Anti arrhythmia

• Teaching purpose


  • To Master the classification and specific drug of antiarrhythmic drugs
  • To grasp pharmacological effect, mechanism, clinical use and adverse effect of Lidocaine, Propranolol, Amiodarone, and Verapamil
  • To understand the basic mechanism of antiarrhythmic drugs
• Cardiac Action Potential


  • The flow of ions across cell membranes generates the currents that make up cardiac action potentials(AP)
  • The factors that determine the magnitude of individual currents and their modulation by drugs can be explained at the cellular and molecular levels
  • Most antiarrhythmic drugs affect more than one ion current, and many exert ancillary effects such as modification of cardiac contractility or autonomic nervous system function
  • Antiarrhythmic drugs usually exert multiple actions and can be beneficial or harmful in individual patients
• Normal Sinus Rhythm


  • Heart rhythm is determined by SA node = Cardiac Pacemaker
  • Called sinus rhythm
  • Normal sinus rate 60-100 beats/min
• Cardiac Action Potential (AP)

  1. Phase 0: Rapid depolarization caused by a transient opening of fast Na channels

  2. Phase 1: Initial repolarization, open K channel: transient outward hyperpolarizing K+ current, large increase in slow inward Ca++ occurs at the same time

  3. Phase 2: Plateau phase prolongs AP duration vs APs in nerves and skeletal muscle

  4. Phase 3: Repolarization, K channels open, Inactivation of Ca++ channels

  5. Phase 4: Resting membrane potential, AP depolarizes cells to threshold -70mV
• Excitatory


  • Refers to the capacity to produce AP and repolarization after being stimulated for myocardial cells
  • Conductivity is determined by the depolarization rate of 0 phase
  • Fast response automatic cell: depolarization rate of 0 phase is decided by Na+ flow
  • Slow reaction cell: depolarization rate of 0 phase is decided by Ca+ influx
  • Inhibition of Na+ influx and Ca+ influx can slows the conduction
• Effective refractory period (ERP)


  • A period that phase 0 depolarization to repolarization to membrane potential -60mV
  • ERP reflects the shortest time that Na+ channel recovery
  • More high ERP value, longer "no reaction time" in myocardial cells, and less prone to rapid arrhythmia
• Arrhythmia


  • Irregular rhythm
  • Abnormal Rate
  • Conduction abnormality
• Classification of Arrhythmias


  • Tachycardiac arrhythmias: Atrial flutter, Atrial fibrillation (AF), Ventricular-premature beats (Contractions), Ventricular-tachycardia (VT), Ventricular fibrillation (VF)
  • Bradycardiac arrhythmias: Bundle branch blocks, Sinus bradycardia (Sick Sinus Syndrome)
• Cause of arrhythmia


  • Abnormal automaticity: The SA node shows the fastest rate of phase 4 depolarization and, therefore, exhibits a higher rate of discharge than that occurring in other pacemaker cells exhibiting automaticity
  • Abnormalities in impulse conduction: Normal - Impulses from higher pacemaker centers are normally conducted down pathway that bifurcate to activate the entire ventricular surface, Unidirectional block - reentry is the most common cause of arrhythmias
• Causes of arrhythmia


  • Cardiac Diseases: Coronary heart diseases, Acute heart infarction, Heart failure, Cardiac ischemia, Hypertension
  • Metabolic Diseases: Diabetes, Hyperlipidemia, Thyroid disease
  • Side-effects of Some Drugs: Digoxin
  • Ion Channel Diseases: Long Q-T syndrome, Brugada syndrome
  • Neurohormonal Factors: Hypokalaemia
  • Other Factors: Smoking, Drinking excess alcohol
• First choice antiarrhythmic drugs


  • Sinus tachycardia - propranolol
  • Supraventricular tachyarrhythmia - verapamil
  • Ventricular tachyarrhythmia - lidocaine
  • Rapid ventricular arrhythmias caused by strong glycoside poisoning - phenytoin sodium
  • Atrial fibrillation and atrial flutter - digoxin
  • Broad spectrum - amiodarone, propafenone
• Classification of Antiarrhythmic Drugs

  • Class I: Sodium Channel Blockers
  • Class IA: Quinidine, Procainamide, Disopyraminde
  • Class IB: Lidocaine, Mexiletine
  • Class IC: Flecainide, Encainide, Propafenone
  • Class II: Beta-Adrenergic Blockers: Propranolol, Metoprolol
  • Class III: Drugs that Prolong Repolarization: Amiodarone, Sotalol, Dofetilide
  • Class IV: Calcium Channel Blockers: Verapamil, Diltiazem, Bepridil
• Mechanism of Antiarrhythmic Drugs


  • Lower Automaticity
  • Reduce delayed afterdepolarizations (DADs)
  • Change conduction
  • Extend ERP
• Class IA drug


  • Lengthens the action potential (right shift)
  • Mechanism of action: Block fast (Na+) channels in "Activated/Open state", ↓ Rate and rise of action potential, Block (K+) channels, ↑ Duration of action potential
• Class IA Antiarrhythmics


