Neuromuscular Nondepolarizing Agent, Nicotinic Antagonist, Neuromuscular blocking agent, (close to doxacurium) Cisatracurium is the 1R-cis 1'R-cis isomer of atracurium. Atracurium and Cisatracurium undergo spontaneous non-organ-dependent Hofmann degradation at physiological pH and temperature. Ligand of small conductance Ca2+-activated K+ (SKca) channels
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11 moreTitle: Protein binding of atracurium and other short-acting neuromuscular blocking agents and their interaction with human cholinesterases Foldes FF, Deery A Ref: British Journal of Anaesthesia, 55:31S, 1983 : PubMed
The interaction of three new non-depolarizing neuromuscular blocking agents--atracurium, vecuronium and Duador--on human red cell acetylcholinesterase (AChE; EC 3.1.1.7) and human plasma butyrylcholinesterase (BuChE; EC 3.1.1.8) was investigated. The binding of these neuromuscular blockers to human plasma proteins (protein binding) was also studied with a new method not requiring dialysis. For sake of comparison the protein binding and the interaction of tubocurarine and pancuronium with AChE and BuChE were observed also. None of the drugs studied was a substrate of AChE or BuChE. All had a relatively weak inhibitory effect on AChE (I50 greater than 10(-5) mol litre-1 in assay systems containing 5% haemolysed red cells). Of the three new neuromuscular blockers, vecuronium and Duador were relatively potent inhibitors of BuChE (I50 less than 10(-5) mol litre-1 in assay systems containing 5% plasma), but less potent than pancuronium (I50 = 6.1 X 10(-8) mol litre-1). All neuromuscular blocking drugs tested, especially vecuronium and pancuronium, were strongly (77-91%) bound to plasma proteins.
Atracurium, a new non-depolarizing neuromuscular blocking agent, was studied in 70 patients anesthetized with fentanyl, thiopental, and nitrous oxide-oxygen. The dose found to produce 95% twitch inhibition (ED95) was 0.2 mg/kg. The onset time from injection to maximum depression of twitch was 4.0 minutes at this dose; the duration to 95% recovery was 44.1 minutes. Twice the ED95 dose (0.4 mg/kg) had an onset time of 1.7 minutes and a duration of 63.5 minutes. No cardiovascular effects were observed in this dosage range. At higher doses (0.5 and 0.6 mg/kg) arterial pressure decreased 13% and 20% and heart rate increased 5% and 8%, respectively. Sixteen patients received at least four successive doses of atracurium. No clinically significant cumulative effect could be shown when recovery from 25% to 75% of control twitch height was compared for initial and final doses in the series. Atracurium spontaneously decomposes at physiologic pH via the Hofmann elimination reaction and may also undergo ester hydrolysis independent of plasma cholinesterase. These proposed pathways of inactivation may explain the lack of cumulative effect and the drug's intermediate duration of action. Based on the results of this study, atracurium offers several clinical advantages and should undergo more extensive clinical trials.
        
Title: The pharmacology of atracurium: a new competitive neuromuscular blocking agent Hughes R, Chapple DJ Ref: British Journal of Anaesthesia, 53:31, 1981 : PubMed
Atracurium besylate, 2,2'-(3,11-dioxo-4,10-dioxatridecylene)-bis-[6,7-dimethoxy-1-(3,4-dimethoxy-benzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolinium] dibenzenesulphonate, is one of a new series of competitive neuromuscular blocking agents. An i.v. dose of 0.25 mg kg-1 produced complete paralysis in anaesthetized cats, dogs and rhesus monkeys; paralysis was of medium duration and was readily antagonized by neostigmine. Vagal blockade occurred only after doses 8--16 times greater than the full neuromuscular paralysing dose and effects on sympathetic mechanisms were minimal. Hypotension and bradycardia were evident after supramaximal doses of 4 mg kg-1 i.v. and these effects, together with circulatory depression, were probably attributable to histamine release. In vitro studies have shown that the non-enzymic decomposition of atracurium by "Hofmann Elimination" was enhanced by increasing pH. In vivo neuromuscular paralysis was significantly reduced when the arterial pH was increased. There were indications that neither the liver nor the kidney plays a major role in the metabolism and elimination of unchanged drug. These results are of sufficient interest to merit the evaluation of atracurium in anaesthetized man.
