Neuromuscular Blocking Agents: Mechanism Of Action

Distinctions Between Depolarizing & Nondepolarizing Blockade

Neuromuscular blocking agents are divided into two classes: depolarizing and nondepolarizing (Table 11–1). This division reflects distinct dif-ferences in the mechanism of action, response to peripheral nerve stimulation, and reversal of block.

MECHANISM OF ACTION

Similar to ACh, all neuromuscular blocking agents are quaternary ammonium compounds whose positively charged nitrogen imparts an affinity to nicotinic ACh receptors. Whereas most agents have two quaternary ammonium atoms, a few have one quaternary ammonium cation and one tertiary amine that is protonated at physiological pH.

Depolarizing muscle relaxants very closely resemble ACh and readily bind to ACh receptors, generating a muscle action potential. Unlike ACh, however, these drugs are not metabolized by ace-tylcholinesterase, and their concentration in the synaptic cleft does not fall as rapidly, resulting in a prolonged depolarization of the muscle end-plate.

Continuous end-plate depolarization causes muscle relaxation because opening of perijunctional sodium channels is time limited (sodium channels rapidly “inactivate” with continuing depolarization) (Figure 11–3). After the initial excitation and open-ing (Figure 11–3B), these sodium channels inacti-vate (Figure 11–3C) and cannot reopen until the end-plate repolarizes. The end-plate cannot repolar-ize as long as the depolarizing muscle relaxant con-tinues to bind to ACh receptors; this is called a phase I block. After a period of time, prolonged end-plate depolarization can cause poorly understood changes in the ACh receptor that result in a phase II block, which clinically resembles that of nondepolarizing muscle relaxants.

Nondepolarizing muscle relaxants bind ACh receptors but are incapable of inducing the confor-mational change necessary for ion channel opening. Because ACh is prevented from binding to its recep-tors, no end-plate potential develops. Neuromuscular blockade occurs even if only one α subunit is blocked. Thus, depolarizing muscle relaxants act as ACh receptor agonists, whereas nondepolarizing muscle relaxants function as competitive antago-nists. This basic difference in mechanism of action explains their varying effects in certain disease states. For example, conditions associated with a chronic decrease in ACh release (eg, muscle denervation injuries) stimulate a compensatory increase in the number of ACh receptors within muscle membranes. These states also promote the expression of the imma-ture (extrajunctional) isoform of the ACh receptor, which displays low channel conductance properties and prolonged open-channel time. This up-regulation causes an exaggerated response to depolarizing mus-cle relaxants (with more receptors being depolarized), but a resistance to nondepolarizing relaxants (more receptors that must be blocked). In contrast, condi-tions associated with fewer ACh receptors (eg, down-regulation in myasthenia gravis) demonstrate a resistance to depolarizing relaxants and an increased sensitivity to nondepolarizing relaxants.