Zaleplon Explained

Watchedfields:changed
Verifiedrevid:470635467
Imagel:Zaleplon skeletal.svg
Widthl:110
Imager:Zaleplon-from-xtal-Mercury-3D-bs.png
Widthr:180
Tradename:Sonata, others
Dailymedid:Zaleplon
Addiction Liability:Moderate
Routes Of Administration:By mouth
Class:nonbenzodiazepine
Atc Prefix:N05
Atc Suffix:CF03
Legal Br:B1
Legal Br Comment:[1]
Legal Uk:Class C
Legal Us:Schedule IV
Bioavailability:30% (oral)[2]
Metabolism:Liver aldehyde oxidase (91%), CYP3A4 (9%)[3]
Elimination Half-Life:1 hr
Excretion:Kidney
Cas Number:151319-34-5
Pubchem:5719
Iuphar Ligand:4345
Drugbank:DB00962
Chemspiderid:5517
Unii:S62U433RMH
Kegg:D00530
Chebi:10102
Chembl:1521
Iupac Name:N-(3-(3-cyanopyrazolo[1,5-''a''] pyrimidin-7-yl)phenyl)-N-ethylacetamide
C:17
H:15
N:5
O:1
Smiles:CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Stdinchi:1S/C17H15N5O/c1-3-21(12(2)23)15-6-4-5-13(9-15)16-7-8-19-17-14(10-18)11-20-22(16)17/h4-9,11H,3H2,1-2H3
Stdinchikey:HUNXMJYCHXQEGX-UHFFFAOYSA-N

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.[4] It was developed by King Pharmaceuticals and approved for medical use in the United States in 1999.[5]

Medical uses

Zaleplon is slightly effective in treating insomnia,[6] 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.[7] [8] [9] 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.[7] However, zaleplon has not been empirically shown to increase total sleep time.[9] [7]

Zaleplon does not significantly affect driving performance the morning following bedtime administration or 4 hours after middle-of-the-night administration. [10] It may have advantages over benzodiazepines with fewer adverse effects.[11]

Special populations

Zaleplon is not recommended for chronic use in the elderly.[12] 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 during pregnancy or lactation. Clinicians should devote more attention when prescribing for patients with a history of alcohol or drug abuse, psychotic illness, or depression.[13]

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.[14]

Adverse effects

The adverse effects of zaleplon are similar to the adverse effects of benzodiazepines, although with less next-day sedation,[15] 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.[16] [17]

Sleeping pills, including zaleplon, have been associated with an increased risk of death.[18]

Some evidence suggests zaleplon is not as chemically reinforcing and exhibits far fewer rebound effects when compared with other nonbenzodiazepines, or Z-drugs.[19]

Interactions

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

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.[20] Diphenhydramine, a weak inhibitor of aldehyde oxidase, has not been found to affect the pharmacokinetics of zaleplon.[20]

Pharmacology

Mechanism of action

Zaleplon is a high-selectivity,[21] 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.[22] [23] Unlike nonselective benzodiazepine drugs and zopiclone, which distort the sleep pattern, zaleplon appears to induce sleep without disrupting the normal sleep architecture.[24]

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.[25]

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[26] [27]

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] All of these metabolites are inactive.[2] When taken orally, zaleplon reaches maximum concentration in about 45 minutes.[2]

Chemistry

Zaleplon is classified as a pyrazolopyrimidine.[28] 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.[3] It has a constant octanol-water partition coefficient of log P = 1.23 in the pH range between 1 and 7.[3]

Synthesis

The synthesis starts with the condensation of 3-acetylacetanilide[29] [30] (1) with N,N-dimethylformamide dimethyl acetal (DMFDMA)[31] 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.[32]

Some individuals use a different delivery method than prescribed, such as insufflation, to induce effects faster.[33]

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.[34] [35]

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.[36] The substances with the 2nd shortest period, which is of 24 hours, are zolpidem and ramelteon.

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.[37] The other hypnotics used as "no-go pills" are temazepam and zolpidem, which both have longer mandatory recovery periods.

