CARDIAC ARRHYTHMIA Catherine Seger Medicinal Chemistry

Types of Arrhythmias –Ventricular Cardiac Action Potential Ion Channels of Interest Classification of Anti-arrhythmic drugs Drugs and Re-entry Class I Drugs Class III Drugs Side Effects Alternative Treatments and Future Drug Development TOPICS COVERED

MECHANISMS OF CARDIAC ARRHYTHMIAS Triggered Automatic Normal Abnormal Re-entrant

VENTRICULAR RE-ENTRY Abnormal pattern of depolarization through the heart Functional Anatomic

THE CARDIAC ACTION POTENTIAL

ION CHANNELS RELEVENT TO THE CARDIAC ACTION POTENTIAL

Antiarrhythmic Drug Pathways

THE VAUGHAN WILLIAMS CLASSIFICATION SYSTEM OF ANTI- ARRHYTHMIC DRUGS ClassBasic Mechanism I-Sodium Channel BlockadeReduce phase 0 slope and peak of action potential IA Moderate reduction in phase 0 slope; increase APD; increase ERP IBSmall reduction in phase 0 slope; reduce APD; decrease ERP ICPronounced reduction in phase 0 slope; no effect on APD or ERP II-Beta-blockadeDelay repolarization (phase 3) and thereby increase action potential duration and effective refractory period. III-potassium-channel blockadeProlongation of APD and increase ERP; no effect on phase 0 IV-Calcium channel blockadeBlock L-type calcium-channels; most effective at SA and AV nodes; reduce rate and conduction.

HOW THESE DRUGS AFFECT RE-ENTRY Class I: retards conduction enough so that beat still gets through normal cardiac tissue but not through any weakened tissue Class III: prolongs refractoriness

CLASS I IA –moderate IB –weakest IC –strongest

CLASS IA

CLASS IA-Procainamide Procainamide N-Acetyl Procainamide

CLASS IB

CLASS IB-Lidocaine

CLASS IC

CLASS IC-flecainide

Cardiac Side Effects-Proarrhythmia Potential re-entrant circuit can be turned into an actual re-entrant circuit Increased incidence of death in the case of myocardial infarction

Class III

CLASS III-Sotalol

Torsades des Pointes Long Q-T syndrome Polymorhic Ventricular Tachycardia IA drugs can also cause this Blocking of potassium channels and prolonging repolarization

ALTERNATIVE TREATMENTS Ablation Implanantable Cardioverter Defibrillators (ICDs)

ICD Placement In the Heart

FUTURE OF DRUG DEVELOPMENT Drugs with defibrillating effects –Sotalol –Tedisamil Sympathomimetic-modulates cAMP Protects Gap junctions and enhances Ca 2+ uptake by SR Drugs affecting Ion Channelopathy –hyperphosphorylation Drugs or Devices?

Antiarrhythmic Drug Pathways