cardiac arrhythmia catherine seger medicinal chemistry
TRANSCRIPT
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CARDIAC ARRHYTHMIA
Catherine SegerMedicinal Chemistry
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• 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
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MECHANISMS OF CARDIAC ARRHYTHMIAS
•Triggered•Automatic
•Normal•Abnormal
•Re-entrant
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VENTRICULAR RE-ENTRY
•Abnormal pattern of depolarization through the heart
•Functional•Anatomic
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THE CARDIAC ACTION POTENTIAL
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ION CHANNELS RELEVENT TO THE CARDIAC ACTION
POTENTIAL
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Antiarrhythmic Drug Pathways
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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.
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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
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CLASS I• IA
– moderate
• IB– weakest
• IC– strongest
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CLASS IA
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CLASS IA-Procainamide
Procainamide
N-Acetyl Procainamide
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CLASS IB
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CLASS IB-Lidocaine
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CLASS IC
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CLASS IC-flecainide
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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
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Class III
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CLASS III-Sotalol
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Torsades des Pointes
•Long Q-T syndrome•Polymorhic Ventricular Tachycardia•IA drugs can also cause this
•Blocking of potassium channels and prolonging repolarization
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ALTERNATIVE TREATMENTS
• Ablation• Implanantable
Cardioverter Defibrillators (ICDs)
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ICD Placement In the Heart
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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?
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Antiarrhythmic Drug Pathways