Identification

Name
Doxacurium
Commonly known or available as Doxacurium chloride
Accession Number
DB01135  (APRD00934, DB01334)
Type
Small Molecule
Groups
Approved
Description

Doxacurium chloride is a long-acting, nondepolarizing skeletal muscle relaxant for intravenous administration.

Structure
Thumb
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Doxacurium chlorideM78TVM3G5Z83348-52-1APADFLLAXHIMFU-UHFFFAOYSA-L
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
NuromaxLiquid1 mgIntravenousAbbvie1992-12-312012-11-03Canada
NuromaxInjection1 mg/1mLIntravenousAbbott2010-12-082010-12-09Us
Categories
UNII
P40015Y3WW
CAS number
106791-39-3
Weight
Average: 1035.2223
Monoisotopic: 1034.535134458
Chemical Formula
C56H78N2O16
InChI Key
GBLRQXKSCRCLBZ-UHFFFAOYSA-N
InChI
InChI=1S/C56H78N2O16/c1-57(23-19-37-33-45(65-7)53(69-11)55(71-13)49(37)39(57)27-35-29-41(61-3)51(67-9)42(30-35)62-4)21-15-25-73-47(59)17-18-48(60)74-26-16-22-58(2)24-20-38-34-46(66-8)54(70-12)56(72-14)50(38)40(58)28-36-31-43(63-5)52(68-10)44(32-36)64-6/h29-34,39-40H,15-28H2,1-14H3/q+2
IUPAC Name
6,7,8-trimethoxy-2-methyl-2-(3-{[4-oxo-4-(3-{6,7,8-trimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinolin-2-ium-2-yl}propoxy)butanoyl]oxy}propyl)-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinolin-2-ium
SMILES
COC1=CC(CC2C3=C(OC)C(OC)=C(OC)C=C3CC[N+]2(C)CCCOC(=O)CCC(=O)OCCC[N+]2(C)CCC3=CC(OC)=C(OC)C(OC)=C3C2CC2=CC(OC)=C(OC)C(OC)=C2)=CC(OC)=C1OC

Pharmacology

Indication

Used to provide skeletal muscle relaxation as an adjunct to general anesthesia, for endotracheal intubation or to facilitate mechanical ventilation.

Pharmacodynamics

Doxacurium chloride is a long-acting, nondepolarizing skeletal muscle relaxant. The neuromuscular block produced by doxacurium chloride may be antagonized by anticholinesterase agents. As with other nondepolarizing neuromuscular blocking agents, the more profound the neuromuscular block at reversal, the longer the time and the greater the dose of anticholinesterase required for recovery of neuromuscular function. Doxacurium chloride is approximately 2.5 to 3 times more potent than pancuronium and 10 to 12 times more potent than metocurine.

Mechanism of action

Doxacurium chloride binds competitively to cholinergic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in a block of neuromuscular transmission (non-depolarizing). This action is antagonized by acetylcholinesterase inhibitors, such as neostigmine.

TargetActionsOrganism
ANeuronal acetylcholine receptor subunit alpha-2
antagonist
Human
UMuscarinic acetylcholine receptor M2
antagonist
Human
Absorption
Not Available
Volume of distribution
  • 0.11-0.43 L/kg [Healthy Young Adult Patients]
  • 0.17-0.55 L/kg [Kidney Transplant Patients]
  • 0.17-0.35 L/kg [Liver Transplant Patients]
Protein binding

Approximately 30%.

Metabolism

In vivo data from humans suggest that doxacurium chloride is not metabolized and that the major elimination pathway is excretion of unchanged drug in urine and bile.

Route of elimination

In vivo data from humans suggest that NUROMAX is not metabolized and that the major elimination pathway is excretion of unchanged drug in urine and bile.

Half life

99 minutes in normal healthy adults.

