Cisatracurium

Identification

Summary

Cisatracurium is a skeletal muscle relaxant used to facilitate tracheal intubation, muscle relaxation in surgery, or mechanical ventilation.

Brand Names
Nimbex
Generic Name
Cisatracurium
DrugBank Accession Number
DB00565
Background

Cisatracurium is a non-depolarising neuromuscular blocking agent of the benzylisoquinolinium class, available in its salt form, cisatracurium besylate.1,2 Cisatracurium has an intermediate duration of action and is one of the most commonly used neuromuscular blocking agents in intensive care.2,3. Cisatracurium acts on cholinergic receptors, blocking neuromuscular transmission. This action is antagonized by acetylcholinesterase inhibitors such as neostigmine.1,2 Cisatracurium is an R-cis-R-cis isomer of atracurium and has approximately 3 times its neuromuscular blocking potency.1 Compared to atracurium, cisatracurium produces a lower degree of histamine release.3

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 929.16
Monoisotopic: 928.507428607
Chemical Formula
C53H72N2O12
Synonyms
  • (1r,2r,1'r,2'r)-2,2'-{pentane-1,5-diylbis[oxy(3-oxopropane-3,1-diyl)]}bis[1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium]
  • Cisatracurium cation
  • Cisatracurium ion

Pharmacology

Indication

Cisatracurium is indicated as an adjunct to general anesthesia to facilitate tracheal intubation in adults and pediatric patients 1 month to 12 years of age. Cisatracurium is also indicated to provide skeletal muscle relaxation during surgery in adults and pediatric patients 2 to 12 years of age as a bolus or infusion maintenance and for mechanical ventilation in the ICU in adults.5

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Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

The dose required to produce 95% suppression of twitch response to nerve stimulation (ED95) of cisatracurium is 0.05 mg/kg in adults receiving opioid/nitrous oxide/oxygen anesthesia.3,5 The degree and duration of the neuromuscular block produced by cisatracurium increases in a dose-dependent manner, while the time to maximum neuromuscular block decreases.3 Compared to other neuromuscular blocking agents, it is intermediate in its onset and duration of action.2 Cisatracurium acts on cholinergic receptors, blocking neuromuscular transmission. This action is antagonized by acetylcholinesterase inhibitors such as neostigmine.1

The use of cisatracurium may lead to residual paralysis, as well as a higher risk of seizure. Medication errors increase the risk of death, and the use of certain drugs may potentiate the neuromuscular blocking action of cisatracurium.5

Mechanism of action

Like other non-depolarising neuromuscular blocking agents, cisatracurium binds competitively to cholinergic receptors in motor end-plate neurons, blocking acetylcholine from accessing the receptors.5 Therefore, in the presence of cisatracurium, an end-plate potential cannot be developed. Ion channels remain closed, the cell does not depolarize, and an action potential is not transmitted.1

TargetActionsOrganism
ANeuronal Acetylcholine (nACh) Receptor Subunits
antagonist
Humans
UAcetylcholine receptor subunit alpha
antagonist
Humans
UMuscarinic acetylcholine receptor M2
antagonist
Humans
Absorption

The pharmacokinetics of cisatracurium follow a two-compartment open model.4,5 Cisatracurium is metabolized into laudanosine and monoquaternary alcohol metabolite (MQA). Following the IV infusion of cisatracurium, the Cmax of laudanosine and MQA were 6% and 11% of the parent compound, respectively.5

Compared to young patients, the volume of distribution of cisatracurium is slightly larger in elderly patients, which also leads to longer half-life values. The plasma clearance of cisatracurium was not affected by age. Patients with hepatic impairment have a slightly higher volume of distribution and plasma clearance values; however, these minor pharmacokinetic differences are not considered clinically significant. Additionally, the pharmacokinetic parameters of cisatracurium in patients with end-stage renal disease were similar to those detected in healthy adult patients.5

Volume of distribution

Cisatracurium has a volume of distribution at steady state of 145 mL/kg.5 The volume of distribution of cisatracurium besylate is small due to its relatively large molecular weight and high polarity.4

Protein binding

The binding of cisatracurium to plasma proteins has not been successfully studied due to its rapid degradation at physiologic pH.5

Metabolism

The degradation of cisatracurium is largely independent of liver metabolism. Cisatracurium undergoes Hofmann elimination (a pH and temperature-dependent chemical process) to form laudanosine and the monoquaternary acrylate metabolite. Non-specific plasma esterases hydrolyze the monoquaternary acrylate metabolite to form the monoquaternary alcohol metabolite (MQA). The MQA can also undergo Hofmann elimination, but the rate of this process is slower than the one detected for cisatracurium. Laudanosine is further metabolized to desmethyl metabolites that are conjugated with glucuronic acid and excreted in the urine. Laudanosine may cause transient hypotension and, in higher doses, cerebral excitatory effects when administered to several animal species; however, the effects of laudanosine in humans have not been established.5