Notes and References

  1. Web site: Anvisa . Brazilian Health Regulatory Agency . 31 March 2023 . 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. live . https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 . 3 August 2023 . 16 August 2023 . . pt-BR . 4 April 2023.
  2. Rosen AS, Fournié P, Darwish M, Danjou P, Troy SM . Zaleplon pharmacokinetics and absolute bioavailability . Biopharmaceutics & Drug Disposition . 20 . 3 . 171–175 . April 1999 . 10211871 . 10.1002/(sici)1099-081x(199904)20:3<171::aid-bdd169>3.0.co;2-k .
  3. Web site: 20859 S009, 011 FDA Approved Labeling Text 12.10.07 . . 21 March 2023.
  4. Elie R, Rüther E, Farr I, Emilien G, Salinas E . 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 . 10485636 . 10.4088/JCP.v60n0806 .
  5. Web site: Sonata (zaleplon) Capsules CIV . DailyMed . 21 March 2023.
  6. Huedo-Medina TB, Kirsch I, Middlemass J, Klonizakis M, Siriwardena AN . 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 . 23248080 . 3544552 . 10.1136/bmj.e8343 .
  7. Book: Bhandari P, Sapra A . Zaleplon . 2020. http://www.ncbi.nlm.nih.gov/books/NBK551571/ . StatPearls. Treasure Island (FL). StatPearls Publishing. 31855398. 8 July 2020.
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  17. Vermeeren A, Riedel WJ, van Boxtel MP, Darwish M, Paty I, Patat A . 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 . 11905433 .
  18. Kripke DF . Mortality Risk of Hypnotics: Strengths and Limits of Evidence . Drug Safety . 39 . 2 . 93–107 . February 2016 . 26563222 . 10.1007/s40264-015-0362-0 . 7946506 . free .
  19. Lader MH . Implications of hypnotic flexibility on patterns of clinical use . International Journal of Clinical Practice. Supplement . 116 . 14–9 . January 2001 . 11219327 .
  20. Wang JS, DeVane CL . Pharmacokinetics and drug interactions of the sedative hypnotics . Psychopharmacology Bulletin . 37 . 1 . 10–29 . 2003 . 14561946 . 10.1007/BF01990373 . 1543185 . 28 December 2008 . https://web.archive.org/web/20070709230745/http://www.medworksmedia.com/psychopharmbulletin/pdf/12/010-029_PB%20W03_Wang_final.pdf . 9 July 2007 . dead .
  21. 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. Noguchi H, Kitazumi K, Mori M, Shiba T . Binding and neuropharmacological profile of zaleplon, a novel nonbenzodiazepine sedative/hypnotic . European Journal of Pharmacology . 434 . 1–2 . 21–28 . January 2002 . 11755161 . 10.1016/S0014-2999(01)01502-3 .
  22. Patat A, Paty I, Hindmarch I . Pharmacodynamic profile of Zaleplon, a new non-benzodiazepine hypnotic agent . Human Psychopharmacology . 16 . 5 . 369–392 . July 2001 . 12404558 . 10.1002/hup.310 . 21096374 .
  23. Rowlett JK, Spealman RD, Lelas S, Cook JM, Yin W . Discriminative stimulus effects of zolpidem in squirrel monkeys: role of GABA(A)/alpha1 receptors . Psychopharmacology . 165 . 3 . 209–215 . January 2003 . 12420154 . 10.1007/s00213-002-1275-z . 37632215 .
  24. Noguchi H, Kitazumi K, Mori M, Shiba T . Binding and neuropharmacological profile of zaleplon, a novel nonbenzodiazepine sedative/hypnotic . European Journal of Pharmacology . 434 . 1–2 . 21–28 . January 2002 . 11755161 . 10.1016/S0014-2999(01)01502-3 .
  25. Dündar Y, Dodd S, Strobl J, Boland A, Dickson R, Walley T . 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 . 15252823 . 10.1002/hup.594 . 10888200 .
  26. Noguchi H, Kitazumi K, Mori M, Shiba T . Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats . Journal of Pharmacological Sciences . 94 . 3 . 246–51 . March 2004 . 15037809 . 10.1254/jphs.94.246 . free .
  27. Petroski RE, Pomeroy JE, Das R, Bowman H, Yang W, Chen AP, Foster AC . 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 . 16399882 . 10.1124/jpet.105.096701 . 46510829 .
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  31. 10.1021/jo00193a045. Convenient preparation of N,N-dimethylacetamide dimethyl acetal. The Journal of Organic Chemistry. 49. 19. 3659–3660. 1984. Salomon RG, Raychaudhuri SR .
  32. Web site: Sonata®(zaleplon)Capsules.
  33. Paparrigopoulos T, Tzavellas E, Karaiskos D, Liappas I . Intranasal zaleplon abuse . The American Journal of Psychiatry . 165 . 11 . 1489–90 . November 2008 . 18981079 . 10.1176/appi.ajp.2008.08030452 . 5 April 2011 . 5 July 2010 . https://web.archive.org/web/20100705104126/http://ajp.psychiatryonline.org/cgi/content/full/165/11/1489-a . dead .
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  36. Web site: Medication Database – AMAS.
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