Oxazepam

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Oxazepam
Oxazepam2D.svg
Oxazepam3Dan2.gif
Clinical data
Legal status
Routes oral
Identifiers
ATC code ?
PubChem CID 4616
DrugBank DB00842
ChemSpider 4455 YesY
UNII 6GOW6DWN2A YesY
KEGG D00464 YesY
ChEBI CHEBI:7823 YesY
ChEMBL CHEMBL568 YesY
Chemical data
Formula C15H11ClN2O2 
 YesY (what is this?)  

Oxazepam[1] (marketed in English-speaking countries under the brand names Alepam, Medopam, Murelax, Noripam, Opamox, Ox-Pam, Purata, Serax and Serepax, as Vaben in Israel, as Sobril and Oxascand in Sweden, as Oxapax in Denmark, as Sobril and Alopam in Norway, as Sobril or Oxascand in Iceland and Sweden, Zaxpam in India, and Praxiten in Croatia), (marketed in French-speaking countries as Seresta) is a short-to-intermediate-acting 3-hydroxy benzodiazepine derivative.[2][3] Oxazepam is used extensively since the 1960s for the treatment of anxiety and insomnia and in the control of symptoms of alcohol withdrawal. It is a metabolite of diazepam, prazepam, and temazepam,[4] and has moderate amnesic, anxiolytic, anticonvulsant, hypnotic, sedative, and skeletal muscle relaxant properties compared to other benzodiazepines.[5]

Indications

It is an intermediate-acting benzodiazepine with a slow onset of action,[6] so it is usually prescribed to individuals who have trouble staying asleep, rather than falling asleep. It is commonly prescribed for anxiety disorders with associated tension, irritability, and agitation. It is also prescribed for drug and alcohol withdrawal, and for anxiety associated with depression. Physicians may use oxazepam outside its approved indications to treat social phobia, post-traumatic stress disorder, insomnia, premenstrual syndrome, and other conditions.[7]

Oxazepam DOJ.jpg

Dosage

  • Mild/moderate anxiety - 10 to 15 mg, three or four times daily[8]
  • Severe anxiety - 15 to 30 mg, three or four times daily[8]
  • Symptoms related to alcohol withdrawal - 15 to 30 mg, three or four times daily[9]

Availability

  • In the United Kingdom, oxazepam is available generically in the form of 10-, 15-, and 30-mg tablets.
  • In Finland, it is available generically in 15-, 30- and 50-mg tablets.
  • In France and the Netherlands, it is available in 10- and 50-mg tablets.
  • In Australia, it is available in 5-, 7.5-, 10-, 15-, and 30-mg tablets.
  • In Canada, it is available in 10-, 15-, and 30-mg tablets that can be split in half.
  • In Sweden, it is available in 5-, 10-, 15-, and 25-mg tablets.
  • In Norway, it is available in 5-, 10-, 15-, and 25-mg tablets.
  • In Iceland, it is available in 10-, 15-, and 25-mg tablets.

[10]

Usage

Oxazepam, along with diazepam, nitrazepam, and temazepam, were the four benzodiazepines listed on the pharmaceutical benefits scheme and represented 82% of the benzodiazepine prescriptions in Australia in 1990-1991.[11]

Side effects

The side effects of oxazepam are similar to those of other benzodiazepines, and may include dizziness, drowsiness, headache, memory impairment, paradoxical excitement, and anterograde amnesia, but does not affect transient global amnesia.[citation needed] Side effects due to rapid decrease in dose or abrupt withdrawal from oxazepam may include abdominal and muscle cramps, convulsions, depression, inability to fall asleep or stay asleep, sweating, tremors, or vomiting.[12]

Contraindications

Oxazepam is contraindicated in myasthenia gravis, chronic obstructive pulmonary disease, and limited pulmonary reserve, as well as severe hepatic disease.

Special precautions

Benzodiazepines require special precautions if used in the elderly, during pregnancy, in children, alcohol- or drug-dependent individuals, and individuals with comorbid psychiatric disorders.[13] Benzodiazepines including oxazepam are lipophilic drugs and rapidly penetrate membranes, so rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines in late pregnancy, especially high doses, may result in floppy infant syndrome.[14]

Pregnancy

Oxazepam when taken during late in pregnancy, the third trimester, causes a definite risk to the neonate including a severe benzodiazepine withdrawal syndrome including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. 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.[15]

Tolerance, dependence and withdrawal

Oxazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, addiction, and benzodiazepine withdrawal syndrome. Withdrawal from oxazepam or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can occur, though, at standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible by a slow and gradual dose reduction regimen.[16]

