Flumazenil

Flumazenil

Systematic (IUPAC) name
ethyl 12-fluoro- 8-methyl- 9-oxo- 2,4,8- triazatricyclo [8.4.0.02,6] tetradeca- 1(10),3,5,11,13- pentaene- 5-carboxylate
Clinical data
Trade names	Romazicon
AHFS/Drugs.com	monograph
Pregnancy cat.	B3(AU) C
Legal status	?
Routes	Intravenous
Pharmacokinetic data
Metabolism	Hepatic
Half-life	7-15 min (initial) 20-30 min (brain) 40-80 min (terminal)
Excretion	Urine 90-95% Feces 5-10%
Identifiers
CAS number	78755-81-4
ATC code	V03AB25
PubChem	CID 3373
DrugBank	APRD00974
ChemSpider	3256 Y
UNII	40P7XK9392 Y
KEGG	D00697 Y
ChEBI	CHEBI:5103 Y
ChEMBL	CHEMBL407 Y
Synonyms	ethyl 8-fluoro- 5,6-dihydro- 5-methyl- 6-oxo- 4H- imidazo [1,5-a] [1,4] benzodiazepine- 3-carboxylate
Chemical data
Formula	C15H14FN3O3
Mol. mass	303.288 g/mol
SMILES	eMolecules & PubChem
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 Y Key:OFBIFZUFASYYRE-UHFFFAOYSA-N Y
Y(what is this?)  (verify)

A vial of flumazenil solution for injection

Flumazenil (also known as flumazepil, code name Ro 15-1788, trade names Anexate, Lanexat, Mazicon, Romazicon) is a benzodiazepine antagonist available for injection only, and the only benzodiazepine receptor antagonist on the market today.

It was first introduced in 1987 by Hoffmann-La Roche under the trade name Anexate, but only approved by the FDA on December 20, 1991. Some years ago an oral preparation was under development ^[1], though it had low bio-availability and was thus abandoned. There is hope that oral flumazenil or other benzodiazepine antagonists such as B-carbolines will be developed in the future.

Uses

Flumazenil is of benefit in patients who become excessively drowsy after benzodiazepines are used for either diagnostic or therapeutic procedures.^[2]

It has been used as an antidote in the treatment of benzodiazepine overdoses.^[2] It reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine binding site on the GABA_A receptor. There are many complications that must be taken into consideration when used in the acute care setting.^[2]

It has been found to be effective in overdoses of non-benzodiazepine sleep enhancers, namely zolpidem and zaleplon.^[3]

There is some evidence that flumazenil is effective for protracted benzodiazepine withdrawal (or benzodiazepine post-withdrawal syndrome) with promising results ^[4][5][6], though larger studies with more regular dosing intervals are needed to confirm this. There have also been some studies investigating the drugs effect in reducing benzodiazapine tolerance ^[7][8], with promising results. In binding to the benzodiazepine receptor, flumazenil may reset the receptors sensitivity, restoring the receptor to its pre-drug affinity. ^[9]

It has also been used in hepatic encephalopathy, though results have been mixed.^[10][11]

The onset of action is rapid and usually effects are seen within one to two minutes. The peak effect is seen at six to ten minutes. The recommended dose for adults is 200 μg every 1–2 minutes until the effect is seen, to a maximum of 3 mg per hour. It is available as a clear, colourless solution for intravenous injection, containing 500 μg in 5 mL.

Many benzodiazepines (including midazolam) have longer half-lives than flumazenil. Therefore, repeat doses of flumazenil may be required to prevent recurrent symptoms of overdosage once the initial dose of flumazenil wears off. It is hepatically metabolised to inactive compounds which are excreted in the urine. Subjects who are physically dependent on benzodiazepines may suffer benzodiazepine withdrawal symptoms, including seizure, upon administration of flumazenil.

It is not recommended for routine use in those with a decreased level of consciousness.^[12]

PET radioligand

Radiolabeled with the radioactive isotope carbon-11 flumazenil may be used as a radioligand in neuroimaging with positron emission tomography to visualize the distribution of GABA_A receptors in the human brain.^[13]

Clinical pharmacology

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 humans.

