C h a p t e r 1 8 Neuromuscular Physiology and Pharmacology

Abstract

• The neuromuscular junction contains the distal nerve terminal, synaptic cleft, and muscle end plate and provides an array of receptors and substrates for drug action. Neuromuscular transmission is predominately dependent on acetylcholine as the natural transmitter. Acetylcholine, when released from the prejunctional nerve terminal, binds to typical acetylcholine receptors (AChRs) that are present either prejunctionally or postjunctionally within the neuromuscular junction and, depending on their structural composition, are classified into the usual muscle subtype AChRs or a variety of neuronal subtype AChRs. • Muscle relaxants have multiple sites of action. Although the major actions occur by mechanisms and at sites described as agonistic and antagonistic actions at postjunctional receptors for depolarizing and nondepolarizing muscle relaxants (NDMRs), this description of neuromuscular drug action is a simplistic one. Neuromuscular transmission is impeded by NDMRs because they prevent access of acetylcholine to its preferred recognition site on the postjunctional nicotinic AChR. • If the concentration of NDMR is increased, another, noncompetitive action—block of the ion channel—is superimposed. The postjunctional paralytic effects of muscle relaxants can be enhanced by the actions of the relaxant on prejunctional AChRs, which modulate the release of acetylcholine. The latter can be documented as fade that occurs with increased frequency of stimulation. Fade can also be seen when the postjunctional AChRs alone are functionally blocked (e.g., by bungarotoxin) or when the number of AChRs (e.g., myasthenia gravis) is decreased. Hence, the neuromuscular junction is a complex and dynamic system in which the phenomena produced by drugs are composites of actions that vary with the drug, dose, activity at the nerve terminal and muscle, time after administration, presence of anesthetics or other drugs, and age and condition of the patient. • Inhibition of muscle acetylcholinesterase enzyme by anticholinesterases (e.g. neostigmine) increases the concentration of acetylcholine, which can compete with and displace the NDMRS and thus reverse the paralysis. These anticholinesterase drugs (e.g., neostigmine) also have other effects, including those on nerve terminals and on the receptor, by an allosteric mechanism. Acute bolus or prolonged administration of anticholinesterases can have deleterious effects on neuromuscular function in otherwise healthy patients. A modified cyclodextrin such as sugammadex is a novel and innovative class of compound that reverses paralysis of only steroidal muscle relaxants by encapsulation of this series of compounds. • Depolarizing compounds (e.g., succinylcholine) initially react with the acetylcholine recognition site and, like the transmitter, open AChR ion channels during depolarization of the end-plate membrane. Unlike the transmitter, they are not subject to hydrolysis by acetylcholinesterase and therefore remain in the junction. Soon after the administration of succinylcholine, some receptors are desensitized, and, although occupied by the agonist, they do not open to allow current to flow to depolarize the muscle membrane area. • If the depolarizing relaxant is applied in higher-than-usual concentrations or is allowed to remain at the junction for a long time, then other neuromuscular effects occur. Depolarizing relaxants have effects on prejunctional structures, and PART II: Anesthetic Physiology 424 Despite the fact that cholinergic neurotransmission in the neuromuscular junction is the most widely studied synapse within the nervous system, complete knowledge of its workings has not yet been achieved. This is an area of continuing interest for many researchers worldwide. The physiology of neuromuscular transmission could be analyzed and understood at the most simple level by using the classic model of nerve signaling to muscle through the acetylcholine receptor (AChR). The mamma-lian neuromuscular junction is the prototypical and most extensively studied synapse. Research has provided more detailed information on processes that, within the clas-sic scheme, can modify neurotransmission and response to drugs. One example is the role of qualitative or quan-titative changes in AChRs that modify neurotransmis-sion and the response to drugs. 1-3 In myasthenia gravis, for example, the decrease in AChRs results in decreased efficiency of neurotransmission (and therefore muscle weakness) 4 and altered sensitivity to neuromuscular relaxants. 3 Another example is the importance of nerve-related (prejunctional) changes that alter neurotransmis-sion and the response to anesthetic drugs. 5-7 Yet, muscle relaxants act in ways that are not encompassed by the classic scheme of a unitary site of action. The observa-tion that muscle relaxants can have prejunctional effects 5 or that some nondepolarizing muscle relaxants (NDMRs) can also have agonist-like stimulatory actions on the receptor, 8 whereas others have effects not explainable by purely postsynaptic actions on muscle, 9-11 has provided new insight into some previously unexplained obser-vations. Although muscle relaxants are known to have effects on the presynaptic and postsynaptic receptors of the neuromuscular junction, recent evidence indi-cates that they can react with nicotinic and muscarinic AChRs other than those in muscle, including receptors on the carotid sinus, on the vagus to the heart, and on bronchial smooth muscle. 9-13 Although this multifac-eted action-response scheme makes the physiologic and