VA Class:MS300

AHFS Class:

• Neuromuscular Blocking Agents 12:20.20

Associated Monographs

• Atracurium Besylate

• Cisatracurium Besylate

• Pancuronium Bromide

• Rocuronium Bromide

• Succinylcholine Chloride

• Vecuronium Bromide

Neuromuscular blocking agents are drugs that cause skeletal muscle relaxation and are classified as depolarizing or nondepolarizing (competitive) agents.

Skeletal Muscle Relaxation

Neuromuscular blocking agents are used to produce skeletal muscle relaxation during surgery after general anesthesia has been induced. When neuromuscular blocking drugs are used to provide the necessary muscle relaxation during surgery, operating conditions may be improved and a lighter level of anesthesia may be used.

Neuromuscular blocking agents also are used to facilitate endotracheal intubation and prevent laryngospasm. A neuromuscular blocking agent with a rapid onset of action (e.g., succinylcholine, rocuronium) generally is preferred in emergency situations when rapid intubation (e.g., rapid sequence intubation) is required.410,421,424

Neuromuscular blocking agents also have been used to facilitate mechanical ventilation in the intensive care unit (ICU).341,352,420,421,423 Long-term use of neuromuscular blocking agents in the ICU has been associated rarely with prolonged paralysis and/or skeletal muscle weakness.341,350,351,352,354,420 Whenever neuromuscular blocking agents are used in the ICU, the benefits versus risks of such therapy must be considered and patients should be assessed frequently to determine the need for continued paralysis.350,351,352,354,421 (See Cautions: Precautions and Contraindications.)

Neuromuscular blocking agents (generally succinylcholine) also have been used during electroconvulsive therapy† to reduce muscle contractions and reduce the risk of serious patient injury. In addition, neuromuscular blocking agents have been used for symptomatic control of muscular spasms in various seizure states† including tetanus, status epilepticus, drug intoxication, eclampsia, and those resulting from black widow spider bites. The drugs can modify the muscular component of these seizure states, but the underlying CNS process is unaffected. Management of these states should be directed to more specific modes of treatment of the underlying cause before a neuromuscular blocking agent is employed.

Neuromuscular blocking agents are classified as depolarizing or nondepolarizing based on their mechanism of action.420,421,424 (See Pharmacology.) Succinylcholine is the only currently available depolarizing neuromuscular blocking agent.424 Nondepolarizing neuromuscular blocking agents include atracurium, cisatracurium, pancuronium, rocuronium, and vecuronium; these drugs are further characterized based on their structure as a benzylisoquinolinium (atracurium, cisatracurium) or aminosteroid (rocuronium, vecuronium, pancuronium) compound.424

The choice of a specific neuromuscular blocking agent should be individualized based on factors such as the clinical setting (surgical or ICU), duration of procedure, anesthetic technique, patient condition, and adverse effects and pharmacokinetic profile (onset and duration) of the drug.341,420,421 A neuromuscular blocking agent with a rapid onset of action (e.g., succinylcholine, rocuronium) is desirable for short procedures lasting less than 3 minutes.420,421,423 Because of its rapid onset (less than 1 minute after IV administration) and short duration of action (approximately 4-6 minutes), succinylcholine traditionally has been considered the drug of choice for rapid sequence intubation; however, the drug is associated with serious adverse effects (e.g., bradycardia, hyperkalemia, malignant hyperthermia).410,420,421,424 If succinylcholine cannot be used, rocuronium (which has the most similar pharmacokinetic profile) generally is recommended as an alternative.410,420,421,424 Clinical studies have shown that rocuronium can produce similar intubating conditions to succinylcholine when given in sufficient doses (e.g., at least 1 mg/kg); however, succinylcholine is more likely to achieve excellent intubating conditions and remains clinically superior to rocuronium with respect to its shorter duration of action.410,350,421 Vecuronium, atracurium, and cisatracurium have acceptable onsets of action and may be suitable for certain procedures depending on the urgency of the situation.421 Pancuronium is not appropriate for emergency intubation because of its slow onset and long duration of action, but may be used for other indications (e.g., mechanical ventilation) in which rapid onset and short duration of action are not as important.352,421 Although priming-dose regimens of nondepolarizing neuromuscular blocking agents have been used to accelerate the onset of these drugs, this technique is limited clinically because of the potential for respiratory compromise.421 The potential for neuromuscular blocking agents to cause adverse cardiovascular effects also should be considered in patients undergoing surgery; since rocuronium, cisatracurium, and vecuronium are associated with minimal cardiac effects, these drugs usually are preferred.421 Pancuronium has prominent vagolytic effects and generally should not be used in patients who cannot tolerate an increase in heart rate (e.g. those with cardiovascular disease).341,420,421,423 Cisatracurium or atracurium may be particularly useful in patients with renal or hepatic impairment since these drugs undergo Hofmann degradation and are not dependent on renal and hepatic pathways for elimination.341,353,354,420

