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Record Information
Version2.0
Creation Date2009-07-21 20:28:09 UTC
Update Date2014-12-24 20:25:54 UTC
Accession NumberT3D2955
Identification
Common NameLevobupivacaine
ClassSmall Molecule
DescriptionLevobupivacaine is an amino-amide local anaesthetic drug belonging to the family of n-alkylsubstituted pipecoloxylidide. It is the S-enantiomer of bupivacaine. Levobupivacaine hydrochloride is commonly marketed by AstraZeneca under the trade name Chirocaine. Compared to bupivacaine, levobupivacaine is associated with less vasodilation and has a longer duration of action. It is approximately 13 per cent less potent (by molarity) than racemic bupivacaine.Levobupivacaine is indicated for local anaesthesia including infiltration, nerve block, ophthalmic, epidural and intrathecal anaesthesia in adults; and infiltration analgesia in children. Adverse drug reactions (ADRs) are rare when it is administered correctly. Most ADRs relate to administration technique (resulting in systemic exposure) or pharmacological effects of anesthesia, however allergic reactions can rarely occur. [Wikipedia]
Compound Type
  • Amide
  • Amine
  • Anesthetic
  • Anesthetic, Local
  • Drug
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
(-)-Bupivacaine
(S)-1-Butyl-2',6'-pipecoloxylidide
(S)-Bupivacaine
Chirocaine
L-(-)-1-Butyl-2',6'-pipecoloxylidide
L-(-)-Bupivacaine
Levobupivacaine hydrochloride
Chemical FormulaC18H28N2O
Average Molecular Mass288.428 g/mol
Monoisotopic Mass288.220 g/mol
CAS Registry Number27262-47-1
IUPAC Name(2S)-1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide
Traditional Name(-)-bupivacaine
SMILES[H][C@]1(CCCCN1CCCC)C(O)=NC1=C(C)C=CC=C1C
InChI IdentifierInChI=1S/C18H28N2O/c1-4-5-12-20-13-7-6-11-16(20)18(21)19-17-14(2)9-8-10-15(17)3/h8-10,16H,4-7,11-13H2,1-3H3,(H,19,21)/t16-/m0/s1
InChI KeyInChIKey=LEBVLXFERQHONN-INIZCTEOSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as piperidinecarboxamides. Piperidinecarboxamides are compounds containing a piperidine ring substituted with a carboxamide functional group.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPiperidines
Sub ClassPiperidinecarboxylic acids and derivatives
Direct ParentPiperidinecarboxamides
Alternative Parents
Substituents
  • 2-piperidinecarboxamide
  • Piperidinecarboxamide
  • M-xylene
  • Xylene
  • Monocyclic benzene moiety
  • Benzenoid
  • Tertiary aliphatic amine
  • Tertiary amine
  • Carboximidic acid
  • Carboximidic acid derivative
  • Azacycle
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Amine
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organopnictogen compound
  • Organic oxygen compound
  • Organic nitrogen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
  • 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (CHEBI:6149 )
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
Pathways
NameSMPDB LinkKEGG Link
Levobupivacaine PathwayNot AvailableNot Available
Applications
Biological Roles
Chemical Roles
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
Solubility9.77e-02 g/L
LogP3.6
Predicted Properties
PropertyValueSource
Water Solubility0.098 g/LALOGPS
logP3.31ALOGPS
logP4.52ChemAxon
logS-3.5ALOGPS
pKa (Strongest Acidic)13.62ChemAxon
pKa (Strongest Basic)8ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area32.34 ŲChemAxon
Rotatable Bond Count5ChemAxon
Refractivity90.19 m³·mol⁻¹ChemAxon
Polarizability34.45 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-006t-6920000000-20e4e8d5c09a52a31c75JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0079-0970000000-e665f05dc8da9fafd8f0JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00dl-2900000000-6396ddc6fc9d5e9b6c64JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0ac0-9200000000-befeaee90e72918d68b3JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-000i-0290000000-e01610a30f93d9c5ec2aJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-00ri-0970000000-e26949f880557c6da815JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00xr-3900000000-56dfe5d9cd7f629f17e3JSpectraViewer
Toxicity Profile
Route of ExposureThe plasma concentration of levobupivacaine following therapeutic administration depends on dose and also on route of administration, because absorption from the site of administration is affected by the vascularity of the tissue. Peak levels in blood were reached approximately 30 minutes after epidural administration, and doses up to 150 mg resulted in mean Cmax levels of up to 1.2 ug/mL.
