THE ROLE OF CHANGES IN EXTRACELLULAR AND INTRACELLULAR HYDROGEN ION CONCENTRATION IN THE ACTION OF LOCAL ANESTHETIC BASES

¹ From the Lilly Research Laboratories, Indianapolis, Indiana, and The Marine Biological Laboratory, Woods Hole, Massachusetts

1. Certain theoretical considerations have been presented in an attempt to interpret the gradations in anesthetic effects which are exerted on simple organisms (fertilized eggs and larvae of the sea urchin, Arbacia punctulata) by basic anesthetics at varying levels of extracellular and intracellular pH.

2. The apparent dissociation constants, at 25°C., for sixteen basic local anesthetics are presented for ionic strengths up to µ = 2.0.

3. For each of sixteen basic local anesthetics it is found that the extracellular concentrations of undissociated molecules required to produce 50 percent reduction in the rate of cell division of fertilized Arbacia eggs is independent of the extracellular pH, provided the intracellular pH is held constant. A similar result is obtained for the effect of thirteen basic local anesthetics on the movement of Arbacia larvae. These observations indicate that the basic local anesthetics penetrate these living cells principally, and in most cases entirely, in the form of undissociated molecules.

4. For each of two representative local anesthetics it is found that a partial pressure of carbon dioxide sufficient to increase the cytoplasmic concentration of local anesthetic cations corresponding to a given extracellular concentration of undissociated local anesthetic molecules also increases the anesthetic effectiveness of the substance at each concentration of undissociated molecules. Conversely, a concentration of ammonia sufficient to decrease the cytoplasmic concentration of local anesthetic cations corresponding to a given extracellular concentration of undissociated local anesthetic molecules decreases the anesthetic effectiveness. These results are interpreted to mean that it is the local anesthetic cation, and not the undissociated molecule, which is active inside the cell in producing the anesthetic effect.

5. Since the intracellular pH of living cells is in general much lower than that of their normal suspension medium (5), the equilibrium concentration of local anesthetic cations inside the cell, and the equilibrium concentration of total local anesthetic inside the cell are greatly in excess of those outside the cell.

It is suggested that one factor which tends to make basic anesthetics local anesthetics is that cells at the site of application require so large an amount of anesthetic to satisfy the laws of membrane penetration that relatively little anesthetic is left for production of a generalized anesthesia.

A second factor tending to make basic anesthetics local anesthetics is the extraordinary tendency of the anesthetic cations to escape from solution in intracellular aqueous phases into a state of adsorption on, or combination with, cellular constituents. Experimental data bearing on this point will be presented in more detail in subsequent publications.