pass When: the refractory period is shorter than the conduction time or on recovery it passes if the other side is slowly excited esp. at AV node, Atrial or Ventricular Walls Normal Damaged
    • C). Molecular & Genetic Basis of Arrhythmias as in several congenital & acquired cardiac arrhythmias; there is either increased inward current or decreased outward current during the plateau,
    • Types of Arrhythmias
    • TACHYARRHYTHMIA • Atrial – Supraventricular Tachycardia • (Pulse Rapid, Regular, Ectopic Beats) – Atrial Fibrillation • Ventricle – Ventricular Tacharrhythmia – Ventricular Fibrillation
    • Brady-arrhythmias: ( rate < 60 beats/min.), Tachy-arrhythmias: ( rate >100 beats/min.),
    • Sinus Bradycardia may be due to: hypothermia, hypothyroidism, cholestatic jaundice, raised intracranial pressure, β-blockers, digitalis etc., IHDs, sick sinus syndrome- fibrosis of the atrium & sinus node. Heart Block • conduction block at any level in the conducting system; Prolongation of PR interval > 0.22 s & then gradually P waves don’t conduct. ( 1st – 3rd degree block ) • block lower than the Bundle of His produces Bundle Branch Block; widening of QRS complex up to 0.11 s ( N: < 0.10 s) .
    • Sick Sinus Syndrome sinus arrest & junctional escape beats (J). P waves are inverted in the cavity leads
    • Complete Heart Block Congenital Complete Heart Block: QRS complex is narrow with rate 52 beats/min. Acquired Complete Heart Block: QRS complex is broad with rate 38 beats/min.
    • Tachy-arrhythmias: ( rate >100 beats/min.), may be due to Exercise, Emotion, Pain, Fever, Infection, Acute Myocardial Infarction, Acute Heart Failure, Acute Pulmonary Embolism, Hypovolemia, Pregnancy, Anemia, Hyperthyroidism, Pheochromocytoma, Excess Sympathetic or Reduced Parasympathetic Stimulation, etc.
    • Tachycardias are more symptomatic if the arrhythmia is fast & sustained Supraventricular Tachycardia: Sinus Tachycardia, Atrial Fibrillation, Atrial Flutter, Ventricular Tachyarrhythmias: Ventricular Tachycardia, Ventricular Fibrillation, The Brugada syndrome, Torsades de pointes, Ventricular Premature Beats.
    • ECG (Ambulatory Record ) Supra Ventricular Tachycardia
    • Supra-Ventricular Tachycardia at atrium or AV junction e.g., Atrial Premature Beats conducts to the ventricles with a slightly prolonged PR interval Premature P waves are different from the sinus P waves
    • A prolonged QT interval in Supra-ventricular Tachycardia
    • P waves= Atrial rate is 150/min. R-waves=Ventricular rate is 75/min. Atrial Tachycardia with IInd Degree AV. Block
    • F= flutter waves; flutter rate= 240/min. Every fourth F wave is transmitted to the ventricles; Ventricular rate= 60/min. Atrial Flutter
    • Atrial Fibrillation ( Irregular Rhythm Atrial Rate 300 To 600 /Min.) Ventricular Rate Depends On Atrial Regularity At Av Node Entry
    • Atrioventricular Junctional Tachycardia AV Nodal re-entry Tachycardia QRS complex are narrow & P waves not visible Atrioventricular re-entry Tachycardia After narrow QRS complexes the tachycardia P waves are clearly seen. During sinus rhythm of WPW Syndrome short PR interval & δ waves ( arrow ) Atrial Fibrillation in the WPW Syndrome. Tachycardia with broad QRS complexes with fast & irregular ventricular rate
    • Familial Atrial Fibrillation: there is increased inward current of potassium mutation of the gene for subunits of the slow delayed rectifier potassium current,
    • Ventricular Ectopics Ventricular Ectopics of different morphology A pair of PVCs Frequent PVCs Following PVCs, non - sustained, a brief run of Ventricular Tachycardia
    • Ventricular Fibrillation ( Post Myocardial Infarction ) Ventricular Ectopic followed by fibrillation
    • Torsade de pointes ( which is associated with syncope and sudden death ) decreased outward current of Potassium due to: mutation in gene of potassium channels leading to decreased repolarization & long QT subtypes 1, 2, 5 & 6.
