MUSCLE RELAXANTS

MUSCLE RELAXANTS

" / would have everie man write what he knozves and no more."—MONTAIGNE BRITISH JOURNAL OF ANAESTHESIA APRIL 1976 VOLUME 48, NO. 4 EDITORIAL 6TH WO...

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" / would have everie man write what he knozves and no more."—MONTAIGNE

BRITISH JOURNAL OF ANAESTHESIA APRIL 1976

VOLUME 48, NO. 4

EDITORIAL 6TH WORLD CONGRESS OF ANAESTHESIOLOGY

MUSCLE RELAXANTS

There was a time when the pharmacology of the myoneural blocking agents seemed to be delightfully simple. Acetylcholine, the transmitter substance produced by the motor nerve endings, passed across the synaptic deft to the end-plate region of the muscle fibre, discharging the polarizing voltage of the muscle membrane to the point at which it became unstable and a propagated impulse spread centrifugally from the end-plate to the remainder of the muscle fibre leading to its contraction. Acetylcholine was the key— the end-plate receptor was the lock. The ability to produce myoneural block was possessed by a large number of substances, all of which had the characteristic of resembling acetylcholine, in that they contained one quaternary nitrogen atom or a similar quaternary organic group. Thus they fitted the lock but the bolt could not be shot home. In more scientific terms, the myoneural blockers resembled acetylcholine sufficiently in chemical structure to compete with it at the end-plate receptors. The early literature described tubocurarine or gallamine as "competitive blockers". The "depolarizing blockers" had an even stronger similarity to acetylcholine and competed more successfully with acetylcholine at the end-plate than did the so-called competitive blockers. The problems of the responses of different species to the myoneural agents have bedevilled the presentation of a logical pharmacology. Decamethonium, for example, was largely antagonized by neostigmine in the dog, in which it had many characteristics of a non-depolarizing blocker, while manifest non-

depolarizing blockers are apparently able to depolarize denervated muscle, as does decamethonium. Subsequently it became apparent that the quality of the block produced by decamethonium, and later by suxamethonium, changes as the effect of the drug persists. Some of this change may be attributable to the presence of an inexcitable area on the investing membrane of the muscle—immediately outside the end-plate area proper—which becomes repolarized shortly after the arrival of decamethonium. This area, it was presumed, impeded centrifugal spread of an impulse initiated by the arrival of further acetylcholine at the end-plate. The issue was further complicated when Zaimis propounded the concept of dual block, a phenomenon which varied from muscle to muscle in the same species and from species to species in the same muscle. Indeed some workers have been so uncertain about this concept that they refer to "phase II block". A further difficulty is that, in some stages, the myoneural block may be antagonized by neostigmine whereas in others it seems to be intensified. Classical theories die hard, but in the field of neuromuscular pharmacology some modifications of established views are needed to explain recent findings. There can be little doubt that the presynaptic site (motor nerve ending) is an important area of activity of muscle relaxants. In some species, it appears to be the most responsive site to the action of both depolarizing and non-depolarizing agents. Indeed agents such as suxamethonium appear to have at

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Additional copies of this issue of the Britishjournal of Anaesthesia are being distributed in Mexico as part of our new publisher's promotion at the 6th World Congress. Our appearance at the Congress is intended to bring the attention of new readers to the important role of this Journal as an international vehicle of communication in anaesthesia and it is also a gesture of goodwill to the large number of anaesthetists in almost every country of the world who are established subscribers and readers.

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Phase II block is present when anticholinesterase agents appreciably improve neuromuscular conduction. The possibility of desensitization block (phase III block ?) in man would be manifest only by a failure of the end-plate to respond to acetylcholine in the presence of a normal resting end-plate potential. Confusion has arisen from the use of the terms post-tetanic potentiation and post-tetanic facilitation. Two different events may occur following tetanic stimulation of a motor nerve. One, reflecting an increase in the rate of release of mobilizable acetylcholine, is presynaptic in origin; the other, the result of alterations in contractility of muscle, is postsynaptic. It is proposed that when the event is demonstrably a result of presynaptic changes, it should be referred to as post-tetanic facilitation of transmission (PTFT), to distinguish it from posttetanic augmentation of contraction (PTAC). In studying the response to tetanic stimulation of motor nerves, it is recommended that tetanic rates of more than 100 Hz are unsuitable for man, and rates of more than 200 Hz should not be used, as the interval between the stimuli approaches the refractory period of mammalian neuromuscular conduction. It is also recommended that the latency between the end of a tetanus (recommended duration 2-10 s) and the post-tetanic stimulus should be standardized in any experimental protocol. These recommendations are not definitive, but they are proposed in the hope that, in spite of the growing awareness of the complexity of the action of drugs at the myoneural junction, the subject will not be complicated further by semantic ambiguities. A. R. Hunter S. A. Feldman

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least three sites of action—which may explain the multiphasic activity that follows prolonged administration of this drug. The classical views on structure-activity relationships must be revised, since it is evident that potent neuromuscular blocking agents exist with only one quaternary ammonium group, and that the "interonium" distance may be outside the 1.0-1.4 run range. The demonstration that tubocurarine is in fact a mono-quaternary ammonium compound at a biological pH and that dimethyl curare probably has the bisquaternary structure previously attributed to tubocurarine, has added further confusion. It was with a view to these ends that an international group of workers active in this field gathered at Westminster Hospital in December 1975 to try to establish areas of agreement and to define some of the problems which have beset the full understanding of the action of the myoneural blockers. It was possible to achieve a degree of agreement as to what was meant by a number of terms used in this work: these are delineated below. It is hoped that their more firm definition will lead to progress in this difficult field. It was considered desirable to retain the terms "depolarizing" and "non-depolarizing" as descriptions of the two main groups of myoneural blocking agents. Although these terms do not necessarily describe the mode of the neuromuscular block produced by these drugs, the non-depolarizing agents (with the possible exception of AH 8165 in the chick biventer cervicis muscle) do not cause depolarization of the postsynaptic membrane. The use of "dual block" to describe the events following the prolonged administration of depolarizing agents, in man, is considered confusing and the terms phase I and phase II block are to be preferred.

BRITISH JOURNAL OF ANAESTHESIA