Why do some drugs preferentially block open sodium channels?

Area of Science:

• Pharmacology
• Biophysics
• Molecular Biology

Background:

• Antiarrhythmics and local anesthetics are known to block sodium channels, particularly during depolarization.
• Two distinct phases of sodium channel blocking occur: a transient phase and a maintained phase during depolarization.

Purpose of the Study:

• To present a structural analysis prompted by new results on the transient and maintained phases of sodium channel drug blocking.
• To develop a size criterion explaining differential drug access to sodium channels during maintained depolarizations.

Main Methods:

• Structural analysis of drug-channel interactions.
• Analysis of drug access pathways during transient and maintained depolarizations.
• Development of a size-based criterion for drug blocking.

Main Results:

• Identified two major phases of sodium channel blocking: transient and maintained.
• Proposed that open channel blocking occurs via an aqueous pathway for intracellular drug forms during transient phases.
• Developed a simple size criterion that explains why certain drugs are excluded from the pathway during maintained depolarizations.

Conclusions:

• The study provides a structural basis for understanding the distinct mechanisms of transient and maintained sodium channel blocking.
• A size criterion is crucial for determining drug accessibility to sodium channels during different phases of depolarization.
• These findings advance the understanding of how antiarrhythmic and local anesthetic drugs interact with sodium channels.