What Is Atracurium Besilate?
Atracurium besilate is a medication that belongs to a class of drugs known as non-depolarizing neuromuscular blocking agents. These agents are used during surgery to induce muscle relaxation and temporary paralysis. Atracurium is often employed with general anesthesia to facilitate intubation, mechanical ventilation, and surgical procedures.
Atracurium works by blocking the action of acetylcholine at the neuromuscular junction, preventing the transmission of nerve impulses to the muscles. This results in muscle relaxation and paralysis.
Atracurium has an intermediate duration of action, meaning it provides muscle relaxation for a moderate period. The effects are reversible with the administration of drugs like neostigmine.
Unlike other neuromuscular blocking agents, atracurium is metabolized primarily by non-specific tissue esterases in the body, independent of liver or kidney function.
Atracurium typically has a relatively rapid onset of action, making it suitable for procedures where quick muscle relaxation is needed.
Using neuromuscular blocking agents like atracurium requires careful monitoring by trained healthcare professionals. These medications are used under the supervision of anesthesiologists or other healthcare providers with expertise in anesthesia and critical care.
As with any medication, there can be side effects and contraindications. Healthcare providers must consider the patient’s health status and medical history when prescribing and administering atracurium besilate.
On intravenous injection, both atracurium besilate and cisatracurium besilate undergo spontaneous degradation via Hofmann elimination (a non-enzymatic breakdown process occurring at physiological pH and temperature) to produce laudanosine and other metabolites. There is also ester hydrolysis by non-specific plasma esterases. The metabolites have no neuromuscular blocking activity.
About 80% of atracurium besilate is bound to plasma proteins. Atracurium besilate and its metabolites cross the placenta in clinically insignificant amounts. Excretion of atracurium and cisatracurium is in urine and bile, mostly as metabolites. The elimination half-life has been reported to be about 20 minutes for atracurium and 22 to 29 minutes for cisatracurium, but laudanosine has an elimination half-life of about 3 to 6 hours.
Atracurium and cisatracurium are degraded by Hofmann elimination and metabolized by non-specific plasma esterases. Hofmann elimination is generally believed to be the main degradation route, but in-vitro work suggests ester hydrolysis is more important. Both routes are independent of renal and hepatic function, and no dosage reduction is recommended for elderly patients or those with impaired renal or hepatic function. However, the elimination half-life of atracurium is slightly longer in elderly patients and those with hepatic cirrhosis compared with young and healthy patients, although others have found no change in the pharmacokinetics of atracurium in senior patients.
Renal and hepatic involvement in the metabolism of atracurium may explain any tendency to reduced elimination, but this does not appear clinically significant. Although clearance of cisatracurium has been reported to be reduced in patients with renal failure, this has an insignificant effect on its pharmacodynamics. Differences in the pharmacokinetics of cisatracurium in patients with hepatic impairment have been reported to be minor.
The primary biotransformation product of atracurium and cisatracurium is laudanosine; it has no clinical neuromuscular blocking activity but has been associated with CNS stimulation in animal studies. It is more lipid soluble than atracurium and cisatracurium and has a half-life of around 3 hours compared with one of approximately 20 minutes for atracurium. Higher plasma-laudanosine concentrations have been reported in patients with renal failure than in patients with normal renal function. The elimination half-life of laudanosine was significantly greater in patients with hepatic cirrhosis and in elderly patients than in healthy and young patients. High plasma-laudanosine concentrations were also seen in 10 critically ill patients with acute respiratory distress syndrome; no adverse effects were noted.
Laudanosine crosses the blood-brain barrier in man. The concentration of laudanosine in the CSF increases during an infusion of atracurium, and the CSF-to-plasma ratio gradually increases. A ratio of 0.14 was found at 125 to 140 minutes during an infusion of atracurium at a mean rate of 510 micrograms/kg per hour. No evidence of CNS stimulation has been reported in man, although patients given atracurium had a 20% higher mean arterial-thiopental concentration at awakening compared with patients given vecuronium, suggesting that laudanosine may have had a minor stimulatory effect on the CNS. The blood-brain barrier effectively prevents a very high concentration of laudanosine from reaching the CNS, and it is unlikely that concentrations enough to provoke seizures will be reached. Cisatracurium may be associated with the production of less laudanosine than atracurium.
Uses and Administration
Competitive neuromuscular blockers act by competing with acetylcholine for receptors on the motor end-plate of the neuromuscular junction to produce blockade. The muscles that produce rapid movements, such as muscles of the face, are the first to be affected, followed by those of the limbs and torso; the least affected are those of the diaphragm. The paralysis is reversible, with recovery occurring in reverse order. Restoration of normal neuromuscular function can be hastened by increasing the concentration of acetylcholine at the motor end-plate by giving an anticholinesterase such as neostigmine.
