Neuromuscular Blockade - Neuromuscular Junction
The NMJ (Fig. 13.1) is a chemical synapse located in the peripheral nervous system. The NMJ is composed of the neuronal presynaptic terminal, where acetylcholine (ACh) is stored in specialized organelles known as synaptic vesicles, and the postsynaptic muscle cell (motor endplate), where high densities (up to 10,000/μm2 at the synapse) of the nicotinic AChRs are found.
voltage-dependent calcium channels
In response to an action potential in the nerve, voltage-dependent calcium channels, which are highly concentrated in close proximity to synaptic vesicles, open and cause a rapid influx of calcium into the nerve terminal increasing its intracellular concentrations to approximately 100 μM. This influx of calcium lasts only about 0.5 milliseconds but is sufficient enough to induce fusion of synaptic vesicles with the plasma membrane to release stored ACh. ACh then diffuses across the synaptic cleft where two molecules of ACh bind to a single nicotinic AChR.
Postjunctional nicotinic AChRs
Postjunctional nicotinic AChRs are glycoproteins composed of five subunits (two α and one each of β, δ, and ε) with the two α-subunits constituting the binding sites for ACh and NMBDs. When two molecules of ACh are bound, the AChR undergoes a conformational change (activation) that allows influx of sodium and calcium into the muscle cell to depolarize the membrane and causes contraction. Once depolarization occurs, repolarization begins with the efflux of potassium and the cessation of sodium and calcium entry. At this point, the AChR becomes inactivated. The amount of ACh released and the number of postsynaptic AChRs is much greater than that actually needed to induce contraction. This is termed the “safety factor” for neuromuscular transmission and plays a crucial role in certain pathologic conditions. After triggering depolarization, ACh diffuses into the synaptic cleft where it is rapidly hydrolyzed (within 15 milliseconds) by acetylcholinesterase (AChE) into choline and acetate. Choline is subsequently recycled to synthesize new ACh in the motor nerve terminal.
Prejunctional nicotinic AChRs
Prejunctional nicotinic AChRs are located on the presynaptic nerve terminal and are responsible for augmenting depolarization of the nerve terminal during high frequency stimulation, thereby enhancing ACh release. Antagonism of these receptors by nondepolarizing NMBDs is the mechanism by which these agents produce fade on the train of four (TOF).