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Cisatracurium (formerly recognized as 51W89,^[1] and marketed as Nimbex) is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. It is a bisbenzyltetrahydroisoquinolinium agent with an intermediate duration of action. Cisatracurium is one of the ten isomers of the parent molecule, atracurium.^[2] Moreover, cisatracurium represents approximately 15% of the atracurium mixture.^[3]

History

The generic name cisatracurium was conceived by scientists at Burroughs Wellcome Co. (now part of GlaxoSmithKline) by combining the name "atracurium" with "cis" [hence cisatracurium] because the molecule is one of the three cis-cis isomers comprising the ten isomers of the parent, atracurium.^[2] Atracurium itself was invented at Strathclyde University and licensed to Burroughs Wellcome Co., Research Triangle Park, NC, for further development and subsequent marketing as Tracrium. As the secondary pharmacology of atracurium was being developed, it became clear that the primary clinical disadvantage of atracurium was likely to be its propensity to elicit histamine release. To address this issue, a program was initiated to investigate the individual isomer constituents of atracurium to identify and isolate the isomer(s) associated with the undesirable histamine effects as well as identify the isomer that might possibly retain the desirable properties without the histamine release. Thus, in 1989, D A Hill and G L Turner, PhD (both chemists at Burroughs Wellcome Co., Dartford, UK) first synthesized cisatracurium as an individual isomer molecule. The pharmacological research of cisatracurium and the other individual isomers^[4] was then developed further primarily by R. Brandt Maehr and William B. Wastila, PhD (both of whom were pharmacologists within the Division of Pharmacology at Burroughs Wellcome Co.) in collaboration with John J. Savarese MD (who at the time was an anesthesiologist in the Dept. of Anesthesia, Harvard Medical School at the Massachusetts General Hospital, Boston, MA). Thereafter, the entire clinical development of cisatracurium was completed in a record short period from 1992 to 1994: the team of scientists was led by J. Neal Weakly PhD, Martha M. Abou-Donia PhD, and Steve Quessy PhD, in the Division of Clinical Neurosciences at Burroughs Wellcome Co., Research Triangle Park, NC. By the time of its approval for human use, in 1995, by the US Food and Drug Administration, Burroughs Wellcome Co. had merged with Glaxo Inc., and cisatracurium was approved to be marketed as Nimbex by GlaxoWellcome Inc. The trade name "Nimbex" was derived from inserting an "i" to the original proposal "Nmbex," which stood for excellent Neuromuscular blocker.

Preclinical pharmacology

In vitro studies using human plasma indicated that cisatracurium spontaneously degrades at physiological pH via Hofmann elimination to yield laudanosine and the quaternary monoacrylate. Subsequent ester hydrolysis of the monoacrylate generates the monoquaternary alcohol, although the rate-limiting step is Hofmann elimination.^[3] In rat plasma, cisatracurium is also metabolized by non-specific carboxylesterases (a rate-limiting step) to the monoquaternary alcohol and the monoquaternary acid.^[3]

Clinical pharmacology

As is evident with the parent molecule, atracurium,^[5]^[6] cisatracurium is also susceptible to degradation by Hofmann elimination and ester hydrolysis as components of the in vivo metabolic processes.^{[citation needed]} See the atracurium page for information on Hofmann elimination in vivo versus the Hofmann degradation chemical reaction.

Because Hofmann elimination is a temperature- and plasma pH-dependent process, cisatracurium's rate of degradation in vivo is highly influenced by body pH and temperature just as it is with the parent molecule, atracurium: thus, an increase in body pH favors the elimination process,^{[citation needed]} whereas a decrease in temperature slows down the process.

One of the metabolites of cistracurium via Hofmann elimination is laudanosine - see the atracurium page for further discussion of the issue regarding this metabolite. 80% of cisatracurium is metabolized eventually to laudanosine and 20% is metabolized hepatically or excreted renally.^{[citation needed]} 10-15% of the dose is excreted unchanged in the urine.^{[citation needed]}

Since Hofmann elimination is an organ-independent chemodegradative mechanism, there is little or no risk to the use of cisatracurium in patients with liver or renal disease when compared with other neuromuscular-blocking agents.^[7]

The two reverse ester linkages in the bridge between the two isoquinolinium groups make atracurium and cisatracurium poor targets for plasma cholinesterase, unlike mivacurium which has two conventional ester linkages.

Adverse effects

Histamine release - hypotension, reflex tachycardia and cutaneous flush

Unlike the parent, atracurium, cisatracurium affords a much better pharmacological profile with respect to eliciting histamine release.

Bronchospasm - Pulmonary compliance

To date, cisatracurium has not been reported to elicit bronchospasm at doses that are clinically prescribed.