To investigate the relationship between total body weight (TBW) or body mass index (BMI) and atracurium reversal time.
METHODS:
The study population comprised 25 patients with TBW < 80 kg and 25 patients with TBW > or = 80 kg anaesthetised with midazolam, thiopentone, fentanyl, nitrous oxide and halothane. Neuromuscular block was induced with 0.5 mg.kg-1 atracurium and maintained with doses of 0.15 mg.kg-1. Neuromuscular transmission was recorded using train-of-four (TOF) nerve stimulation and mechanomyography. Neostigmine, 0.07 mg.kg-1, was administered when the first twitch in TOF had recovered to 10% of control. Reversal time was defined as: time from administration of neostigmine until TOF ratio recovered to 0.70.
RESULTS:
There was no difference in reversal time between patients with TBW < 80 kg (7.2 +/- 2.6 min, mean +/- SD), and patients with TBW > or = 80 kg (6.9 +/- 3.6 min). When patients were grouped according to BMI there was no difference in reversal time between groups with low BMI (6.9 +/- 2.6 min) or high BMI (7.1 +/- 3.6 min). There was, furthermore, no difference in reversal time between the 15 patients in the study population with the smallest TBW or BMI and the 15 patients with the greatest TBW or BMI. There was no correlation between TBW or BMI and reversal time.
CONCLUSION:
When atracurium-induced neuromuscular block is antagonised with 0.07 mg.kg-1 neostigmine. TBW or BMI have no influence on reversal time.
This review discusses concepts of isomers, stereoisomers, chirality, and enantiomers as applied to drugs used in anaesthesia. The inhalational anaesthetics enflurane and isoflurane are examples of stereoisomers. A chiral centre is formed when a carbon or quaternary nitrogen atom is connected to four different atoms. A molecule with one chiral centre is then present in one of two possible configurations termed enantiomers. A racemate is a mixture of both enantiomers in equal proportions. Many of the drugs used in anaesthesia are racemic mixtures (the inhalation anaesthetics, local anaesthetics, ketamine, and others). The shape of the atracurium molecule is comparable to that of a dumb-bell:the two isoquinoline groups representing the two bulky ends connected by an aliphatic chain. In each isoquinoline group there are two chiral centres, one formed by a carbon and the other by a quaternary nitrogen atom. From a geometric point of view, the connections from the carbon atom to a substituted benzene ring and from the quaternary nitrogen to the aliphatic chain may point in the same direction (cis configuration) or in opposite directions (trans configuration). The two isoquinoline groups in atracurium are paired in three geometric configurations: cis-cis, trans-trans, or cis-trans. However, the two chiral centres allow each isoquinoline group to exist in one of four stereoisometric configurations. In the symmetrical atracurium molecule, the number of possible stereoisomers is limited to ten. Among these, 1 R-cis, 1'R-cis atracurium was isolated and its pharmacologic properties studied. This isomer, named cis-atracurium, offers clinical advantages over the atracurium mixture, principally due to the lack of histamine-releasing propensity and the higher neuromuscular blocking potency. The ester groups appear in one of two steric configurations true and reverse esters. In the true esters, oxygen is positioned between the nitrogen atom and the carbonyl group, while in the reverse esters in its positioned on the other side of the carbonyl group. True esters, suxamethonium and mivacurium, are hydrolysed by the enzyme plasma cholinesterase (butyrylcholinesterase), albeit at different rates. The more rapid degradation of suxamethonium is responsible for its fast onset and short duration of action in comparison with mivacurium. The reverse esters, atracurium, cisatracurium, and remifentanil, are hydrolysed by nonspecific esterases in plasma (carboxyesterases). Remifentanil is hydrolysed rapidly; the degradation leads to its inactivation and short duration of action. Cis-atracurium is preferentially degraded and inactivated by a process known as Hofmann elimination. In a second step, one of the degradation products, the monoester acrylate, is hydrolysed by a nonspecific esterase.
