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Neuromuscular Blocking Agents


The peripherally acting skeletal muscle relaxants characteristically interfere with the transmission of impulses from motor nerves to skeletal muscle fibers at the neuromuscular junction, thus reducing or abolishing motor activity. The skeletal muscle paralysis that ensues is not associated with depression of the CNS. Animals are fully conscious throughout the period of immobilization unless an anesthetic or hypnotic agent is administered concurrently.

Neuromuscular transmission can be modified either at the axonal membrane (prejunctional blockade) or at the cholinergic receptors in the sarcolemma (postjunctional blockade).

There are no clinically useful drugs that act prejunctionally, but a number of important substances can impair the synthesis, storage, and release of acetylcholine, thus resulting in prejunctional blockade at the motor endplate and consequently paralysis. Examples of prejunctional blocking agents include biotoxins, electrolytes, local anesthetics or other drugs, and antibiotics. Biotoxins include black widow spider venom, which depletes acetylcholine stores; botulinum toxin, which decreases acetylcholine release; tetradotoxin from the puffer fish and saxitoxin from shellfish, which block Na+-conducting channels; and grayanotoxin found in rhododendrons, which facilitates excessive Na+ entry through the sarcolemma, leading to constant depolarization of the membrane. Electrolytes include excess Mg2+, which inhibits release of acetylcholine from the axon and uncouples the excitation-contraction process by competing with Ca2+; and depleted Ca2+ levels, which decrease release of acetylcholine and impairment of excitation-contraction coupling. Local anesthetics in high concentration can stabilize membranes by blocking both Na+ and K+ channels; hemicholinium can inhibit synthesis of acetylcholine by blocking choline uptake into the nerve. Antibiotics, such as the aminoglycosides, polymyxins, tetracyclines, and lincosamides, appear to act by decreasing the availability of Ca2+ at membrane-binding sites on the axonal terminal and perhaps by reducing the sensitivity of the nicotinic receptors to acetylcholine.

Postjunctional blocking agents are used clinically and act either by blocking the nicotinic receptors in a competitive fashion (nondepolarizing agents) or by interacting with these receptors in a manner that does not allow the membrane to repolarize so that paralysis results (depolarizing agents). The mechanisms involved in the latter case are not fully understood. All of the neuromuscular blocking agents are structurally similar to acetylcholine (actually two molecules linked end-to-end). The depolarizing agents are usually simple linear structures, and the nondepolarizing agents are more complex bulky molecules. With a single exception (vecuronium), all have a quaternary nitrogen in their structure, which makes these drugs poorly lipid soluble.

The members of this group of peripherally acting skeletal muscle relaxants are often referred to as curarizing agents because of their relationships with the curare alkaloids that were first used clinically. The currently available drugs, which interact with nicotinic cholinergic receptors on skeletal muscle cells and render them inaccessible to the transmitter function of acetylcholine (and thus produce a flaccid paralysis) include tubocurarine, metocurine (dimethyltubocurarine), gallamine, pancuronium, alcuronium, atracurium, vecuronium, and fazadinium.

In general, nondepolarizing muscle relaxants are not absorbed from the GI tract and must be administered parenterally, usually IV. Plasma-protein binding is insignificant, and there is rapid equilibration but only within the extracellular fluid. The blood-brain and blood-placental barriers are rarely crossed. Tubocurarine, metocurine, and gallamine are not biotransformed to any extent and are excreted unchanged, principally in the urine but sometimes in bile. The other members of the group undergo metabolic transformation to some degree, and the metabolites are excreted by both renal and biliary routes in most instances. The elimination half-lives at standard dosages are 60–100 min, and the duration of paralysis is 30–60 min, except in the case of atracurium and vecuronium, which have shorter actions of ~20–30 min.

After IV administration of these agents, the skeletal muscles become totally flaccid and nonresponsive to neuronal stimulation. Muscles capable of rapid movement, such as those of the eye, are paralyzed before the larger muscles of the head and neck, which are followed by those of the limbs and body. Lastly, the diaphragm becomes paralyzed, and respiration ceases. If ventilation is controlled (tracheal intubation and positive-pressure ventilation), there are no adverse effects, and full recovery ensues in reverse order, with the diaphragm regaining function first. All of the currently used nondepolarizing muscle relaxants have cardiovascular effects, many of which are mediated by autonomic and histamine receptors. Tubocurarine and, to a much lesser extent, metocurine result in hypotension, which probably results from the liberation of histamine and, in larger doses, from ganglionic blockade. Premedication with an antihistamine reduces tubocurarine-induced hypotension. Pancuronium causes a moderate increase in heart rate and, to a lesser degree, cardiac output. Gallamine increases heart rate by both a vagolytic action and sympathetic stimulation.