Atracurium and cisatracurium are competitive benzyl-isoquinolinium neuromuscular blockers. The commercial preparation of atracurium is a mixture of 10 stereo-isomers; cisatracurium constitutes about 15%. Cisatracurium, the R-cis, 1 R-cis-isomer of atracurium, is about three times more potent than the mixture of isomers of atracurium. After an intravenous dose of atracurium, muscle relaxation begins in about 2 minutes and lasts 15 to 35 minutes; onset may be slightly slower for cisatracurium.
Atracurium besilate and cisatracurium besilate are used for endotracheal intubation, muscle relaxation in general anesthesia for surgical procedures, and aid controlled ventilation. Doses of neuromuscular blockers need to be carefully titrated for individual patients according to response and may vary with the procedure, the other drugs, and the state of the patient; monitoring of the degree of the block is recommended to reduce the risk of overdosage.
For atracurium besilate, the usual initial dose for adults and children over one month is 300 to 600 micrograms/kg by intravenous injection. Subsequent doses of 100 to 200 micrograms/kg may be given as necessary, typically every 15 to 25 minutes, for maintenance in prolonged procedures. The initial dose should be given for 60 seconds in patients with cardiovascular disease.
Atracurium besilate may also be given by continuous intravenous infusion at 5 to 10 micrograms/kg per minute to maintain neuromuscular block during prolonged procedures. Somewhat higher infusion rates may be used in patients undergoing controlled ventilation in intensive care.
Cisatracurium is given as the besilate, but doses are expressed as the base. Cisatracurium 1 mg is equivalent to about 1.34 mg of cisatracurium besilate. The usual initial dose for adults is 150 micrograms/kg by intravenous injection. The neuromuscular block may be extended with a 30 micrograms/kg maintenance dose every 20 minutes. The usual initial dose for children one month and over is 150 micrograms/kg. The neuromuscular block may be extended in children aged two years and over with a maintenance dose of 20 micrograms/kg every 9 minutes.
The BNFC suggests that a 30 micrograms/kg maintenance dose, repeated about every 20 minutes, may be given to younger children aged one month and over; however, such use is unlicensed in the UK. Cisatracurium besilate may also be given by continuous intravenous infusion to adults and children over two years of age at an initial rate equivalent to cisatracurium three micrograms/kg per minute, followed by a rate of 1 to 2 micrograms/kg per minute after stabilization.
Administration in Infants and Children
Children generally require larger doses of competitive neuromuscular blockers on a weight basis than adolescents or adults to achieve similar degrees of neuromuscular blockade and may recover more quickly. In contrast, neonates and infants under one year are more sensitive, and usual doses may produce prolonged neuromuscular blockade (see also above for some suggested doses).
Competitive neuromuscular blockers have been used to reduce the intensity of muscle contractions and minimize trauma in patients receiving ECT. Still, suxamethonium is generally preferred because of its short duration of action.
Intravenous Regional Anesthesia
Competitive neuromuscular blockers and/or opioid analgesics have been added to the local anesthetic used in intravenous regional anesthesia to improve the quality of anesthesia. However, atracurium and mivacurium might be unsuitable for such use.
Various drugs have been tried in the treatment of postoperative shivering. There are reports of neuromuscular blockers being used to treat shivering after cardiac surgery to reduce cardiovascular stress; one study has suggested that vecuronium might be preferable to pancuronium as it does not increase myocardial work and may be associated with fewer complications.
Neuromuscular blockers are generally incompatible with alkaline solutions, for example, barbiturates such as thiopental sodium. It is good practice not to give neuromuscular blockers in the same syringe or simultaneously through the same needle as other drugs.
The manufacturers state that cisatracurium is incompatible with ketorolac trometamol or propofol emulsion; in addition, lactated Ringer’s injection with glucose 5% or lactated Ringer’s solution should not be used as a diluent when preparing solutions of cisatracurium for infusion.
In a stability study, solutions of cisatracurium (as the besilate) in concentrations of 2 or 10 mg/mL were stable for at least 90 days when stored in the original vials at 4° either exposed to or protected from light; similar solutions stored at 23° were stable for at least 45 days. Solutions of 2 mg/mL stored in plastic syringes at 4° or 23° were stable for at least 30 days. Solutions of 0.1, 2, or 5 mg/mL in 5% glucose injection or 0.9% sodium chloride injection in PVC minibags were stable for at least 30 days stored at 4°; the 5 mg/mL solution was also stable for at least 30 days stored at 23°.
