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. 1977 Apr 1;69(4):475–496. doi: 10.1085/jgp.69.4.475

The pH-dependent rate of action of local anesthetics on the node of Ranvier

PMCID: PMC2215051  PMID: 16078

Abstract

Local anesthetic solutions were applied suddenly to the outside of single myelinated nerve fibers to measure the time course of development of block of sodium channels. Sodium currents were measured under voltage clamp with test pulses applied several times per second during the solution change. The rate of block was studied by using drugs of different lipid solubility and of different charge type, and the external pH was varied from pH 8.3 to pH 6 to change the degree of ionization of the amine compounds. At pH 8.3 the half-time of action of amine anesthetics such as lidocaine, procaine, tetracaine, and others was always less than 2 s and usually less than 1 s. Lowering the pH to 6.0 decreased the apparent potency and slowed the rate of action of these drugs. The rate of action of neutral benzocaine was fast (1 s) and pH independent. The rate of action of cationic quaternary QX-572 was slow (greater than 200 s) and also pH independent. Other quaternary anesthetic derivatives showed no action when applied outside. The result is that neutral drug forms act much more rapidly than charged ones, suggesting that externally applied local anesthetics must cross a hydrophobic barrier to reach their receptor. A model representing diffusion of drug into the nerve fiber gives reasonable time courses of action and reasonable membrane permeability coefficients on the assumption that the hydrophobic barrier is the nodal membrane. Arguments are given that there may be a need for reinterpretation of many published experiments on the location of the anesthetic receptor and on which charge form of the drug is active to take into account the effects of unstirred layers, high membrane permeability, and high lipid solubility.