The criteria for selecting a neuromuscular blocking agent in the ICU differ from the criteria used during surgery.420 In the ICU, it is more important to consider a drug that does not accumulate with long-term use rather than a drug with a rapid onset and short duration of action.421 Cisatracurium and atracurium are less likely to accumulate with prolonged use because of their lack of dependence on renal and hepatic pathways for elimination, and therefore may be the preferred neuromuscular blocking agents in this setting.420,421

Although the nondepolarizing agents and the depolarizing agents may be mutually antagonistic under some circumstances, various neuromuscular blocking agents are often used together. Succinylcholine, because of its short duration of action, may be used to facilitate intubation prior to a nondepolarizing agent; however, the effects of succinylcholine should be allowed to dissipate before the nondepolarizing agent is given. If tachyphylaxis develops to the effects of a depolarizing agent after prolonged or repeated administration, a nondepolarizing agent may be substituted to maintain neuromuscular blockade.

Since neuromuscular blocking agents have no known effect on consciousness, pain, or cerebration, these drugs should be used in conjunction with adequate levels of general anesthesia, and only after appropriate analgesics and sedatives are administered.359,421,423 To avoid distress to the patient, neuromuscular blocking agents generally should be administered only after unconsciousness has been induced.421,424

Administration

Neuromuscular blocking agents are usually administered IV because of the need for careful control of their effects. For infants or other patients in whom a suitable vein is not accessible, succinylcholine may be administered IM. For specific procedures and techniques of administration, specialized references should be consulted.

Dosage

Dosage of neuromuscular blocking agents must be carefully adjusted according to individual requirements and response and should be no larger than that necessary for adequate muscle relaxation. The use of a peripheral nerve stimulator (in conjunction with clinical assessments) is recommended to accurately monitor the degree of neuromuscular blockade and recovery, determine the need for additional doses, and minimize the possibility of overdosage.350,351,352,353,354,421,423

Adverse Effects

Adverse effects of neuromuscular blocking agents consist principally of extensions of the pharmacologic actions of the drugs. The potential for adverse effects varies considerably among the different neuromuscular blocking agents depending on their affinity for extrajunctional cholinergic receptors.420,422

Neuromuscular blocking agents can stimulate nicotinic and muscarinic receptors outside the neuromuscular junction, predominantly causing adverse cardiac effects.420,422 Among the nondepolarizing neuromuscular blocking agents, pancuronium is associated with the greatest potential for cardiac effects because of its affinity for muscarinic receptors in the parasympathetic and peripheral sympathetic nervous systems; tachycardia usually results from vagolytic and sympathomimetic effects.420,422,423 Rocuronium also exhibits some vagal blocking activity and has been associated with transient tachycardia.350,420 The remaining nondepolarizing neuromuscular blocking agents (cisatracurium, atracurium, vecuronium) have weaker affinities for these extrajunctional receptors and cause minimal or no clinically important cardiovascular effects at the recommended doses.351,353,354,420 While succinylcholine does not have a direct effect on the myocardium, the drug stimulates autonomic ganglia and muscarinic receptors, which can cause bradycardia.349,420 All of the neuromuscular blocking agents have histamine-releasing properties that can also result in hypotension and tachycardia; atracurium and succinylcholine have the greatest potential for histamine release, while pancuronium, cisatracurium, vecuronium, and rocuronium are associated with minimal or no histamine-releasing activity at the recommended doses.350,352,353,354,420,423

