Fundamental properties of local anesthetics:: Half-maximal blocking concentrations for tonic block of Na+ and K+ channels in peripheral nerve

Local anesthetics suppress excitability by interfering with ion channel function. Ensheathment of peripheral nerve fibers, however, impedes diffusion of drugs to the ion channels and may influence the evaluation of local anesthetic potencies. Investigating ion channels in excised membrane patches avoids these diffusion barriers. We investigated the effect of local anesthetics with voltage-dependent Na+ and K+ channels in enzymatically dissociated sciatic nerve fibers of Xenopus laevis using the patch clamp method. The outside-out configuration was chosen to apply drugs to the external face of the membrane. Local anesthetics reversibly blocked the transient Na+ inward current, as well as the steady-state K+ outward current. Half-maximal tonic inhibiting concentrations (IC50), as obtained from concentration-effect curves for Na+ current block were: tetracaine 0.7 mu M, etidocaine 18 mu M, bupivacaine 27 mu M, procaine 60 mu M, mepivacaine 149 mu M, and Lidocaine 204 mu M. The values for voltage-dependent K+ current block were: bupivacaine 92 mu M, etidocaine 176 mu M, tetracaine 946 mu M, lidocaine 1118 mu M, mepivacaine 2305 mu M, and procaine 6302 mu M. Correlation of potencies with octanol:buffer partition coefficients (logP(0)) revealed that ester-bound local anesthetics were more potent in blocking Na+ channels than amide drugs. Within these groups, lipophilicity governed local anesthetic potency. We conclude that local anesthetic action on peripheral nerve ion channels is mediated via lipophilic drug-channel interactions. Implications: Half-maximal blocking concentrations of commonly used local anesthetics for Na+ and K+ channel block were determined on small membrane patches of peripheral nerve fibers. Because drugs can directly diffuse to the ion channel in this model, these data result from direct interactions of the drugs with ion channels.