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Route of elimination

The predominant elimination mechanism of cisatracurium is Hofmann elimination, a chemical process dependent on pH and temperature (approximately 80% in healthy surgical patients). The liver and kidney play a minor role in the elimination of cisatracurium (about 20%); however, they have a significant role in the metabolism of cisatracurium metabolites.5

In healthy male patients (n=6) given 14C-cisatracurium, 4% of the recovered dose was found in feces, and 95% was found in urine, mostly as conjugated metabolites. Less than 10% of the cisatracurium dose was excreted as the unchanged patent drug. In another group of patients with Foley catheters for surgical management given non-radiolabeled cisatracurium (n=12), 15% of the cisatracurium dose was excreted unchanged in urine.5

Half-life

Cisatracurium has an elimination half-life of 22 minutes.5

Clearance

Cisatracurium has a plasma clearance of 4.57 mL/min/kg.5

Adverse Effects
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Toxicity

Overdosage with neuromuscular blocking agents such as cisatracurium may result in neuromuscular block beyond the time needed for surgery and anesthesia. Maintenance of a patent airway and controlled ventilation until recovery of normal neuromuscular function is the primary treatment for overdose cases. To facilitate further recovery, a cholinesterase inhibitor in conjunction with an appropriate cholinergic inhibitor may be administered once recovery from the neuromuscular block begins. If complete neuromuscular blockade is evident or suspected, cholinesterase inhibitors should not be administered. The reversal of paralysis may not be sufficient to maintain a patent airway and an appropriate level of spontaneous ventilation.5

The long-term carcinogenicity of cisatracurium has not been evaluated. In an in vitro mouse lymphoma forward gene mutation assay, cisatracurium besylate led to mutations in the presence and absence of exogenous metabolic activation. Other assays did not show evidence of mutagenicity or clastogenicity.5

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of CNS depression can be increased when Cisatracurium is combined with 1,2-Benzodiazepine.
AcetazolamideThe risk or severity of CNS depression can be increased when Cisatracurium is combined with Acetazolamide.
Acetic acidAcetic acid may increase the neuromuscular blocking activities of Cisatracurium.
AcetophenazineThe risk or severity of CNS depression can be increased when Cisatracurium is combined with Acetophenazine.
Acetyl sulfisoxazoleAcetyl sulfisoxazole may increase the neuromuscular blocking activities of Cisatracurium.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Cisatracurium besylate80YS8O1MBS96946-42-8XXZSQOVSEBAPGS-DONVQRBFSA-L
International/Other Brands
Nimbex (AbbVie) / Nimbex Preservative Free (AbbVie) / Nimbium (GlaxoSmithKline)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Cisatracurium Besylate InjectionSolution2 mg / mLIntravenousAccord Healthcare IncNot applicableNot applicableCanada flag
Cisatracurium Besylate InjectionSolution2 mg / mLIntravenousPfizer Canada Ulc2015-06-012019-03-28Canada flag
Cisatracurium Besylate InjectionSolution2 mg / mLIntravenousMylan PharmaceuticalsNot applicableNot applicableCanada flag
Cisatracurium Besylate Injection (preservative-free)Solution2 mg / mLIntravenousMylan PharmaceuticalsNot applicableNot applicableCanada flag
Cisatracurium Besylate Injection Multi-doseSolution2 mg / mLIntravenousFresenius KabiNot applicableNot applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Aj-cisatracuriumSolution2 mg / mLIntravenousAgila Jamp Canada IncNot applicableNot applicableCanada flag
Aj-cisatracuriumSolution2 mg / mLIntravenousAgila Jamp Canada IncNot applicableNot applicableCanada flag
CisatracuriumInjection, solution2 mg/1mLIntravenousFresenius Kabi USA, LLC2015-02-26Not applicableUS flag
CisatracuriumInjection, solution2 mg/1mLIntravenousFresenius Kabi USA, LLC2015-02-26Not applicableUS flag
CisatracuriumInjection, solution10 mg/1mLIntravenousFresenius Kabi USA, LLC2015-02-26Not applicableUS flag