Prolonged recovery of neuromuscular function after cessation of neuromuscular blocking drugs can occur due to accumulation of the neuromuscular blocking agent (or its metabolites) or concomitant use of certain drugs and appears to be more common with the longer-acting agents (e.g., pancuronium, vecuronium).352,420,421 Complications include various degrees of residual muscle weakness and/or paralysis, which can result in respiratory complications.352,420,421

Hypersensitivity reactions, including anaphylaxis, have been reported rarely with all neuromuscular blocking agents; such reactions have been life-threatening or fatal in some cases.350,351,352,353,354,422

Manifestations associated with histamine release (other than cardiac effects) may include cutaneous effects such as flushing, erythema, pruritus, urticaria, wheal formation, and pulmonary effects such as wheezing and bronchospasm. (See Pharmacology.)

Malignant hyperthermia is a rare but often fatal adverse reaction associated with the use of neuromuscular blocking agents and/or potent inhalation anesthetics. Succinylcholine and halothane are the agents most commonly associated with this condition. Heredity appears to be a factor in this reaction, because several families have been shown to have high incidence of hyperthermia. Malignant hyperthermia is manifested by a rapid, profound elevation in body temperature and sometimes extreme muscular rigidity unresponsive to the neuromuscular blocking agents. Because malignant hyperthermia can occur even in the absence of a recognized precipitating factor, clinicians should be vigilant for its possible development and prepared for its management in any patient undergoing general anesthesia. As soon as malignant hyperthermia is recognized, all anesthetic agents should be discontinued and IV dantrolene therapy initiated. IV dantrolene is used in conjunction with supportive measures which include administering oxygen, treating metabolic acidosis, and instituting cooling procedures if necessary; urinary output should be maintained and serum electrolytes should be monitored. Large IV doses of procainamide hydrochloride have also been reported to occasionally be effective in reversing the condition.

Prolonged or repeated use of depolarizing agents may produce tachyphylaxis and phase II blockade and, therefore, multiple fractional doses of these agents should generally not be used.

Precautions and Contraindications

Because neuromuscular blocking agents can severely compromise respiratory function and cause respiratory paralysis if not used correctly, these drugs should be administered only by individuals who are experienced in their use and complications.350,351,352,353,354,359,421,424 For specific procedures and techniques of administration, specialized references should be consulted. Facilities and personnel necessary for intubation, administration of oxygen, and respiratory support should be immediately available whenever these agents are used.350,351,352,353,354,359,424 Dispensing and administration precautions (e.g., storage segregation, warning labels, access limitations) should be taken to ensure that neuromuscular blocking agents are not administered without adequate respiratory support.425 Affixing warning labels to storage containers and final administration containers is recommended to clearly communicate that respiratory paralysis can occur and ventilator support is required.425 The Institute for Safe Medication Practices (ISMP) recommends the following wording for these containers: “Warning: Paralyzing agent—causes respiratory arrest—patient must be ventilated”.425 If respiratory paralysis occurs, primary attention should be given to reestablishment of adequate respiratory exchange by maintenance of an adequate airway, control of respiration, and oxygen administration. Ventilatory support should be continued until complete respiratory recovery is assured.