The adverse effects of competitive neuromuscular blockers are generally similar, although they differ in their propensity to cause histamine release and associated cardiovascular effects. The latter appears rare with the amino steroidal blockers and the benzylisoquinoline blocker cisatracurium. Competitive neuromuscular blockers with vagolytic activity may produce tachycardia and a rise in blood pressure. Blockers that lack an effect on the vagus will not counteract the bradycardia produced during anesthesia by the other drugs employed or vagal stimulation.
Reduction in blood pressure with compensatory tachycardia may occur with some competitive neuromuscular blockers, partly because of sympathetic ganglion blockade or histamine release. Reduction in gastrointestinal motility and tone may occur due to ganglionic blockade. Histamine release may also lead to wheal-and-flare effects at the injection site, flushing, occasionally bronchospasm, and rarely anaphylactoid reactions. Malignant hyperthermia has been associated rarely with competitive neuromuscular blockers. Some competitive neuromuscular blockers such as pancuronium, tubocurarine, and vecuronium can cause a decrease in the partial thromboplastin time and prothrombin time.
In overdosage, there is prolonged apnoea due to paralysis of the intercostal muscles and diaphragm, with cardiovascular collapse and the effects of histamine release.
Atracurium and its isomer cisatracurium have no significant vagal or ganglionic blocking activity at recommended doses. Cisatracurium does not induce histamine release and is associated with greater cardiovascular stability. For possible risks from their major metabolite laudanosine, see Biotransformation under the Pharmacokinetics section.
Effects on Body Temperature
Competitive neuromuscular blockers are not considered a trigger factor for malignant hyperthermia; however, there have been rare cases of apparent association. Two cases of mild malignant hyperthermia have been reported where tubocurarine was probably the triggering drug. Each episode developed in a member of a family known to be susceptible to malignant hyperthermia despite preventive measures such as prophylactic cooling and avoidance of potent inhalation anesthetics and depolarising neuromuscular blockers. Another case was associated with the use of pancuronium.
There have been reports of severe anaphylactoid reactions after use of atracurium or cisatracurium. For a discussion of hypersensitivity reactions associated with neuromuscular blockers, see under Suxamethonium Chloride.
Treatment of Adverse Effects
It is essential to maintain assisted respiration in patients who have received a competitive neuromuscular blocker until spontaneous breathing is fully restored; in addition, a cholinesterase inhibitor such as neostigmine is usually given intravenously, with atropine or glycopyrronium, to hasten reversal of the neuromuscular block. Patients must be closely monitored after the block reversal to ensure muscle relaxation does not return.
Severe hypotension may require intravenous fluid replacement and cautious use of a pressor agent; the patient should be positioned to facilitate venous return from the muscles.
Giving an antihistamine before induction of neuromuscular blockade may help to prevent histamine-induced adverse effects in patients with asthma or those susceptible to bronchospasm.
Patients who have received a neuromuscular blocker should always have their respiration assisted or controlled until the drug has been inactivated or antagonized.
Atracurium and other competitive neuromuscular blockers should be used with great care in respiratory insufficiency, pulmonary disease, and dehydrated or severely ill patients. The response to neuromuscular blockers is often unpredictable in patients with neuromuscular disorders, and they should be used with great care in these patients. Caution is also needed in patients with a history of conditions such as asthma, where the release of histamine would be a hazard. Care is also required in patients with a history of hypersensitivity to any neuromuscular blocker because high rates of cross-sensitivity have been reported.
To discuss hypersensitivity reactions associated with neuromuscular blockers, see under Adverse Effects of Suxamethonium Chloride. Resistance to the effects of competitive neuromuscular blockers may occur in patients with burns (see below). The effect of competitive neuromuscular blockers may vary in patients with hepatic impairment: resistance appears to occur to some, such as doxacurium, merocrine, pancuronium, and tubocurarine, while the dosage of others, including mivacurium and rocuronium, may need to be reduced because of prolonged action.
Competitive neuromuscular blockers excreted mainly in the urine should be used with caution in renal impairment; a reduction in dosage may be necessary. Doses may need to be reduced in infants and neonates because of increased sensitivity to competitive muscle relaxants. Doses in obese patients should usually be based on the patient’s ideal body weight rather than actual body weight.
