Clorazepate

Source: Wikipedia, the free encyclopedia.
Clorazepate
Clinical data
Trade namesTranxene, Tranxilium, Novo-Clopate
Other namesClorazepate dipotassium
AHFS/Drugs.comMonograph
MedlinePlusa682052
Routes of
administration
Oral
ATC code
Legal status
Legal status
Renal
Identifiers
  • 7-Chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid
JSmol)
  • O=C(O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
  • InChI=1S/C16H11ClN2O3/c17-10-6-7-12-11(8-10)13(9-4-2-1-3-5-9)19-14(16(21)22)15(20)18-12/h1-8,14H,(H,18,20)(H,21,22) checkY
  • Key:XDDJGVMJFWAHJX-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Clorazepate, sold under the brand name Tranxene among others, is a

desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.[2]

It was patented in 1965 and approved for medical use in 1967.[3]

Medical uses

Clorazepate is used in the treatment of anxiety disorders and insomnia. It may also be prescribed as an anticonvulsant or muscle relaxant.[4] It is also used as a premedication.[5]

Clorazepate is prescribed principally in the treatment of

alcohol withdrawal and epilepsy, although it is also a useful anxiolytic because of its long half-life. The normal starting dosage range of clorazepate is 15 to 60 mg per day. The drug is to be taken two to four times per day. Dosages as high as 90 to 120 mg per day may be used in the treatment of acute alcohol withdrawal. In the United States and Canada, clorazepate is available in 3.75, 7.5, and 15 mg capsules or tablets. In Europe, tablet formations are 5 mg, 10 mg, 20 mg and 50 mg.[6] Clorazepate SD (controlled release) is available and may have a reduced incidence of adverse effects. The sustained-release formulation of clorazepate has some advantages in that, if a dose is missed, less profound fluctuations in blood plasma levels occur, which may be helpful to some people with epilepsy at risk of break-through seizures.[7]

Adverse effects

Adverse effects of clorazepate include

alcohol use disorder or a history of aggressive behavior and anger are at greater risk of developing paradoxical reactions to benzodiazepines.[7]

In September 2020, the U.S. Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of non-medical use, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.[8]

Tolerance, dependence and withdrawal

Delirium has been noted from discontinuation from clorazepate.[9] A

sweating, and diarrhea.[10]

Interactions

All

antimycotics inhibit the metabolism of benzodiazepines and may result in increased plasma levels with resultant enhancement of adverse effects. Phenytoin, phenobarbital, and carbamazepine have the opposite effect, with coadministration leading to increased metabolism and decreased therapeutic effects of clorazepate.[7]

Contraindications and special caution

Benzodiazepines require special precaution if used in the elderly, children, alcohol- or drug-dependent individuals and individuals with

Clorazepate if used late in pregnancy, the

Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.[12]

Special precaution is required when using clorazepate in the elderly because the elderly metabolise clorazepate more slowly, which may result in excessive drug accumulation. Additionally the elderly are more sensitive to the adverse effects of benzodiazepines compared to younger individuals even when blood plasma levels are the same. Use of benzodiazepines in the elderly is only recommended for 2 weeks and it is also recommended that half of the usual daily dose is prescribed.[7]

Pharmacology

Clorazepate is a "classical" benzodiazepine. Other classical benzodiazepines include

desmethyl-diazepam, which is a partial agonist of the GABAA receptor and has a half life of 20–179 hours; a small amount of desmethyldiazepam is further metabolised into oxazepam. Clorazepate exerts its pharmacological properties via increasing the opening frequency of the chloride ion channel of GABAA receptors. This effect of benzodiazepines requires the presence of the neurotransmitter GABA and results in enhanced inhibitory effects of the neurotransmitter GABA acting on GABAA receptors.[7] Clorazepate, like other benzodiazepines, is widely distributed and is highly bound to plasma proteins; clorazepate also crosses readily over the placenta and into breast milk. Peak plasma levels of the active metabolite desmethyl-diazepam are seen between 30 minutes and 2 hours after oral administration of clorazepate. Clorazepate is completely metabolised to desmethyl-diazepam in the gastrointestinal tract and thus the pharmacological properties of clorazepate are largely due to desmethyldiazepam.[7]

Chemistry

Clorazepate is used in the form of a dipotassium salt. It is unusual among benzodiazepines in that it is freely soluble in water.

Clorazepate can be synthesized starting from 2-amino-5-chlorobenzonitrile, which upon reaction with phenylmagnesium bromide is transformed into 2-amino-5-chlorbenzophenone imine.[14][15][16] Reacting this with aminomalonic ester gives a heterocyclization product, 7-chloro-1,3-dihydro-3-carbethoxy-5-phenyl-2H-benzodiazepin-2-one. Upon hydrolysis using an alcoholic solution of potassium hydroxide forms a dipotassium salt, chlorazepate.

Legal status

In the United States, clorazepate is listed under Schedule IV of the Controlled Substances Act.[17]

References

  1. ^ 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.
  2. S2CID 24414335. Archived from the original
    on 2009-07-20. Retrieved 2009-05-31.
  3. .
  4. ^ a b National Institutes of Health (2003). "Clorazepate". National Library of Medicine. Archived from the original on 20 May 2008. Retrieved 19 July 2008.
  5. PMID 17551699
    .
  6. ^ Tranxene prescribing information in the Netherlands (Dutch language); accessed 2007-03-08.
  7. ^ ]
  8. ^ "FDA expands Boxed Warning to improve safe use of benzodiazepine drug". U.S. Food and Drug Administration (FDA). 23 September 2020. Retrieved 23 September 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  9. PMID 27202
    .
  10. ^ .
  11. .
  12. .
  13. .
  14. ^ US 3516988, Schmitt J, "1,4 benzodiazepine-2-ones having a carboxylic acid ester or amide group in the 3-position", issued 23 June 1970 
  15. ^ DE 1518764, Schmitt J, "Verfahren zur Herstellung von Orthoaminoarylcetiminen [Process for the preparation of orthoaminoarylcetimins]", published 1971-11-04, assigned to Etablissements Clin-Byla S.A. 
  16. ^ Schmitt J, Comoy P, Suguet M, Calief G, Muer J, Clim T, et al. (1969). "Sur des nouvelles benzodiazepines hydrosolubles douées d'une puissante activité sur le système nerveux central" [On new water-soluble benzodiazepines endowed with a powerful activity on the central nervous system.]. Chim. Ther. (in French). 4: 239.
  17. ^ "List of Schedule 4 (IV) Controlled Substances". Drugs.com. Retrieved 27 March 2024.

External links