Neuromuscular Blocking Agents
Skeletal muscle relaxation can be produced by deep inhalational anesthesia, regional nerve block, or neuromuscular blocking agents (commonly called muscle relaxants). In 1942, Harold Griffith pub-lished the results of a study using an extract of cu-rare (a South American arrow poison) during anes-thesia. Following the introduction of succinylcholine as a “new approach to muscular relaxation,” these agents rapidly became a routine part of the anesthe-siologist’s drug arsenal. However, as noted by Beecher and Todd in 1954: “[m]uscle relaxants giv-en inappropriately may provide the surgeon with optimal [operating] conditions in . . . a patient [who] is paralyzed but not anesthetized—a state [that] is wholly unacceptable for the patient.” In other words, muscle relaxation does not ensure un- consciousness, amnesia, or analgesia.
Association between a motor neuron and a mus-cle cell occurs at the neuromuscular junction (Figure 11–1). 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 depo-larizes its terminal, an influx of calcium ions through voltage-gated calcium channels into the nerve cyto-plasm allows storage vesicles to fuse with the ter-minal plasma membrane and release their contents
(acetylcholine [ACh]). The ACh molecules diffuse across the synaptic cleft to bind with nicotinic cholin-ergic receptors on a specialized portion of the muscle membrane, the motor end-plate. Each neuromuscu-lar junction contains approximately 5 million of these receptors, but activation of only about 500,000 recep-tors is required for normal muscle contraction.
The structure of ACh receptors varies in differ-ent tissues and at different times in development. Each ACh receptor in the neuromuscular junction normally consists of five protein subunits; two α subunits; and single β, δ, and ε subunits. Only the two identical α subunits are capable of binding ACh molecules. If both binding sites are occupied by ACh, a conformational change in the subunits briefly (1 ms) opens an ion channel in the core of the recep-tor (Figure 11–2). The channel will not open if ACh binds on only one site. In contrast to the normal (ormature) junctional ACh receptor, another isoform contains a γ subunit instead of the ε subunit. This isoform is referred to as the fetal or immature recep-tor because it is in the form initially expressed in fetal muscle. It is also often referred to as extrajunc-tional because, unlike the mature isoform, it may be located anywhere in the muscle membrane, inside or outside the neuromuscular junction when expressed in adults.
Cations flow through the open ACh receptor channel (sodium and calcium in; potassium out), generating an end-plate potential. The contents of a single vesicle, a quantum of ACh (104 molecules per quantum), produce a miniature end-plate potential. The number of quanta released by each nerve impulse, normally at least 200, is very sensi-tive to extracellular ionized calcium concentration; increasing calcium concentration increases the
number of quanta released. When enough recep-tors are occupied by ACh, the end-plate potential will be sufficiently strong to depolarize the perijunc-tional membrane. Voltage-gated sodium channels within this portion of the muscle membrane open when a threshold voltage is developed across them, as opposed to end-plate receptors that open when ACh is applied ( Figure 11–3). Perijunctional areas of muscle membrane have a higher density of these sodium channels than other parts of the membrane. The resulting action potential propagates along the muscle membrane and T-tubule system, opening sodium channels and releasing calcium from the sarcoplasmic reticulum. This intracellular calcium allows the contractile proteins actin and myosin to interact, bringing about muscle contraction. The
amount of ACh released and the number of recep-tors subsequently activated will normally far exceed the minimum required for the initiation of an action potential. The nearly 10-fold margin of safety is lost in Eaton–Lambert myasthenic syndrome (decreased release of ACh) and myasthenia gravis (decreased number of receptors).
ACh is rapidly hydrolyzed into acetate and choline by the substrate-specific enzyme acetylcho-linesterase. This enzyme (also called specific cholin-esterase or true cholinesterase) is embedded into the motor end-plate membrane immediately adjacent to the ACh receptors. After unbinding ACh, the recep-tors’ ion channels close, permitting the end-plate to repolarize. Calcium is resequestered in the sarco-plasmic reticulum, and the muscle cell relaxes.
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