Structure-activity relations for frequency-dependent sodium channel block in nerve by local anesthetics.

Different local anesthetic drug structures differ significantly in their capabilities for producing frequency (f)-dependent sodium channel block. Voltage-clamped frog myelinated nerve preparations have been utilized in order to investigate structure-activity relations for several modes of local anesthetic drug action, including the kinetics of f-dependent excitability block. Lipid solubility has been shown to be an important determinant of closed channel blocking potency, at least within the amide-linked series of local anesthetics. The ester-linked (beta blockers) and ester-linked local anesthetics appear to be relatively more potent at closed channel block than drugs of the amide-linked series. In addition, f-dependent block increments are greater for drugs of lower lipid solubility, supporting the "modulated drug receptor" hypothesis that intracellular drug forms participate in the open channel binding involved in f-dependent blocking. Finally, molecular size has been shown to be a very important determinant of closed channel block escape rates with smaller drug structures showing faster escape rates from f-dependent increments in channel block.