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[New evolvement of antiarrhythmic drugs]
1Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan.
Abstract:
The Cardiac Arrhythmia Suppression Trial (CAST) casted serious doubts on the usefulness of Class I antiarrhythmic drugs, causing us to turn our attention from drugs impairing conduction of excitation in the myocardium by blocking sodium channels toward those producing increased refractoriness of myocardial cells by blocking potassium channels. This change in the direction of thinking from the "Na+ channel paradigm" to "K+ channel paradigm" resulted in the generation of newly synthetized Class III drugs that have the common electrophysiological property of suppressing outward K+ currents (IK, IK1, Ito) without affecting inward currents (INa, ICa). However, their reversed use-dependence of action potential duration prolonging effect contributes to their untoward action of proarrhythmias. It is still controversial if ion channel blockers acting solely on a certain kind of ion channels are more beneficial than drugs having compound actions such as amiodarone or sotalol. Molecular biology, if combined with arrhythmology, is expected to provide new chemical and pharmacological bases for creating novel antiarrhythmic drugs.
Insights
The Cardiac Arrhythmia Suppression Trial shifted focus from sodium channel blockers to potassium channel blockers for antiarrhythmic drugs. New Class III drugs suppress outward potassium currents but can cause proarrhythmias, necessitating further research.
Area of Science:
- Cardiovascular pharmacology
- Cardiac electrophysiology
- Molecular cardiology
Context:
- The Cardiac Arrhythmia Suppression Trial (CAST) questioned the efficacy of Class I antiarrhythmic drugs targeting sodium channels.
- This led to a paradigm shift towards Class III antiarrhythmic drugs that target potassium channels.
Purpose:
- To explore the shift from sodium channel blockers to potassium channel blockers in antiarrhythmic drug development.
- To discuss the electrophysiological properties and limitations of newly synthesized Class III drugs.
- To examine the ongoing debate regarding single-target versus multi-target antiarrhythmic agents.
Summary:
- Newly developed Class III antiarrhythmic drugs selectively suppress outward potassium currents (IK, IK1, Ito) without affecting inward currents (INa, ICa).
- A key concern is their reversed use-dependence, which can paradoxically prolong action potential duration and induce proarrhythmias.
- The relative benefits of drugs targeting specific ion channels versus those with compound actions (e.g., amiodarone, sotalol) remain controversial.
Impact:
- The findings highlight the challenges in developing safer and more effective antiarrhythmic therapies.
- Advances in molecular biology combined with arrhythmology research are crucial for designing novel antiarrhythmic drugs.
- This research informs future drug discovery efforts aiming to overcome the proarrhythmic potential of current therapies.