Pharmacology

Oxazepam is an intermediate-acting benzodiazepine of the 3-hydroxy family; it acts on benzodiazepine receptors, resulting in increased effect of GABA to the GABAA receptor which results in inhibitory effects on the central nervous system.[17][18] The half-life of oxazepam is four to 15 hours.[19] It has been shown to suppress cortisol levels.[20] Oxazepam is the most slowly absorbed and has the slowest onset of action of all the common benzodiazepines according to one British study.[21]

Oxazepam is an active metabolite formed during the breakdown of diazepam, nordazepam, and certain similar drugs. It may be safer than many other benzodiazepines in patients with impaired liver function because it does not require hepatic oxidation, but rather, it is simply metabolized by glucuronidation, so oxazepam is less likely to accumulate and cause adverse reactions in the elderly or people with liver disease. Oxazepam is similar to lorazepam in this respect. (1) Preferential storage of oxazepam occurs in some organs, including the heart of the neonate. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate, and withdrawal of oxazepam during pregnancy and breast feeding is recommended, as oxazepam is excreted in breast milk.[22]

Interactions

As oxazepam is an active metabolite of diazepam, an overlap in possible interactions is likely with other drugs or food, with exception of the pharmacokinetic CYP450 interactions (e.g. with cimetidine). Precautions and following the prescription are required when taking oxazepam (or other benzodiazepines) in combinations with antidepressant medication (SSRIs such as Prozac, Zoloft, and Paxil, or multiple reuptake inhibitors such as Wellbutrin, Cymbalta, or Effexor), potent painkillers (opioids, e.g. morphine, oxycodone or methadone). Concurrent use of these medicines (as well as other benzodiazepines) can interact in a way that is difficult to predict. Drinking alcohol when taking oxazepam is not recommended. Concomitant use of oxazepam and alcohol can lead to increased sedation, severe problems with coordination (ataxia), decreased muscle tone, and in severe cases or in predisposed patients, even to life-threatening intoxications with respiratory depression, coma, and collapse. Concomitant use of alcohol and oxazepam (as well as other benzodiazepines) also increases the risk of an addiction.[citation needed]

Overdose

Oxazepam is generally less toxic in overdose than other benzodiazepines.[23] Important factors which affect the severity of a benzodiazepine overdose include the dose ingested, the age of the patient, and health status prior to overdose. Benzodiazepine overdoses can be much more dangerous if a coingestion of other CNS depressants such as opiates or alcohol has occurred. Symptoms of an oxazepam overdose include:[24][25][26]

Misuse

Oxazepam has the potential for misuse, defined as taking the drug to achieve a high, or continuing to take the drug in the long term against medical advice.[27] Benzodiazepines, including diazepam, oxazepam, nitrazepam, and flunitrazepam, accounted for the largest volume of forged drug prescriptions in Sweden from 1982 to 1986. During this time, a total of 52% of drug forgeries were for benzodiazepines, suggesting they were a major prescription drug class of abuse.[28]

However, due to its slow rate of absorption and its slow onset of action,[21] oxazepam has a relatively low potential for abuse compared to some other benzodiazepines, such as temazepam, flunitrazepam, or triazolam, which have a high potential for abuse similar to barbiturate abuse potential.[29]

Legal status

Oxazepam is a Schedule IV drug under the Convention on Psychotropic Substances.[30]

Chemistry

6-Chloro-2-chloromethyl-4-phenylquinazolin-3-oxide undergoes treatment with sodium hydroxide, giving 7-chloro-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-on-4-oxide. This undergoes an acetoxylation reaction of the third position of the benzodiazepine ring, using acetic anhydride, (which resembles the Polonovski reaction), giving 7-chloro-1,3-dihydro-3-acetoxy-5-phenyl-2H-benzodiazepin-2-one. Subsequent hydrolysis of the product's acetyl group gives oxazepam.[31][32][33][34][35][36]

Oxazepam synthesis.png

Carcinogenicity

Oxazepam is listed as a possible carcinogen (Group 2b) by the IARC.