Laudanosine - Epileptic foci

Cisatracurium undergoes Hofmann elimination as a primary route of chemodegradation: consequently one of the metabolites from this process is laudanosine, a tertiary amino alkaloid reported to be a modest CNS stimulant with epileptogenic activity^[8] and cardiovascular effects such as low blood pressure and a slowed heart rate.^[9] As a tertiary amine, Laudanosine is unionised and readily crosses the blood–brain barrier. Presently, there is little evidence that laudanosine accumulation and related toxicity will likely ever be seen with the doses of cisatracurium that are administered in clinical practice especially given that the plasma concentrations of laudanosine generated are lower with cisatracurium than those seen with atracurium.^[9]

Research

A recent study showed that cisatracurium pretreatment effectively decreases the incidence and severity of pain induced by propofol general anaesthesia. ^[10]

References

^ Meretoja OA, Taivainen T, Wirtavuori K (Jan 1995). "Pharmacodynamic effects of 51W89, an isomer of atracurium, in children during halothane anaesthesia". Br J Anaesth 74 (1): 6–11. doi:10.1093/bja/74.1.6. PMID 7880708.
^ ^a ^b Stenlake JB, Waigh RD, Dewar GH, Dhar NC, Hughes R, Chapple DJ, Lindon JC, Ferrige AG. (1984). "Biodegradable neuromuscular blocking agents. Part 6. Stereochemical studies on atracurium and related polyalkylene di-esters.". Eur J Med Chem 19 (5): 441–450.
^ ^a ^b ^c Dear GJ, Harrelson JC, Jones AE, Johnson TE, Pleasance S (1995). "Identification of urinary and biliary conjugated metabolites of the neuromuscular blocker 51W89 by liquid chromatography/mass spectrometry". Rapid Commun Mass Spectrom 9 (14): 1457–1464. doi:10.1002/rcm.1290091425. PMID 8534894.
^ Wastila WB, Maehr RB, Turner GL, Hill DA, Savarese JJ (Jul 1996). "Comparative pharmacology of cisatracurium (51W89), atracurium, and five isomers in cats". Anesthesiol 85 (1): 169–177. doi:10.1097/00000542-199607000-00023. PMID 8694363.
^ Stiller RL, Cook DR, Chakravorti S. (1985). "In vitro degradation of atracurium in human plasma". Br J Anaesth 57 (11): 1085–1088. doi:10.1093/bja/57.11.1085. PMID 3840382.
^ Nigrovic V, Fox JL. (1991). "Atracurium decay and the formation of laudanosine in humans". Anesthesiol 74 (3): 446–454. doi:10.1097/00000542-199103000-00010. PMID 2001023.
^ Katzung, Bertram G. (2011). Basic and clinical pharmacology. (12th ed.). New York: Mcgraw-Hill. ISBN 978-0071764018.
^ Standaert FG (Dec 1985). "Magic bullets, science, and medicine". Anesthesiol 63 (6): 577–578. doi:10.1097/00000542-198512000-00002. PMID 2932980.
^ ^a ^b Fodale V, Santamaria LB (Jul 2002). "Laudanosine, an atracurium and cisatracurium metabolite". Eur J Anaesthesiol 19 (7): 466–473. doi:10.1017/s0265021502000777. PMID 12113608.
^ Kim YH (Apr 2014). "Cisatracurium pretreatment with tourniquet reduces propofol injection pain: a double-blind randomized controlled trial..". J Int Med Res. 42 (2): 360–7. doi:10.1177/0300060514522602. PMID 24573971.

UpToDate Contents

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1. Anesthesia for the patient with myasthenia gravis
2. 重症患者における神経筋遮断剤の使用 use of neuromuscular blocking medications in critically ill patients
3. Anesthesia for patients with chronic obstructive pulmonary disease
4. Anesthesia for tonsillectomy with or without adenoidectomy in children
5. 成人における選択的脊椎手術のための麻酔 anesthesia for elective spine surgery in adults

English Journal

High-performance liquid chromatography assay with programmed flow elution for cisatracurium in human plasma: Application to pharmacokinetics in infants and children.