    • Torsade de pointes ( a short lived atypical ventricular tachycardia which arises when ventricular repolarization is greatly prolonged - long QT syndrome: may be due to decreased K+, Mg+, Ca++ or drugs ) may be dangerous if resulting in ventricular fibrillation. a brief period of idioventricular rhythm
    • The Brugada Syndrome: ( which is characterized by ventricular fibrillation & sudden death ) increased outward current of Sodium due to: mutation in gene of sodium channels leading to congenital long QT subtype 3 syndrome
    • The Brugada Syndrome ( an inheritable condition ) Idiopathic Spontaneous Ventricular Fibrillation with ST - Elevation in V1 – V3 Right Bundle Branch Block
    • Holter Recording: sudden increase in heart rate at 11:00 & 13:00 0 clock
    • Ambulatory ECG ST depression with silent myocardial ischaemia
    • Treatment of arrhythmia
    • Why arrhythmias should be treated? Arrhythmias may cause: Sudden Death, Stroke ( emboli ) Syncope, Heart Failure, Dizziness, Palpitation, or Asymptomatic at all. because
    • Asymptomatic or Minimally Symptomatic Arrhythmias are usually not treated because anti-arrhythmic drugs themselves can precipitate lethal arrhythmias;
    • Treatment of arrhythmias is needed only if • cardiac output is reduced, or if • some arrhythmias can precipitate serious / lethal rhythm disturbances e.g., ventricular fibrillations.
    • Cardiac Output is decreased due to: Increased rate of contraction Decreased rate of contraction Asynchronised rate of contraction
    • The major anti-arrhythmic mechanisms 1. Sodium Channel Blockade 2. Sympathetic Blockade at heart 3. Prolongation of Effective Refractory Period 4. Calcium Channel Blockade
    • Thanks for patience Listening
    • Anti-arrhythmic Drugs Dr. Ashfaq Ahmad
    • 1. DRUGS: Classification Class I ( Na Channel Blockers -Membrane-depressants ): Sub-Class Ia: Disopyramide - Ventriculr Dysrhymia Procainamid - Paroxysmal atrial Fibrillation due to Quinidin vagal overactivity Ib: Lidocaine Tocainid Ventricular Tachycardia & Fibrillation Mexilitine immidiate after MI Phenytoin Ic: Flecainide - Paroxysmal atrial Fibrillation Propofenone - Recurrent Tacharrhythmias ( wolff Moricizine Parkin-son white syndrome)
    • Class II ( Beta Blockers ): Atenolol Metoprolol Propranolol Acebutol Esmolol Class III ( K+ Channels Blockers ) Prolong Action Potential Amiodarone Sotal Bretylium Ibutilide Dofetil Class IV ( Ca Channel Blockers ) Verapamil Diltiazem Bepridil
    • Class V ( Miscellaneous ): Adenosine Magnesium sulphate Digoxin Isoprenaline Atropine 2. Catheter Ablation: 3. Implantable Cardioversion Defibrillator ( ICD ):
    • Pharmacological Properties Pharmacokinetics: Bioavailability (>80%): Digitalis, Quinidine, Ia drugs, Ib except Lidocaine, Sotalol First-pass metabolism: Lidocaine, Moricizine, Ic, Beta blockers
    • Routes of administration: Only Oral: Disopyramide, Acebutalol, Propofenone, Moricizine, Tocainide, Sotalol, Mexilitine, Flecainide. Only Parenteral: Lidocaine, Esmolol, Ibutilide, Bretylium, Adenosine, MgSO4 Oral + Parenteral: Ia, Amiodarone, Propranolol, Ca-Blockers, Digitalis
    • Half-Life: Short: Lidocaine (2hrs), Adenosine(<10 sec), Esmolol (10 min) Long: Digoxin (36hrs), Phenytoin (<42hrs), Amiodarone (weeks). Intermediate (4 - 20 hrs): All Others
