Eszopiclone: Wikis

  
  

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Eszopiclone
Systematic (IUPAC) name
(S)-6-(5-Chloro-2-pyridinyl)- 7-oxo- 6,7-dihydro- 5H-pyrrolo[3,4-b]pyrazin-5-yl- 4-methyl- 1-piperazinecarboxylate
Identifiers
CAS number 138729-47-2
ATC code N05CF04 [1]
PubChem 969472
DrugBank APRD00431
ChemSpider 839530
Chemical data
Formula C17H17ClN6O3 
Mol. mass 388.808 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Protein binding 52-59%
Metabolism Hepatic oxidation and demethylation (CYP3A4 and CYP2E1-mediated)
Half life 6 hours
Excretion Renal
Therapeutic considerations
Licence data

US FDA:link

Pregnancy cat. C(US)
Legal status Schedule IV (US)
Routes Oral
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Eszopiclone, marketed by Sepracor under the brand-name Lunesta, is a nonbenzodiazepine hypnotic agent (viz., a sedative) used as a treatment for insomnia. Eszopiclone is the active dextrorotatory stereoisomer of zopiclone, and belongs to the class of drugs known as cyclopyrrolones.

Eszopiclone is a short acting nonbenzodiazepine sedative hypnotic. It has been shown to be safe and effective short term treatment in the elderly and safe in younger adults for 6–12 months. All clinical trials of eszopiclone published so far are industry funded by the pharmaceutical manufacturer of eszopiclone, Sepracor.[2] Eszopiclone (Lunesta) along with other "Z Drugs" including zolpidem (Ambien), zaleplon (Sonata) are the most commonly prescribed sedative hypnotics in the USA. There were 43 million prescriptions issued for insomnia medications during 2005 in the USA which generated a total of $2.7 billion for pharmaceutical companies.[3]

Contents

Pharmacology

Eszopiclone acts on benzodiazepine "receptors" on GABA neurons as an agonist.[4] Eszopiclone is rapidly absorbed after oral administration, with serum levels peaking between 1 and 1.3 hours.[5] The elimination half-life of eszopiclone is approximately 6 hours and is extensively metabolized by oxidation and demethylation. Approximately 52% to 59% of a dose is weakly bound to plasma protein. Cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1 are involved in the biotransformation of eszopiclone; thus, drugs that induce or inhibit these CYP isozymes may affect the metabolism of eszopiclone. Less than 10% of the orally administered dose is excreted in the urine as racemic zopiclone.[6] In terms of benzodiazepine receptor binding and relevant potency, 3 mg of eszopiclone is equivalent to 10 mg of diazepam.[7]

Indications

Eszopiclone's mechanism of action is via the benzodiazepine receptor-GABA complex. Other drugs which are similar to eszopiclone and also work via the benzodiazepine receptor-GABA complex include benzodiazepines, zaleplon, and zolpidem. Behavioral therapies, particularly cognitive behavioral therapy, and lifestyle changes show significant long-term efficacy as treatments for chronic insomnia.[8]

Dosages

For treatment to improve sleep onset and/or sleep maintenance the recommended dose is 2mg–3mg for adult patients (aged 18–64 years) and 2mg for older adult patients aged 65 years or older. The 1mg dose is for older adult patients whose problems are related to sleep onset.[9]

Side effects

Eszopiclone has fewer anticholinergic side effects than racemic zopiclone.[10] The following side effects may occur from usage of eszopiclone (Lunesta):[11]

Common side effects can include:

Less common side effects can include:

neuropsychiatric adverse effects reported include;[12]

If a person does not sleep immediately after taking eszopiclone or if they get up shortly after taking the medication they may experience dizziness, lightheadedness, hallucinations (seeing things or hearing voices that are not there), as well as problems with coordination and memory.