  • Pharmacological Effects: Decreases ectopic automaticity, Depresses cardiac excitability, Decreases conduction, Slows SA node, Increases effective refractory period, Vasodilatation
  • Electrophysiological Mechanism: Use-dependent block of sodium channels, Blocks potassium channels, Prolongs action potential duration, Blocks alpha adrenergic receptors, Blocks muscarinic receptors
  • Pharmacokinetics: 70-80% bioavailable by oral administration, 80% bound to albumin and glycoprotein, Primarily by hepatic metabolism, Elimination half-life is 6-8 hours
  • Therapeutic Use: Broad-spectrum antiarrhythmic drugs - atrial, atrioventricular, and ventricular tachyarrhythmia, Clinically used for atrial fibrillation, atrial flutter, and Ventricular Tachycardia
  • Toxicity: Torsades de pointes, Cinchonism syndrome, Syncope, Hypersensitivity reactions
• Class IB Agent


  • Shortens the action potential (left shift)
  • Mechanism of action: Block fast (Na+) channels in "Activated/Open state", ↓ Rate and rise of action potential, ↓ Residual (Na+) "plateau" influx, ↓ Length of Phase 2
• Class Ib Antiarrhythmics


  • Uses: Ventricular tachycardias
  • Examples: Lidocaine, Mexiletine
  • Selective action on Purkinje fibers - only effective for ventricular arrhythmias, no effect on atria
• Lidocaine


  • Mechanism of action: In addition to sodium channel blockade, lidocaine can shorten phase 3 repolarization and decrease the duration of the action potential
  • Pharmacokinetics: Extensive first-pass hepatic metabolism, Only 3% of orally administered in the plasma, Elimination half-life is 1-2 hours, 70% bound to albumin and glycoprotein
• Quinidine


  Used for the treatment of atrial fibrillation, atrial flutter, and Ventricular Tachycardia
• Because of its cardiac and extracardiac side effects, the use of Quinidine has decreased considerably in recent years and is now largely restricted to patients with normal heart
• Toxicity of Quinidine


  • Torsades de pointes
  • Cinchonism syndrome (for example, blurred vision, tinnitus, headache, disorientation, and psychosis)
  • Syncope
  • Hypersensitivity reactions
• Class IB Agent


  Shortens the action potential (left shift)
• Mechanism of action of Class IB Agents


  1. Block fast (Na+) channels in "Activated/Open state"

  2. ↓ Rate and rise of action potential

  3. ↓ Residual (Na+) "plateau" influx

  4. ↓ Length of Phase 2
• Uses of Class IB Agents

  Ventricular tachycardias
• Class IB Agents


  • Lidocaine
  • Mexiletine
• Class IB Agents


  • Selective action on Purkinje fibers - only effective for ventricular arrhythmias, no effect on atria
• Mechanism of action of Lidocaine


  In addition to sodium channel blockade, lidocaine can shorten phase 3 repolarization and decrease the duration of the action potential
• Pharmacokinetics of Lidocaine


  • Extensive first-pass hepatic metabolism
  • Only 3% of orally administered in the plasma
  • Elimination half-life is 1-2 hours
  • 70% bound to albumin and glycoprotein
• Routine prophylactic use of lidocaine in acute ischemia may actually increase total mortality, possibly by increasing the incidence of asystole and is not the standard of care
• Class IC Agent


  Dose not significantly affect the action potential (no shift)
• Mechanism of action of Class IC Agents


  1. Block (Na+) channels in "Activated/Open state"

  2. ↓ rate and rise of action potential
• Uses of Class IC Agents

  Paroxysmal atrial fibrillation
• Class IC Agents


  • Flecainide
  • Encainide
  • Propafenone
• Pharmacological Effects of Flecainide


  • Suppresses phase 0 upstroke in Purkinje and myocardial fibers, causing marked slowing of conduction in all cardiac tissue, with a minor effect on the duration of the action potential and refractoriness
  • Blocks potassium channels leading to increased action potential duration
• Comparison of effect on Na+ channel and ERP between Class IA, IB, and IC drugs

  • Sodium channel blockade: IC > IA > IB
  • Increasing the ERP: IA>IC>IB (lowered)
• Class II Agent (Beta-Blockers)


  • Mechanism of action: Beta (1) blockade (↓ Sympathetic tone)
  • ↓ AVN conduction (Propranolol also shows some class I effect)
• Uses of Class II Agents (Beta-Blockers)


  • ↓ AVN Conduction
  • ↓ Tachyarrhythmias, best for supraventricular tachyarrhythmias
  • ↓ Post-MI mortality
• Propranolol (nonselective)


  Proved to reduce the incidence of sudden arrhythmatic death after myocardial infarction
• Metoprolol


  Reduce the risk of bronchospasm
• Esmolol


  A very short-acting β1-adrenergic blocker that is used by intravenous route in acute arrhythmias occurring during surgery or emergencies