The association between a motor neuron and a muscle cell occurs at the neuromuscular junction (Figure 8–1). The cell membranes of the neuron and muscle fiber are separated by a narrow (20-nm) gap, the synaptic cleft. As a nerve’s action potential depolarizes its terminal, an influx of calcium ions through voltage-gated calcium channels into the nerve cytoplasm allows storage vesicles to fuse with the terminal plasma membrane and release their contents (acetylcholine [ACh]). The ACh molecules diffuse across the synaptic cleft to bind with nicotinic cholinergic receptors on a specialized portion of the muscle membrane, the motor end-plate.
The neuromuscular junction. ACh, acetylcholine; AChE, acetylcholinesterase; JF, junctional folds. (Modified with permission from David A. Greenberg, Michael J. Aminoff, Roger P. Simon. Clinical Neurology, 9e. New York, NY: McGraw Hill; 2021.)
ACh is rapidly hydrolyzed into acetate and choline by the substrate-specific enzyme acetylcholinesterase. This enzyme is embedded into the motor end-plate membrane immediately adjacent to the ACh receptors. After unbinding ACh, the receptors’ ion channels close, permitting the end-plate to repolarize. Calcium is resequestered in the sarcoplasmic reticulum, and the muscle cell relaxes.
DISTINCTIONS BETWEEN DEPOLARIZING & NONDEPOLARIZING BLOCKADE
Neuromuscular blocking agents are divided into two classes: depolarizing and nondepolarizing. This division reflects distinct differences in the mechanism of action, response to peripheral nerve stimulation, and reversal of block.
Similar to ACh, all neuromuscular blocking agents are quaternary ammonium compounds whose positively charged nitrogen imparts an affinity for nicotinic ACh receptors. 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 acetylcholinesterase, 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 the opening of perijunctional sodium channels is time limited (sodium channels rapidly “inactivate” with continuing depolarization). After the initial excitation and opening, these sodium channels inactivate and cannot reopen until the end-plate repolarizes. The end-plate cannot repolarize as long as the depolarizing muscle relaxant continues to bind to ACh receptors; this is called a phase I block. More 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 conformational change necessary for ion channel opening. Because ACh is prevented from binding to its receptors, no end-plate potential develops. Neuromuscular blockade occurs even if only one α subunit is blocked.
Depolarizing muscle relaxants act as Ach receptor agonists, whereas nondepolarizing muscle relaxants function ...