Increased risk of depression

It has been claimed that insomnia causes depression and hypothesized that insomnia medications may help to treat depression. However, an analysis of data of clinical trials submitted to the FDA concerning the drugs zolpidem, zaleplon and eszopiclone found that these sedative hypnotic drugs more than doubled the risks of developing depression compared to those taking placebo pills. Hypnotic drugs therefore may be contraindicated in patients suffering from or at risk of depression. Hypnotics were found to be more likely to cause depression than to help it. Studies have found that long term users of sedative hypnotic drugs have a markedly raised suicide risk as well as an overall increased mortality risk. Cognitive-behavioral therapy (CBT) for insomnia on the other hand has been found to both improve sleep quality as well as general mental health.[13]

Elderly

Sedative hypnotic drugs including eszopiclone are more commonly prescribed to the elderly than to younger patients despite benefits of medication being generally unimpressive. Care should be taken in choosing an appropriate hypnotic drug and if drug therapy is initiated it should be initiated at the lowest possible dose to minimise side effects.[14] An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, including eszopiclone appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.[15]

Dependence

Eszopiclone is a schedule IV controlled substance under the Controlled Substances Act. Use of benzodiazepines and similar benzodiazepine-like drugs such as eszopiclone may lead to physical and psychological dependence. The risk of abuse and dependence increases with the dose and duration of usage and concomitant use of other psychoactive drugs. The risk is also greater in patients with a history of alcohol or drug abuse or history of psychiatric disorders. Tolerance may develop after repeated use of benzodiazepines and benzodiazepine-like drugs for a few weeks. Eszopiclone was studied for up to 6 months in a group of patients which showed no signs of tolerance or dependence in a study funded and carried out by Sepracor. Insomnia itself can result from dependence or substance withdrawal symptoms. Causes of insomnia include chronic anxiety, depression, alcohol or substance abuse or withdrawal, adverse or withdrawal effects from medication, or age-related changes in sleep[16]

Abuse

A study of abuse potential of eszopiclone found that in persons with a known history of benzodiazepine abuse eszopiclone at doses of 6 and 12 mg produced euphoric effects similar to those of diazepam 20 mg . The study found that at these doses which are two or more times greater than the maximum recommended doses, a dose-related increase in reports of amnesia and hallucinations was observed for both eszopiclone (lunesta) as well as for diazepam (Valium).[11]

Withdrawal symptoms

If a person has taken Eszopiclone for longer than 1–2 weeks they should not stop taking the medication abruptly and should consult their doctor. Usually doctors will direct a slow reduction in dosage to minimise withdrawal symptoms. Particularly after abrupt cessation of medication, withdrawal symptoms may include:[17]

Overdose

Eszopiclone is dangerous in overdose. Signs of eszopiclone overdose reported included dulled mental status, ST-elevation coronary vasospasm, troponemia, ventricular fibrillation arrest and prolonged coma (lasting up to 48 hours).[18][19] Texas poison control centers reported that during 2005-2006 there were 525 total eszopiclone overdoses recorded in the state of Texas, the majority of which being intentional suicide attempts.[20]

Controversy

The Journal of Clinical Sleep Medicine published a paper which had carried out a systematic review of the medical literature concerning insomnia medications including eszopiclone. The review found that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry. It was found that the odds ratio for finding results favorable to industry in industry-sponsored trials was 3.6 times higher than non-industry-sponsored studies. The paper found that there is little research into hypnotics that is independent from the drug manufacturers. The author was concerned that there is no discussion of adverse effects of sedative hypnotics discussed in the medical literature such as significant increased levels of infection, cancers and increased mortality in eszopiclone and other sedative hypnotic drugs and an overemphasis on the positive effects. The author concluded by stating that "major hypnotic trials are needed to more carefully study potential adverse effects of hypnotics such as daytime impairment, infection, cancer, and death and the resultant balance of benefits and risks."[21]