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Selected References

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  1. Armstrong C. M., Hille B. The inner quaternary ammonium ion receptor in potassium channels of the node of Ranvier. J Gen Physiol. 1972 Apr;59(4):388–400. doi: 10.1085/jgp.59.4.388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. DODGE F. A., FRANKENHAEUSER B. Membrane currents in isolated frog nerve fibre under voltage clamp conditions. J Physiol. 1958 Aug 29;143(1):76–90. doi: 10.1113/jphysiol.1958.sp006045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Finkelstein A. Water and nonelectrolyte permeability of lipid bilayer membranes. J Gen Physiol. 1976 Aug;68(2):127–135. doi: 10.1085/jgp.68.2.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Frazier D. T., Narahashi T., Yamada M. The site of action and active form of local anesthetics. II. Experiments with quaternary compounds. J Pharmacol Exp Ther. 1970 Jan;171(1):45–51. [PubMed] [Google Scholar]
  5. Friberger P., Aberg G. Some physiochemical properties of the racemates and the optically active isomers of two local anaesthetic compounds. Acta Pharm Suec. 1971 Sep;8(4):361–364. [PubMed] [Google Scholar]
  6. Gutknecht J., Tosteson D. C. Diffusion of weak acids across lipid bilayer membranes: effects of chemical reactions in the unstirred layers. Science. 1973 Dec 21;182(4118):1258–1261. doi: 10.1126/science.182.4118.1258. [DOI] [PubMed] [Google Scholar]
  7. Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol. 1977 Apr;69(4):497–515. doi: 10.1085/jgp.69.4.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hille B. The permeability of the sodium channel to organic cations in myelinated nerve. J Gen Physiol. 1971 Dec;58(6):599–619. doi: 10.1085/jgp.58.6.599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Izutsu K. T. Intracellular pH, H ion flux and H ion permeability coefficient in bullfrog toe muscle. J Physiol. 1972 Feb;221(1):15–27. doi: 10.1113/jphysiol.1972.sp009735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Koppenhöfer E., Vogel W. Wirkung von Tetrodotoxin und Tetraäthylammoniumchlorid an der Innenseite der Schnürringsmembran von Xenopus laevis. Pflugers Arch. 1969;313(4):361–380. doi: 10.1007/BF00593959. [DOI] [PubMed] [Google Scholar]
  11. Kwant W. O., Seeman P. The membrane concentration of a local anesthetic (chlorpromazine). Biochim Biophys Acta. 1969;183(3):530–543. doi: 10.1016/0005-2736(69)90167-9. [DOI] [PubMed] [Google Scholar]
  12. Mozhayeva G. N., Naumov A. P. Tetraethylammonium ion inhibition of potassium conductance of the nodal membrane. Biochim Biophys Acta. 1972 Dec 1;290(1):248–255. doi: 10.1016/0005-2736(72)90067-3. [DOI] [PubMed] [Google Scholar]
  13. Narahashi T., Frazier D. T., Moore J. W. Comparison of tertiary and quaternary amine local anesthetics in their ability to depress membrane ionic conductances. J Neurobiol. 1972;3(3):267–276. doi: 10.1002/neu.480030309. [DOI] [PubMed] [Google Scholar]
  14. Narahashi T., Frazier D. T. Site of action and active form of procaine in squid giant axons. J Pharmacol Exp Ther. 1975 Sep;194(3):506–513. [PubMed] [Google Scholar]
  15. Narahashi T., Frazier T., Yamada M. The site of action and active form of local anesthetics. I. Theory and pH experiments with tertiary compounds. J Pharmacol Exp Ther. 1970 Jan;171(1):32–44. [PubMed] [Google Scholar]
  16. Narahashi T., Moore J. W., Poston R. N. Anesthetic blocking of nerve membrane conductances by internal and external applications. J Neurobiol. 1969;1(1):3–22. doi: 10.1002/neu.480010103. [DOI] [PubMed] [Google Scholar]
  17. RITCHIE J. M., GREENGARD P. On the active structure of local anesthetics. J Pharmacol Exp Ther. 1961 Aug;133:241–245. [PubMed] [Google Scholar]
  18. Ritchie J. M., Greengard P. On the mode of action of local anesthetics. Annu Rev Pharmacol. 1966;6:405–430. doi: 10.1146/annurev.pa.06.040166.002201. [DOI] [PubMed] [Google Scholar]
  19. Ritchie J. M. Mechanism of action of local anaesthetic agents and biotoxins. Br J Anaesth. 1975 Feb;47 Suppl:191–198. [PubMed] [Google Scholar]
  20. Ritchie J. M., Ritchie B. R. Local anesthetics: effect of pH on activity. Science. 1968 Dec 20;162(3860):1394–1395. doi: 10.1126/science.162.3860.1394. [DOI] [PubMed] [Google Scholar]
  21. Ritchie J. M., Ritchie B., Greengard P. The active structure of local anesthetics. J Pharmacol Exp Ther. 1965 Oct;150(1):152–159. [PubMed] [Google Scholar]
  22. Ritchie J. M., Ritchie B., Greengard P. The effect of the nerve sheath on the action of local anesthetics. J Pharmacol Exp Ther. 1965 Oct;150(1):160–164. [PubMed] [Google Scholar]
  23. SKOU J. C. Local anaesthetics. VI. Relation between blocking potency and penetration of a monomolecular layer of lipoids from nerves. Acta Pharmacol Toxicol (Copenh) 1954;10(4):325–337. doi: 10.1111/j.1600-0773.1954.tb01349.x. [DOI] [PubMed] [Google Scholar]
  24. SKOU J. C. Local anesthetics. I. The blocking potencies of some local anesthetics and of butyl alcohol determined on peripheral nerves. Acta Pharmacol Toxicol (Copenh) 1954;10(3):281–291. doi: 10.1111/j.1600-0773.1954.tb01344.x. [DOI] [PubMed] [Google Scholar]
  25. Strobel G. E., Bianchi C. P. The effects of pH gradients on the action of procaine and lidocaine in intact and desheathed sciatic nerves. J Pharmacol Exp Ther. 1970 Mar;172(1):1–17. [PubMed] [Google Scholar]
  26. Strobel G. E., Bianchi C. P. The effects of pH gradients on the uptake and distribution of C14-procaine and lidocaine in intact and desheathed sciatic nerve trunks. J Pharmacol Exp Ther. 1970 Mar;172(1):18–32. [PubMed] [Google Scholar]
  27. TAYLOR R. E. Effect of procaine on electrical properties of squid axon membrane. Am J Physiol. 1959 May;196(5):1071–1078. doi: 10.1152/ajplegacy.1959.196.5.1071. [DOI] [PubMed] [Google Scholar]
  28. Vierhaus J., Ulbricht W. Effect of a sudden change in sodium concentration on repetitively evoked action potentials of single nodes of Ranvier. Pflugers Arch. 1971;326(1):76–87. doi: 10.1007/BF00586795. [DOI] [PubMed] [Google Scholar]
  29. Vierhaus J., Ulbricht W. Rate of action of tetraethylammonium ions on the duration of action potentials in single Ranvier nodes. Pflugers Arch. 1971;326(1):88–100. doi: 10.1007/BF00586796. [DOI] [PubMed] [Google Scholar]
  30. Wagner H. H., Ulbricht W. Saxitoxin and procaine act independently on separate sites of the sodium channel. Pflugers Arch. 1976 Jun 29;364(1):65–70. doi: 10.1007/BF01062913. [DOI] [PubMed] [Google Scholar]

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