Chemistry:Zaleplon

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Short description: Medication used to treat insomnia
Zaleplon
Zaleplon skeletal.svg Zaleplon-from-xtal-Mercury-3D-bs.png
Clinical data
Trade namesSonata, Starnoc, Andante, others
AHFS/Drugs.comMonograph
MedlinePlusa601251
Routes of
administration		By mouth
Drug classPyrazolopyrimidine
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability30% (oral)[1]
MetabolismLiver aldehyde oxidase (91%), CYP3A4 (9%)[2]
Elimination half-life1 hr[1]
ExcretionKidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC17H15N5O
Molar mass305.341 g·mol−1
3D model (JSmol)
  (verify)

Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class.[3] It was developed by King Pharmaceuticals and approved for medical use in the United States in 1999.[4]

Medical uses

Zaleplon is slightly effective in treating insomnia,[5] primarily characterized by difficulty falling asleep. Zaleplon significantly reduces the time required to fall asleep by improving sleep latency and may therefore facilitate sleep induction rather than sleep maintenance.[6][7][8] Due to its ultrashort elimination half-life, zaleplon may not be effective in reducing premature awakenings; however, it may be administered to alleviate middle-of-the-night awakenings.[6] However, zaleplon has not been empirically shown to increase total sleep time.[8][6]

Zaleplon does not significantly affect driving performance the morning following bedtime administration or 4 hours after middle-of-the-night administration. [9] It may have advantages over benzodiazepines with fewer adverse effects.[10]

Special populations

Zaleplon is not recommended for chronic use in the elderly.[11] The elderly are more sensitive to the adverse effects of zaleplon such as cognitive side effects. Zaleplon may increase the risk of injury among the elderly. It should not be used while in pregnancy or lactation, and in patients with a history of alcohol or drug abuse, psychotic illness or depression, clinicians should devote more attention.[12]

In addition, some contend the efficacy and safety of long-term use of these agents remains to be enumerated, but nothing concrete suggests long-term use poses any direct harm to a person.[13]

Adverse effects

The adverse effects of zaleplon are similar to the adverse effects of benzodiazepines, although with less next-day sedation,[14] and in two studies zaleplon use was found not to cause an increase in traffic accidents, as compared to other hypnotics currently on the market.[15][16]

Sleeping pills, including zaleplon, have been associated with an increased risk of death.[17]

Some evidence suggests zaleplon is not as chemically reinforcing and exhibits far fewer rebound effects when compared with other nonbenzodiazepines, or Z-drugs.[18]

Interactions

The CYP3A4 liver enzyme is a minor metabolic pathway for zaleplon, normally metabolizing about 9% of the drug.[2] CYP3A4 inducers such as rifampicin, phenytoin, carbamazepine, and phenobarbital can reduce the effectiveness of zaleplon, and therefore the FDA suggests that other hypnotic drugs be considered in patients taking a CYP3A4 inducer.[2]

Additional sedation has been observed when zaleplon is combined with thioridazine, but it is not clear whether this was due to merely an additive effect of taking two sedative drugs at once or a true drug-drug interaction.[19] Diphenhydramine, a weak inhibitor of aldehyde oxidase, has not been found to affect the pharmacokinetics of zaleplon.[19]

Pharmacology

Mechanism of action

Zaleplon is a high-selectivity,[20] high-affinity ligand of positive modulator sites of GABAA receptors, which enhances GABAergic inhibition of neurotransmission in the central nervous system. The ultrashort half-life gives zaleplon a unique advantage over other hypnotics because of its lack of next-day residual effects on driving and other performance-related skills.[21][22] Unlike nonselective benzodiazepine drugs and zopiclone, which distort the sleep pattern, zaleplon appears to induce sleep without disrupting the normal sleep architecture.[23]

