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The drugs in this chapter are divided into 2 dissimilar groups. The neuromuscular blocking drugs, which act at the skeletal myoneural junction, are used to produce muscle paralysis to facilitate surgery or assisted ventilation. The spasmolytic drugs, most of which act in the CNS, are used to reduce abnormally elevated tone caused by neurologic or muscle end plate disease.
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NEUROMUSCULAR BLOCKING DRUGS
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A. Classification and Prototypes
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Skeletal muscle contraction is evoked by a nicotinic cholinergic transmission process. Blockade of transmission at the end plate (the postsynaptic structure bearing the nicotinic receptors) is clinically useful in producing muscle relaxation, a requirement for surgical relaxation, tracheal intubation, and control of ventilation. The neuromuscular blockers are quaternary amines structurally related to acetylcholine (ACh). Most are antagonists (nondepolarizing type), and the prototype is tubocurarine. One neuromuscular blocker used clinically, succinylcholine, is an agonist at the nicotinic end plate receptor (depolarizing type).
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B. Nondepolarizing Neuromuscular Blocking Drugs
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All agents are given parenterally. They are highly polar drugs and do not cross the blood-brain barrier. Drugs that are metabolized (eg, mivacurium, withdrawn in the USA) or eliminated in the bile (eg, rocuronium) have shorter durations of action (10–20 min) than those eliminated by the kidney (eg, metocurine, pancuronium, pipecuronium, and tubocurarine) which usually have durations of action of 35–60 min. In addition to hepatic metabolism, atracurium clearance involves rapid spontaneous breakdown (Hofmann elimination) to form laudanosine and other products. At high blood levels, laudanosine may cause seizures. Cisatracurium, a stereoisomer of atracurium, is also inactivated spontaneously but forms less laudanosine and currently is one of the most commonly used muscle relaxants in clinical practice.
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2. Mechanism of action
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Nondepolarizing drugs prevent the action of ACh at the skeletal muscle end plate (Figure 27–1). They act as surmountable blockers. (That is, the blockade can be overcome by increasing the amount of agonist [ACh] in the synaptic cleft.) They behave as though they compete with ACh at the receptor, and their effect is reversed by cholinesterase inhibitors. Some ...