Clearance
  • 2.66 mL/min/kg [Healthy Young Adult Patients]
  • 1.23 mL/min/kg [Kidney Transplant Patients]
  • 2.3 mL/min/kg [Liver Transplant Patients]
  • 1.75 +/- 0.16 mL/min/kg [Elderly patients (70-83 yrs)]
  • 2.54 +/- 0.24 mL/min/kg [younger patients (19-39 yrs)]
Toxicity

Overdosage with neuromuscular blocking agents may result in neuromuscular block beyond the time needed for surgery and anesthesia.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
1,10-PhenanthrolineThe therapeutic efficacy of Doxacurium can be decreased when used in combination with 1,10-Phenanthroline.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Doxacurium is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when Doxacurium is combined with 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when Doxacurium is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Doxacurium is combined with 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Doxacurium is combined with 5-methoxy-N,N-dimethyltryptamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when Doxacurium is combined with 7-Nitroindazole.
AbacavirAbacavir may decrease the excretion rate of Doxacurium which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Doxacurium which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Doxacurium which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Martinez EA, Wooldridge AA, Hartsfield SM, Mealey KL: Neuromuscular effects of doxacurium chloride in isoflurane-anesthetized dogs. Vet Surg. 1998 May-Jun;27(3):279-83. [PubMed:9605239]
External Links
Human Metabolome Database
HMDB0015266
KEGG Drug
D00760
KEGG Compound
C07549
PubChem Compound
5284551
PubChem Substance
46506733
ChemSpider
54249
ChEBI
59819
ChEMBL
CHEMBL1237123
Therapeutic Targets Database
DAP000350
PharmGKB
PA164744927
RxList
RxList Drug Page
Wikipedia
Doxacurium_chloride
ATC Codes
M03AC07 — Doxacurium chloride

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous1 mg/1mL
LiquidIntravenous1 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility9.02e-05 mg/mLALOGPS
logP3.44ALOGPS
logP-2.5ChemAxon
logS-7.1ALOGPS
pKa (Strongest Acidic)18.41ChemAxon
pKa (Strongest Basic)-4.1ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count14ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area163.36 Å2ChemAxon
Rotatable Bond Count29ChemAxon
Refractivity302.15 m3·mol-1ChemAxon
Polarizability113.56 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.9919
Blood Brain Barrier+0.9419
Caco-2 permeable+0.6166
P-glycoprotein substrateSubstrate0.8274
P-glycoprotein inhibitor INon-inhibitor0.5903
P-glycoprotein inhibitor IIInhibitor0.6915
Renal organic cation transporterNon-inhibitor0.5328
CYP450 2C9 substrateNon-substrate0.8563
CYP450 2D6 substrateNon-substrate0.7468
CYP450 3A4 substrateSubstrate0.6802
CYP450 1A2 substrateNon-inhibitor0.9149
CYP450 2C9 inhibitorNon-inhibitor0.963
CYP450 2D6 inhibitorNon-inhibitor0.9124
CYP450 2C19 inhibitorNon-inhibitor0.9355
CYP450 3A4 inhibitorNon-inhibitor0.8601
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9305
Ames testNon AMES toxic0.6828
CarcinogenicityNon-carcinogens0.9133
BiodegradationNot ready biodegradable0.8219
Rat acute toxicity2.7335 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8508
hERG inhibition (predictor II)Non-inhibitor0.5553
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Drug binding
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
CHRNA2
Uniprot ID
Q15822
Uniprot Name
Neuronal acetylcholine receptor subunit alpha-2
Molecular Weight
59764.82 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Liu M, Dilger JP: Synergy between pairs of competitive antagonists at adult human muscle acetylcholine receptors. Anesth Analg. 2008 Aug;107(2):525-33. doi: 10.1213/ane.0b013e31817b4469. [PubMed:18633030]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
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. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Hou VY, Hirshman CA, Emala CW: Neuromuscular relaxants as antagonists for M2 and M3 muscarinic receptors. Anesthesiology. 1998 Mar;88(3):744-50. [PubMed:9523819]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Identical protein binding
Specific Function
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name
BCHE
Uniprot ID
P06276
Uniprot Name
Cholinesterase
Molecular Weight
68417.575 Da
References
  1. Basta SJ, Savarese JJ, Ali HH, Embree PB, Schwartz AF, Rudd GD, Wastila WB: Clinical pharmacology of doxacurium chloride. A new long-acting nondepolarizing muscle relaxant. Anesthesiology. 1988 Oct;69(4):478-86. [PubMed:2972233]
  2. Dresner DL, Basta SJ, Ali HH, Schwartz AF, Embree PB, Wargin WA, Lai AA, Brady KA, Savarese JJ: Pharmacokinetics and pharmacodynamics of doxacurium in young and elderly patients during isoflurane anesthesia. Anesth Analg. 1990 Nov;71(5):498-502. [PubMed:2145783]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 09:15