A meta-analysis of randomized, controlled clinical trials which compared benzodiazepines against zaleplon or other Z-drugs such as zolpidem, zopiclone, and eszopiclone has found few clear and consistent differences between zaleplon and the benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.[24]

Zaleplon should be understood as an ultrashort-acting sedative-hypnotic drug for the treatment of insomnia. Zaleplon increases EEG power density in the δ-frequency band and a decrease in the energy of the θ-frequency band[25][26]

Pharmacokinetics

Zaleplon is primarily metabolised by aldehyde oxidase into 5-oxozaleplon, and its half-life may be affected by substances which inhibit or induce aldehyde oxidase. According to urine analysis, about 9% of zaleplon is metabolized by CYP3A4 to form desethylzaleplon, which is quickly metabolized by aldehyde oxidase to 5-oxodesethylzaleplon.[2][1] All of these metabolites are inactive.[1] When taken orally, zaleplon reaches maximum concentration in about 45 minutes.[1]

Chemistry

Zaleplon is classified as a pyrazolopyrimidine.[27] Pure zaleplon in its solid state is a white to off-white powder with very low solubility in water, as well as low solubility in ethanol and propylene glycol.[2] It has a constant octanol-water partition coefficient of log P = 1.23 in the pH range between 1 and 7.[2]

Synthesis

Zaleplon synthesis[28][29]

The synthesis starts with the condensation of 3-acetylacetanilide[30][31] (1) with N,N-dimethylformamide dimethyl acetal (DMFDMA)[32] to give the eneamide (2). The anilide nitrogen is then alkylated by means of sodium hydride and ethyl iodide to give 3. The first step in the condensation with 3-amino-4-cyanopyrazole can be visualized as involving an addition-elimination reaction sequence on the eneamide function to give a transient intermediate such as 5. Cyclization then leads to formation of the fused pyrimidine ring to afford zaleplon (6).

Society and culture

Recreational use

Zaleplon has the potential to be a drug of recreational use, and has been found to have an addictive potential similar to benzodiazepine and benzodiazepine-like hypnotics.[33]

Some individuals use a different delivery method than prescribed, such as insufflation, to induce effects faster.[34]

Sonata 10-mg capsules

Anterograde amnesia can occur and can cause one to lose track of the amount of zaleplon already ingested, prompting the ingesting of more than originally planned.[35][36]

Aviation use

The Federal Aviation Administration allows zaleplon with a 12-hour wait period and no more than twice a week, which makes it the sleep medication with the shortest allowed waiting period after use.[37] The substances with the 2nd shortest period, which is of 24 hours, are zolpidem and ramelteon.[37]

