THE SITE OF ACTION AND ACTIVE FORM OF LOCAL ANESTHETICS. I. THEORY AND pH EXPERIMENTS WITH TERTIARY COMPOUNDS

摘要: In an attempt to determine the active form and site of action tertiary amine local anesthetics, blocking potency two lidocaine derivatives, 6211 ( pKa 6.3) 6603 (pKa 9.8), was compared when they were applied either outside or inside squid axon membrane at different pH values. Changes in external between 7.0 9.0 internal 8.0 had no effect on potential with control experiments. When externally, exhibited same 9.0. internally, however, it blocked more strongly than 8.0. 7.0, whereas, showed The logarithm dose needed block by 50% (ED50) plotted as a function well documented assumption that only uncharged is freely permeable through nerve membrane. If one assumes anesthetics 1) internally externally present form, 2) charged 3) theoretical ED50-pH curves for perfectly fit experimental results. also against concentrations above three possible forms, resultant dose-response are compatible concept being active. support this, constant decreased increase medium. not affected change. On cytoplasm partially completely follows change, depending various conditions such fiber diameter availability diffusion barrier, most existing data literature concerning change anesthetic can be accounted model. concluded penetrate forms from forms.