DrugBank: Flumazenil (DB01205)

targets (3)

Identification

Name

Flumazenil

Accession Number

DB01205 (APRD00974)

Type

small molecule

Groups

approved

Description

Fumazenil is an imidazobenzodiazepine derivative and a potent benzodiazepine receptor antagonist that competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex, thereby reversing the effects of benzodiazepine on the central nervous system.

Structure

Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure

Synonyms

Flumazenilo [Spanish]
Flumazenilum [Latin]

Salts

Not Available

Brand names

Name	Company
Anexate
Flumazepil
Lanexat
Mazicon
Romazicon

Brand mixtures

Not Available

Categories

GABA Modulators
Antidotes

CAS number

78755-81-4

Weight

Average: 303.2884
Monoisotopic: 303.101919534

Chemical Formula

C₁₅H₁₄FN₃O₃

InChI Key

InChIKey=OFBIFZUFASYYRE-UHFFFAOYSA-N

InChI

InChI=1S/C15H14FN3O3/c1-3-22-15(21)13-12-7-18(2)14(20)10-6-9(16)4-5-11(10)19(12)8-17-13/h4-6,8H,3,7H2,1-2H3

Plain Text

IUPAC Name

ethyl 12-fluoro-8-methyl-9-oxo-2,4,8-triazatricyclo[8.4.0.0^{2,6}]tetradeca-1(10),3,5,11,13-pentaene-5-carboxylate

SMILES

CCOC(=O)C1=C2CN(C)C(=O)C3=C(C=CC(F)=C3)N2C=N1

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Organic

Classes

Lactams
Benzoyl Derivatives
Benzamides

Substructures

Carboxylic Acids and Derivatives
Acetates
Amino Ketones
Ethers
Benzene and Derivatives
Aliphatic and Aryl Amines
Halobenzenes
Imidazoles
Heterocyclic compounds
Aromatic compounds
Carboxamides and Derivatives
Lactams
Imines
Benzoyl Derivatives
Cyanamides
Aryl Halides
Benzamides
Anilines

Pharmacology

Indication

For the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anesthesia has been induced and/or maintained with benzodiazepines, and where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures. Also for the management of benzodiazepine overdose as an adjunct for appropriate supportive and symptomatic measures.

Pharmacodynamics

Flumazenil antagonizes the CNS effects produced by benzodiazepines, but does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids.

Mechanism of action

Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man.

Absorption

Not Available

Volume of distribution

0.9 to 1.1 L/kg

Protein binding

Protein binding is approximately 50%, mostly (66%) to albumin. Protein binding is reduced in patients with hepatic cirrhosis.

Metabolism

Hepatic. Flumazenil is completely (99%) metabolized. The major metabolites of flumazenil identified in urine are the de-ethylated free acid and its glucuronide conjugate.

Route of elimination

Flumazenil is completely (99%) metabolized. Elimination of radiolabeled drug is essentially complete within 72 hours, with 90% to 95% of the radioactivity appearing in urine and 5% to 10% in the feces.

Half life

Initial distribution half-life is 4 to 11 minutes and the terminal half-life is 40 to 80 minutes. Prolongation of the half-life to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients. Compared to adults, the elimination half-life in pediatric patients was more variable, averaging 40 minutes (range: 20 to 75 minutes).

Clearance

1 L/hr/kg [healthy volunteers receiving a 5-minute infusion of a total of 1 mg]

Toxicity

In clinical studies, most adverse reactions to flumazenil were an extension of the pharmacologic effects of the drug in reversing benzodiazepine effects.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacoeconomics

Manufacturers

Akorn strides llc
App pharmaceuticals llc
Baxter healthcare corp anesthesia and critical care
Bedford laboratories
Claris lifesciences ltd
Hikma farmaceutica (portugal) sa
Sandoz canada inc
Teva parenteral medicines inc
Hoffmann la roche inc

Packagers

Dosage forms

Form	Route	Strength
Solution	Intravenous

Prices

Unit description	Cost	Unit
Romazicon 0.1 mg/ml vial	25.14 USD	ml
Flumazenil 0.1 mg/ml vial	1.63 USD	ml

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Not Available

Properties

State

solid

Experimental Properties

Property	Value	Source
melting point	201-203 °C	PhysProp
water solubility	128 mg/L	Not Available
logP	1.00	MFG DATA SHEET

Predicted Properties

Property	Value	Source
water solubility	1.04e+00 g/l	ALOGPS
logP	1.54	ALOGPS
logP	0.33	ChemAxon
logS	-2.5	ALOGPS
pKa (strongest basic)	3.27	ChemAxon
physiological charge	0	ChemAxon
hydrogen acceptor count	3	ChemAxon
hydrogen donor count	0	ChemAxon
polar surface area	64.43	ChemAxon
rotatable bond count	3	ChemAxon
refractivity	87.93	ChemAxon
polarizability	29.97	ChemAxon

References

Synthesis Reference

Not Available

General Reference

Ngo AS, Anthony CR, Samuel M, Wong E, Ponampalam R: Should a benzodiazepine antagonist be used in unconscious patients presenting to the emergency department? Resuscitation. 2007 Jul;74(1):27-37. Epub 2007 Feb 15. Pubmed
Olkkola KT, Ahonen J: Midazolam and other benzodiazepines. Handb Exp Pharmacol. 2008;(182):335-60. Pubmed
Maeda S, Miyawaki T, Higuchi H, Shimada M: Effect of flumazenil on disturbance of equilibrium function induced by midazolam. Anesth Prog. 2008 Fall;55(3):73-7. Pubmed

