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Identification
NameLorazepam
Accession NumberDB00186  (APRD00116)
Typesmall molecule
Groupsapproved
Description

A benzodiazepine used as an anti-anxiety agent with few side effects. It also has hypnotic, anticonvulsant, and considerable sedative properties and has been proposed as a preanesthetic agent. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
(±)-LorazepamNot AvailableNot Available
LormetazepamNot AvailableNot Available
MethyllorazepamNot AvailableNot Available
N-MethyllorazepamNot AvailableNot Available
O-ChlorooxazepamNot AvailableNot Available
O-ChloroxazepamNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AlmazineNot Available
AnxiedinNot Available
AtivanWyeth
IdalpremNot Available
LorabenzNot Available
LorsilanNot Available
SomagerolNot Available
TemestaWyeth
WypaxNot Available
Brand mixturesNot Available
Categories
CAS number846-49-1
WeightAverage: 321.158
Monoisotopic: 320.011932988
Chemical FormulaC15H10Cl2N2O2
InChI KeyInChIKey=DIWRORZWFLOCLC-UHFFFAOYSA-N
InChI
InChI=1S/C15H10Cl2N2O2/c16-8-5-6-12-10(7-8)13(19-15(21)14(20)18-12)9-3-1-2-4-11(9)17/h1-7,15,21H,(H,18,20)
IUPAC Name
7-chloro-5-(2-chlorophenyl)-3-hydroxy-2,3-dihydro-1H-1,4-benzodiazepin-2-one
SMILES
OC1N=C(C2=CC=CC=C2Cl)C2=C(NC1=O)C=CC(Cl)=C2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzodiazepines
SubclassNot Available
Direct parentBenzodiazepines
Alternative parentsChlorobenzenes; Aryl Chlorides; Secondary Carboxylic Acid Amides; Polyamines; Carboxylic Acids; Organochlorides
Substituentschlorobenzene; benzene; aryl chloride; aryl halide; secondary carboxylic acid amide; carboxamide group; polyamine; carboxylic acid derivative; carboxylic acid; organochloride; organohalogen; organonitrogen compound
Classification descriptionThis compound belongs to the benzodiazepines. These are organic compounds containing a benzene ring fused to either isomers of diazepine(unsaturated seven-member heterocycle with two nitrogen atoms replacing two carbon atoms).
Pharmacology
IndicationFor the management of anxiety disorders, and for treatment of status epilepticus.
PharmacodynamicsLorazepam, a benzodiazepine not transformed to active metabolites, is used to treat anxiety, status epilepticus, and for sedation induction and anterograde amnesia.
Mechanism of actionLorazepam binds to an allosteric site on GABA-A receptors, which are pentameric ionotropic receptors in the CNS. Binding potentiates the effects of the inhibitory neurotransmitter GABA, which upon binding opens the chloride channel in the receptor, allowing chloride influx and causing hyperpolerization of the neuron.
AbsorptionReadily absorbed with an absolute bioavailability of 90% when given orally. When intramuscularly administered, lorazepam is completely and rapidly absorbed. It achieves max serum concentration in 3 hours. The max serum concentration of a 4 mg dose is 48 ng/mL.
Volume of distribution

1.3 L/kg. Unbound lorazepam can cross the blood-brain-barrier via passive diffusion.

Protein binding91±2% bound to plasma proteins when given parenterally. When given orally, it is 85% bound to plasma proteins.
Metabolism

Lorazepam is hepatically metabolized and is extensively conjugated to the 3-0-phenolic glucuronide. This is an inactive metabolite and is eliminated mainly by the kidneys.