        
Title: [Profile of the effect of succinylcholine after pre-curarization with atracurium, vecuronium or pancuronium] Ebeling BJ, Keienburg T, Hausmann D, Apffelstaedt C Ref: Anasthesiol Intensivmed Notfallmed Schmerzther, 31:304, 1996 : PubMed
OBJECTIVE The depolarizing muscle relaxant succinylcholine (SCh) may cause several side effects including muscle fasciculations and postoperative myalgia. These can be attenuated or even prevented by prior administration of a non-depolarizing muscle relaxant. A study was conducted to detect any difference between clinically established approaches concerning the successful prevention of muscular side effects and the influence on the time profile of SCh action.
METHODS:
The study included 64 patients (ASA status I or II) who underwent elective surgery under general anesthesia. The patients were divided into four groups; the demographic data did not differ significantly between the groups (see table 1). Before the injection of SCh (1 mg/kg) for intubation, the control group received saline (K), the other groups 5 mg Atracurium (A), 1 mg Vecuronium (V), or 1 mg Pancuronium (P), respectively. Neuromuscular block was quantified after train-of-four (TOF) stimulation of the tibial nerve by accelerometry at the toe. The first response was used to determine the onset time, duration of effect, and recovery index. It was noted whether SCh led to muscular activity. Postoperatively, patients were asked whether they experienced any muscular sequelae. Statistical significance was assessed at the 5% probability level by the Mann-Whitney-U test and the CHi2 test (Fisher's exact test, if appropriate).
RESULTS:
SCh caused a complete neuromuscular block in all patients. Most patients in the control group exhibited muscular contractions than in the other groups (see table 2), but only two patients reported light myalgia. There was no statistically significant difference between the four groups in the onset time and the recovery index of SCh. The duration of the effect was significantly reduced by atracurium (7.5 min) or vecuronium (8.2 min) as compared to the placebo (11.8 min) and pancuronium (13.5 min) (see figure).
CONCLUSION:
The prolonged duration of the SCh effect after pancuronium is probably due to the known inhibition of cholinesterase by pancuronium. The short duration of action after Atracurium and Vecuronium can be explained by the competitive antagonism at the receptor causing an increased amount of unbound SCh. The duration of the SCh effect may be influenced according to clinical needs by the choice of the non-depolarizing muscle relaxant. The significantly reduced duration of complete neuromuscular block after Atracurium or Vecuronium as precurarizing agents may be advantageous in cases where a fast recovery of spontaneous breathing is essential. If a reduction of the SCh blockade has to be avoided, Pancuronium should be selected for prior administration.
        
Title: Administration of 51W89 by infusion--a comparison with atracurium-- preliminary communication Mellinghoff H, Diffenbach C, Buzello W Ref: Acta Anaesthesiologica Scandinavica Supplementum, 106:95, 1995 : PubMed
Recovery from the effects of muscle relaxants can occur either spontaneously by their metabolism in the body or by elimination via the normal excretion pathways, or by the administration of pharmacologic antagonists. The decision as to whether spontaneous recovery should be allowed to take place or pharmacologic reversal should be induced depends upon several factors, principal among them being the duration of action of the muscle relaxant used, its dose, and the time that is available. The recovery times of most relaxants, including atracurium and vecuronium, are such as to require antagonism if adequate recovery is to be attained quickly. An agent such as mivacurium may, however, allow complete spontaneous recovery to take place without the use of antagonists.