Categories

ATC Codes
M03AC11 — Cisatracurium
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as benzylisoquinolines. These are organic compounds containing an isoquinoline to which a benzyl group is attached.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Isoquinolines and derivatives
Sub Class
Benzylisoquinolines
Direct Parent
Benzylisoquinolines
Alternative Parents
Tetrahydroisoquinolines / Dimethoxybenzenes / Phenoxy compounds / Anisoles / Alkyl aryl ethers / Aralkylamines / Dicarboxylic acids and derivatives / Tetraalkylammonium salts / Carboxylic acid esters / Azacyclic compounds
show 6 more
Substituents
Alkyl aryl ether / Amine / Anisole / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Benzylisoquinoline / Carbonyl group / Carboxylic acid derivative
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
QX62KLI41N
CAS number
96946-41-7
InChI Key
YXSLJKQTIDHPOT-LJCJQEJUSA-N
InChI
InChI=1S/C53H72N2O12/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/h14-17,30-35,42-43H,11-13,18-29H2,1-10H3/q+2/t42-,43-,54-,55-/m1/s1
IUPAC Name
(1R,2R)-1-[(3,4-dimethoxyphenyl)methyl]-2-(3-{[5-({3-[(1R,2R)-1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium-2-yl]propanoyl}oxy)pentyl]oxy}-3-oxopropyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium
SMILES
COC1=CC2=C(C=C1OC)[C@@H](CC1=CC(OC)=C(OC)C=C1)[N@@+](C)(CCC(=O)OCCCCCOC(=O)CC[N@@+]1(C)CCC3=C(C=C(OC)C(OC)=C3)[C@H]1CC1=CC(OC)=C(OC)C=C1)CC2

References

Synthesis Reference

Arad O., et al. (2013). Process for producing cisatracurium and associated intermediates (U.S. Patent No. 2013/0041154 A1). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/c3/a4/c7/67ee80a0faa6dc/US20130041154A1.pdf

General References
  1. Strawbridge AD, Khanna NR, Hauser JM: Cisatracurium . [Article]
  2. Szakmany T, Woodhouse T: Use of cisatracurium in critical care: a review of the literature. Minerva Anestesiol. 2015 Apr;81(4):450-60. Epub 2014 Apr 10. [Article]
  3. Bryson HM, Faulds D: Cisatracurium besilate. A review of its pharmacology and clinical potential in anaesthetic practice. Drugs. 1997 May;53(5):848-66. doi: 10.2165/00003495-199753050-00012. [Article]
  4. Kisor DF, Schmith VD: Clinical pharmacokinetics of cisatracurium besilate. Clin Pharmacokinet. 1999 Jan;36(1):27-40. doi: 10.2165/00003088-199936010-00003. [Article]
  5. FDA Approved Drug Products: Nimbex (cisatracurium besylate) injection for intravenous use [Link]
Human Metabolome Database
HMDB0240286
PubChem Compound
62886
PubChem Substance
46506666
ChemSpider
56615
RxNav
319864
ChEBI
140621
ChEMBL
CHEMBL1201248
ZINC
ZINC000238809664
Therapeutic Targets Database
DAP000196
PharmGKB
PA164744925
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Cisatracurium_besilate

