On the Principles of Postsynaptic Action of Neuromuscular Blocking Agents

In this chapter, the evidence concerning the mechanism of postsynaptic action of neuromuscular blocking agents will be discussed. Although it could certainly be argued that the important facts about tubocurarine were all known long before the voltage clamp was invented, it could not be argued that the reasons for its behaviour were understood. The emphasis in this chapter will be on the fundamental molecular effects of the drugs, rather than on the phenomena which they are empirically observed to produce. These limitations on the scope of this chapter reduce considerably the work that will be dealt with in any detail, because the amount of knowledge about molecular mechanisms of action is surprisingly small. This statement may seem odd in view of the vast amount of work that has been done on the neuromuscular junction, and on drugs that affect it. But inspection of the literature soon reveals that almost all of this work is done by methods that are not capable of giving rigorous information about mechanisms. For example, a blocking drug is often described as “competitive” for no better reason than that it fails to produce a depolarization; indeed, even membrane potential often is not directly observed, so perhaps one should say that it fails to behave as though it were producing a depolarization. This sort of statement can surely not be defended by any pharmacologist as an adequate definition of what is meant by “competitive”. Similarly, the details of the mechanisms of action of those blockers that produce a depolarization have, with a few exceptions, yet to be investigated by modern electrophysiological methods.