The effects of competitive neuromuscular blockers are increased by metabolic or respiratory acidosis and hypokalaemia, hypermagnesaemia, hypocalcemia, hypophosphatemia, and dehydration. Increased body temperature and reduced hypothermia may also enhance Competitive neuromuscular blockade. In contrast to other competitive neuromuscular blockers, a reduction in body temperature may necessitate a dosage reduction for atracurium and its isomer cisatracurium since cooling reduces the inactivation rate of atracurium and cisatracurium. Still, physiological variations in body temperature and pH will not significantly affect their action.
The dose requirements of competitive neuromuscular blockers are increased in patients with burns, correlating with both the extent of the burn and the time after injury. This resistance is usually not seen in patients with less than 10% body-surface burns, but if more than 40% of the body surface is affected, the dose of competitive blocker may need to be up to five times higher than in patients without burns. Resistance peaks about two weeks after injury, persists for many months in patients with significant burns and decreases gradually with healing of the burn.
The resistance mechanism is multifactorial but may be partly explained by increased protein binding, increased volume of distribution, and increased numbers of acetylcholine receptors at the motor end-plate, requiring more muscle relaxants to produce a given effect. Despite the high doses of competitive relaxants required, recovery from neuromuscular blockade is not seriously impaired, and their effects can be reversed with usual doses of anticholinesterase.
The effect of cardiopulmonary bypass on the pharmacokinetics and pharmacodynamics of competitive neuromuscular blockers can be complex, but generally, their dosage may need to be reduced. Although the intensity of neuromuscular blockade of most competitive neuromuscular blockers is reduced by hypothermia used during cardiopulmonary bypass, their use during this procedure is associated with rises in plasma concentrations, reduced clearance, and prolongation of the elimination half-life. Various mechanisms, including reduced distribution to highly perfused tissues such as the lungs, have been proposed to explain this effect. For atracurium, it is a reduction in the temperature-dependent inactivation by Hofmann elimination during hypothermia that enables lower doses to be used.
The effect of competitive neuromuscular blockers may vary in patients with hepatic impairment. Still, alterations in the pharmacokinetics of atracurium and cisatracurium in patients with hepatic impairment are not clinically significant, and a reduction in dosage is not generally recommended.
Caution is needed if competitive neuromuscular blockers are given to patients with neuromuscular disease since severe complications have been reported. Increased response may be seen in patients with paraplegia or quadriplegia, but resistance has been reported in patients with hemiplegia. Increased response also may occur in patients with amyotrophic lateral sclerosis, neurofibromatosis, and poliomyelitis; this is of little concern unless the respiratory muscles are involved when prolonged apnoea may occur. Patients with myasthenia gravis usually show increased sensitivity to competitive neuromuscular blockers, although small doses have been given without complications.
During remission of myasthenia gravis, a normal response is usual, but since remission is often incomplete, small intermittent doses are advised. A significantly greater exaggeration of response is seen in patients with the myasthenic syndrome. Normal and increased responses have been reported in patients with myotonias or muscular dystrophy, but exquisite sensitivity occurs in patients with ocular muscular dystrophy. A normal response to competitive relaxants may be expected in patients with multiple sclerosis, muscular denervation, Parkinson’s disease, and tetanus.
A review of the pharmacokinetics of neuromuscular blockers in pregnancy concluded that atracurium and mivacurium are the best choice in pregnancy since their actions are predictable; their duration of action is either unchanged or only slightly prolonged. Atracurium also has a low umbilical to maternal vein concentration (uv/mv) ratio. In general, choosing a neuromuscular blocker with a low uv/mv ratio and a short duration of action is advisable, and injecting the lowest dose is required to produce adequate surgical conditions.
Atracurium 300 micrograms/kg given to 26 women undergoing cesarean section, with subsequent incremental doses of 100 or 200 micrograms/kg if necessary, produced good surgical relaxation in all patients without complications. Of the 26 neo-nates delivered, respiration was established within 90 seconds in 21, with an Apgar score of 10 at 5 minutes. The remaining five neo-nates were delivered by cesarean section because of fetal distress and were slower to start breathing.
A study of 22 women in the immediate postpartum period found the onset and duration of cisatracurium to be significantly shorter when compared with nonpregnant patients.
Although some differences in the pharmacokinetics of atracurium and cisatracurium have been reported in patients with renal impairment, the duration of their neuromuscular blocking action is not significantly dependent on renal function, and usual doses may be given to such patients. Atracurium has been given by infusion to patients with end-stage renal failure when the initial dose required for induction of neuromuscular block was 37% higher than that required by patients without renal impairment.