Mechanism of ToxicityLevobupivacaine is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.
MetabolismLevobupivacaine is extensively metabolized with no unchanged levobupivacaine detected in urine or feces. In vitro studies using [14 C] levobupivacaine showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. In vivo, the 3-hydroxy levobupivacaine appears to undergo further transformation to glucuronide and sulfate conjugates. Metabolic inversion of levobupivacaine to R(+)-bupivacaine was not evident both in vitro and in vivo. Route of Elimination: Following intravenous administration, recovery of the radiolabelled dose of levobupivacaine was essentially quantitative with a mean total of about 95% being recovered in urine and feces in 48 hours. Of this 95%, about 71% was in urine while 24% was in feces. Half Life: 3.3 hours
Toxicity ValuesLD50: 5.1mg/kg in rabbit, intravenous; 18mg/kg in rabbit, oral; 207mg/kg in rabbit, parenteral; 63mg/kg in rat, subcutaneous.
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the production of local or regional anesthesia for surgery and obstetrics, and for post-operative pain management
Minimum Risk LevelNot Available
Health EffectsAcute exposure to cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to organophosphate pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to organophosphate pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.
Symptomsnervousness, tingling around the mouth, tinnitus, tremor, dizziness, blurred vision, seizures, depression (drowsiness, loss of consciousness, respiratory depression and apnea). [Wikipedia]
TreatmentIf the compound has been ingested, rapid gastric lavage should be performed using 5% sodium bicarbonate. For skin contact, the skin should be washed with soap and water. If the compound has entered the eyes, they should be washed with large quantities of isotonic saline or water. In serious cases, atropine and/or pralidoxime should be administered. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime or obidoxime), though the use of '-oximes' has been found to be of no benefit, or possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally.
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01002
HMDB IDHMDB15137
PubChem Compound ID92253
ChEMBL IDCHEMBL1201193
ChemSpider ID83289
KEGG IDC07887
UniProt IDNot Available
OMIM ID
ChEBI ID6149
BioCyc IDNot Available
CTD IDNot Available
Stitch IDLevobupivacaine
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkLevobupivacaine
References
Synthesis Reference

Hooshang Shahriari Zavareh, Graham Anthony Charles Frampton, “Process for preparing levobupivacaine and analogues thereof.” U.S. Patent US5777124, issued February, 1985.

MSDSNot Available
General References
  1. Burlacu CL, Buggy DJ: Update on local anesthetics: focus on levobupivacaine. Ther Clin Risk Manag. 2008 Apr;4(2):381-92. [18728849 ]
  2. Leone S, Di Cianni S, Casati A, Fanelli G: Pharmacology, toxicology, and clinical use of new long acting local anesthetics, ropivacaine and levobupivacaine. Acta Biomed. 2008 Aug;79(2):92-105. [18788503 ]
  3. Drugs.com [Link]
  4. Gaval-Cruz M, Weinshenker D: mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse. Mol Interv. 2009 Aug;9(4):175-87. [Link]
  5. http://www.orgyn.com/resources/genrx/D003445.asp [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Voltage-gated sodium channel activity
Specific Function:
Tetrodotoxin-resistant channel that mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which sodium ions may pass in accordance with their electrochemical gradient. Plays a role in neuropathic pain mechanisms.
Gene Name:
SCN10A
Uniprot ID:
Q9Y5Y9
Molecular Weight:
220623.605 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. [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. [17016423 ]