Clorazepate: Wikis

  

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Clorazepate
Systematic (IUPAC) name
7-chloro-2,3-dihydro-2-oxo-5-phenyl-
1
H-1,4-benzodiazepine-3-carboxylic acid
Identifiers
CAS number 23887-31-2
57109-90-7 (potassium salt)
ATC code N05BA05
PubChem 2809
DrugBank APRD00881
ChemSpider 10617010
Chemical data
Formula C 16H11ClN2O3  
Mol. mass 314.72
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 91%
Metabolism Hepatic
Half life 48 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat. D(US)
Legal status Schedule IV(US)
Routes Oral
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Clorazepate (marketed under the brand names Tranxene and Novo-Clopate), is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. Clorazepate was discontinued in February 2006 in the United Kingdom.[1] Clorazepate is a prodrug for desmethyldiazepam which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.[2]

Contents

Indications

Clorazepate is used in the treatment of anxiety disorders and insomnia. It may also be prescribed as an anticonvulsant or muscle relaxant.[3]

Clorazepate is principally prescribed 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.[4] Clorazepate SD (controlled release) is available in 11.25 and 22.5 mg tablets. Clorazepate SD is only prescribed when the patient has become adjusted to a certain dosage, and is taken once a day. Clorazepate is available in generic form. Clorazepate begins to act on the central nervous system within one or two hours, and its effects may be felt for an entire day or longer in some individuals. It is contraindicated for those with impaired renal or hepatic function.

Pharmacology

Clorazepate is a "classical" benzodiazepine. Other classical benzodiazepines include alprazolam, diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, bromazepam and flurazepam.[5] Clorazepate is a long acting benzodiazepine drug.[6] Clorazepate produces the metabolite desmethyl-diazepam which has a half life of 36 – 200 hours.[7]

Interactions

All sedatives or hypnotics eg other benzodiazepines, alcohol, antihistamines, opiates, neuroleptics, sleep aids are likely to magnify the effects of clorazepate on the central nervous system. Drugs which may interact with clorazepate include, digoxin, disulfiram, fluoxetine, isoniazid, ketoconazole, levodopa, metoprolol, hormonal contraceptives, probenecid, propranolol, rifampin, theophylline, valproic acid.[3]

Cimetidine, trade name Tagamet, inhibits breakdown of Clorazepate, and leads to increased levels of the drug in the system.[8]

Clorazepate DOJ.jpg

Tolerance, dependence and withdrawal

In humans tolerance to the anticonvulsant effects of clorazepate occurs frequently with regular use.[9] Regular use of benzodiazepines causes the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome including symptoms such as anxiety, apprehension, tremor, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Withdrawal from benzodiazepines should be gradual as abrupt withdrawal from high doses of benzodiazepines may cause confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. Abrupt withdrawal from lower doses may cause depression, nervousness, rebound insomnia, irritability, sweating, and diarrhoea.[10]

Contraindications and special caution

Benzodiazepines require special precaution if used in the elderly, children, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.[11]

Chlorazepate if used late in pregnancy, the third trimester, causes a definite risk a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the new born 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]

Legal status

Clorazepate is listed under Schedule IV of the Controlled Substances Act.

See also

References

  1. ^ National electronic Library for Medicines. "SPC (Product Licence) Changes". E-Communications Team at the London and South East Medicines Information Service based at Guy’s Hospital London. http://www.nelm.nhs.uk/en/NeLM-Area/Other-Lib-Updates/SPC-Changes/502132. Retrieved 19 December 2008.  
  2. ^ Ochs HR, Greenblatt DJ, Verburg-Ochs B, Locniskar A (October 1984). "Comparative single-dose kinetics of oxazolam, prazepam, and clorazepate: three precursors of desmethyldiazepam". J Clin Pharmacol 24 (10): 446–51. PMID 6150943. http://jcp.sagepub.com/cgi/content/abstract/24/10/446.  
  3. ^ a b National Institutes of Health (2003). "Clorazepate". National Library of Medicine. http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682052.html. Retrieved 19 July 2008.  
  4. ^ Tranxene prescribing information in the Netherlands (Dutch language); accessed 2007-03-08
  5. ^ Braestrup C; Squires RF. (1 April 1978). "Pharmacological characterization of benzodiazepine receptors in the brain". Eur J Pharmacol 48 (3): 263–70. doi:10.1016/0014-2999(78)90085-7. PMID 639854.  
  6. ^ The Committee on the Review of Medicines (CRM) (March 29, 1980). "Systematic review of the benzodiazepines. Guidelines for data sheets on diazepam, chlordiazepoxide, medazepam, clorazepate, lorazepam, oxazepam, temazepam, triazolam, nitrazepam, and flurazepam. Committee on the Review of Medicines". Br Med J. 280 (6218): 910–2. doi:10.1136/bmj.280.6218.910. PMID 7388368.  
  7. ^ Professor heather Ashton (April 2007). "BENZODIAZEPINE EQUIVALENCY TABLE". http://www.bcnc.org.uk/equivalence.html. Retrieved September 23, 2007.  
  8. ^ Divoll M; Greenblatt DJ, Abernethy DR, Shader RI (November 1982). "Cimetidine impairs clearance of antipyrine and desmethyldiazepam in the elderly". J Am Geriatr Soc 30 (11): 684–9. PMID 6813365.  
  9. ^ Loiseau P (1983). "[Benzodiazepines in the treatment of epilepsy]". Encephale 9 (4 Suppl 2): 287B–292B. PMID 6373234.  
  10. ^ Committee on the Review of Medicines (March 29, 1980). "Systematic review of the benzodiazepines. Guidelines for data sheets on diazepam, chlordiazepoxide, medazepam, clorazepate, lorazepam, oxazepam, temazepam, triazolam, nitrazepam, and flurazepam. Committee on the Review of Medicines" (pdf). Br Med J. 280 (6218): 910–2. doi:10.1136/bmj.280.6218.910. PMID 7388368. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1601049&blobtype=pdf.  
  11. ^ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM. et al. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome.". Ann Pharm Fr 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.  
  12. ^ McElhatton PR. (Nov-December 1994). "The effects of benzodiazepine use during pregnancy and lactation". Reprod Toxicol. 8 (6): 461–75. doi:10.1016/0890-6238(94)90029-9. PMID 7881198.  

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