BRIEF REVIEW Local Anesthetics: A Century of Progress John A. Yagiela, D.D.S., Ph.D. Section of Oral Biology, UCLA School of Dentistry, Los Angeles, California Summary One century after the clinical introduction of cocaine, local anesthesia remains the most important method of pain control in dentistry. Many local anesthetics have been marketed since 1884, and it is likely that attempts to produce drugs that enhance anesthetic efficacy, reduce systemic and lo- cal toxicity, and increase nociceptive selectivity, will continue. In addition, new methods of drug ad- ministration have been and will be developed to achieve these goals. Of fundamental importance to such improvements are investigations into the pharmacology of drugs with local anesthetic activi- ty and anatomical and physiologic studies pertaining to the reasons why local anesthetics some- times fail to achieve desired results. This paper reviews recent advances in our understanding of these drugs and their clinical use. Introduction Mechanism of Action This issue of Anesthesia Progress marks the 1 00th The mechanism by which local anesthetics inhibit anniversary of the clinical introduction of cocaine by nerve conduction has proved elusive to investiga- Koller and its subsequent application to nerve block tors. It is firmly established that drugs such as lido- in dentistry by Halsted. Since then, there have been caine and procaine block propagation of the action a number of notable advances, including the addi- potential by interfering with the increase in sodium tion of epinephrine for enhanced anesthesia and conductance normally caused by depolarization of reduced systemic toxicity, the discovery of procaine the axolemma. This effect on membrane permeabil- as a nonaddicting alternative to cocaine, and the ity is rather specific; for example, potassium conduc- synthesis of lidocaine, an amide with improved tance is much less affected by these agents. What anesthetic efficacy and reduced allergenicity. These remains controversial, however, is the manner in achievements have been accompanied by similar which sodium conductance is depressed. progress in administration techniques and equip- For many years it was believed that local anesthet- ment (Table 1). Many of these advances were ics provided pain relief by interfering with a normal prompted by recognized deficiencies of existing regulatory function of calcium ions on sodium con- drugs and methodologies and were made possible ductance.4-6 According to this hypothesis, calcium by fundamental investigations of anatomy, physiol- ions bound to phospholipid molecules on the exteri- ogy, and pharmacology. It is likely that future ad- or side of the neuronal membrane prevented sodi- vances will depend even more heavily on informa- um ions from entering the cell. Nerve depolarization, tion gained from the study of nerve conduction, however, would cause the release of calcium and per- inflammation, and pain mechanisms. mit the explosive, if transient, influx of sodium. Local This paper reviews selectively the pharmacology anesthetics were thought to compete with calcium for and therapeutic use of local anesthetics in dentis- its binding sites; however, the drug molecules would try. Particular attention will be placed on recent in- remain bound during membrane depolarization and formation and on possible future developments; the prevent the sodium-dependent action potential from reader is referred to any of several excellent sources propagating. Several lines of evidence now indicate for a more general survey of local anesthesia.'-3 that this chain of events does not accurately portray the basis of local anesthesia. For example, Narahashi and Frazier7 conclusively showed that local anesthet- ics work from the inside surface of the nerve mem- Accepted for publication December 28, 1984. Address reprint requests to Dr. John Yagiela, UCLA School brane, and various investigators89 have found that of Dentistry, Center for the Health Sciences, Los Angeles, CA direct competition for binding sites does not occur be- 90024. tween calcium and all local anesthetics (e.g., non- MARCH/APRIL 1985 47 TABLE 1. Historical Landmarks in Local Anesthesia ionized forms) nor does it seem to be directly involved in local anesthetic block. Although the correspon- Date Event dence between anesthetic potency and calcium dis- 1859 Isolation of cocaine in pure form by Niemann placement from cell membranes remains of in- 1884 Clinical introduction of cocaine Koller terest,10 it is likely that both variables are independent by measures of the ability of anesthetic molecules to 1884 Halsted performs first inferior alveolar nerve block penetrate hydrophobic regions of the nerve 1901 Epinephrine used by Braun as a "chemical membrane. tourniquet" Modern theories of local anesthesia can be divid- 1904 Synthesis of procaine by Einhorn ed into two categories according to the postulated site 1920 Anesthetic cartridge and syringe marketed by Cook of action: membrane lipids or the sodium channel. 