Four neuromuscular blocking drugs, doxacurium, mivacurium, pipecuronium, and rocuronium have been or are about to be introduced into clinical practice. The purpose of this MiniReview is to describe their pharmacology, to consider their place in clinical anaesthetic practice, and to examine whether the needs of the clinician have been met. Two of the agents (doxacurium, mivacurium) are benzylisoquinolines resembling atracurium and two (pipecuronium, rocuronium) are aminosteroids related to pancuronium and vecuronium. Two (doxacurium, pipecuronium) are long-acting compounds, similar in duration of action to pancuronium, although the need for such a profile is questionable. Rocuronium has an intermediate duration of action and produces its maximum effect within two minutes which is much more rapid than any other non-depolarizing relaxant and this is probably a result of its poor potency. However, the onset of paralysis is not as quick as after succinylcholine. Mivacurium is unique because it is metabolized by plasma cholinesterase which produces a rapid recovery although slower than succinylcholine. All of the new drugs are devoid of serious cardiovascular or other side effects. The anaesthetist is now presented with an armamentarium of safe, nondepolarizing muscle relaxants with varying durations of action. However, the rapid onset and recovery associated with succinylcholine are unique and important in the urgent control of a patient's airway and respiration. The indications for succinylcholine will not disappear and the search for a non-polarizing replacement will continue.
        
Title: Suxamethonium and atracurium: sequential and simultaneous administration Harper NJ, Chadwick IS, Linsley A Ref: European Journal of Anaesthesiology, 10:13, 1993 : PubMed
The interaction between suxamethonium and atracurium was investigated during anaesthesia with thiopentone, fentanyl, enflurane and nitrous oxide in oxygen with controlled ventilation. Electromyographic data (Relaxograph, Datex) from 30 patients in three, equal groups were analyzed. Group 1 received atracurium 0.23 mg kg-1. Group 2 received suxamethonium 1 mg kg-1 followed by atracurium 0.23 mg kg-1 when the EMG had recovered to 20% of its control value: a sequence intended to be representative of clinical practice. Group 3 received suxamethonium 1 mg kg-1 and atracurium 0.23 mg kg-1 in rapid succession. Plasma cholinesterase concentrations and Dibucaine and fluoride numbers were within normal limits in all patients. Suxamethonium given for endotracheal intubation (group 2) neither potentiated the subsequent atracurium blockade nor delayed spontaneous recovery. When suxamethonium and atracurium were given in rapid succession (group 3), the duration of suxamethonium blockade was reduced considerably but the recovery from the atracurium component of the blockade was not significantly different from groups 1 and 2. Although the intubation score at 60s was no worse in group 3, the duration of profound blockade suitable for intubation was reduced to such an extent that the simultaneous administration of suxamethonium and atracurium cannot be recommended in clinical practice when there is a requirement for rapid endotracheal intubation.
        
Title: Electroconvulsive therapy and the chronic use of pseudocholinesterase- inhibitor (echothiophate iodide) eye drops for glaucoma. A case report Messer GJ, Stoudemire A, Knos G, Johnson GC Ref: General Hospital Psychiatry, 14:56, 1992 : PubMed
A case is presented in which a patient who required treatment with electroconvulsive therapy had a history of being treated with pseudocholinesterase-inhibitor eye drops (echothiophate iodide) for glaucoma. As treatment with this antiglaucoma agent contraindicated the use of succinylcholine for a minimum of 10-14 days, the short-acting nondepolarizing agent atracurium was employed instead. The anesthetic management of this patient is described as a guide for clinicians facing similar clinical situations.