A reversal agent should be readily available during administration of the nondepolarizing neuromuscular blocking agents.350,351,352,353,354,359,421 Pharmacologic reversal may be needed during a failed intubation attempt or to accelerate postoperative recovery of neuromuscular function.359,421 Competitive blockade produced by the nondepolarizing agents may be antagonized by IV administration of cholinesterase inhibitors such as neostigmine methylsulfate, pyridostigmine bromide, or edrophonium chloride, which produce an excess of acetylcholine at the motor end-plate. An anticholinergic agent such as atropine or glycopyrrolate is often administered in conjunction with a cholinesterase inhibitor to counteract the adverse muscarinic effects (e.g., bradycardia, hypotension, salivation) of the cholinesterase inhibitor. Sugammadex, a selective relaxant binding agent, may be used to reverse the effects of rocuronium or vecuronium in adults after surgery.340,342,343,344,345,346 To minimize the risk of residual neuromuscular blockade, pharmacologic reversal should only be attempted after some degree of spontaneous recovery has occurred; patients should be monitored closely until adequate recovery of normal neuromuscular function is assured (i.e., ability to maintain satisfactory ventilation and a patent airway).355,356,357,358,421 No effective antagonist is available to reverse the characteristic phase I depolarization block produced by succinylcholine. However, depending on the dose and duration of succinylcholine administration, phase I block may transition to a phase II block.349 Fully established phase II block may occasionally be antagonized by the use of small, repeated doses of a cholinesterase inhibitor. Prolonged administration of the depolarizing agents may lead to desensitization of the motor end-plate resulting in a prolonged neuromuscular blockade unresponsive to the anticholinesterases.

In the intensive care setting, long-term use of neuromuscular blocking drugs to facilitate mechanical ventilation may be associated with prolonged paralysis and/or skeletal muscle weakness that may be noted first during attempts to wean such patients from the ventilator. Typically, such patients are receiving concurrent drug therapy (e.g., broad-spectrum anti-infectives, opiate agonists, corticosteroids) and may have electrolyte imbalances and/or diseases known to produce electrolyte imbalances, renal or hepatic impairment, hypoxic episodes of varying duration, acid-base imbalances, and/or extreme debilitation, any of which may enhance the effects of a neuromuscular blocking agent. Additionally, patients immobilized for extended periods of time frequently may develop symptoms consistent with disuse muscle atrophy. The recovery period may vary from regaining movement and strength in all muscles to initial recovery of the facial and small muscles of the extremities, followed by recovery of the remaining muscles. Rarely, recovery of muscle strength and movement may be over an extended period of time and may even require occasional rehabilitation. Therefore, when there is a need for long-term mechanical ventilation, the benefits of such therapy must be weighed against the risks. To reduce the possibility of prolonged neuromuscular blockade and other complications that might occur following long-term use of neuromuscular blocking drugs in intensive care settings, these drugs should be administered in carefully adjusted doses by or under the supervision of experienced clinicians familiar with appropriate peripheral nerve stimulator muscle monitoring techniques. Continuous monitoring of neuromuscular transmission should be considered during both therapy and recovery in patients receiving the drugs long term in the intensive care setting. Additional doses of neuromuscular blocking drugs should not be given before there is a definite response to nerve stimulation tests. If no response is elicited, administration of the drug should be discontinued until a response returns.

All neuromuscular blocking agents should be used with caution in patients with renal, hepatic, or pulmonary impairment, or respiratory depression, and in geriatric or debilitated patients. The drugs should be used with extreme caution, if at all, in patients with myasthenia gravis. Other conditions that are associated with increased response to the neuromuscular blocking agents are the myasthenic syndrome associated with lung cancer, dehydration, thyroid disorders, collagen diseases, porphyria, and familial periodic paralysis. Potent inhalation anesthetics and neuromuscular blocking agents should be avoided if possible in patients who have experienced malignant hyperthermia and in members of their families, and the possibility that this reaction could occur in any patient undergoing general anesthesia should be considered. (See Cautions: Adverse Effects.) During the first month of life, neonates are particularly sensitive to the action of most nondepolarizing agents and respond with prolonged neuromuscular blockade to usual doses of the drugs.