Gao J1, Yang T1, Ye M2, Zhang X1, Tian G1, Zhen Q1, Ding M3.Author information 1Key Laboratory of Clinical Laboratory Diagnostics, Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, PR China.2Department of Anesthesiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, PR China.3Key Laboratory of Clinical Laboratory Diagnostics, Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, PR China. Electronic address: dingmin@cqmu.edu.cn.AbstractA high-performance liquid chromatography (HPLC) assay with fluorescence detection (FLD) for quantification of cisatracurium in human plasma was developed and fully validated. Liquid-liquid extraction was employed for sample preparation. The separation was carried out on a C18 column with ternary mobile phase composed of 30mmolL(-1) phosphate buffer (pH 3.0), acetonitrile and methanol (60:35:5, v/v/v). Verapamil was used as the internal standard. The isocratic elution with programmed flow rate was employed by setting at 0.8mLmin(-1) from 0 to 3.5min, 0.5mLmin(-1) from 3.5 to 6min, and 1.0mLmin(-1) from 6 to 10min. The fluorescence detection was performed at 236nm for excitation and 324nm for emission. The assay was linear from 50 to 2800ngmL(-1), with a detection limit of 12ngmL(-1). The correlation coefficient (r) for linear regression was 0.9997. The intra-day coefficients of variation (CVs) were less than 2.0%, and the inter-day CVs were less than 4.0%. The mean recoveries were in the range of 92.1-100.4%. The total HPLC run time was less than 10min. The developed HPLC method was fast, simple, sensitive, accurate and suitable for studying the pharmacokinetics of cisatracurium in infants and children after intravenous administration.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.J Chromatogr B Analyt Technol Biomed Life Sci.2014 Apr 1;955-956:58-63. doi: 10.1016/j.jchromb.2014.02.023. Epub 2014 Feb 23.
A high-performance liquid chromatography (HPLC) assay with fluorescence detection (FLD) for quantification of cisatracurium in human plasma was developed and fully validated. Liquid-liquid extraction was employed for sample preparation. The separation was carried out on a C18 column with ternary mob
PMID 24631811

Cisatracurium pretreatment with tourniquet reduces propofol injection pain: A double-blind randomized controlled trial.

Kim YH1, Namgung J, Lim CH.Author information 1Department of Anaesthesia and Pain Medicine, Ansan Hospital, Korea University College of Medicine, Ansan, Republic of Korea.AbstractOBJECTIVES: To investigate the efficacy of pretreatment with cisatracurium for prevention of pain associated with propofol injection, and compare its efficacy with that of lidocaine.
The Journal of international medical research.J Int Med Res.2014 Apr;42(2):360-7. doi: 10.1177/0300060514522602. Epub 2014 Feb 26.
OBJECTIVES: To investigate the efficacy of pretreatment with cisatracurium for prevention of pain associated with propofol injection, and compare its efficacy with that of lidocaine.METHODS: Patients undergoing general anaesthesia were randomized to receive normal saline (control group), lidocaine (
PMID 24573971

Effects of interventions on survival in acute respiratory distress syndrome: an umbrella review of 159 published randomized trials and 29 meta-analyses.

Tonelli AR1, Zein J, Adams J, Ioannidis JP.Author information 1Department of Pulmonary, Allergy, and Critical Care Medicine, Respiratory Institute, Cleveland, OH, USA.AbstractPURPOSE: Multiple interventions have been tested in acute respiratory distress syndrome (ARDS). We examined the entire agenda of published randomized controlled trials (RCTs) in ARDS that reported on mortality and of respective meta-analyses.
Intensive care medicine.Intensive Care Med.2014 Mar 26. [Epub ahead of print]
PURPOSE: Multiple interventions have been tested in acute respiratory distress syndrome (ARDS). We examined the entire agenda of published randomized controlled trials (RCTs) in ARDS that reported on mortality and of respective meta-analyses.METHODS: We searched PubMed, the Cochrane Library, and Web
PMID 24667919

Japanese Journal

Presynaptic M1, M2, and A1 receptors play roles in tetanic fade induced by pancuronium or cisatracurium

BORNIA ELAINE CAMPANA SANCHES,BANDO ERIKA,MACHINSKI MIGUEL Jr,PEREIRA MONALISA WOLSKI,ALVES-DO-PRADO WILSON
Journal of anesthesia 23(4), 513-519, 2009-11-20
NAID 10027264734

Comparative fading responses induced by mivacurium, cisatracurium, and d-tubocurarine in the evoked muscular compound action potentials of the cat

SUZUKI TAKAHIRO,MUNAKATA KAZUHIKO,WATANABE NAOTO,FUKANO NAOKO,SAEKI SHIGERU,OGAWA SETSURO
Journal of anesthesia 17(2), 98-103, 2003-05-20
NAID 50000854127

Recovery from neuromuscular blockade after either bolus and prolonged infusions of cisatracurium or rocuronium using either isoflurane or propofol-based anesthetics

