Desensitization Block

The acetylcholine receptor, because of its flexibility and the fluidity of the lipid around it, is capable of existing in a number of conformational states.^{[49] [52] [53] [54]} Because the resting receptor is free of agonist, its channel is closed. The second state exists when two molecules of agonists are bound to the α-subunit of the receptor, and the receptor has undergone the conformation change that opens the channel and allows ions to flow. These reactions are the bases of normal neuromuscular transmission. Some receptors that bind to agonists, however, do not undergo the conformation change to open the channel. Receptors in these states are called desensitized (i.e., they are not sensitive to the channel-opening actions of agonists). They bind agonists with exceptional avidity, but the binding does not result in the opening of the channel. The mechanisms by which desensitization occurs are not known. The receptor macromolecule, 1000 times larger by weight than most drugs or gases, provides many places at which the smaller molecules may act. The interface between lipid and receptor protein provides additional potential sites of reaction. Several different conformations of the protein are known, and because acetylcholine cannot cause the ion channel to open in any of them, they all are included in the functional term desensitization. Some evidence suggests that desensitization is accompanied by phosphorylation of a tyrosine unit in the receptor protein.^{[55] [56]}

Although agonists (e.g., succinylcholine) induce desensitization, the receptors are in a constant state of transition between resting and desensitized states whether agonists are present or not. Agonists to promote the transition to a desensitized state or, because they bind very tightly to desensitized receptors, trap a receptor in a desensitized state. Antagonists also bind tightly to desensitized receptors and can trap molecules in these states. This action of antagonists is not competitive with that of acetylcholine; it may be augmented by acetylcholine if the latter promotes the change to a desensitized state. Desensitization can lead to significant misinterpretations of data. Superficially, the preparation seems to be normal, but its responsiveness to agonists or antagonists is altered. One variety occurs very rapidly, within a few milliseconds after application of an agonist. This may explain the increased sensitivity to nondepolarizers after prior administration of succinylcholine. There also is the phenomenon caused by prolonged administration of depolarizing relaxants and known as phase II block (see "Phase II Block"). This frequently is referred to as a desensitization blockade but should not be, because desensitization of

870

Many other drugs used by anesthetists also promote the shift of receptors from a normal state to a desensitized state.^{[52] [53] [54]} These drugs, some of which are listed in Table 22-1 , can weaken neuromuscular transmission by reducing the margin of safety that normally exists at the neuromuscular junction, or they can cause an apparent increase in the capacity of nondepolarizing agents to block transmission. These actions are independent of the classic effects based on competitive inhibition of acetylcholine. The presence of desensitized receptors means that fewer receptor channels than usual are available to carry transmembrane current. The production of desensitized receptors decreases the efficacy of neuromuscular transmission. If many receptors are desensitized, insufficient normal ones are left to depolarize the motor end plate, and neuromuscular transmission will not occur. Even if only some receptors are desensitized, neuromuscular transmission will be impaired, and the system will be more susceptible to block by conventional antagonists such as tubocurarine or pancuronium.