External Links

Resource	Link
KEGG Drug	D00697
KEGG Compound	C07825
PubChem Compound	3373
PubChem Substance	46507438
ChemSpider	3256
BindingDB	26263
ChEBI	5103
ChEMBL	5103
Therapeutic Targets Database	DAP000685
PharmGKB	PA449659
Drug Product Database	2249561
RxList	http://www.rxlist.com/cgi/generic3/flumazenil.htm
Drugs.com	http://www.drugs.com/cdi/flumazenil.html
Wikipedia	http://en.wikipedia.org/wiki/Flumazenil

ATC Codes

V03AB25

AHFS Codes

28:92.00

PDB Entries

Not Available

FDA label

show (244 KB)

MSDS

show (51.1 KB)

Interactions

Drug Interactions

Not Available

Food Interactions

Not Available

Targets
1. Gamma-aminobutyric-acid receptor subunit alpha-1 Pharmacological action: yes Actions: antagonist GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel Organism class: human UniProt ID: P14867 Gene: GABRA1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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 Wingrove PB, Safo P, Wheat L, Thompson SA, Wafford KA, Whiting PJ: Mechanism of alpha-subunit selectivity of benzodiazepine pharmacology at gamma-aminobutyric acid type A receptors. Eur J Pharmacol. 2002 Feb 15;437(1-2):31-9. Pubmed Whitwam JG, Amrein R: Pharmacology of flumazenil. Acta Anaesthesiol Scand Suppl. 1995;108:3-14. Pubmed 2. Gamma-aminobutyric acid receptor subunit gamma-2 Pharmacological action: yes Actions: antagonist GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel Organism class: human UniProt ID: P18507 Gene: GABRG2 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Padgett CL, Lummis SC: The F-loop of the GABA A receptor gamma2 subunit contributes to benzodiazepine modulation. J Biol Chem. 2008 Feb 1;283(5):2702-8. Epub 2007 Oct 31. Pubmed Wingrove PB, Safo P, Wheat L, Thompson SA, Wafford KA, Whiting PJ: Mechanism of alpha-subunit selectivity of benzodiazepine pharmacology at gamma-aminobutyric acid type A receptors. Eur J Pharmacol. 2002 Feb 15;437(1-2):31-9. Pubmed Whitwam JG, Amrein R: Pharmacology of flumazenil. Acta Anaesthesiol Scand Suppl. 1995;108:3-14. Pubmed 3. Gamma-aminobutyric-acid receptor subunit alpha-5 Pharmacological action: yes Actions: antagonist GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel Organism class: human UniProt ID: P31644 Gene: GABRA5 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Clement Y, Le Guisquet AM, Venault P, Chapouthier G, Belzung C: Pharmacological alterations of anxious behaviour in mice depending on both strain and the behavioural situation. PLoS One. 2009 Nov 11;4(11):e7745. doi: 10.1371/journal.pone.0007745. Pubmed

Targets

1. Gamma-aminobutyric-acid receptor subunit alpha-1

Pharmacological action: yes
Actions: antagonist

GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel

Organism class: human
UniProt ID: P14867 Link_out

Gene: GABRA1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

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
Wingrove PB, Safo P, Wheat L, Thompson SA, Wafford KA, Whiting PJ: Mechanism of alpha-subunit selectivity of benzodiazepine pharmacology at gamma-aminobutyric acid type A receptors. Eur J Pharmacol. 2002 Feb 15;437(1-2):31-9. Pubmed
Whitwam JG, Amrein R: Pharmacology of flumazenil. Acta Anaesthesiol Scand Suppl. 1995;108:3-14. Pubmed

2. Gamma-aminobutyric acid receptor subunit gamma-2

Pharmacological action: yes
Actions: antagonist

GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel

Organism class: human
UniProt ID: P18507 Link_out

Gene: GABRG2 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Padgett CL, Lummis SC: The F-loop of the GABA A receptor gamma2 subunit contributes to benzodiazepine modulation. J Biol Chem. 2008 Feb 1;283(5):2702-8. Epub 2007 Oct 31. Pubmed
Wingrove PB, Safo P, Wheat L, Thompson SA, Wafford KA, Whiting PJ: Mechanism of alpha-subunit selectivity of benzodiazepine pharmacology at gamma-aminobutyric acid type A receptors. Eur J Pharmacol. 2002 Feb 15;437(1-2):31-9. Pubmed
Whitwam JG, Amrein R: Pharmacology of flumazenil. Acta Anaesthesiol Scand Suppl. 1995;108:3-14. Pubmed

3. Gamma-aminobutyric-acid receptor subunit alpha-5

Pharmacological action: yes
Actions: antagonist

GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel

Organism class: human
UniProt ID: P31644 Link_out

Gene: GABRA5 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Clement Y, Le Guisquet AM, Venault P, Chapouthier G, Belzung C: Pharmacological alterations of anxious behaviour in mice depending on both strain and the behavioural situation. PLoS One. 2009 Nov 11;4(11):e7745. doi: 10.1371/journal.pone.0007745. Pubmed

Comments

Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:20