1928 Tetracaine synthesized by Eisleb The "lateral phase separation" theory of Trudell'1 is 1943 a prominent example of the former group. The term Lidocaine synthesized by Lofgren "lateral phase separation" refers to the situation 1947 Bjorn and Huldt introduce lidocaine into clinical where highly ordered membrane lipids (gel phase) dentistry coexist with areas of disordered lipids (sol phase). 1947 Novocol Company markets first dental aspirating This arrangement permits easy lateral compression syringe of the membrane through conversion of part of the 1956 Synthesis of mepivacaine by Ekenstam fluid sol phase to the more dense, more compact gel 1957 Synthesis of bupivacaine by Ekenstam organization, a reconfiguration that can then accom- 1957 Cook-Waite Laboratories introduces harpoon modate conformational changes in protein necessary aspirating syringe for opening of the sodium channel (Fig. 1). Local 1959 Prilocaine synthesized by L6fgren anesthetics inhibit sodium conductance according to 1959 Disposable sterile needles this therory by so disordering the membrane lipid marketed bilayer that the sol-to-gel transition cannot occur, and 1971 Etidocaine synthesized by Takman conformational shifts of the sodium channel are 1976 High-pressure syringe developed for intraligamentary precluded. This mechanism of action readily ac- anesthesia counts for the close relationship between anesthet- 1983 Bupivacaine marketed in cartridge form ic potency and lipid solubility; it also provides for the Out IIn c~zQ u~~~ SAl la 2a 1- " . Fig.1-Postulated mechanisms of action of local anesthetics. (1) Resting sodium channel. M = activation gate; H = inactivation gate. (2) Open channel permitting the influx of sodium ions. Lateral compression of the membrane permits translocation of the M gate. (3) Inactivated channel. Closure of the H gate precludes sodium entry, and the channel is refractory to further stimulation. (la) Insertion of a local anesthetic disorders the membrane such that opening of the M gate is prevented. (2a) Cationic local anesthet- ic crosses the open sodium channel to reach its receptor and prevent sodium influx. Neutral anesthetic molecules (not shown) may also bind but do not require the channel to be open for effective diffusion. (3a) Local anesthetic binding is enhanced when the channel is inactivated, and conversion of the channel to the resting state is impeded. Two separate sites of action are depict- ed. Binding to the receptor on the channel exterior impedes sodium entry by an allosteric mechanism (not illustrated). 48 ANESTHESIA PROGRESS structural diversity of the many unrelated compounds receptor sites has been obtained by Huang and that share in the ability to reversibly depress nerve Ehrenstein,19 who measured local anesthetic binding conduction. Until recently, it was thought that a major to batrachotoxin-activated sodium channels. It may limitation of the theory was that it could not explain be that the future will witness a fusion of current lipid the anesthesia caused by permanently charged and channel receptor theories as more specific infor- hydrophilic molecules, such as some experimental mation is obtained about lipid-protein rplationships analogues of lidocaine. Several studies have recently and their interactions with local anesthetic molecules. shown, however, that even charged anesthetics can interact with lipid bilayers at one or more sites12 and Pharmacology that this interaction may be selective for the inner half Local anesthetics can depress conduction in all ex- of the plasma membrane.13 citable tissues: peripheral nerves, neurons in the The theory that best explains the neurophysiology brain and spinal cord, and cardiac, skeletal, and of conduction block holds that the sodium channel it- mooth muscle. Dosage restrictions and accurate self is the site of action.14 Figure 1 outlines the nor- placement of anesthetic solutions adjacent to the tar- mal cycling of a sodium channel and how a local get nerves, but not some specific property of the anesthetic could potentially disrupt its function. drugs themselves, yield selective regional anesthe- Usually, most sodium channels of a nerve membrane sia. Systemic reactions, usually attributed to the are in the resting state (1). An appropriate stimulus central nervous system and less frequently to the causes the channel (specifically its M gate) to open cardiovascular system, occur when plasma concen- transiently and permit sodium (Na +) to flow inward trations increase beyond safe limits (e.g.,