The larger extracellular fluid volume in patients with chronic renal failure could explain the increase. Although the pharmacokinetics of atracurium and cisatracurium are not appreciably different in renal impairment, those of their metabolites may be. Therefore, neuromuscular function should be monitored during the use of atracurium.
The etiology of resistance to competitive blockers is unclear but might be due to pharmacodynamic or pharmaco-kinetic alterations associated with disease states such as burn injuries, hepatic impairment, or therapy with other drugs. One review noted that there had been numerous case reports of resistance to competitive neuromuscular blockers; most had been associated with the use of single doses or short-term intermittent therapy, but more recent reports had documented resistance during continuous infusions in 9 patients, of whom 7 had received atracurium and 2 rocuronium.
Resistance to atracurium had followed 2 different patterns. Patients had required either usual or raised doses for initial control, but both groups had subsequently required progressive increases. Most patients with resistance to atracurium were successfully managed by transfer to pancuronium or doxacurium.
Atracurium might be unsuitable for neuromuscular blockade of a limb isolated with a tourniquet to provide a bloodless field for surgery. Atracurium undergoes non-enzymatic degradation in plasma and would, therefore, continue to degrade locally, leading to a loss of blockade in the limb, which further doses could not correct unless the tourniquet was deflated.
Some drugs may influence neuromuscular transmission and thus interfere with the action of both competitive and depolarising neuromuscular blockers, resulting in potentiation or antagonism of neuromuscular block. Some interactions may be advantageous, such as reversing competitive neuromuscular block by anticholinesterases. Adverse interactions are potentially more severe in patients with impaired neuromuscular function.
Drug interactions affecting neuromuscular blockers of either type (competitive and depolarising) and those specific to competitive neuromuscular blockers are discussed below.
Lidocaine, procainamide, quinidine, and verapamil all have some neuromuscular blocking activity and may enhance the block produced by neuromuscular blockers. Large doses of lidocaine may reduce the release of acetylcholine and act directly on the muscle membrane. Quinidine has a curare-like action at the neuromuscular junction and depresses the muscle action potential. If given during recovery from the neuromuscular block, it can result in muscle weakness and apnoea, and it should be avoided, if possible, in the immediate postoperative period. For details regarding interactions with calcium-channel blockers, see below.
Some antibacterials in very high concentrations can produce muscle paralysis that may be additive to or synergistic with that produced by neuromuscular blockers. The neuromuscular block produced by antibacterials may be enhanced in patients with intracellular potassium deficiency, low plasma-calcium concentration, neuromuscular disease, or a tendency to a high plasma-antibacterial concentration, for example, after large doses or renal impairment. The interaction is more important for competitive neuromuscular blockers. The antibacterials most commonly implicated are aminoglycosides, lincosamides, polymyxins, and, more rarely, tetracyclines.
The aminoglycosides reduce the release of, and sensitivity to, acetylcholine, and their effect can be reversed, at least in part, by calcium, fampridine, or an anticholinesterase. The interaction can occur with aminoglycosides given by most routes. There are reports of potentiation of neuromuscular blockade occurring with many different aminoglycoside-neuromuscular blocker combinations, and all aminoglycosides should be used with extreme caution during surgery and in the postoperative period.
The lincosamides (clindamycin and lincomycin) can prolong the action of muscle relaxants, producing a neuromuscular block that may be difficult to reverse with calcium or anticholinesterases. Patients should be monitored for prolonged paralysis.
There have been reports of prolonged apnoea after using polymyxins (colistin, polymyxin B) with a neuromuscular blocker. The block is difficult to reverse; calcium may be partially successful, but neostigmine may increase the block.
Tetracyclines have weak neuromuscular blocking properties; potentiation of the neuromuscular block has been reported in patients with myasthenia gravis. Reversal of the block may be partly achieved with calcium, but the value of anticholinesterases is questionable.
The ureidopenicillins (azlocillin and mezlocillin) and the closely related piperacillin are reported to prolong the block produced by vecuronium.
Vancomycin has been reported to increase neuromuscular blockade by vecuronium. Prolonged paralysis and apnoea have occurred in a patient recovering from suxamethonium-induced blockade after being given vancomycin.
Anticholinesterases, including ecothiopate, edrophonium, galantamine, neostigmine, pyridostigmine, rivastigmine, and possibly donepezil, antagonize the effect of competitive neuromuscular blockers. Some anticholinesterases, such as neostigmine, inhibit acetylcholinesterase and plasma cholinesterase and are used clinically to antagonize competitive neuromuscular blockade. Conversely, anticholinesterases enhance the action of depolarising muscle relaxants such as suxamethonium, thus prolonging neuromuscular block, although suxamethonium-induced phase II block can be reversed with an anticholinesterase.