        
Title: Atracurium administration, as an infusion, to induce neuromuscular blockade in clinically normal and temporarily immune-suppressed cats Ilkiw JE, Forsyth SF, Hill T, Gregory CR Ref: J Am Vet Med Assoc, 197:1153, 1990 : PubMed
Atracurium besylate, a nondepolarizing neuromuscular blocking agent, was administered by infusion to 10 cats that were anesthetized with isoflurane and oxygen to allow transplantation of a myocutaneous flap. Five of the cats were given cyclosporine (20 mg/kg of body weight, PO q 12 h in divided doses) for 2 days prior to anesthesia, and prednisolone (0.25 mg/kg, PO) on the morning of surgery. The other 5 cats were not given either drug. Neuromuscular blockade was assessed, using the train-of-four stimulation, and throughout surgery, the infusion rate was adjusted to maintain the first-twitch response (T1) at 90 to 95% depression from baseline. At completion of surgery, atracurium was discontinued, and the infusion rate and the time for recovery (the time for the train-of-four ratio to increase from 50 to 75%) were recorded. Once the train-of-four ratio had been stable for 10 minutes, edrophonium (0.5 mg/kg), a cholinesterase inhibitor, was administered IV, and neuromuscular blockade was monitored for another 10 minutes. Mean (+/- SD) duration of the atracurium infusion was 302.1 +/- 70.5 minutes for the control group and was 323.9 +/- 61.7 minutes for the cats given cyclosporine and prednisolone. In the cats of the control group, the infusion rate required to induce 90 to 95% T1 depression from baseline was 3.7 +/- 0.7 micrograms/kg/min. This rate was not significantly different from that of 2.8 +/- 1.2 micrograms/kg/min in cats given cyclosporine and prednisolone. Significant difference in recovery time was not evident between the control group and the treated group (6.4 +/- 4.5 minutes vs 6.2 +/- 2.5 minutes).
        
Title: The effect of the organophosphate trichlorfon on the neuromuscular blocking activity of atracurium in halothane-anesthetized horses Hildebrand SV, Hill Td, Holland M Ref: J Vet Pharmacol Ther, 12:277, 1989 : PubMed
To determine whether cholinesterase inhibition by an organophosphate would influence atracurium's neuromuscular blockade, six horses were anesthetized and paralyzed with atracurium (total of five injections per horse) on experimental Day 1, then were given trichlorfon (64 mg/kg per os) 6 days later. On Day 7, horses were anesthetized and paralyzed in the same manner as on experimental Day 1. Blood was taken to measure serum cholinesterase activity prior to anesthesia on Days 1 and 7. No significant difference was noted in atracurium's neuromuscular blocking activity between the 2 experimental days (P less than 0.05), despite Day 7 cholinesterase activity that was 16% of pre-trichlorfon values. For atracurium Injections 1 and 2-5, 85 and 43 micrograms/kg of atracurium, respectively, were required to produce a 95-99% reduction in hoof twitch. The time from injection to maximum twitch reduction was approximately 9 min after Injection 1 and 5 min after subsequent injections. Time from injection to maximum twitch reduction was significantly longer for Injection 1 than Injections 2-5 on both experimental days. The time from maximum twitch reduction until 10% recovery was approximately 8 min, with no significant difference between experimental days. The time for twitch recovery from 10 to 75% was approximately 17 min for all injections. Antagonism of atracurium with edrophonium caused the twitch height to return to pre-atracurium strength in approximately 7 min. Edrophonium caused a significant increase in arterial blood pressure. Heart rate change was variable after edrophonium
Mivacurium chloride (BW B1090U) is a new, short-acting non-depolarizing neuromuscular blocking agent. It is a synthetic bis-benzylisoquinolinium diester, which is hydrolysed rapidly by plasma cholinesterase. This study compares mivacurium, atracurium and vecuronium by continuous i.v. infusion. The duration of mivacurium infusion ranged from 29.5 to 286 min. The steady state infusion rates necessary to maintain 95 (SEM 4)% twitch suppression were: mivacurium 8.3 (0.7) micrograms kg-1 min-1; atracurium 7.9 (0.4) micrograms kg-1 min-1; vecuronium 1.2 (0.3) micrograms kg-1 min-1. Following infusions of mivacurium, various recovery times (for example: 25-75%, 6.9 (0.3) min; 25-95%, 11.0 (0.4) min; 5-95% 14.5 (0.4) min) did not differ significantly from those following single bolus doses. Recovery times following cessation of mivacarium infusions were approximately 50% of those for equivalent durations of infusion of atracurium (10.9 (0.3) min for 25-75% recovery and 26.6 (0.4) min for 5-95% recovery). For vecuronium, corresponding recovery times were 13.8 (0.9) and 32.0 (1.2) min, respectively. Comparative recovery times for mivacurium were 40-50% of those for vecuronium. There was a significant correlation between the infusion rate of mivacurium required to maintain 95% twitch depression and the plasma cholinesterase activity of individual subjects.
