Relationship between structure and sodium channel blockade by lidocaine and its amino-alkyl derivatives

We examined the relationship between the physicochemical properties and the sodium channel-blocking actions of lidocaine and four of its amino-alkyl derivatives. The homologues differ in lipid solubility (log p 2.7-4.1), pKa (6.9-9.0), and molecular weight (248.5-290.7). Macroscopic sodium currents were measured in rabbit atrial myocytes by the whole-cell configuration of patch-clamp technique; single-channel currents were measured by the cell-attached configuration. Lidocaine and its homologues produced two patterns of block: tonic block and frequency-dependent block. Tonic block was highly correlated with lipid solubility and pKa. The single-channel studies suggest that tonic block results when the drug interacts with channel state(s) that precede opening. Block of open channels does not appear to play a prominent role in tonic block. The rate of recovery from block was the major determinant of the magnitude of frequency-dependent block. Highly lipid-soluble homologues showed rapid recovery from block and little frequency-dependent block. Drugs with lower lipid solubility and high pKa showed slower recovery from block and greater frequency-dependent block. The seemingly different requirements for tonic and frequency-dependent block can be explained by drug interaction at a single receptor site.