    • Active Metabolites of: Quinidine, Procainamide, Propofenone, Adenosine
    • Mechanism of Action
    • Aim of the Treatment is to make the depolarized tissues silent
    • - 85 influx eflux Absolute Refractory Period Relative R.P. E after depolarization D Threshold Phase 0: Depolarization; Rapid Sodium Influx; Resting voltage has become positive. Phase 1: Early Repolarization; brief K+ & Cl- eflux Phase 2: Plateu phase; Ca++ influx Phase 3: Rapid repolarization; K+ & Cl- eflux Phase 4 ( automaticity ): Ratio of Na+/K+ permeability; cellular electrolyte balance is slowly restored. Slow Diastolic Depolarization; Until the threshold potential is reached. Early & Delayed - after depolarization may occur during relative refractory period before the phase 4, due to myocardial damage, so leading to arrhythmias. Early & Delayed depolarizations interrupt Phase 3
    • The anti-arrhythmic drugs: a). Decrease: automaticity, Conduction,& Ecitability The automaticity of ectopic sites more than at SA Node by 1) reducing the ratio of sodium & potassium permeability so the membrane-potential during phase 4 stabilizes closer to potassium equilibrium at which K+ movement is stopped 2) or by increasing the threshold ( making more positive ),
    • ii). the conduction & excitability of depolarized tissues by reducing: excitatory currents to a level below for propagation, due to decreased available ‘un blocked channels’
    • b). Increase: the refractory period more at depolarized tissues than in normally polarized tissues by prolongation of recovery time of the channels which are still able to reach the rested state thus extra-systoles are unable to propagate at all; later impulses propagate more slowly and are subject to bidirectional block in re-entry arrhythmias.
    • Na Blockade(mainly): Ia, Ib, Ic, Phenytoin, Amiodarone, Na Blockade (Some): Beta-blockers, Ca blockers
    • Beta-Blockade(Mainly): Esmolol, Propranolol Beta-Blockade (Some): Bretylium, Sotalol, Propofenone, Amiodarone (irreversible)
    • Beta Blockers, Na+ & Ca++ Blockers Phase 4 slope decreased
    • K+ Channel Blockade: Amiodarone, Sotalol, Bretylium, Ibutilide
    • K+ Blockers, Adenosine, Na+ Blockers Increased duration of Action Potential
    • Ca-Blockade(mainly): Verapamil, Diltiazem Ca-Blockade (some): Amiodarone, Procainamide, Disopyramide, MgCl
    • Cardiac Effects
    • Pacemaker Activity Depressed (SA node/ Ectopic Sites): Ia (except Disopyramide), Ib, Ic, II, III (except Ibutilide), IV, Adenosine (No effect) Action Potential (Prolonged duration): Ia, III
    • Refractory period Atrial / Ventricular (prolonged): Ia, Ib, II, III (except Bretylium) (some): Ic, IV AV Node (Prolonged): II, III, IV, Adenosine, AV Node (some): Ib, Ic, Bretylium, Ibutilide PR-Interval (Prolonged): II, III (except Bretylium, Ibutilide)
    • QRS Duration (Prolonged): Ia, Ib QT Interval (Prolonged): Ia, III
    • Other Effects
    • Anti-muscarinic: Quinidine, Disopyramide Cholinomimetic: Digitalis Sympathomimetic: Bretylium
    • Alpha-blocking: Quinidine Beta-blocking (Mainly): Esmolol, Propranolol, Sotalol, Bretylium Some: Adenosine, Amiodarone, Quinidine, Procainamide, Ca-blockers Ganglion blocking: Procainamide, Bretylium,
    • USES: 1. To relieve symptoms due to: • AV node re-entry tachycardia, • WPW syndrome, • Atrial fibrillation or flutter or • tachycardia. ( Class Ic or Class III ; Anticoagulants if needed, Catheter Ablation )
