Flumazenil

Source: Wikipedia, the free encyclopedia.
Flumazenil
Clinical data
Trade namesAnexate, Lanexat, Mazicon, Romazicon
Other namesethyl 8-fluoro- 5,6-dihydro- 5-methyl- 6-oxo- 4H- imidazo [1,5-a] [1,4] benzodiazepine- 3-carboxylate
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: B3
Routes of
administration		IV
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismHepatic
Elimination half-life7–15 min (initial)
20–30 min (brain)
40–80 min (terminal)
ExcretionUrine 90–95%
Feces 5–10%
Identifiers
  • Ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate
JSmol)
  • Fc(c1)ccc-2c1C(=O)N(C)Cc3n2cnc3C(=O)OCC
  • 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 checkY
  • Key:OFBIFZUFASYYRE-UHFFFAOYSA-N checkY
  (verify)
A vial of flumazenil solution for injection

Flumazenil (also known as flumazepil, code name Ro 15-1788[3]) is a selective GABAA receptor antagonist[4] administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (particularly in cases of overdose), through competitive inhibition.

It was first characterized in 1981,

benzodiazepine overdoses and to help reverse anesthesia. Administration of flumazenil by sublingual lozenge and topical cream has also been tested.[6][7]

Medical uses

Flumazenil benefits patients who become excessively drowsy after use of

therapeutic procedures.[8]

The drug has been used as an

GABA/benzodiazepine receptor complex. There are many complications that must be taken into consideration when used in the acute care setting.[8]
These include lowered seizure threshold, agitation, and anxiousness. Flumazenil's short half-life requires multiple doses. Because of the potential risks of withdrawal symptoms and the drug's short half-life, patients must be carefully monitored to prevent recurrence of overdose symptoms or adverse side effects.

Flumazenil is also sometimes used after surgery to reverse the sedative effects of benzodiazepines. This is similar to

opioids
following surgery. Administration of the drug requires careful monitoring by an anesthesiologist due to potential side effects and serious risks associated with over-administeration. Likewise, post-surgical monitoring is also necessary because flumazenil can mask the apparent metabolization ("wearing off") of the drug after removal of patient life-support and monitoring equipment.

Flumazenil has been effectively used to treat overdoses of non-benzodiazepine hypnotics, such as zolpidem, zaleplon and zopiclone (also known as "Z-drugs").[9]

It may also be effective in reducing

hypersomnias, such as idiopathic hypersomnia.[6]

The drug has also been used in hepatic encephalopathy. It may have beneficial short‐term effects in people with cirrhosis, but there is no evidence for long-term benefits.[10]

The onset of action is rapid, and effects are usually 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, up 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.[citation needed] Additional doses may be needed within 20 to 30 minutes if evidence of oversedation reappears.[11]

Many benzodiazepines (including

symptoms once the initial dose of flumazenil wears off.[citation needed
]

It is hepatically metabolised to inactive compounds which are excreted in the urine. Individuals who are physically dependent on benzodiazepines may experience

benzodiazepine withdrawal symptoms, including seizures
, upon rapid administration of flumazenil.

It is not recommended for routine use in those with a decreased

level of consciousness.[12]

In terms of drug enforcement initiatives, diversion control programs and required post-marketing surveillance of adverse events, orders for flumazenil may trigger a prescription audit to the search for benzodiazepine misuse and for clinically significant adverse reactions related to their use.[13]

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 GABAA receptors in the human brain.[14]

Treatment for benzodiazepine dependence & tolerance

Epileptic patients who have become tolerant to the anti-seizure effects of the benzodiazepine clonazepam became seizure-free for several days after treatment with 1.5 mg of flumazenil.[15] Similarly, patients who were dependent on high doses of benzodiazepines (median dosage 333 mg diazepam-equivalent) were able to be stabilised on a low dose of clonazepam after 7–8 days of treatment with flumazenil.[16]

Flumazenil has been tested against placebo in benzodiazepine-dependent subjects. Results showed that typical benzodiazepine withdrawal effects were reversed with few to no symptoms.[17] Flumazenil was also shown to produce significantly fewer withdrawal symptoms than saline in a randomized, placebo-controlled study with benzodiazepine-dependent subjects. Additionally, relapse rates were much lower during subsequent follow-up.[18]

In vitro studies of tissue cultured cell lines have shown that chronic treatment with flumazenil enhanced the benzodiazepine binding site where such receptors have become more numerous and uncoupling/down-regulation of GABAA has been reversed.[19][20][21] After long-term exposure to benzodiazepines, GABAA receptors become down-regulated and uncoupled. Growth of new receptors and recoupling after prolonged flumazenil exposure has also been observed. It is thought this may be due to increased synthesis of receptor proteins.[22]

Flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks.[23] This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.

Low-dose, slow

subcutaneous flumazenil administration is a safe procedure for patients withdrawing from long-term, high-dose benzodiazepine dependency.[24] It has a low risk of seizures even amongst those who have experienced convulsions when previously attempting benzodiazepine withdrawal.[25]

In Italy, the gold standard for treatment of high-dose benzodiazepine dependency is 8–10 days of low-dose, slowly infused flumazenil.[26] One addiction treatment centre in Italy has used flumazenil to treat over 300 patients who were dependent on high doses of benzodiazepines (up to 70 times higher than conventionally prescribed) with physicians being among the clinic's most common patients.[27]

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.[28] It also exhibits weak partial agonism of GABAA receptor complexes that contain α6-type monomers; the clinical relevance of this is unknown.[29]

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, and most anesthetics) and does not reverse the effects of opioids. It will however antagonize the action of non-benzodiazepine

z-drugs, such as zolpidem and zopiclone, because they act via the benzodiazepine site of the GABA receptor[30] - it has been used to successfully treat z-drug overdose.[30][31][32]

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.

Availability

Flumazenil is sold under a wide variety of brand names worldwide like Anexate, Lanexat, Mazicon, Romazicon. In India it is manufactured by Roche Bangladesh Pharmaceuticals and USAN Pharmaceuticals.[citation needed]

See also

References

  1. FDA
    . Retrieved 22 Oct 2023.
  2. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  3. S2CID 4340263
    .
  4. S2CID 24494744
    .
  5. PMID 2903780
    .
  6. ^
    S2CID 44236050
    .
  7. ^ Clinical trial number NCT01183312 for "Flumazenil for the Treatment of Primary Hypersomnia" at ClinicalTrials.gov
  8. ^
    ISBN 978-0-07-136001-2
    .
  9. ISBN 978-0-07-147914-1
    .
  10. PMID 28796283
    .
  11. ISBN 978-1-264-25807-9
    .
  12. ISBN 978-0-07-141640-5
    .
  13. S2CID 12973546
    .
  14. PMID 12764053
    .
  15. S2CID 41180892
    .
  16. S2CID 28979824
    .
  17. PMID 8803645
    .
  18. S2CID 21255719
    .
  19. PMID 16084060
    .
  20. PMID 15659288
    .
  21. PMID 15531382
    .
  22. S2CID 9033302
    .
  23. S2CID 41351863
    .
  24. S2CID 27167585
    .
  25. S2CID 42432213
    .
  26. PMID 21320225
    .
  27. PMID 22509854
    .
  28. PMID 23126253
    .
  29. PMID 8632757
    .
  30. ^
    PMID 23404347
    .
  31. S2CID 34655918
    .
  32. S2CID 34525063
    .

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Flumazenil&oldid=1215353768"