Flumazenil does not antagonize all of 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.

In animals pretreated with high doses of benzodiazepines over several weeks, Flumazenil injection elicited symptoms of benzodiazepine withdrawal, including seizures. A similar effect was seen in adult human subjects.

Pharmacodynamics

Intravenous Flumazenil has been shown to antagonize sedation, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers.

The duration and degree of reversal of sedative benzodiazepine effects are related to the dose and plasma concentrations of Flumazenil.

Chemistry

Gerecke, M.; Hunkeler, W.; Kyburz, E.; Mohler, H.; Pieri, L.; Pole, P.; 1982, U.S. Patent 4,316,839.

See also

• Benzodiazepine overdose
• Benzodiazepine
• Bretazenil
• Imidazenil

References

1. ^ Higgitt, Lader and Fonagy, 1986
2. ^ ^{a b c} Goldfrank, Lewis R. (2002). Goldfrank's toxicologic emergencies. New York: McGraw-Hill Medical Publ. Division. ISBN 0-07-136001-8. http://books.google.com/?id=HVYyRsuUEc0C&pg=PA948&dq=flumazenil+not+to+be+used+in+overdose. 
3. ^ Nelson, Lewis H.; Flomenbaum, Neal; Goldfrank, Lewis R.; Hoffman, Robert Louis; Howland, Mary Deems; Neal A. Lewin (2006). Goldfrank's toxicologic emergencies. New York: McGraw-Hill, Medical Pub. Division. ISBN 0-07-147914-7. 
4. ^ Professor Malcolm Lader (1992). "A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal". Journal of Psychopharmacology. http://www.bcnc.org.uk/flumazenil.html.
5. ^ Lader MB, Morton SV. A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal. JPsychopharmacol. 1992; 6: 19-28.
6. ^ Saxon L, Hjemdahl P, Hiltunen AJ, Borg S (May 1997). "Effects of flumazenil in the treatment of benzodiazepine withdrawal--a double-blind pilot study" (PDF). Psychopharmacology (Berl.) 131 (2): 153–60. doi:10.1007/s002130050278. PMID 9201803. http://www.springerlink.com/content/2vpf562teffglej5/fulltext.pdf
7. ^ Savic I, Widen L, Stone-Elander S. Feasibility of reversing benzodiazepine tolerance with flumazenil. Lancet 1991; 337: 133-137.
8. ^ Savic, Widen and Stone-Elander, 1991)
9. ^ Nutt and Costello, 1988
10. ^ Goulenok C, Bernard B, Cadranel JF, et al. (March 2002). "Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis". Aliment. Pharmacol. Ther. 16 (3): 361–72. doi:10.1046/j.1365-2036.2002.01191.x. PMID 11876688. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0269-2813&date=2002&volume=16&issue=3&spage=361. 
11. ^ Als-Nielsen B, Gluud LL, Gluud C (2004). Als-Nielsen, Bodil. ed. "Benzodiazepine receptor antagonists for hepatic encephalopathy". Cochrane Database Syst Rev (2): CD002798. doi:10.1002/14651858.CD002798.pub2. PMID 15106178. 
12. ^ Wood, Lawrence D. H.; Hall, Jesse B.; Schmidt, Gregory D. 1952 (2005). Principles of critical care. McGraw-Hill Professional. ISBN 0-07-141640-4. http://books.google.com/?id=Ss7gzGwk78gC&pg=RA11-PA1505&lpg=RA11-PA1505&dq=flumazenil+not+recommended+in+overdose. 
13. ^ Alexander Hammers, Matthias J. Koepp, Mark P. Richardson, Rene Hurlemann, David J. Brooks & John S. Duncan (June 2003). "Grey and white matter flumazenil binding in neocortical epilepsy with normal MRI. A PET study of 44 patients". Brain 126 (Pt 6): 1300–1308. doi:10.1093/brain/awg138. PMID 12764053. http://brain.oxfordjournals.org/cgi/content/abstract/126/6/1300. 

Other

• Romazicon product information, Roche USA

External links

• Flumazenil drug label/data at Daily Med from U.S. National Library of Medicine, National Institutes of Health.