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FIGURE 9-1 Subunit organization of the nicotinic ACh receptor and relatedpentameric ligand-gated ion channels.

For each subunit (MW -40-60 kDa), the amino terminal region (~210 amino acids) is at the extracellular surface, followed by 4 transmembrane domains (TM^TM^), with a small carboxyl terminus at the extracellular surface. Five subunits aggregate to form the receptor/pore/ion channel; the a-helical TM2 regions from each subunit of the pentameric receptor line the internal pore of the receptor. One disulfide motif is conserved throughout the family of receptors.

FIGURE 9-1 Subunit organization of the nicotinic ACh receptor and relatedpentameric ligand-gated ion channels.

For each subunit (MW -40-60 kDa), the amino terminal region (~210 amino acids) is at the extracellular surface, followed by 4 transmembrane domains (TM^TM^), with a small carboxyl terminus at the extracellular surface. Five subunits aggregate to form the receptor/pore/ion channel; the a-helical TM2 regions from each subunit of the pentameric receptor line the internal pore of the receptor. One disulfide motif is conserved throughout the family of receptors.

plate (an end plate depolarized from -80 to -55 mV by a depolarizing blocking agent is resistant to further depolarization by ACh). The exact sequence from fasciculations to paralysis is influenced by such factors as the anesthetic agent used concurrently, the type of muscle, and the rate of drug adminis- tration. The characteristics of depolarization and competitive blockade are contrasted in Table 9-2.

SEQUENCE AND CHARACTERISTICS OF PARALYSIS Following intravenous administration of an appropriate dose of a competitive antagonist, motor weakness progresses to a total flaccid paralysis. Small, rapidly moving muscles (e.g., those of the eyes, jaw, and larynx) relax before those of the limbs and trunk. Ultimately, intercostal muscles and finally the diaphragm are paralyzed, and respiration then ceases. Recovery of muscles usually occurs in the reverse order to that of their paralysis, and thus the diaphragm ordinarily is the first muscle to regain function.

After a single intravenous dose of 10-30 mg of a depolarizing agent such as succinylcholine, muscle fasciculations, particularly over the chest and abdomen, occur briefly; relaxation occurs within 1 minute, becomes maximal within 2 minutes, and generally disappears within 5 minutes. Transient apnea usually occurs at the time of maximal effect. Muscle relaxation of longer duration is achieved by continuous intravenous infusion. After infusion is discontinued, the effects of the drug usually disappear rapidly because of its rapid hydrolysis by plasma and hepatic butyryl-cholinesterase. Muscle soreness may follow the administration of succinylcholine. Small prior doses of competitive blocking agents have been employed to minimize fasciculations and muscle pain caused by succinylcholine, but this procedure is controversial because it increases the requirement for the depolarizing drug.

During prolonged depolarization, muscle cells may lose significant quantities of K+ and gain Na+, Cl-, and Ca2+. In patients in whom there has been extensive injury to soft tissues, the efflux of K+ following continued administration of succinylcholine can be life-threatening. Thus, there are many conditions for which succinylcholine administration is contraindicated or should be undertaken with great caution. Under clinical conditions, with increasing concentrations of succinylcholine and over time, the block may convert slowly from a depolarizing to a nondepolarizing type (termed phase I and phase II blocks). This change in the nature of the blockade produced by succinylcholine (from phase I to phase II) presents an additional complication with long-term infusions (see Table 9-3).

Central Nervous System

Tubocurarine and other quaternary neuromuscular blocking agents are virtually devoid of central effects following ordinary clinical doses because of their inability to penetrate the blood—brain barrier.

AUTONOMIC GANGLIA AND MUSCARINIC SITES Neuromuscular blocking agents show variable potencies in producing ganglionic blockade. Clinical doses of tubocurarine produce partial blockade both at autonomic ganglia and at the adrenal medulla, resulting in a fall in blood pressure and tachycardia. Pancuronium shows less ganglionic blockade at standard clinical doses.

Competitive Agents

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