References

  1. ^ WHO International Working Group for Drug Statistics Methodology (August 27, 2008). "ATC/DDD Classification (FINAL): New ATC 5th level codes". WHO Collaborating Centre for Drug Statistics Methodology. http://www.whocc.no/atcddd/new_atc_ddd.html#ATCDDD_FINAL. Retrieved 2008-09-05. 
  2. ^ McCrae CS; Ross A, Stripling A, Dautovich ND (2007). "Eszopiclone for late-life insomnia". Clin Interv Aging 2 (3): 313–26. PMID 18044182. 
  3. ^ McKenzie WS; Rosenberg M (2007). "What every dentist should know about the "z-sedatives"". J Mass Dent Soc 56 (53): 44–5. PMID 18069595. 
  4. ^ Jufe GS (July–August 2007). "[New hypnotics: perspectives from sleep physiology]". Vertex 18 (74): 294–9. PMID 18265473. 
  5. ^ Halas CJ (January 1, 2006). "Eszopiclone". Am J Health Syst Pharm 63 (1): 41–8. doi:10.2146/ajhp050357. PMID 16373464. 
  6. ^ Najib J (April 2006). "Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia". Clin Ther 28 (4): 491–516. doi:10.1016/j.clinthera.2006.04.014. PMID 16750462. 
  7. ^ Professor Ashton (April 2007). "BENZODIAZEPINE EQUIVALENCE TABLE". http://www.benzo.org.uk/bzequiv.htm. Retrieved 21 March 2008. 
  8. ^ Becker PM (September 2006). "Treatment of sleep dysfunction and psychiatric disorders". Curr Treat Options Neurol 8 (5): 367–75. doi:10.1007/s11940-006-0026-6. PMID 16901376. 
  9. ^ &Na;, (2005). "Eszopiclone: esopiclone, estorra, S-zopiclone, zopiclone–Sepracor". Drugs R D 6 (2): 111–5. doi:10.2165/00126839-200506020-00006. PMID 15777104. 
  10. ^ Patil PA, Kothekar MA (October 2006). "Development of safer molecules through chirality". Indian J Med Sci 60 (10): 427–37. doi:10.4103/0019-5359.27676. PMID 17006031. http://www.indianjmedsci.org/article.asp?issn=0019-5359;year=2006;volume=60;issue=10;spage=427;epage=437;aulast=Patil. 
  11. ^ a b rxlist. "Lunesta". http://www.rxlist.com/cgi/generic/lunesta_ad.htm. Retrieved 22 March 2008. 
  12. ^ Duggal HS (2007). "New-onset transient hallucinations possibly due to eszopiclone: a case study". Prim Care Companion J Clin Psychiatry 9 (6): 468–9. doi:10.4088/PCC.v09n0611e. PMID 18185832.& PMC 2139930. http://www.psychiatrist.com/pcc/pccpdf/v09n06/v09n0611.pdf#page=5. 
  13. ^ Kripke DF (August 21, 2007). "Greater incidence of depression with hypnotic use than with placebo". BMC Psychiatry 7: 42. doi:10.1186/1471-244X-7-42. PMID 17711589.& PMC 1994947. http://www.biomedcentral.com/1471-244X/7/42. 
  14. ^ Tariq SH, Pulisetty S (February 2008). "Pharmacotherapy for insomnia". Clin Geriatr Med 24 (1): 93–105, vii. doi:10.1016/j.cger.2007.08.009. PMID 18035234. 
  15. ^ Bain KT (June 2006). "Management of chronic insomnia in elderly persons". Am J Geriatr Pharmacother 4 (2): 168–92. doi:10.1016/j.amjopharm.2006.06.006. PMID 16860264. 
  16. ^ Brielmaier BD (January 2006). "Eszopiclone (Lunesta): a new nonbenzodiazepine hypnotic agent". Proc (Bayl Univ Med Cent). 19 (1): 54–9. PMID 16424933. 
  17. ^ MedlinePlus (January 8, 2001). "Eszopiclone". National Institutes of Health. http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a605009.html. Retrieved 21 March 2008. 
  18. ^ Lovett B; Watts D, Grossman M (July 2007). "Prolonged coma after eszopiclone overdose". Am J Emerg Med 25 (6): 735 (e5–6). doi:10.1016/j.ajem.2006.12.021. PMID 17606111. 
  19. ^ Miller AH, Bruggman AR, Miller MM (October 2006). "Lunesta overdose: ST-elevation coronary vasospasm, troponemia, and ventricular fibrillation arrest". Am J Emerg Med 24 (6): 741–6. doi:10.1016/j.ajem.2006.02.001. PMID 16984850. http://linkinghub.elsevier.com/retrieve/pii/S0735-6757(06)00049-0. 
  20. ^ Forrester MB (October 2007). "Eszopiclone ingestions reported to Texas poison control centers, 2005 2006". Hum Exp Toxicol 26 (10): 795–800. doi:10.1177/0960327107084045. PMID 18025051. 
  21. ^ Kripke DF (December 15, 2007). "Who should sponsor sleep disorders pharmaceutical trials?". J Clin Sleep Med 3 (7): 671–3. PMID 18198797. 

See also

External links








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