Because of the risk of anaphylaxis, appropriate precautionary measures (including the immediate availability of emergency treatment for anaphylaxis) should be taken whenever neuromuscular blocking agents are administered.352 Because of the potential for cross-sensitivity, particular caution should be taken in individuals who have previously experienced an anaphylactic reaction to any neuromuscular blocking agent (depolarizing or nondepolarizing).352

Resistance to nondepolarizing neuromuscular blocking agents can develop in burn patients and may be substantial.300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316 The magnitude of resistance depends on the extent of thermal injury and elapsed time since the burn,300,301,302,303,304,305,306,307 with patients having burns that extend over 25-30% or more of body surface area being most likely to exhibit resistance (increasing with increased injury) and the resistance only becoming apparent 1 week or longer after the burn.301,302,303,304,305,306,307 Such resistance generally peaks 2 or more weeks after the burn,302,303,304,306 persists for several months or longer,302,304 and decreases gradually with healing.301,302,304,306 The mechanism of this resistance appears to be complex, and may involve pharmacokinetic, pharmacodynamic, and pathophysiologic factors.301,302,303,305,306,307,312,313,314 While reductions in the free (unbound)-fraction of circulating plasma concentrations of the drugs may contribute to this resistance,301,302,303,305,312,313 the magnitude of such resistance cannot be explained entirely by such alterations in protein binding of the drugs.302,303,305,306,312,313 It also has been suggested that changes in the number of acetylcholine receptors and/or in anticholinesterase activity may contribute to this resistance,301,302,303,305,306,307,315,316 but some evidence does not support this suggestion.303,313 Other mechanisms (e.g., circulating substances in plasma that bind to or inactivate the drugs) also have been suggested.301,305,314,316 The possible need for substantially increased doses of nondepolarizing agents in burn patients should be considered.300,301,302,303,304,305,306,307,308,309,310,311,312

Succinylcholine should be used with caution in patients with electrolyte disturbances, especially hyperkalemia, and in digitalized patients because depolarizing agents may cause release of intracellular potassium into the plasma. The resulting hyperkalemia is particularly great in patients with severe burns or trauma, spinal cord injuries, or degenerative or dystrophic muscle diseases, and in paraplegic patients. Hypokalemia can lead to depressed membrane excitability of skeletal muscle and potentiate the effects of the nondepolarizing agents. When suspected of being abnormal, serum potassium concentrations should be determined before administering neuromuscular blocking agents. High magnesium concentrations partially block the release of ACh from the motor nerve ending and can potentiate the effects of both depolarizing and nondepolarizing agents. Hypocalcemia can increase the excitability of muscles and potentiate the effects of neuromuscular blocking agents, particularly the nondepolarizing agents.

Succinylcholine should be used with caution in patients with fractures or muscular spasms, as the initial muscle fasciculation caused by the drugs may result in additional trauma. Hypothermia tends to decrease the intensity and duration of a nondepolarizing block, but increases the intensity and duration of a depolarizing block; hyperthermia causes the opposite effects. Patients with severe hepatic impairment may have decreased plasma concentrations of pseudocholinesterase. In these patients, the duration of action of succinylcholine may be increased because of reduced metabolism.

Pediatric Precautions

Some preparations of neuromuscular blocking agents may contain benzyl alcohol as a preservative.327,328,329,330,331,332 Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.333,334,335,336,337,338 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.333,334,335,336,337,338 Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible,333,335 the American Academy of Pediatrics states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.333

Pregnancy

Pregnancy

It is not known whether administration of neuromuscular blocking agents during vaginal delivery has immediate or delayed adverse effects on the fetus or whether it increases the likelihood that resuscitation of the neonate will be necessary. Neuromuscular blocking agents should be used with caution and dosage reduced as necessary in pregnant women receiving magnesium sulfate during delivery, since the neuromuscular blockade may be potentiated and its reversal impeded. Since neuromuscular blocking agents may cross the placenta, the possibility of respiratory depression in neonates should be considered following cesarean section in which a neuromuscular blocking agent is administered to the mother. Neuromuscular blocking agents should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. Animal reproduction studies have not been performed with many neuromuscular blocking agents; however, some of the agents have been shown to be potentially teratogenic (e.g., atracurium).

Concurrent administration of several drugs has been reported to affect patient response to neuromuscular blocking agents.