Military use

The United States Air Force uses zaleplon as one of the hypnotics approved as a "no-go pill" to help aviators and special-duty personnel sleep in support of mission readiness (with a four-hour restriction on subsequent flight operation). "Ground tests" are required prior to authorization being issued to use the medication in an operational situation.[38] The other hypnotics used as "no-go pills" are temazepam and zolpidem, which both have longer mandatory recovery periods.[38]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "Zaleplon pharmacokinetics and absolute bioavailability". Biopharmaceutics & Drug Disposition 20 (3): 171–175. April 1999. doi:10.1002/(sici)1099-081x(199904)20:3<171::aid-bdd169>3.0.co;2-k. PMID 10211871. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "20859 S009, 011 FDA Approved Labeling Text 12.10.07". FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020859s011lbl.pdf. 
  3. ↑ "Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic. Zaleplon Clinical Study Group". The Journal of Clinical Psychiatry 60 (8): 536–44. August 1999. doi:10.4088/JCP.v60n0806. PMID 10485636. 
  4. ↑ "Sonata (zaleplon) Capsules CIV". https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=451261. 
  5. ↑ "Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration". BMJ 345: e8343. December 2012. doi:10.1136/bmj.e8343. PMID 23248080. 
  6. ↑ 6.0 6.1 6.2 "Zaleplon". StatPearls. Treasure Island (FL): StatPearls Publishing. 2020. https://www.ncbi.nlm.nih.gov/books/NBK551571/. Retrieved 2020-07-08. 
  7. ↑ "Clinical evaluation of zaleplon in the treatment of insomnia". Nature and Science of Sleep 2: 115–126. 2010-07-20. doi:10.2147/nss.s6853. PMID 23616704. 
  8. ↑ 8.0 8.1 "Zaleplon: a review of its use in the treatment of insomnia". Drugs 60 (2): 413–445. August 2000. doi:10.2165/00003495-200060020-00014. PMID 10983740. 
  9. ↑ "Residual effects of sleep medication on driving ability". Sleep Medicine Reviews 8 (4): 309–25. August 2004. doi:10.1016/j.smrv.2004.02.001. PMID 15233958. 
  10. ↑ "Benefit-risk assessment of zaleplon in the treatment of insomnia". Drug Safety 28 (4): 301–18. 2005. doi:10.2165/00002018-200528040-00003. PMID 15783240. 
  11. ↑ American Geriatrics Society 2012 Beers Criteria Update Expert Panel (April 2012). "American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults". Journal of the American Geriatrics Society 60 (4): 616–31. doi:10.1111/j.1532-5415.2012.03923.x. PMID 22376048. 
  12. ↑ "The art of prescribing. Risks and benefits of non-benzodiazepine receptor agonists in the treatment of acute primary insomnia in older adults". Perspectives in Psychiatric Care 42 (3): 196–200. August 2006. doi:10.1111/j.1744-6163.2006.00070.x. PMID 16916422. 
  13. ↑ "Management of chronic insomnia in elderly persons". The American Journal of Geriatric Pharmacotherapy 4 (2): 168–92. June 2006. doi:10.1016/j.amjopharm.2006.06.006. PMID 16860264. 
  14. ↑ "Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia". The Annals of Pharmacotherapy 32 (6): 680–91. June 1998. doi:10.1345/aph.17111. PMID 9640488. 
  15. ↑ "A general model of the effects of sleep medications on the risk and cost of motor vehicle accidents and its application to France". PharmacoEconomics 19 (1): 69–78. January 2001. doi:10.2165/00019053-200119010-00005. PMID 11252547. 
  16. ↑ "Differential residual effects of zaleplon and zopiclone on actual driving: a comparison with a low dose of alcohol". Sleep 25 (2): 224–31. March 2002. PMID 11905433. 
  17. ↑ "Mortality Risk of Hypnotics: Strengths and Limits of Evidence". Drug Safety 39 (2): 93–107. February 2016. doi:10.1007/s40264-015-0362-0. PMID 26563222. 
  18. ↑ "Implications of hypnotic flexibility on patterns of clinical use". International Journal of Clinical Practice. Supplement (116): 14–9. January 2001. PMID 11219327. 
