1. CARDIAC ARRHYTHMIA Catherine Seger Medicinal Chemistry

2. 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

3. MECHANISMS OF CARDIAC ARRHYTHMIAS Triggered Automatic Normal Abnormal Re-entrant

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

5. THE CARDIAC ACTION POTENTIAL

6. ION CHANNELS RELEVENT TO THE CARDIAC ACTION POTENTIAL

7. Antiarrhythmic Drug Pathways

8. 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.

9. 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

10. CLASS I IA –moderate IB –weakest IC –strongest

11. CLASS IA

12. CLASS IA-Procainamide Procainamide N-Acetyl Procainamide

13. CLASS IB

14. CLASS IB-Lidocaine

15. CLASS IC

16. CLASS IC-flecainide

17. 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

18. Class III

19. CLASS III-Sotalol

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

21. ALTERNATIVE TREATMENTS Ablation Implanantable Cardioverter Defibrillators (ICDs)

22. ICD Placement In the Heart

23. 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?

24. Antiarrhythmic Drug Pathways