General Anesthetics

General anesthetics, particularly enflurane and isoflurane, and to a lesser extent, halothane, can potentiate the effects of nondepolarizing neuromuscular blocking agents.350,351,352,353,354 The response to depolarizing agents may also be affected, but to a lesser extent.

Anti-infective Agents

Aminoglycoside antibiotics are believed to inhibit neuromuscular transmission. These drugs have been reported to increase or prolong skeletal muscle relaxation produced by the neuromuscular blocking agents when the antibiotics were administered parenterally or intraperitoneally during surgery and have reinstated neuromuscular blockade when administered parenterally postoperatively. Kanamycin, neomycin, and streptomycin appear to have the greatest potential for causing this effect. Potentiation of neuromuscular blockade has been reported following oral administration of some of the aminoglycoside antibiotics, but not as frequently as with parenteral use. The polymyxin antibiotics (polymyxin B sulfate, colistin, colistimethate sodium) and, to a lesser extent, another polypeptide antibiotic, capreomycin sulfate, and clindamycin and lincomycin have also been reported to potentiate effects of neuromuscular blocking agents. If any of these anti-infective agents is used before, during, or after surgical procedures in which a neuromuscular blocking agent is administered, the possibility of prolonged duration of neuromuscular blockade (or recurarization, particularly postoperatively) should be considered. Reversible cholinesterase inhibitors (edrophonium chloride, neostigmine methylsulfate) and IV calcium sometimes reverse neuromuscular blockade produced by neuromuscular blocking agents and potentiated by the aminoglycoside antibiotics. IV calcium (but not the cholinesterase inhibitors) has occasionally been successful in reversing neuromuscular blockade produced by neuromuscular blocking agents and potentiated by the polymyxins.

Anticonvulsants

In patients receiving chronic therapy with carbamazepine or phenytoin, the duration of neuromuscular blockade with nondepolarizing agents may be shorter than anticipated and the degree of blockade for a given dose may be decreased. Therefore, such patients should be monitored closely for reduced effectiveness of nondepolarizing neuromuscular blocking agents and the dose (e.g., rate of IV infusion) adjusted accordingly. The mechanism of this resistance is not known, but receptor up-regulation may be a contributing factor.

Diazepam

There have been conflicting reports concerning the effects of concurrent administration of diazepam and nondepolarizing neuromuscular blocking agents. Some reports indicate that IV diazepam may increase the intensity and duration of the neuromuscular blockade produced by gallamine (no longer commercially available in the US). Other studies have failed to confirm this interaction.

Opiate Analgesics

The central respiratory depressant effects of the opiate analgesics can add to the respiratory depressant effects of the neuromuscular blocking agents. Extreme caution should be used when administering opiates during surgery or in the immediate postoperative period in patients who have received neuromuscular blocking agents.

Potassium-depleting Agents

Potassium-depleting drugs such as the thiazide diuretics, furosemide, ethacrynic acid, chlorthalidone, the carbonic anhydrase inhibitors, amphotericin B, the corticosteroids, or corticotropin may cause prolonged neuromuscular blockade in patients receiving nondepolarizing agents.

Other Drugs

Multiple doses of quinine or quinidine, β-adrenergic blocking agents (e.g., propranolol), and excessively high IV doses of lidocaine have been shown to potentiate the effects of both types of neuromuscular blocking agents. These drugs are believed to interfere with the ionic permeability of the post-junctional membrane. The drugs can cause apnea when given postoperatively to patients thought to have recovered from neuromuscular blockade and can increase neuromuscular blockade when given simultaneously with the neuromuscular blocking agents.

Parenteral administration of magnesium sulfate may raise serum magnesium concentrations sufficiently to potentiate the neuromuscular blocking agents. When magnesium sulfate is administered for the management of toxemia of pregnancy, the neuromuscular blockade induced by a blocking agent may be potentiated and its reversal impeded. If a neuromuscular blocking agent is used in a pregnant woman receiving magnesium sulfate, the drug should be used with caution and its dosage reduced as necessary.