JELLISH WS
Anesth Analg 91, 1250-1255, 2000
NAID 30012751767

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リンク元	「シサトラクリウム」

「シサトラクリウム」

Cisatracurium besilate
Systematic (IUPAC) name
	5-[3-[(1R,2R)-1-[(3,4-dimethoxyphenyl)methyl]-6,7-; dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-2-yl]; propanoyloxy]pentyl 3-[(1R,2R)-1-[(3,4-dimethoxy; phenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-; 1H-isoquinolin-2-yl]propanoate Benzenesulfonate (1:2)
Clinical data
AHFS/Drugs.com	monograph
Pregnancy; category	B;
Legal status	Worldwide: prescription-only medicine;
Routes of; administration	IV use only
Pharmacokinetic data
Bioavailability	100% (IV)
Metabolism	80% Hofmann degradation/ Hepatic
Biological half-life	20–29 minutes
Excretion	10-15% unchanged
Identifiers
CAS Registry Number	96946-42-8
ATC code	M03AC11
PubChem	CID: 62886
DrugBank	DB00565
UNII	80YS8O1MBS
ChEBI	CHEBI:3721
ChEMBL	CHEMBL1200641
Chemical data
Formula	C53H72N2O12+2
Molecular mass	929.145 g/mol
	SMILES [O-]S(=O)(=O)c1ccccc1.[O-]S(=O)(=O)c1ccccc1.O=C(OCCCCCOC(=O)CC[N@@+]2([C@@H](c1c(cc(OC)c(OC)c1)CC2)Cc3ccc(OC)c(OC)c3)C)CC[N@+]5(C)[C@@H](c4cc(OC)c(OC)cc4CC5)Cc6ccc(OC)c(OC)c6 ;
	InChI InChI=1S/C53H72N2O12.2C6H6O3S/c1-54(22-18-38-32-48(62-7)50(64-9)34-40(38)42(54)28-36-14-16-44(58-3)46(30-36)60-5)24-20-52(56)66-26-12-11-13-27-67-53(57)21-25-55(2)23-19-39-33-49(63-8)51(65-10)35-41(39)43(55)29-37-15-17-45(59-4)47(31-37)61-6;27-10(8,9)6-4-2-1-3-5-6/h14-17,30-35,42-43H,11-13,18-29H2,1-10H3;21-5H,(H,7,8,9)/q+2;;/p-2/t42-,43-,54-,55-;;/m1../s1 ; Key:XXZSQOVSEBAPGS-DONVQRBFSA-L ;
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英: cisatracurium
関: 筋弛緩薬

筋弛緩薬;四級アンモニウム;神経筋遮断薬;競合性

[1] Meretoja OA, Taivainen T, Wirtavuori K (Jan 1995). "Pharmacodynamic effects of 51W89, an isomer of atracurium, in children during halothane anaesthesia". Br J Anaesth 74 (1): 6–11. doi:10.1093/bja/74.1.6. PMID 7880708.

[Stenlake1984-2] Stenlake JB, Waigh RD, Dewar GH, Dhar NC, Hughes R, Chapple DJ, Lindon JC, Ferrige AG. (1984). "Biodegradable neuromuscular blocking agents. Part 6. Stereochemical studies on atracurium and related polyalkylene di-esters.". Eur J Med Chem 19 (5): 441–450.

[Dear1995-3] Dear GJ, Harrelson JC, Jones AE, Johnson TE, Pleasance S (1995). "Identification of urinary and biliary conjugated metabolites of the neuromuscular blocker 51W89 by liquid chromatography/mass spectrometry". Rapid Commun Mass Spectrom 9 (14): 1457–1464. doi:10.1002/rcm.1290091425. PMID 8534894.

[4] Wastila WB, Maehr RB, Turner GL, Hill DA, Savarese JJ (Jul 1996). "Comparative pharmacology of cisatracurium (51W89), atracurium, and five isomers in cats". Anesthesiol 85 (1): 169–177. doi:10.1097/00000542-199607000-00023. PMID 8694363.

[Stiller1985-5] Stiller RL, Cook DR, Chakravorti S. (1985). "In vitro degradation of atracurium in human plasma". Br J Anaesth 57 (11): 1085–1088. doi:10.1093/bja/57.11.1085. PMID 3840382.

[Nigrovic1991-6] Nigrovic V, Fox JL. (1991). "Atracurium decay and the formation of laudanosine in humans". Anesthesiol 74 (3): 446–454. doi:10.1097/00000542-199103000-00010. PMID 2001023.

[7] Katzung, Bertram G. (2011). Basic and clinical pharmacology. (12th ed.). New York: Mcgraw-Hill. ISBN 978-0071764018.

[Standaert-8] Standaert FG (Dec 1985). "Magic bullets, science, and medicine". Anesthesiol 63 (6): 577–578. doi:10.1097/00000542-198512000-00002. PMID 2932980.

[Fodale-9] Fodale V, Santamaria LB (Jul 2002). "Laudanosine, an atracurium and cisatracurium metabolite". Eur J Anaesthesiol 19 (7): 466–473. doi:10.1017/s0265021502000777. PMID 12113608.

[pmid_.3D_24573971-10] Kim YH (Apr 2014). "Cisatracurium pretreatment with tourniquet reduces propofol injection pain: a double-blind randomized controlled trial..". J Int Med Res. 42 (2): 360–7. doi:10.1177/0300060514522602. PMID 24573971.

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cisatracurium