title: Relationship between structure and sodium channel blockade by lidocaine and its amino-alkyl derivatives.
abstract: 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.
authors.affiliation: Department of Medicine Duke University Medical Center, Durham, North Carolina 27766.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: D J
authors.initials: DJ
authors.lastname: Wendt
authors.forename: A O
authors.initials: AO
authors.lastname: Grant
mesh_terms: D000818:Animals; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D008055:Lipids / Q000737:chemistry; D008970:Molecular Weight; D009206:Myocardium / Q000166:cytology; D018408:Patch-Clamp Techniques; D011817:Rabbits; D026941:Sodium Channel Blockers; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D008055:Lipids; D026941:Sodium Channel Blockers; C061598:RAD 242; C092207:RAD 243; C092208:L 30; C092206:RAD 244; D008012:Lidocaine