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
  • Baxter healthcare corp anesthesia and critical care
  • Baxter healthcare corp anesthesia critical care
  • Bedford laboratories div ben venue laboratories inc
  • Hospira inc
  • Marsam pharmaceuticals llc
  • Teva parenteral medicines inc
  • Abbott laboratories
Packagers
  • Abbott Laboratories Ltd.
  • Baxter International Inc.
  • Bedford Labs
  • Ben Venue Laboratories Inc.
  • GlaxoSmithKline Inc.
  • Hospira Inc.
  • Patheon Inc.
  • Teva Pharmaceutical Industries Ltd.
Dosage Forms
FormRouteStrength
SolutionParenteral2.00 mg
SolutionIntravenous10 mg
Injection, solution2 mg/1ml
Injection, solutionIntravenous bolus5 MG/ML
Injection, solution2 MG/ML
Injection, solution5 MG/ML
Injection, solutionIntravenous bolus2 MG/ML
Injection, solution
Injection, solutionIntravenous10 mg/1mL
Injection, solutionIntravenous2 mg/1mL
Injection, solutionParenteral2 mg/ml
Injection, solutionParenteral
Injection, solutionParenteral5 mg/ml
InjectionIntravenous10 mg/1mL
InjectionIntravenous10 mg/5mL
InjectionIntravenous2 mg/1mL
InjectionIntravenous20 mg/10mL
InjectionIntravenous200 mg/20mL
Injection, solutionIntravenous10 mg/5mL
Injection, solutionIntravenous20 mg/10mL
Injection, solutionIntravenous200 mg/20mL
SolutionParenteral2 mg/ml
Solution2 mg/1ml
Solution2 mg/ml
SolutionIntravenous2 mg / mL
Injection, solutionIntravenous2 mg/ml
SolutionParenteral13.38 mg
InjectionIntravenous10 mg
SolutionIntravenous6.690 mg
Injection, solutionIntravenous10 mg
Injection, solutionIntravenous150 mg
Injection, solutionIntravenous20 mg
Injection, solutionIntravenous5 mg
Injection, solutionIntravenous50 mg
LiquidIntravenous2 mg / mL
LiquidIntravenous10 mg / mL
Injection, solutionIntravenous5 mg/2.5ml
InjectionIntravenous50 mg/25ml
Injection, solutionIntravenous150 mg/30ml
InjectionParenteral2 MG/ML
SolutionIntravenous5 mg
Injection, solution5 mg/1ml
Prices
Unit descriptionCostUnit
Nimbex 10 mg/ml vial13.8USD ml
Nimbex 2 mg/ml vial2.91USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5453510No1995-09-262012-09-26US flag
CA2087104No1998-08-182011-07-12Canada flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP-2.12Nimbex (cisatracurium besylate) FDA label
Predicted Properties
PropertyValueSource
Water Solubility2.32e-05 mg/mLALOGPS
logP3.41ALOGPS
logP-0.96Chemaxon
logS-7.6ALOGPS
pKa (Strongest Acidic)19.02Chemaxon
pKa (Strongest Basic)-4.1Chemaxon
Physiological Charge2Chemaxon
Hydrogen Acceptor Count10Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area126.44 Å2Chemaxon
Rotatable Bond Count26Chemaxon
Refractivity280.68 m3·mol-1Chemaxon
Polarizability104.19 Å3Chemaxon
Number of Rings6Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.9847
Blood Brain Barrier+0.9291
Caco-2 permeable-0.5966
P-glycoprotein substrateSubstrate0.6828
P-glycoprotein inhibitor IInhibitor0.7177
P-glycoprotein inhibitor IIInhibitor0.5808
Renal organic cation transporterNon-inhibitor0.5871
CYP450 2C9 substrateNon-substrate0.7994
CYP450 2D6 substrateNon-substrate0.7779
CYP450 3A4 substrateSubstrate0.6527
CYP450 1A2 substrateNon-inhibitor0.8244
CYP450 2C9 inhibitorNon-inhibitor0.7179
CYP450 2D6 inhibitorNon-inhibitor0.791
CYP450 2C19 inhibitorNon-inhibitor0.7048
CYP450 3A4 inhibitorNon-inhibitor0.7338
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8547
Ames testNon AMES toxic0.544
CarcinogenicityNon-carcinogens0.5302
BiodegradationReady biodegradable0.8169
Rat acute toxicity2.6124 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6043
hERG inhibition (predictor II)Inhibitor0.6507
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-340.5874517
predicted
DarkChem Lite v0.1.0
[M-H]-332.8833517
predicted
DarkChem Lite v0.1.0
[M-H]-293.16223
predicted
DeepCCS 1.0 (2019)
[M+H]+342.1155517
predicted
DarkChem Lite v0.1.0
[M+H]+333.8848517
predicted
DarkChem Lite v0.1.0
[M+H]+295.05765
predicted
DeepCCS 1.0 (2019)
[M+Na]+339.9729517
predicted
DarkChem Lite v0.1.0
[M+Na]+332.8057517
predicted
DarkChem Lite v0.1.0
[M+Na]+301.13345
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Receptor binding
Specific Function
Ionotropic receptor with a probable role in the modulation of auditory stimuli. Agonist binding may induce an extensive change in conformation that affects all subunits and leads to opening of an i...

Components:
References
  1. Tuba Z, Maho S, Vizi ES: Synthesis and structure-activity relationships of neuromuscular blocking agents. Curr Med Chem. 2002 Aug;9(16):1507-36. [Article]
  2. FDA Approved Drug Products: Nimbex (cisatracurium besylate) injection for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Ion channel activity
Specific Function
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
Gene Name
CHRNA1
Uniprot ID
P02708
Uniprot Name
Acetylcholine receptor subunit alpha
Molecular Weight
54545.235 Da
References
  1. Fanelli V, Morita Y, Cappello P, Ghazarian M, Sugumar B, Delsedime L, Batt J, Ranieri VM, Zhang H, Slutsky AS: Neuromuscular Blocking Agent Cisatracurium Attenuates Lung Injury by Inhibition of Nicotinic Acetylcholine Receptor-alpha1. Anesthesiology. 2016 Jan;124(1):132-40. doi: 10.1097/ALN.0000000000000907. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
G-protein coupled acetylcholine receptor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM2
Uniprot ID
P08172
Uniprot Name
Muscarinic acetylcholine receptor M2
Molecular Weight
51714.605 Da
References
  1. Patterson E, Scherlag BJ, Zhou J, Jackman WM, Lazzara R, Coscia D, Po S: Antifibrillatory actions of cisatracurium: an atrial specific M2 receptor antagonist. J Cardiovasc Electrophysiol. 2008 Aug;19(8):861-8. doi: 10.1111/j.1540-8167.2008.01123.x. Epub 2008 Mar 21. [Article]

Drug created at June 13, 2005 13:24 / Updated at June 19, 2024 12:15