A number of agents can potentiate the activity of neuromuscular blockers. These include other peripherally acting skeletal muscle relaxants, inhalant anesthetics (halothane, methoxyflurane), antibiotics (aminoglycosides, polymyxins, tetracyclines, and lincosamides), and various other drugs (quinidine, procaine, lidocaine, diazepam, and barbiturates). Several states, such as hyper- and hypomagnesemia, hypokalemia, acidosis, and hypothermia, also prolong the action of this group of drugs. Animals with myasthenia gravis are much more susceptible to the action of muscle relaxants.

Indications for the use of nondepolarizing neuromuscular blocking agents include muscle relaxation of the operative field, hypoxemic animals resisting mechanical ventilation, tracheal intubation, animals with unstable cardiovascular function that require anesthesia but cannot tolerate cardiac depression, cesarean section in toxic or high-risk animals, epileptiform convulsions not controllable with usual anticonvulsant agents, tetanus, strychnine poisoning, shivering animals in which the metabolic demand for oxygen should be reduced, and capture of certain exotic species (eg, gallamine used for immobilization of crocodiles). Animals should always be carefully monitored when under the influence of neuromuscular blocking drugs, and support of ventilation is essential.

The action of the competitive relaxants can be reversed by anticholinesterase drugs, especially neostigmine, after the administration of atropine, which eliminates excessive muscarinic responses. This attribute is a great advantage for this group of peripherally acting muscle relaxants.

The selection of dose rates (see Table: Competitive Nondepolarizing Agents and AntagonistsTables) serves only as general guidelines for the use of competitive blocking agents.

Table 1

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Succinylcholine (suxamethonium) is the only commonly used, peripherally acting muscle relaxant that is a depolarizing agent. Decamethonium, the other member of the group, is rarely used clinically.

Depolarizing blocking drugs occupy the postjunctional cholinergic receptors and, by mechanisms that remain obscure, elicit prolonged depolarization of the endplate region. This prevents the synaptic membrane from completely repolarizing, thus rendering the motor endplate unresponsive to the normal action of acetylcholine. Characteristically, succinylcholine elicits transient muscle fasciculations before causing neuromuscular paralysis. The onset of action of succinylcholine is rapid after IV injection (20–50 sec), and the duration of the effect is usually 5–10 min in most species. Succinylcholine is rapidly hydrolyzed by pseudocholinesterases in the plasma and liver in most species, but substantial genetic differences exist.

Other pharmacologic effects are associated with the depolarizing muscle relaxants. After IV administration of succinylcholine, transient muscle fasciculations are usually evident, although general anesthesia tends to attenuate them. Succinylcholine-induced cardiac arrhythmias are many and varied. Succinylcholine stimulates all autonomic cholinergic receptors—both nicotinic and muscarinic. Sudden hyperkalemia may be precipitated by succinylcholine, and muscle pain is seen with the use of succinylcholine in the absence of anesthesia. After recovery from succinylcholine-induced muscle paralysis, muscle damage and even myoglobinuria can develop. Malignant hyperthermia (see Malignant Hyperthermia) or clinical signs related to this syndrome may also follow the use of succinylcholine in susceptible animals.

Factors that can alter the activity of competitive blocking agents (see Competitive Nondepolarizing Agents) can also affect the action of succinylcholine. In addition, previous (within 1 mo) or concurrent use of organophosphate anthelmintics or external parasiticides can have a significant impact on the recovery time from succinylcholine immobilization because of prolonged inhibition of the pseudocholinesterase enzyme systems. A genetically mediated deficiency of pseudocholinesterases also has been identified in certain strains of sheep. Cattle are much more susceptible to the effects of succinylcholine than other species.

The indications for the clinical use of succinylcholine are similar to those for the nondepolarizing agents. However, it must be emphasized that succinylcholine should never be used as an agent for euthanasia or for immobilization for castration without local or general analgesia. The use of succinylcholine for game-cropping procedures is also highly undesirable.

No antagonists are available to reverse the action of the depolarizing muscle relaxants. Continued positive-pressure ventilation until recovery occurs is the only therapy in cases of overdosage.

The IV dose rates for succinylcholine by species are as follows: horses: 0.125–0.20 mg/kg (~8 min recumbency); cattle: 0.012–0.02 mg/kg (~15 min recumbency); dogs: 0.22–1.1 mg/kg (~15–20 min paralysis); and cats: 0.22–1.1 mg/kg (~3–5 min paralysis).

Last full review/revision March 2015 by Patricia M. Dowling, DVM, MSc, DACVIM, DACVCP

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