On the Mode of Action of Local Anesthetics

Abstract

Local anesthetics possess the specific ability to bl ock conduction in nerve in a reversible ma nner and in low concentration. The reactions that occur in the ner ve membrane that allow local anesthetics to achieve this effect are still not clearly defi ned. Howe ver , with the re cent increa se in our knowledge of the nature of the nerve impul se , some idea of the mode of action of local anesthetics is be ginning to form. Measurements of me m brane potentials and ionic move me nt s have strong ly suggested that local anesthetics block cond uct ion by inter fe ring with the sodium and potassium conductance cha ng es that are fundamental to the generation of the nerve impulse . Other studies have indicated that local anesthetic molecule s achieve this conduction block in the form of ca ti ons. Furthermore, studies of structure-activity relations have suggeste d someth ing of the chemical na ture of the re ce ptor in the nerve membrane and the method of interac tion of this receptor with the local anesthetic molecule . Finally, studies of the be ha vior of loca l anesthetics in model systems have suggested a phys icochemical ba sis for the mode of action of local anesthetics on the ne rve membrane. These various aspects of local anesthetic action will be g iven particular emphasis in this review. Many other, perhaps equally important, aspects will be neglected, and the interested reader is there fore referred to the many comprehensive reviews on local anesthetics that have appeared in the last decade (4,14,24,25,56,73,94,104,106,108). ELECTROPHYSIOLOGICAL EFFECTS OF LOCAL ANESTHETICSThe work of Hodgkin, Huxley, Keynes, and ot hers [see (52)] has led in recent year s to a better under standing of the nature of the nerve im pulse . In consequence , it is now possible to expla in the action of local an esthet ics within the fra me wor k of the ionic theory of nervous act ivity .Active nerve membrane.-Local anesthetics increase the threshold for ele ctr ical excitat ion in nerve , slow pr opagation of the impul se, reduce the rate of rise of the action pote nt ial, and eventually bl ock conduct ion [e.g. (85)]. They do this by inter fer ing with the pr oce ss fundamental to the gen eration of the nerve action pote ntial, name ly the large transient rise in the permeability of the me mbrane to sodium ions that is produced by a slight de pola rization of the me mbrane. Taylor (99), Shanes et al. (85), and, more re ce ntly, Blaustein & Goldman (19) used the voltage-clamp me thod to study 1 The survey of th e literature pertaining to this review was concluded in Octo ber 1965. 405 Annu. Rev. Pharmacol. 1966.6:405-430. Downloaded from www.annualreviews.org Access provided by Queens University -Kingston (Canada) on 03/08/15. For personal use only. Quick links to online content Further ANNUAL REVIEWS

A New Guanidine Derivative: Dissociation of the Adrenergic Neuron Blocking Activity From Local Anesthetic Activity

“…Baba and Smith (20) demonstrated that guanethidine increased potential differences and increased 24Na-influx in the frog skin membrane. Guanethidine certainly has these paradoxical actions (10,(18)(19)(20), and such can never be attributed to the membrane stabilizing action of local anesthetics (21)(22)(23)(24). It has been emphasized that guanethidine increases the permeability of the adrenergic nerve ending membrane to sodium ions, thereby, leading to adrenergic neuron blockade (10).…”

Dissociation between intracellular Ca2+ and modulation of [3H]noradrenaline release in chick sympathetic neurons.

“…TEA is known to enhance neuronal Ca21 influx by blocking K+ currents and extending the duration of the nerve action potential (Armstrong & Binstock, 1965). Tetracaine, on the other hand, is a classical local anaesthetic that blocks conduction in neuronal cells and prevents stimulation-induced Ca2`influx (Ritchie & Greengard, 1966). As shown in Each of the images in Fig.…”

[3H]‐tetracaine binding on rat synaptosomes and sodium channels

“…The interference by local anaesthetics with Na+ channels, thus reducing sodium permeability, is well known (Ritchie & Greengard, 1966;Courtney, 1975).…”