    • 2. To prevent sudden death in: • Life-threatening ventricular tachyarrhythmias, • Congenital long QT, • Ventricular Tachycardia. ( Beta-blockers +/- pacemaker, Calcium Channel Blockers, Catheter Ablation, or ICD )
    • 3. Supra-ventricular (Only or mainly): IV, I, Adenosine (Some) 4. Ventricular (Only or Mainly): I, II, Bretylium 5. Both (equally): III (except Bretylium)
    • Adverse Effects Quinidine: GIT, Cinchonism, Idiosyncracy Procainamide: SLE, GIT, Allergic Disopyramide: Atropine like Lidocaine: CNS Propofenone: Taste, constipation, Arrhythmias
    • Amiodarone: Vasodilatation, Accumulation in heart, liver, skin, tears Bretylium: Ganglion blockade Sotalol: Beta blockers like Adenosine: Vasodilatation, Broncho-spasm, Heart Block
    • Contra Indications CCF: Disopyramide, Flecainide, Beta blockers SA Node/AV node Dysfunction: Beta blockers, Ca Channel blockers, Digoxin Myocardial Infarction: Flecainide Prolonged QT Interval: Quinidine, Procainamide, Disopyramide, Sotalol, Bretylium, Amiodarone,Ibutilide
    • 2. Catheter Ablation Three or four electrode - catheters are placed into the heart chambers to record and pace from various sites. Radio – frequency catheter ablation is frequently employed for symptomatic tachy – arrhythmias like: AV re-entry tachycardia or with WPW syndrome: first line therapy to avoid the risk of sudden death . Ventricular & Atrial Tachycardia ( in normal hearts ): easily cured by catheter ablation.
    • Atrial flutter: If not easily managed medically; 90 – 95 % effective. Atrial fibrillation: After AV node ablation & pacemaker implantation a marked symptomatic improvement occurs but anticoagulants are still required. ( successful in 60 – 80 % cases ) Complications: Pulmonary vein stenosis, thrombosis, stroke.
    • X-Ray of a dual-chamber Implantable Cardioverter-defibrillator( IUD ) in a left pectoral position with atrial & ventricular leads 3.CARDIOVERTER DEFIBRILLATOR
    • Termination of ventricular fibrillation by the direct current shock after detecting it correctly Electrogram recorded internally from the ventricular lead of an ICD shows chaotic ventricular activity consistent with ventricular fibrillation The ICD recognizes ventricular tachycardia or fibrillation and automatically delivers pacing or a shock to the heart to cause cardioversion to sinus rhythm
    • ECG – Body manifestation of Depolarization and Repolarization Waves of the Heart
    • Β - agonists Pacemaker potential (Phase 4) Rapid depolarization (Phase 0) Plateau (Phase 2) Repolarisation (Phase 3) Class II Class I Class IV Class III (and Ia)
    • The Conducting System of the Heart
    • PR Interval: Conduction Time From Atria to Ventricles QRS Duration: Ventricular Conduction Time QT Interval: Duration of Ventricular Action Potential QRS Complex: Ventricular Depolarization P – Wave: Atrial Depolarization T – Wave: Ventricular Repolarization
    • Standard Leads (bipolar) Augmented leads (augmented bipolar) Chest Leads (uni-polar)
    • The connections & directions of the current flow
    • Cardiac Vectors: a). The hexaxial Reference System e.g., lead l is O0, lead ll is 600, lead lll is + 1200. b). Direction of the vector: e.g., in lead lll positive & negative deflections are equal, so the mean QRS vector is perpendicula to lead lll