        
Title: Protein binding of atracurium and other short-acting neuromuscular blocking agents and their interaction with human cholinesterases Foldes FF, Deery A Ref: British Journal of Anaesthesia, 55:31S, 1983 : PubMed
The interaction of three new non-depolarizing neuromuscular blocking agents--atracurium, vecuronium and Duador--on human red cell acetylcholinesterase (AChE; EC 3.1.1.7) and human plasma butyrylcholinesterase (BuChE; EC 3.1.1.8) was investigated. The binding of these neuromuscular blockers to human plasma proteins (protein binding) was also studied with a new method not requiring dialysis. For sake of comparison the protein binding and the interaction of tubocurarine and pancuronium with AChE and BuChE were observed also. None of the drugs studied was a substrate of AChE or BuChE. All had a relatively weak inhibitory effect on AChE (I50 greater than 10(-5) mol litre-1 in assay systems containing 5% haemolysed red cells). Of the three new neuromuscular blockers, vecuronium and Duador were relatively potent inhibitors of BuChE (I50 less than 10(-5) mol litre-1 in assay systems containing 5% plasma), but less potent than pancuronium (I50 = 6.1 X 10(-8) mol litre-1). All neuromuscular blocking drugs tested, especially vecuronium and pancuronium, were strongly (77-91%) bound to plasma proteins.
Atracurium, a new non-depolarizing neuromuscular blocking agent, was studied in 70 patients anesthetized with fentanyl, thiopental, and nitrous oxide-oxygen. The dose found to produce 95% twitch inhibition (ED95) was 0.2 mg/kg. The onset time from injection to maximum depression of twitch was 4.0 minutes at this dose; the duration to 95% recovery was 44.1 minutes. Twice the ED95 dose (0.4 mg/kg) had an onset time of 1.7 minutes and a duration of 63.5 minutes. No cardiovascular effects were observed in this dosage range. At higher doses (0.5 and 0.6 mg/kg) arterial pressure decreased 13% and 20% and heart rate increased 5% and 8%, respectively. Sixteen patients received at least four successive doses of atracurium. No clinically significant cumulative effect could be shown when recovery from 25% to 75% of control twitch height was compared for initial and final doses in the series. Atracurium spontaneously decomposes at physiologic pH via the Hofmann elimination reaction and may also undergo ester hydrolysis independent of plasma cholinesterase. These proposed pathways of inactivation may explain the lack of cumulative effect and the drug's intermediate duration of action. Based on the results of this study, atracurium offers several clinical advantages and should undergo more extensive clinical trials.
        
Title: The pharmacology of atracurium: a new competitive neuromuscular blocking agent Hughes R, Chapple DJ Ref: British Journal of Anaesthesia, 53:31, 1981 : PubMed
Atracurium besylate, 2,2'-(3,11-dioxo-4,10-dioxatridecylene)-bis-[6,7-dimethoxy-1-(3,4-dimethoxy-benzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolinium] dibenzenesulphonate, is one of a new series of competitive neuromuscular blocking agents. An i.v. dose of 0.25 mg kg-1 produced complete paralysis in anaesthetized cats, dogs and rhesus monkeys; paralysis was of medium duration and was readily antagonized by neostigmine. Vagal blockade occurred only after doses 8--16 times greater than the full neuromuscular paralysing dose and effects on sympathetic mechanisms were minimal. Hypotension and bradycardia were evident after supramaximal doses of 4 mg kg-1 i.v. and these effects, together with circulatory depression, were probably attributable to histamine release. In vitro studies have shown that the non-enzymic decomposition of atracurium by "Hofmann Elimination" was enhanced by increasing pH. In vivo neuromuscular paralysis was significantly reduced when the arterial pH was increased. There were indications that neither the liver nor the kidney plays a major role in the metabolism and elimination of unchanged drug. These results are of sufficient interest to merit the evaluation of atracurium in anaesthetized man.