SubstrateEnzymesProduct
Lorazepam
    Lorazepam glucuronideDetails
    Route of eliminationWhen a single 2 mg oral dose is give to healthy subjects, 88±4% of the administered dose was recovered in urine and 7±2% was recovered in feces. The percent of administered dose recovered in urine as lorazepam glucuronide was 74±4%. Only 0.3% of the dose was recovered as unchanged lorazepam, and the remainder of the radioactivity represented minor metabolites.
    Half lifeParenteral administration = 14±5 hours; Oral administration = 2 hours.
    Clearance

    Total clearance, parenteral administration = 1.1±0.4 mL/min/kg.

    ToxicityThe most important clinical adverse event caused by lorazepam is respiratory depression. LD50, mouse, oral = 1850 mg/kg.
    Affected organisms
    • Humans and other mammals
    PathwaysNot Available
    SNP Mediated EffectsNot Available
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption + 0.9826
    Blood Brain Barrier + 0.9641
    Caco-2 permeable + 0.8867
    P-glycoprotein substrate Substrate 0.517
    P-glycoprotein inhibitor I Non-inhibitor 0.8866
    P-glycoprotein inhibitor II Non-inhibitor 0.9167
    Renal organic cation transporter Non-inhibitor 0.8812
    CYP450 2C9 substrate Non-substrate 0.7692
    CYP450 2D6 substrate Non-substrate 0.8685
    CYP450 3A4 substrate Substrate 0.5631
    CYP450 1A2 substrate Inhibitor 0.8262
    CYP450 2C9 substrate Non-inhibitor 0.5063
    CYP450 2D6 substrate Non-inhibitor 0.8445
    CYP450 2C19 substrate Inhibitor 0.5065
    CYP450 3A4 substrate Non-inhibitor 0.6563
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6407
    Ames test Non AMES toxic 0.9133
    Carcinogenicity Non-carcinogens 0.7711
    Biodegradation Not ready biodegradable 1.0
    Rat acute toxicity 1.8229 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.999
    hERG inhibition (predictor II) Non-inhibitor 0.8734
    Pharmacoeconomics
    Manufacturers
    • Amneal pharmaceuticals
    • Paddock laboratories inc
    • Pharmaceutical assoc inc
    • Roxane laboratories inc
    • Baxter healthcare corp anesthesia critical care
    • Akorn inc
    • Baxter healthcare corp anesthesia and critical care
    • Bedford laboratories div ben venue laboratories inc
    • Dava pharmaceuticals inc
    • Hospira inc
    • International medication systems ltd
    • Marsam pharmaceuticals llc
    • Taylor pharmaceuticals
    • Watson laboratories inc
    • Bedford laboratories
    • Biovail laboratories inc
    • Quantum pharmics ltd
    • Actavis elizabeth llc
    • American therapeutics inc
    • Excellium pharmaceutical inc
    • Halsey drug co inc
    • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
    • Mutual pharmaceutical co inc
    • Mylan pharmaceuticals inc
    • Par pharmaceutical inc
    • Ranbaxy laboratories ltd
    • Sandoz inc
    • Superpharm corp
    • Usl pharma inc
    • Vintage pharmaceuticals inc
    • Warner chilcott div warner lambert co
    Packagers
    Dosage forms
    FormRouteStrength
    Injection, solutionParenteral2 mg/mL, 4 mg/mL
    Solution, concentrateOral2 mg/mL
    TabletOral0.5 mg, 1 mg, 2 mg
    Prices
    Unit descriptionCostUnit
    LORazepam Intensol 2 mg/ml Concentrate 30ml Bottle44.99USDbottle
    Lorazepam powder20.81USDg
    Lorazepam 4 mg/ml vial9.59USDml
    Lorazepam 2 mg/ml vial2.5USDml
    Ativan 2 mg tablet2.3USDtablet
    Ativan 4 mg/ml vial2.16USDml
    Ativan 1 mg tablet1.96USDtablet
    Lorazepam intensol 2 mg/ml1.6USDml
    Lorazepam-ns 60 mg/60 ml bag1.53USDml
    Ativan 0.5 mg tablet1.37USDtablet
    Lorazepam-d5w 100 mg/100 ml1.16USDml
    Lorazepam-ns 100 mg/100 ml bag1.16USDml
    Lorazepam 2 mg tablet1.01USDtablet
    Ativan 2 mg/ml vial0.9USDml
    Lorazepam 1 mg tablet0.69USDtablet
    Lorazepam 0.5 mg tablet0.55USDtablet
    Ativan 2 mg Sublingual Tablet0.24USDtablet
    Ativan 1 mg Sublingual Tablet0.15USDtablet
    Ativan 0.5 mg Sublingual Tablet0.12USDtablet
    Apo-Lorazepam 2 mg Tablet0.07USDtablet
    Novo-Lorazem 2 mg Tablet0.07USDtablet
    Pms-Lorazepam 2 mg Tablet0.07USDtablet
    Apo-Lorazepam 1 mg Tablet0.05USDtablet
    Novo-Lorazem 1 mg Tablet0.05USDtablet
    Pms-Lorazepam 1 mg Tablet0.05USDtablet
    Apo-Lorazepam 0.5 mg Tablet0.04USDtablet
    Novo-Lorazem 0.5 mg Tablet0.04USDtablet
    Pms-Lorazepam 0.5 mg Tablet0.04USDtablet
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    PatentsNot Available
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    melting point167 °CPhysProp
    water solubility80 mg/LMERCK INDEX (1996)
    logP2.39HANSCH,C ET AL. (1995)
    logS-3.6ADME Research, USCD
    pKa13MERCK INDEX (1996); pK1
    Predicted Properties
    PropertyValueSource
    water solubility1.76e-02 g/lALOGPS
    logP2.98ALOGPS
    logP3.53ChemAxon
    logS-4.3ALOGPS
    pKa (strongest acidic)10.61ChemAxon
    pKa (strongest basic)-2.2ChemAxon
    physiological charge0ChemAxon
    hydrogen acceptor count3ChemAxon
    hydrogen donor count2ChemAxon
    polar surface area61.69ChemAxon
    rotatable bond count1ChemAxon
    refractivity82.7ChemAxon
    polarizability30.33ChemAxon
    number of rings3ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterYesChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleNoChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis Reference