Resistance to competitive neuromuscular blockers has been reported in patients receiving chronic treatment with carbamazepine or phenytoin, and rapid recovery from neuromuscular block may occur. In addition, children on chronic antiepileptic drugs (carbamazepine and/or phenytoin) recover quicker from rocuronium-induced paralysis than those not on antiepileptics. In a study with cisatracurium, faster recovery rates were also recorded in patients receiving acute or chronic treatment with unspecified antiepileptics.
However, atracurium and mivacurium appear unaffected by chronic carbamazepine therapy, and the effect of chronic phenytoin treatment on atracurium has usually been minimal. Although one study did report that epileptic patients receiving one or more antiepileptics had significantly shorter times to recover from atracurium, the authors pointed out that the patient populations were different from those in the previous studies.
A sensitivity report to vecuronium has suggested that acute dosage of phenytoin may increase rather than decrease the effect of competitive neuromuscular blockers.
It has been recommended that atracurium should be used with care in patients receiving anti-oestrogenic drugs after a case of prolonged neuromuscular blockade with atracurium in a patient receiving tamoxifen.
After reports of apnoea, caution has been advised when aprotinin is used with neuromuscular blockers.
There are conflicting reports of the effect of diazepam on neuromuscular blockers; potentiation or antagonism of neuromuscular block and a lack of interaction have all been reported.
There is conflicting evidence for the effect of beta blockers on the activity of neuromuscular blockers. Lack of effect on depolarising neuromuscular block and antagonism or enhancement of both competitive and depolarising block have been reported. The exact mechanism of interaction is not clear. There have also been reports of some neuromuscular blockers, such as atracurium and alcuronium, increasing the hypotension and bradycardia associated with the use of anesthesia in patients receiving beta-blockers; these include reports in patients using beta blockers in eye drops for glaucoma.
Botulinum A toxin
Competitive neuromuscular blockers enhance the neuromuscular block induced by botulinum toxins.
Calcium-channel blockers such as diltiazem, nicardipine, nifedipine, and verapamil enhance the effect of competitive neuromuscular blockers. Verapamil may interfere with the release of acetylcholine, and prolonged use may lead to a reduction in intracellular calcium concentration. Potentiation of the neuromuscular blockade has been reported, and the block may be resistant to reversal with neostigmine; edrophonium may be required. The dose requirement for vecuronium was reduced by as much as 50% in surgical patients receiving diltiazem.
A similar effect was seen with nicardipine, which reduced the requirement for vecuronium in a dose-dependent fashion. The interaction of vecuronium with diltiazem appeared to be due to a pharmacodynamic mechanism, but nicardipine also reduced the plasma clearance of vecuronium, indicating a partial pharmacokinetic mechanism. Nifedipine also caused an increase in the intensity and duration of action of atracurium and vecuronium when given during anesthesia.
Pancuronium or suxamethonium may interact with cardiac glycosides, increasing the incidence of arrhythmias; the interaction is more likely with pancuronium.
Antagonism of the neuromuscular blocking effects of pancuronium and vecuronium has been reported in patients taking corticosteroids. This interaction may occur only with long-term corticosteroid treatment and may be expected with all competitive neuromuscular blockers.
Furosemide, and possibly mannitol, has been reported to enhance tubocurarine neuromuscular block in patients with renal failure, but antagonism of tubocurarine by furosemide has also occurred. Small doses of furosemide (less than 100 micrograms/kg) may inhibit protein kinase, which inhibits muscle contraction and potentiates neuromuscular blockade. In contrast, high doses inhibit phosphodiesterase, increasing cAMP activity and resulting in antagonism of neuromuscular blockade. The potassium-depleting effect of diuretics may enhance the effect of competitive neuromuscular blockers.
Prolonged neuromuscular blockade has been reported in patients given neuromuscular blockers and trimetaphan. Trimetaphan may have direct neuromuscular blocking activity and some activity against plasma cholinesterase.
Neuromuscular blockers are potentiated in a dose-dependent manner by inhalation anesthetics. The dose of neuromuscular blocker may need to be reduced by up to 10% depending on the anesthetic used, its concentration, and the blocker choice; the interaction is of greater clinical importance with competitive blockers. Isoflurane, enflurane, desflurane, and sevoflurane produce the greater potentiation, followed by halothane and cyclopropane. Reversal of competitive block with an anticholinesterase has been reported to be reduced.
