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The Basics
The neuromuscular junction: Motor neurons and muscle cells are separated by the synaptic cleft. Depolarization of the motor neuron results in acetylcholine (ACh) release, which diffuses across the synaptic cleft and binds to nicotinic cholinergic receptors on the muscle cell. Each neuromuscular junction contains approximately 5 million of these receptors, but activation of only about 500,000 receptors is required for normal muscle contraction. ACh is metabolized by acetylcholinesterase.
Neuromuscular blocking agents are divided into two classes: depolarizing and nondepolarizing.
• Nondepolarizing muscle relaxants act as competitive antagonists. ACh receptors are bound 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.
• Depolarizing muscle relaxants 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.
° Phase I block: The end-plate cannot repolarize as long as the depolarizing muscle relaxant continues to bind to ACh receptors. This is phase I block.
° Phase II block: After a period of time, prolonged end-plate depolarization can cause ionic and conformational changes in the ACh receptor that clinically resembles that of nondepolarizing muscle relaxants. This is phase II block.
Disease States and Monitoring
Disease states can affect the neuromuscular junction.
• Muscle denervation: Stimulates a compensatory increase in the number of ACh receptors and promotes expression of extrajunctional ACh receptors, leading to exaggerated response to depolarizing muscle relaxants (with more receptors being depolarized) but a resistance to nondepolarizing relaxants (more receptors that must be blocked).
• Myasthenia gravis: Few ACh receptors lead to resistance to depolarizing relaxants and an increased sensitivity to nondepolarizing relaxants.
• Eaton-Lambert myasthenic syndrome: Decreased release of ACh.
Peripheral nerve stimulators are used to monitor neuromuscular function. Most commonly they are used for tetany (a sustained stimulus of 50–100 Hz) and train-of-four (a series of four twitches in 2 s).
• Fade, a gradual diminution of evoked response during prolonged or repeated nerve stimulation, is indicative of a nondepolarizing block. Adequate clinical recovery correlates well with the absence of fade.
• Phase I depolarization block does not exhibit fade during tetanus or train-of-four, and it does not demonstrate posttetanic potentiation. If enough depolarizer is administered, however, the quality of the block changes to resemble a nondepolarizing block (phase II block).
Succinylcholine
Mechanism of action: Depolarizing muscle relaxant, the only one in clinical use today.
Dosage: 1 to 1.5 mg/kg for intubation; can maintain with infusion or small repeated doses.
Onset: 30 to 60 seconds; typically lasts less than 10 minutes.
Mechanism of termination of action: Diffuses from neuromuscular junction, metabolized by pseudocholinesterase.
Prolonged by: Hypothermia (slightly prolonged); reduced pseudocholinesterase levels as found in pregnancy, liver disease, renal failure (2–20 minutes); abnormal pseudocholinesterase enzyme (heterozygous for atypical pseudocholinesterase results in 20 to 30-minute block, homozygous for atypical pseudocholinesterase results in 4- to 5-hour block).
Clinical note: Dibucaine inhibits normal pseudocholinesterase enzyme by 80% (the dibucaine number) and atypical pseudocholinesterase by 20%. Heterozygous individuals have a dibucaine number of 40% to 60%.
Structure: Two joined ACh molecules.
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