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CARDIAC ARRHYTHMIA
Catherine Seger
Medicinal Chemistry
TOPICS COVERED
• 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
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 ANTIARRHYTHMIC DRUGS
Class
Basic Mechanism
I-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