  19. ↑ 19.0 19.1 "Pharmacokinetics and drug interactions of the sedative hypnotics". Psychopharmacology Bulletin 37 (1): 10–29. 2003. doi:10.1007/BF01990373. PMID 14561946. https://www.medworksmedia.com/psychopharmbulletin/pdf/12/010-029_PB%20W03_Wang_final.pdf. Retrieved 2008-12-28. 
  20. ↑ Binding assays show no binding (IsC50 > 10,000 micromolar) with regards to the 5HT1, 5HT1A, 5-HT2A, 5-HT3, D1, D2, alpha-1 adrenoceptor, alpha-2 adrenoceptor, or M1 receptors. "Binding and neuropharmacological profile of zaleplon, a novel nonbenzodiazepine sedative/hypnotic". European Journal of Pharmacology 434 (1–2): 21–28. January 2002. doi:10.1016/S0014-2999(01)01502-3. PMID 11755161. 
  21. ↑ "Pharmacodynamic profile of Zaleplon, a new non-benzodiazepine hypnotic agent". Human Psychopharmacology 16 (5): 369–392. July 2001. doi:10.1002/hup.310. PMID 12404558. 
  22. ↑ "Discriminative stimulus effects of zolpidem in squirrel monkeys: role of GABA(A)/alpha1 receptors". Psychopharmacology 165 (3): 209–215. January 2003. doi:10.1007/s00213-002-1275-z. PMID 12420154. 
  23. ↑ "Binding and neuropharmacological profile of zaleplon, a novel nonbenzodiazepine sedative/hypnotic". European Journal of Pharmacology 434 (1–2): 21–28. January 2002. doi:10.1016/S0014-2999(01)01502-3. PMID 11755161. 
  24. ↑ "Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis". Human Psychopharmacology 19 (5): 305–22. July 2004. doi:10.1002/hup.594. PMID 15252823. 
  25. ↑ "Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats" (pdf). Journal of Pharmacological Sciences 94 (3): 246–51. March 2004. doi:10.1254/jphs.94.246. PMID 15037809. https://www.jstage.jst.go.jp/article/jphs/94/3/246/_pdf. 
  26. ↑ "Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors". The Journal of Pharmacology and Experimental Therapeutics 317 (1): 369–77. April 2006. doi:10.1124/jpet.105.096701. PMID 16399882. 
  27. ↑ "Zaleplon" (in en). U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/zaleplon. 
  28. ↑ J. P. Dusza et al., U.S. Patent 4,626,538 (1986 to Am. Cyanamid).
  29. ↑ https://en.cnki.com.cn/Article_en/CJFDTotal-ZYSG200205002.htm 《China Pharmacist》 2002-05 Synthesis of Zaleplon.
  30. ↑ "Specific inhibitors of poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferase". The Journal of Biological Chemistry 267 (3): 1569–1575. January 1992. doi:10.1016/S0021-9258(18)45983-2. PMID 1530940. 
  31. ↑ "Trithiocarbonates as a novel class of HDAC inhibitors: SAR studies, isoenzyme selectivity, and pharmacological profiles". Journal of Medicinal Chemistry 51 (13): 3985–4001. July 2008. doi:10.1021/jm800093c. PMID 18558669. 
  32. ↑ "Convenient preparation of N,N-dimethylacetamide dimethyl acetal". The Journal of Organic Chemistry 49 (19): 3659–3660. 1984. doi:10.1021/jo00193a045. 
  33. ↑ "Sonata®(zaleplon)Capsules". https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=6299. 
  34. ↑ "Intranasal zaleplon abuse". The American Journal of Psychiatry 165 (11): 1489–90. November 2008. doi:10.1176/appi.ajp.2008.08030452. PMID 18981079. https://ajp.psychiatryonline.org/cgi/content/full/165/11/1489-a. 
  35. ↑ "Zaleplon and triazolam in humans: acute behavioral effects and abuse potential". Psychopharmacology 145 (1): 39–51. July 1999. doi:10.1007/s002130051030. PMID 10445371. 
  36. ↑ "Zaleplon and triazolam: drug discrimination, plasma levels, and self-administration in baboons". Drug and Alcohol Dependence 61 (1): 55–68. December 2000. doi:10.1016/S0376-8716(00)00123-X. PMID 11064184. 
  37. ↑ 37.0 37.1 "Medication Database – AMAS". https://www.aviationmedicine.com/medication-database. 
  38. ↑ 38.0 38.1 "Fatigue in military aviation: an overview of US military-approved pharmacological countermeasures" (pdf). Aviation, Space, and Environmental Medicine 76 (7 Suppl): C39-51. July 2005. PMID 16018329. https://docserver.ingentaconnect.com/deliver/connect/asma/00956562/v76n7x1/s10.pdf?expires=1335744234&id=68546495&titleid=8218&accname=Guest+User&checksum=D97BA65A8E7071CC3766CF365ED85FA3. 



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