ANTAGONISM OF NEUROMUSCULAR BLOCK

Mechanism of Antagonism

The nondepolarizing relaxants block (see Chapter 13 ) neuromuscular transmission predominantly by competitive antagonism of acetylcholine at the postjunctional receptor. The most straightforward way to overcome their effects is to increase the competitive position of acetylcholine. Two factors are important, the first of which is the concentration of acetylcholine. Increasing the number of molecules of acetylcholine in the junctional cleft changes the agonist-to-antagonist ratio and increases the probability that agonist molecules will occupy the recognition sites of the receptor. It also increases the probability that an unoccupied receptor will become occupied. Normally, only about 500,000 of the 5 million available receptors are activated by a single nerve impulse, and a large number of receptors is in "reserve" and could be occupied by an agonist. The second factor important to the competitive position of acetylcholine is the length of time acetylcholine is in the cleft. Acetylcholine must wait for the antagonist to dissociate spontaneously before it can compete for the freed site. The nondepolarizing relaxants bind to the receptor for slightly less than 1 millisecond, which is longer than the normal lifetime of acetylcholine. The destruction of acetylcholine normally takes place so quickly that most of it is destroyed before any significant number of antagonist molecules have dissociated from the receptor. Prolonging the time during which acetylcholine is in the junction allows time for the available acetylcholine to bind to receptor when the antagonist dissociates from the receptors.