CARDIAC ARRHYTHMIA

Catherine SegerMedicinal 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

Class Basic MechanismI-Sodium Channel Blockade

Reduce phase 0 slope and peak of action potential

IA   Moderate reduction in phase 0 slope; increase APD; increase ERP

IB Small reduction in phase 0 slope; reduce APD; decrease ERP

IC Pronounced reduction in phase 0 slope; no effect on APD or ERP

II-Beta-blockade Delay repolarization (phase 3) and thereby increase action potential duration and effective refractory period.

III-potassium-channel blockade

Prolongation of APD and increase ERP; no effect on phase 0

IV-Calcium channel blockade

Block 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 Ca2+

uptake by SR

• Drugs affecting Ion Channelopathy– hyperphosphorylation

• Drugs or Devices?

Antiarrhythmic Drug Pathways