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).
A number of important substances can impair the synthesis, storage, and release of acetylcholine, resulting in prejunctional blockade at the motor endplate and consequently muscular paralysis. Examples of prejunctional blocking agents include biotoxins, electrolytes, local anesthetics or other drugs, and some antimicrobials.
Biotoxins include: black widow spider venom, which depletes acetylcholine stores; botulinum toxin, which decreases acetylcholine release; tetrodotoxin 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 impair 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.
Antimicrobials, such as the aminoglycosides (eg, gentamicin), polymyxins, tetracyclines, and lincosamides, appear to act by decreasing the availability of Ca2+ at membrane-binding sites on the axonal terminal and/or by reducing the sensitivity of the nicotinic receptors to acetylcholine.
Neuromuscular blocking agents (NMBAs) are either depolarizing (eg, succinylcholine) or nondepolarizing (eg, atracurium). NMBAs used to induce neuromuscular blockade must be chosen carefully, taking into account clinical indications, patient factors, and the procedure being performed.
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. Competitive nondepolarizing NMBAs are competitive acetylcholine (ACh) antagonists that directly bind to postsynaptic nicotinic receptors. This prevents ACh from binding to the receptor and prevents the motor endplate from depolarizing, resulting in muscle paralysis. Based on their chemical structure, competitive nondepolarizing NMBAs are classified as either steroidal (eg, rocuronium, vecuronium, pancuronium) or benzylisoquinolinium (eg, atracurium, cisatracurium, mivacurium).
Generally, nondepolarizing muscle relaxants are not absorbed from the GI tract and must be administered parenterally, usually intravenously. Plasma-protein binding is minimal, and there is rapid equilibration, but only within the extracellular fluid. The blood-brain and blood-placental barriers are rarely crossed. These drugs undergo metabolic transformation to some extent, and the metabolites are excreted by both renal and biliary routes in most instances. The elimination half-lives at standard dosages are 60–100 minutes, and the duration of paralysis is 30–60 minutes, except in the case of atracurium and vecuronium, which have shorter duration of action: ~20–30 minutes.
After intravenous administration of competitive nondepolarizing NMBAs, 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 histaminic receptors. Pancuronium causes a moderate increase in heart rate and, to a lesser extent, cardiac output.
Several agents can potentiate the activity of nondepolarizing NMBAs. These include other peripherally acting skeletal muscle relaxants, inhalant anesthetics (halothane, methoxyflurane), antimicrobials (aminoglycosides, polymyxins, tetracyclines, and lincosamides), and various other drugs (quinidine, procaine, lidocaine, diazepam, and barbiturates). Several metabolic derangements, such as hyper- and hypomagnesemia, hypokalemia, acidosis, and hypothermia, also prolong the action of these drugs. Animals with myasthenia gravis are much more susceptible to the action of muscle relaxants.
Indications for the use of nondepolarizing NMBAs include muscle relaxation for orthopedic and intraocular procedures, 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. Animals should always be carefully monitored when under the influence of NMBAs, and ventilation support is essential.
Neostigmine is the most commonly used antagonist for the reversal of neuromuscular blockade. Neostigmine has the advantages of broad-spectrum reversal of all nondepolarizing NMBAs, low cost, and a large amount of clinical data to support its use. It is typically administered at 0.04 mg/kg, IV. Other reversal agents that may be administered are edrophonium and pyridostigmine. Concurrent administration of atropine or glycopyrrolate with an NMBA antagonist will mitigate the muscarinic effects of the antagonist. Animals must be closely monitored for neuromuscular function, and ventilation support must be continued until blockade reversal is complete.
The selection of dose rates (see Table: Competitive Nondepolarizing Agents and Antagonists) serves only as general guidelines for the use of competitive NMBAs.
Competitive Nondepolarizing Agents and Antagonists
Succinylcholine (suxamethonium) is the only commonly used, peripherally acting muscle relaxant that is a depolarizing NMBA. Decamethonium, the other member of the group, is rarely used clinically.
Depolarizing NMBAs 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 intravenous injection (20–50 seconds), and the duration of the effect is usually 5–10 minutes 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 intravenous 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 administration of succinylcholine in the absence of anesthesia. After recovery from succinylcholine-induced muscle paralysis, muscle damage and even myoglobinuria can develop. Malignant hyperthermia or clinical signs related to this syndrome may also result from the administration of succinylcholine in susceptible animals.
Factors that can alter the activity of competitive NMBAs can also affect the action of succinylcholine. In addition, previous (within 1 month) or concurrent use of organophosphate external parasiticides can have a notable 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 NMBAs. However, it is inhumane to administer succinylcholine as an agent for euthanasia or for immobilization for castration or other procedures without local or general analgesia.
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 minutes recumbency); cattle: 0.012–0.02 mg/kg (~15 minutes recumbency); dogs: 0.22–1.1 mg/kg (~15–20 minutes paralysis); and cats: 0.22–1.1 mg/kg (~3–5 minutes paralysis).