    Igor Lifshitz, “Process for preparing pure crystalline lorazepam.” U.S. Patent US20010039340, issued November 08, 2001.

    US20010039340
    General Reference
    1. Kemper N, Poser W, Poser S: [Benzodiazepine dependence: addiction potential of the benzodiazepines is greater than previously assumed (author’s transl)] Dtsch Med Wochenschr. 1980 Dec 5;105(49):1707-12. Pubmed
    2. Lader M: Short-term versus long-term benzodiazepine therapy. Curr Med Res Opin. 1984;8 Suppl 4:120-6. Pubmed
    3. Maltais F, Laberge F, Laviolette M: A randomized, double-blind, placebo-controlled study of lorazepam as premedication for bronchoscopy. Chest. 1996 May;109(5):1195-8. Pubmed
    4. Heisterkamp DV, Cohen PJ: The effect of intravenous premedication with lorazepam (ativan), pentobarbitone or diazepam on recall. Br J Anaesth. 1975 Jan;47(1):79-81. Pubmed
    5. Milligan DW, Howard MR, Judd A: Premedication with lorazepam before bone marrow biopsy. J Clin Pathol. 1987 Jun;40(6):696-8. Pubmed
    6. FDA label
    External Links
    ResourceLink
    KEGG DrugD00365
    PubChem Compound3958
    PubChem Substance46508468
    ChemSpider3821
    ChEBI52993
    ChEMBLCHEMBL580
    Therapeutic Targets DatabaseDAP000237
    PharmGKBPA450267
    Drug Product Database2243278
    RxListhttp://www.rxlist.com/cgi/generic/loraz.htm
    Drugs.comhttp://www.drugs.com/lorazepam.html
    WikipediaLorazepam
    ATC CodesN05BA06
    AHFS Codes
    • 28:24.08
    PDB EntriesNot Available
    FDA labelshow(540 KB)
    MSDSshow(81.8 KB)
    Interactions
    Drug Interactions
    Drug
    ClozapineIncreased risk of toxicity
    KavaKava may increase the effect of the benzodiazepine, lorazepam.
    TriprolidineThe CNS depressants, Triprolidine and Lorazepam, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
    Valproic AcidValproic acid may increase the serum concentration of Lorazepam by reducing Lorazepam metabolism. The Lorazepam dose should be reduced by 50% during concomitant therapy. Monitor for increased Lorazepam effects and toxicity.
    Food Interactions
    • Avoid alcohol.
    • Avoid excessive quantities of coffee or tea (Caffeine).
    • Take with food.

