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

¹ Department of Physiology and Pharmacology, Duke University Medical Center, Durham, North Carolina; Department of Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico

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

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