Pharmacology

Neuromuscular blocking agents are drugs that cause skeletal muscle relaxation mainly by producing a decreased response to the neurotransmitter acetylcholine (ACh) at the neuromuscular junction of skeletal muscle. Based on the mechanism by which they decrease the effects of ACh, these drugs can be classified as depolarizing or nondepolarizing (competitive) neuromuscular blocking agents:

DEPOLARIZING AGENTS

• Succinylcholine Chloride

NONDEPOLARIZING AGENTS

• Atracurium Besylate
• Cisatracurium Besylate
• Pancuronium Bromide
• Rocuronium Bromide
• Vecuronium Bromide

Although depolarizing and nondepolarizing neuromuscular blocking agents have different mechanisms of action, the similarity of the end result of their pharmacologic actions and of their therapeutic uses permits their discussion as a class.

Neuromuscular blocking agents produce skeletal muscle paralysis mainly by causing a decreased response to ACh at the myoneural junction. At that site, the neurotransmitter normally produces electrical depolarization of the postjunctional membrane of the motor end-plate, leading to conduction of muscle action potential which in turn induces skeletal muscle contraction. The drugs also act prejunctionally on the motor neuron, although the importance of this action is unclear.

Nondepolarizing agents have a high affinity for ACh receptor sites and competitively block access of ACh to the motor end-plate of the myoneural junction. Nondepolarizing agents have little or no agonist activity. Thus, they may block the effects of both the small quantities of ACh that maintain muscle tone and the large quantities of ACh that produce voluntary skeletal muscle contraction, but they do not alter the resting electrical potential of the motor end-plate or cause muscular contractions. There is evidence that nondepolarizing agents also affect ACh release. It has been hypothesized that nondepolarizing agents bind to postjunctional (“curare”) receptors and may thereby interfere with the sodium and potassium flux which is responsible for depolarization and repolarization of the membranes involved in muscle contraction. The degree to which each mechanism of action contributes to the clinical effect of the nondepolarizing agents is unclear and may vary with the specific drug.

Depolarizing agents have a high affinity for ACh receptor sites and like ACh produce depolarization of the motor end-plate at the myoneural junction. Immediately after a single IV dose of a depolarizing agent, transient twitching or fasciculation of the skeletal muscles occurs and is followed by muscle paralysis. Because of their high affinity for ACh receptors and their resistance to acetylcholinesterase, the depolarizing agents produce more prolonged depolarization at the motor end-plate than does ACh. The initial depolarization block is also known as a phase I block and is characterized by well-sustained muscular contractions following both fast (tetanic) and slow (twitch) electrical nerve stimulation; post-tetanic facilitation is absent. Cholinesterase inhibitors may potentiate phase I block and nondepolarizing agents reverse it. With prolonged or repeated administration of a depolarizing agent, the nature of the block changes to a phase II or desensitization block which resembles a nondepolarizing block. Phase II block is characterized by poorly sustained muscle contractions following both fast and slow electrical nerve stimulation and the presence of post-tetanic facilitation. The transition from a phase I to a phase II block is gradual and variable in time course among individuals in contrast to phase I block. Fully established phase II block can be reversed by cholinesterase inhibitors and potentiated by nondepolarizing agents. In neonates and patients with myasthenia gravis, depolarizing agents produce an immediate phase II block, bypassing phase I.

The first muscles to be affected following administration of a neuromuscular blocking agent are those producing fine, rapid movements such as those of the eyes, face, and neck. Muscles of the limbs, abdomen, and chest are affected next, and the diaphragm is affected last. Recovery of muscles generally occurs in the reverse order. Respiratory depression or apnea may result from involvement of the intercostal muscles and diaphragm. Relaxation of the muscles of the tongue, pharynx, and epiglottis may also completely close the airway.