    1. GABA-A receptor (anion channel)

    Kind: protein group

    Organism: Human

    Pharmacological action: yes

    Actions: positive allosteric modulator

    Components

    Name UniProt ID Details
    Gamma-aminobutyric acid receptor subunit alpha-1 P14867 Details
    Gamma-aminobutyric acid receptor subunit alpha-2 P47869 Details
    Gamma-aminobutyric acid receptor subunit alpha-3 P34903 Details
    Gamma-aminobutyric acid receptor subunit alpha-4 P48169 Details
    Gamma-aminobutyric acid receptor subunit alpha-5 P31644 Details
    Gamma-aminobutyric acid receptor subunit alpha-6 Q16445 Details
    Gamma-aminobutyric acid receptor subunit beta-1 P18505 Details
    Gamma-aminobutyric acid receptor subunit beta-2 P47870 Details
    Gamma-aminobutyric acid receptor subunit beta-3 P28472 Details
    Gamma-aminobutyric acid receptor subunit delta O14764 Details
    Gamma-aminobutyric acid receptor subunit epsilon P78334 Details
    Gamma-aminobutyric acid receptor subunit gamma-1 Q8N1C3 Details
    Gamma-aminobutyric acid receptor subunit gamma-2 P18507 Details
    Gamma-aminobutyric acid receptor subunit gamma-3 Q99928 Details
    Gamma-aminobutyric acid receptor subunit pi O00591 Details
    Gamma-aminobutyric acid receptor subunit theta Q9UN88 Details

    References:

    1. ChEMBL Compound Report Card (Accessed December 2013)
    2. Riss J, Cloyd J, Gates J, Collins S: Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. Epub 2008 Mar 31. Pubmed

    2. Translocator protein

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: other

    Components

    Name UniProt ID Details
    Translocator protein P30536 Details

    References:

    1. Venneti S, Lopresti BJ, Wiley CA: The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging. Prog Neurobiol. 2006 Dec;80(6):308-22. Epub 2006 Dec 6. Pubmed
    2. Park CH, Carboni E, Wood PL, Gee KW: Characterization of peripheral benzodiazepine type sites in a cultured murine BV-2 microglial cell line. Glia. 1996 Jan;16(1):65-70. Pubmed
    3. Uusi-Oukari M, Korpi ER: Specific alterations in the cerebellar GABA receptors of an alcohol-sensitive ANT rat line. Alcohol Clin Exp Res. 1991 Mar;15(2):241-8. Pubmed
    4. Miller EI, Wylie FM, Oliver JS: Detection of benzodiazepines in hair using ELISA and LC-ESI-MS-MS. J Anal Toxicol. 2006 Sep;30(7):441-8. Pubmed

    1. UDP-glucuronosyltransferase 2B15

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    UDP-glucuronosyltransferase 2B15 P54855 Details

    References:

    1. Chung JY, Cho JY, Yu KS, Kim JR, Jung HR, Lim KS, Jang IJ, Shin SG: Effect of the UGT2B15 genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteers. Clin Pharmacol Ther. 2005 Jun;77(6):486-94. Pubmed

    Comments
    Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:08