Potentiation of the neuromuscular blocking effects of tubocurarine and atracurium has been reported after the intravenous use of ketamine. Results from studies in vitro suggest that ketamine decreases sensitivity to acetylcholine, and it would be expected to potentiate all neuromuscular blockers, but no interaction was reported for pancuronium. Later studies have not confirmed early data suggesting that ketamine potentiates suxamethonium-induced blockade.
There are conflicting reports on the effects of histamine H2-antagonists on neuromuscular blockade. Cimetidine has been variously reported to prolong suxamethonium-induced paralysis or to have no effect. Famotidine and ranitidine have been reported not to interact with suxamethonium. Cimetidine, but not ranitidine, has been reported to delay recovery from vecuronium-induced neuromuscular block. Neither drug appeared to affect recovery after the use of atracurium.
Antagonism of the neuromuscular blocking effects of competitive neuromuscular blockers has been reported with azathioprine, although the effect may not be clinically important. Azathioprine probably inhibits phosphodiesterase activity at the motor nerve terminal, resulting in increased release of acetylcholine. Some patients receiving ciclosporin intravenously have reported prolonged neuromuscular blockade with atracurium, pancuronium, and vecuronium. This effect has been attributed to an interaction with polyethoxylated castor oil used as the solvent for intravenous ciclosporin. Still, a similar reaction has been reported in a patient receiving ciclosporin orally.
There have been isolated reports of prolonged neuromuscular blockade after using neuromuscular blockers in patients receiving lithium.
Healthy subjects who had undergone regional anesthesia of the forearm experienced symptoms suggestive of local anesthetic toxicity on deflation of the tourniquet cuff when mivacurium and prilocaine had been used together for anesthesia; giving prilocaine or mivacurium alone did not produce such an effect. The suggestion that mivacurium may alter vascular permeability, allowing a more rapid diffusion of prilocaine back into the blood from the tissues, should be investigated.
The interaction between neuromuscular blockers and lidocaine is discussed in Antiarrhythmics above.
Parenteral magnesium salts may potentiate the effects of competitive and depolarising neuromuscular blockers; the neuromuscular block is deepened and prolonged, and the blocker dose may be reduced. Magnesium salts should be used cautiously in the postoperative period, as use shortly after recovery from the neuromuscular block can lead to regularisation. Magnesium salts reduce the release of and sensitivity to acetylcholine, thus contributing to neuromuscular blockade.
Pancuronium appears to be a theoretical hazard in patients receiving MAOIs since it releases stored adrenaline; alcuronium, atracurium, or vecuronium are suitable alternatives.
A competitive neuromuscular blocker given shortly before a depolarising blocker, such as suxamethonium, antagonizes the depolarising neuromuscular block. This interaction has been used clinically to reduce muscle fasciculations caused by suxamethonium and for other adverse effects associated with suxamethonium. To achieve this antagonism, a small, non-paralysing dose of a competitive blocker is given before suxamethonium.
If a paralyzing dose of a competitive blocker is followed sometime later with a dose of suxamethonium, for example, to facilitate abdominal closure, the resulting neuromuscular block is influenced by the competitive blocker used, the depth of the residual block, the dose of suxamethonium, and whether an anticholinesterase is given; antagonism, enhancement, and a combination of the two have been seen.
A competitive blocker is often given after the short-acting suxamethonium to maintain neuromuscular blockade during lengthy procedures. The action of the competitive blocker has been reported to be considerably potentiated and prolonged in these circumstances, and a reduction in the dose of the competitive blocker may be appropriate.
A combination of competitive blockers may have additive or synergistic effects, and the interaction may differ depending on which blocker is given first. Caution is needed if a small dose of a shorter-acting blocker is given near the end of an operation in which a long-acting blocker has been given previously since the resulting block may be greater than expected and much longer than desired.
Resistance to the neuromuscular blocking effects of suxamethonium and vecuronium in a patient was attributed to previous long-term therapy with testosterone, although the exact mechanism could not be explained. See also under Interactions of Suxamethonium Chloride.
Smoking may affect the dose requirements for neuromuscular blockers. One study found that smokers needed more vecuronium than non-smokers; it was considered that the effect might be explained at the receptor level, although increased metabolism of vecuronium could not be excluded. In contrast, an earlier study found the amount of atracurium required was reduced in smokers.
Intravenous salbutamol has been reported to enhance the blockade obtained with pancuronium and vecuronium. See also under Interactions of Suxamethonium Chloride.
Resistance to neuromuscular block with pancuronium, requiring an increase in dosage or transfer to vecuronium, has been reported in patients receiving aminophylline with or without corticosteroid therapy. This effect may be due to inhibiting phosphodiesterase by aminophylline, which results in increased release of acetylcholine at the nerve terminal.