See also

References

  1. ^ NL Patent 6615447
  2. ^ "Benzodiazepine Names". non-benzodiazepines.org.uk. Retrieved 2008-12-29. 
  3. ^ "FASS". Läkemedelsindustriföreningens Service AB. Retrieved 2011-02-03. 
  4. ^ "Oxazepam (IARC Summary & Evaluation, Volume 66, 1996)". IARC. Retrieved 2009-03-12. 
  5. ^ Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Curr. Drug Metab. 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614. 
  6. ^ Galanter, Marc; Kleber, Herbert D. (1 July 2008). The American Psychiatric Publishing Textbook of Substance Abuse Treatment (4th ed.). United States of America: American Psychiatric Publishing Inc. p. 216. ISBN 978-1-58562-276-4. 
  7. ^ http://www.psychatlanta.com/documents/serax.pdf
  8. ^ a b www.drugs.com/dosage/oxazepam Usual_Adult_Dose_for_Anxiety
  9. ^ www.drugs.com/dosage/oxazepam Usual_Adult_Dose_for_Alcohol_Withdrawal
  10. ^ http://webprod5.hc-sc.gc.ca/dpd-bdpp/dispatch-repartition.do?lang=eng
  11. ^ Mant A; Whicker SD; McManus P; Birkett DJ; Edmonds D; Dumbrell D. (December 1993). "Benzodiazepine utilisation in Australia: report from a new pharmacoepidemiological database". Aust J Public Health. 17 (4): 345–9. doi:10.1111/j.1753-6405.1993.tb00167.x. PMID 7911332. 
  12. ^ Oxazepam patient advice including side effects
  13. ^ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM.; Eschalier, A. (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. 
  14. ^ Kanto JH. (May 1982). "Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations". Drugs. 23 (5): 354–80. doi:10.2165/00003495-198223050-00002. PMID 6124415. 
  15. ^ McElhatton PR. (Nov–Dec 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. 
  16. ^ MacKinnon GL; Parker WA. (1982). "Benzodiazepine withdrawal syndrome: a literature review and evaluation". The American journal of drug and alcohol abuse. 9 (1): 19–33. doi:10.3109/00952998209002608. PMID 6133446. 
  17. ^ Skerritt JH; Johnston GA. (May 6, 1983). "Enhancement of GABA binding by benzodiazepines and related anxiolytics". Eur J Pharmacol. 89 (3–4): 193–8. doi:10.1016/0014-2999(83)90494-6. PMID 6135616. 
  18. ^ Oelschläger H. (July 4, 1989). "[Chemical and pharmacologic aspects of benzodiazepines]". Schweiz Rundsch Med Prax. 78 (27–28): 766–72. PMID 2570451. 
  19. ^ Professor heather Ashton (April 2007). "Benzodiazepine equivalency table". Retrieved September 23, 2007. 
  20. ^ Christensen P; Lolk A; Gram LF; Kragh-Sørensen P. (1992). "Benzodiazepine-induced sedation and cortisol suppression. A placebo-controlled comparison of oxazepam and nitrazepam in healthy male volunteers". Psychopharmacology. 106 (4): 511–6. doi:10.1007/BF02244823. PMID 1349754. 
  21. ^ a b Serfaty M, Masterton G (1993). "Fatal poisonings attributed to benzodiazepines in Britain during the 1980s". Br J Psychiatry 163 (3): 386–93. doi:10.1192/bjp.163.3.386. PMID 8104653. 
  22. ^ Olive G; Dreux C. (January 1977). "Pharmacologic bases of use of benzodiazepines in peréinatal medicine". Arch Fr Pediatr. 34 (1): 74–89. PMID 851373. 
  23. ^ Buckley NA, Dawson AH, Whyte IM, O'Connell DL (28 January 1995). "Relative toxicity of benzodiazepines in overdose". BMJ 310 (6974): 219–21. doi:10.1136/bmj.310.6974.219. PMC 2548618. PMID 7866122. 
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  27. ^ Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". J Clin Psychiatry. 66 Suppl 9: 31–41. PMID 16336040. 
  28. ^ Bergman U; Dahl-Puustinen ML. (1989). "Use of prescription forgeries in a drug abuse surveillance network". Eur J Clin Pharmacol. 36 (6): 621–3. doi:10.1007/BF00637747. PMID 2776820. 
  29. ^ Griffiths RR, Wolf B (August 1990). "Relative abuse liability of different benzodiazepines in drug abusers". J Clin Psychopharmacol 10 (4): 237–43. doi:10.1097/00004714-199008000-00002. PMID 1981067. 
  30. ^ http://www.incb.org/pdf/e/list/green.pdf
  31. ^ S.C. Bell, U.S. Patent 3,176,009 (1965)
  32. ^ S.C. Bell, U.S. Patent 3,296,249 (1967)
  33. ^ E. Reeder, L.H. Sternbach, U.S. Patent 3,109,843 (1963)
  34. ^ Bell, S. C.; Sulkowski, T. S.; Gochman, C.; Childress, S. J. (1962). "1,3-Dihydro-2H-1,4-benzodiazepine-2-ones and Their 4-Oxides". The Journal of Organic Chemistry 27 (2): 562. doi:10.1021/jo01049a052. 
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  36. ^ Bell, S. C.; McCaully, R. J.; Childress, S. J. (1968). "General method for preparing 2-acetamidoacetanilides having a second functional group in the 2 posittion and affording an access to 3-acetamido-1,3-dihydro-2H-1,4-benzodiazepin-2-ones". The Journal of Organic Chemistry 33: 216. doi:10.1021/jo01265a041. 

External links