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Chapter: Modern Pharmacology with Clinical Applications: Local Anesthetics

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Neuromuscular Blocking Agents

Depolarizing Blocker (Succinylcholine), Nondepolarizing Blockers: d-Tubocurarine, Atracurium, Mivacurium, Pancuronium, Vecuronium, Rocuronium, and Rapacuronium

NEUROMUSCULAR BLOCKING AGENTS

Depolarizing Blocker (Succinylcholine)

Succinylcholine chloride (Anectine) is the only depolar-izing-type blocker that is in widespread clinical use. It produces neuromuscular block by overstimulation, so that the end plate is unable to respond to further stimula-tion. Structurally, succinylcholine is equivalent to two ACh molecules joined back to back. The resulting 10-carbon atom spacing between the two quaternary am-monium heads is important for activation of the two binding sites on the AChR. Because the succinylcholine molecule is “thin,” binding to the two sites does not ster-ically occlude the open channel, and cations are allowed to flow and depolarize the end plate.

Neuromuscular block with succinylcholine occurs by two sequential events. An initial depolarization of the end plate produces muscle action potentials and fasciculation. Maintained depolarization past the threshold for firing produces NA+ channel inactivation, so that muscle action potentials cannot be generated. This is called phase I, or depolarization block. In the continued presence of succinylcholine, the membrane becomes repolarized, NA+ channel inactivation is re-versed, and muscle membrane excitability is restored. Nonetheless, the neuromuscular block persists because of desensitization of the AChR. This is known as phase II, or desensitization block.

Although the mechanism for phase II block is not completely understood, a series of allosteric transitions in the AChR is suspected. One model to describe this has the AChR in equilibrium among four conforma-tions: resting, active, inactive, and desensitized. Agonists stabilize the active and desensitized states, whereas an-tagonists tend to stabilize the resting and possibly the desensitized state.

Absorption, Metabolism, and Excretion

Succinylcholine is given systemically because the mole-cule is charged and does not easily cross membranes. It is rapidly hydrolyzed by plasma cholinesterase to succinyl-monocholine, which is pharmacologically inactive. Be-cause plasma cholinesterase is synthesized in the liver, neuromuscular block may be prolonged in patients with liver disease. About 10% of succinylcholine is excreted unchanged in the urine. The response to succinylcholine may also be prolonged in individuals with a genetic defect leading to atypical plasma cholinesterase (homozygous incidence of about 1 in 2,500). In this case, the enzyme has a decreased affinity for substrates such as succinylcholine that can be measured by the dibucaine test.

Pharmacological Actions

Succinylcholine acts primarily at the skeletal neuromus-cular junction and has little effect at autonomic ganglia or at postganglionic cholinergic (muscarinic) junctions. Actions at these sites attributed to succinylcholine may arise from the effects of choline. Succinylcholine has no direct action on the uterus or other smooth muscle structures. It does not enter the CNS and does not cross the placental barrier. It may, however, release histamine from mast cells. Because succinylcholine works by stim-ulating rather than blocking end plate receptors, anti-AChEs will not reverse muscle paralysis and may actu-ally prolong the block.

Clinical Uses

The principal advantage of succinylcholine is its rapid and ultra-short action. With intravenous (IV) adminis-tration, succinylcholine produces flaccid paralysis that occurs in less than 1 minute and lasts about 10 minutes. This makes it suitable for short-term procedures, such as endotracheal intubation, setting of fractures, and pre- vention of injury during electroconvulsive therapy. Apart from its rapid onset and brief action, succinyl-choline has few benefits and many disadvantages.

Adverse Effects and Contraindications

Succinylcholine produces muscle fasciculation, which may result in myoglobinuria and postoperative muscle pain. The amount produced depends on the level of physical fitness. Succinylcholine causes contractions of extraocular muscles, posing the danger of transient ele-vated intraocular pressure. Succinylcholine may pro-duce hyperkalemia in patients with large masses of traumatized or denervated muscle (e.g., spinal cord in-jury). Denervated muscle is especially sensitive to de-polarizing drugs because of the increased number of AChRs on the sarcolemma (denervation supersensitiv-ity). Succinylcholine also causes prolonged contraction of the diseased muscles of patients with myotonia or amyotrophic lateral sclerosis.

Succinylcholine-induced hyperkalemia may lead to cardiac arrhythmia and arrest when plasma K+ reaches 7 and 10 mM, respectively. The drug also may precipi-tate a fulminant attack of malignant hyperthermia in susceptible individuals (not to be confused with neu-roleptic malignant hyperpyrexia, which involves do-pamine and the CNS). Treatment in either case consists of cooling the body and administering oxygen and dantrolene sodium (discussed later).

Nondepolarizing Blockers: d-Tubocurarine, Atracurium, Mivacurium, Pancuronium, Vecuronium, Rocuronium, and Rapacuronium

Mechanism of Action

With the exception of succinylcholine, all neuromuscular blocking agents are nondepolarizing. These agents pre-vent excitation of end plate AChRs by acting as re-versible competitive antagonists at the binding sites. The prototype for this group is d-tubocurarine, an alka-loid used as a South American arrow poison. In general, these compounds have two charged heads (e.g., quater-nary ammonium) separated by a “thick” organic moiety (e.g., steroid nucleus). These heads enable attachment of the drug to the two AChR binding sites. However, be-cause of the large intervening moiety, the channel is oc-cluded such that the flow of cations is prevented. Because of the competitive nature of this blockade, the effect of nondepolarizing blockers can be reversed by anti-AChE agents and other procedures that increase the synaptic concentration of ACh.

