THE ACTIVE STRUCTURE OF LOCAL ANESTHETICS

¹ Department of Pharmacology, Albert Einstein College of Medicine, New York, N. Y., and the Department of Biochemistry, Geigy Research Laboratories, Ardsley, New York

A study has been made of the effect of pH on the action of the nitrogen-containing local anesthetics on desheathed preparations of mammalian nonmyelinated nerve fibers. The results provide strong support for the hypothesis that the cation is the active form of local anesthetics and that the uncharged molecule is important only for penetration.

The anesthetics used were the short-acting agent, lidocaine, and the long-acting agent, dibucaine. Both the size of the C elevation of the compound action potential and the electrical threshold were used as indices of the degree of block.

The rate of block is greater when an anesthetic is applied in neutral than in alkaline solution. Furthermore, although little block develops while a nerve is being exposed to a low concentration of dibucaine in alkaline solution, complete block rapidly develops when the nerve is transferred to an anesthetic-free solution at neutral pH. Conduction is restored on returning the nerve to the alkaline anesthetic solution.

Evidence is presented in support of the widely held belief that local anesthetics penetrate nervous tissues more rapidly in their uncharged than in their charged form.

An examination has also been made of the local anesthetic effect of agents whose molecular form is independent of pH. Up to pH 9.0 the effect of n-butanol, benzoyl alcohol and carbachol were independent of pH. At higher pH values, the ability of n-butanol and benzoyl alcohol to block conduction increased.

Increasing the pH of the bathing medium from 7.0 to 9.0 or to 10.5 had little effect on the size of the action potential or on the electrical threshold. These experiments argue strongly against the possibility that the effects of pH on the action of local anesthetics are due to direct effects on the nerve membrane.

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