(British Approved Name, rINN)
International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):
Synonyms: 33A74; Atracurii Besilas; Atracurio, besilato de; Atracurium Besylate; Atrakurio besilatas; Atrakurium-besylát; Atrakuriumbesilaatti; Atrakuriumbesilat; BW-33A; Besilato de atracurio
BAN: Atracurium Besilate
USAN: Atracurium Besylate
INN: Atracurium Besilate [rINN (en)]
INN: Besilato de atracurio [rINN (es)]
INN: Atracurium, Bésilate d’ [rINN (fr)]
INN: Atracurii Besilas [rINN (la)]
INN: Атракурия Безилат [rINN (ru)]
Chemical name: 2,2´-(3,11-Dioxo-4,10-dioxatridecamethylene)bis(1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-veratrylisoquinolinium) di(benzenesulphonate)
Molecular formula: C53H72N2O12,2C6H5O3S =1243.5
ATC code: M03AC04
Read code: y03Jb
Pharmacopoeias. In Europe and the US.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Atracurium Besilate). A white to yellowish-white, slightly hygroscopic powder. It contains 55.0 to 60.0% of the cis-cis isomer, 34.5 to 38.5% of the cis-trans isomer, and 5.0 to 6.5% of the trans-trans isomer. Soluble in water; very soluble in alcohol, in acetonitrile, and in dichloromethane. Store in airtight containers at a temperature of 2° to 8°. Protect from light.
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Atracurium Besylate). A white to off-white solid. It contains not less than 5.0% and not more than 6.5% of the trans-trans isomer, not less than 34.5% and not more than 38.5% of the cis-trans isomer, and not less than 55.0% and not more than 60.0% of the cis-cis isomer. It is unstable at room temperature. Store in airtight containers at a temperature not exceeding 8°. Protect from light.
Synonyms: 51W89 (cisatracurium); Bésilate de Cisatracurium; BW-51W (cisatracurium); BW-51W89 (cisatracurium); Besilato de cisatracurio; Cisatracurio, besilato de; Cisatracurium Besylate
BAN: Cisatracurium Besilate
INN: Cisatracurium Besilate [rINN (en)]
INN: Besilato de cisatracurio [rINN (es)]
INN: Cisatracurium, Bésilate de [rINN (fr)]
INN: Cisatracurii Besilas [rINN (la)]
INN: Цисатракурия Безилат [rINN (ru)]
Chemical name: (1R,1´R,2R,2´R)-2,2´-(3,11-Dioxo-4,10-dioxatridecamethylene)bis(1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-veratrylisoquinolinium) dibenzenesulfonate
ATC code: M03AC11
Read code: y08Xu
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Atracurium Besylate Injection.
Argentina: Gelolagar; Nimbex ; Nimbium; Tracrium; Tracurix; Tracuron;
Australia: Nimbex; Tracrium;
Austria: Nimbex; Tracrium;
Belgium: Nimbex; Tracrium;
Brazil: Abbottracurium; Nimbium; Sitrac ; Tracrium; Tracur;
Chile: Nimbex; Tracrium;
Czech Republic: Nimbex; Tracrium;
Denmark: Nimbex; Tracrium ;
France: Nimbex; Tracrium;
Germany; Nimbex; Tracrium;
Greece: Nimbex; Tracrium;
Hong Kong; Nimbex; Tracrium;
Hungary: Nimbex; Tracrium;
Indonesia: Notrixum; Tracrium; Tramus
Ireland: Nimbex; Tracrium;
Israel: Nycurium; Tracrium;
Italy: Acurmil; Nimbex Tracrium;
Malaysia: Nimbex; Tracrium;
Mexico: Ifacur ; Nimbex; Relatrac Trablok; Tracrium;
Netherlands: Nimbex; Tracrium;
New Zealand: Tracrium;
Poland: Abbocurium; Nimbex; Tracrium;
Portugal: Faulcurium; Nimbex; Tracrium;
Russia: Nimbex; Tracrium;
South Africa: Nimbex; Tracrium;
Singapore: Nimbex ; Tracrium;
Spain: Laurak; Nimbex; Tracrium;
Sweden: Nimbex; Tracrium;
Switzerland: Nimbex; Tracrium;
Thailand: Nimbex; Tracrium;
Turkey: Dematrac; Nimbex; Tracrium;
United Kingdom (UK): Nimbex; Tracrium;
United States of America (USA): Nimbex; Tracrium.