By competing with ACh for cholinergic receptors at the autonomic ganglia, tubocurarine (no longer commercially available in the US) may further affect the autonomic nervous system and produce ganglionic blockade. It has been reported that succinylcholine stimulates the cardiac vagus and subsequently sympathetic ganglia. The histamine-releasing properties of the neuromuscular blocking agents vary according to the specific drug and dose employed. Tubocurarine appears to be a potent stimulator of histamine release; metocurine (no longer commercially available in the US) and succinylcholine also cause histamine release, but to a lesser extent. Atracurium is a less potent stimulator of histamine release than is tubocurarine. Pancuronium appears to release detectable amounts of histamine only at excessive dosages. Vecuronium, cisatracurium, and rocuronium appear to have little, if any, histamine-releasing activity at recommended doses.350,351,353 Neuromuscular blocking agents also exhibit cardiovascular effects to varying degrees. Neuromuscular blocking agents do not affect pain or other sensory perception.

Young and small children may generally require larger doses of neuromuscular blocking agents than adolescents and adults, when calculated on a weight basis, to achieve the same degree of neuromuscular blockade during comparable techniques of anesthesia. Factors that may influence dose-response relationships during childhood include age-related changes in the relative amount of muscle as a proportion of body weight, in renal function, and in the size of the extracellular fluid volume and the resultant apparent volume of distribution for neuromuscular blocking agents.

Pharmacokinetics

Absorption

All neuromuscular blocking agents are poorly absorbed from the GI tract.

The onset of action varies among individual patients and with the various neuromuscular blocking agents and their route of administration, dosage, and the general anesthetic agent employed. In general, the first signs of neuromuscular blockade occur within approximately 2 minutes following IV administration of nondepolarizing agents and maximal effects occur in about 3-6 minutes; maximal effects of succinylcholine usually occur within 1 minute. The onset of action is slower and less predictable following IM administration than after IV injection and for this reason the IM route is seldom used. The duration of action of the individual agents varies widely. After a single dose, redistribution accounts for termination of action of most of the agents; however, after multiple doses, metabolism and excretion as well as further redistribution play a part in determining the duration of action.

Distribution

After IV administration, the drugs are distributed in the extracellular fluid and rapidly reach their site of action at the motor end-plate of the myoneural junction. Most neuromuscular blocking agents cross the blood-brain barrier to a very small extent, if at all. Increased protein binding (possibly to α₁-acid glycoprotein) of nondepolarizing neuromuscular blocking agents with subsequent decreases in the free-fraction of circulating drug may occur in patients with burns.301,302,303,305,312,313,317

Neuromuscular blocking agents may cross the placenta, especially during the first trimester of pregnancy.

Elimination

Succinylcholine is metabolized rapidly by pseudocholinesterase and is excreted in urine as active and inactive metabolites and small amounts of unchanged drug. Pancuronium is eliminated mainly unchanged by the kidneys, although small amounts may be metabolized and some of the drug may be eliminated in the bile.352 Rocuronium is metabolized to a less active metabolite, 17-desacetyl-rocuronium, that is rarely detected in the plasma and urine, and is eliminated principally by the liver.350 Atracurium and cisatracurium undergo rapid metabolism via Hofmann elimination and via nonspecific enzymatic ester hydrolysis; the liver does not appear to play a major role in the metabolism of these drugs.353,354 Atracurium, cisatracurium, and their metabolites, including the metabolic products of Hofmann elimination and nonspecific enzymatic ester hydrolysis, are excreted principally in urine and also in feces via biliary elimination.353,354 The metabolic fate of vecuronium has not been fully characterized. In aqueous solution in vitro, vecuronium undergoes spontaneous deacetylation at the 3α- and/or 17β-positions to form the hydroxy derivatives. The extent of spontaneous deacetylation and/or metabolism of the drug in vivo in humans remains to be clearly determined. Vecuronium and its metabolite(s) appear to be excreted principally in feces via biliary elimination; the drug and its metabolite(s) are also excreted in urine.

Chemistry

Although neuromuscular blocking agents are structurally similar in that most contain quaternary ammonium groups, it is difficult to generalize about the structure-activity relationships of the neuromuscular blocking agents. The presence of multiple quaternary ammonium groups seems to increase each drug's affinity for its receptor sites.

Only references cited for selected revisions after 1984 are available electronically.

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