Pharmacological Actions

d-Tubocurarine blocks nicotinic AChRs in muscle end plates and autonomic ganglia but has no effect on muscarinic AChRs. It does not affect nerve or muscle ex-citability or conduction of action potentials. Because it is charged, it penetrates cells poorly and does not enter the CNS. However, if applied directly to brain or spinal cord, it will block nicotinic AChR in those tissues. In hu-mans, d-tubocurarine has a moderate onset of action (3-4 minutes) followed by progressive flaccid paralysis. The head and neck muscles are affected initially, then the limb muscles, and finally the muscles of respiration. Recovery from paralysis is in the reverse order.

Clinical Uses

Nondepolarizing blockers are used to relax skeletal muscle for surgical procedures, to prevent dislocations and fractures associated with electroconvulsive therapy, and to control muscle spasms in tetanus. They do not produce anesthesia or analgesia.

The degree of blockade can be influenced by body pH and electrolyte balance. Hypokalemia due to diar-rhea, renal disease, or use of potassium-depleting di-uretics potentiates the effect of nondepolarizing block-ers. By contrast, hyperkalemia may oppose the actions of d-tubocurarine but enhance the end plate response to succinylcholine. The effectiveness of d-tubocurarine is reduced by alkalosis.

Newborn children are extremely sensitive to nonde-polarizing muscle relaxants but may require three times as much depolarizing agent as an adult for an equiva-lent degree of block. Like newborn children, patients with myasthenia gravis are very sensitive to paralysis by d-tubocurarine but are resistant to succinylcholine. This altered responsiveness is probably due to the fewer number of functional AChRs at the end plate. Since neonates are very sensitive to d-tubocurarine, the dosage must be reduced and the degree of block closely monitored.

Adverse Effects and Precautions

d-Tubocurarine may cause bronchospasms and hy-potension by release of histamine from mast cells. This may be counteracted by prior treatment with antihista-mines. d-Tubocurarine produces partial block of sympa-thetic ganglia and the adrenal medulla, which may also contribute to hypotension.

Inhalation anesthetics, such as isoflurane, enflurane, halothane, and nitrous oxide, potentiate the action of nondepolarizing blockers, either through modification of end plate responsiveness or by alteration of local blood flow. The extent of potentiation depends on the anesthetic and the depth of anesthesia. The dose of muscle relaxant should be reduced when used with these anesthetics.

Certain antibiotics (e.g., aminoglycosides, macrolides, polymyxins, lincomycin) enhance neuromuscular block-ade by either decreasing ACh release or blocking thepostjunctional response. Procainamide and phenytoin also increase the effects of d-tubocurarine-like drugs.The amount of neuromuscular blocker should be decreased accordingly.

Other Nondepolarizing Blockers of Importance

Atracurium besylate (Tracrium) is a benzylisoquinolin-ium compound like d-tubocurarine. Its actions are simi-lar to those of d-tubocurarine, but its duration of action is shorter (45 minutes) because of spontaneous degra-dation of the molecule (Hofmann elimination). Because of this, atracurium is useful in patients with low or atyp-ical plasma cholinesterase and in patients with renal or hepatic impairment.

Mivacurium chloride (Mivacron) is a newer agent that is chemically related to atracurium. The primary mechanism of inactivation is hydrolysis by plasma cholinesterase. Although it is useful for patients with renal or hepatic disease, some caution is warranted, since these individuals may have reduced plasma cholinesterase as a result of the disease. Mivacurium has an onset of action (1.8 minutes) and duration of effect (20 minutes) only twice that of succinylcholine, and in this respect, it is the most similar to succinylcholine of all of the nondepolarizing agents.

Pancuronium bromide (Pavulon) is a synthetic bis-quaternary agent containing a steroid nucleus (amino steroid), as denoted by the -curonium suffix. It is five times as potent as d-tubocurarine. Unlike d-tubocu-rarine, it does not release histamine or block ganglionic transmission. Like d-tubocurarine, it has a moderately long onset (2.9 minutes) and duration of action (110 minutes). Pancuronium and its metabolite are elimi-nated in the urine.

Vecuronium bromide (Norcuron) is chemically identical to pancuronium except for a tertiary amine in place of a quaternary nitrogen. However, some of the drug will exist as the bisquaternary compound, depend-ing on body pH. Vecuronium has a moderate onset of action (2.4 minutes) and a duration of effect of about 50 minutes. Like pancuronium, it does not block ganglia or vagal neuroeffector junctions, does not release hista-mine, and is eliminated by urinary excretion.

Rocuronium bromide (Zemuron) is a recently ap-proved amino steroid neuromuscular blocking agent. It has a rapid onset of action (1 minute), but its duration of action is intermediate (55 minutes), about that of ve-curonium. On rare occasions, it may release histamine and cause cardiac irregularities. Rapacuronium bromide (Raplon) is the most recent neuromuscular blocking agent approved by the United States Food and Drug Administration (FDA). It is an analogue of vecuronium and is thus categorized as an amino steroid. It has a rapid onset of action (1.5 minutes) and a short to intermediate duration of action (20 minutes). This makes it a suitable alternative to mivacurium or succinylcholine for short procedures. It is eliminated mainly by the liver. Adverse effects are dose dependent; they include tachycardia, hy-potension, and bronchospasm. These effects may be re-lated to the ability of the drug to release a small amount of histamine.

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