Examine individual changes

'{{Drugbox | Watchedfields = changed | verifiedrevid = 470635467 | IUPAC_name = ''N''-(3-(3-cyanopyrazolo[1,5-''a''] pyrimidin-7-yl)phenyl)-''N''-ethylacetamide | image = Zaleplon Structural Formulae V.1.svg | width = 140 | image2 = Zaleplon ball-and-stick.png | width2 = 200 <!--Clinical data--> | tradename = Sonata, Starnoc, Andante | Drugs.com = {{drugs.com|monograph|zaleplon}} | MedlinePlus = a601251 | pregnancy_US = C | legal_US = Schedule IV | routes_of_administration = Oral (medical), intranasal (recreational) <!--Pharmacokinetic data--> | bioavailability = 30% (oral) | metabolism = [[Hepatic]] | elimination_half-life = 1–1.5 h | excretion = [[Renal]] <!--Identifiers--> | CASNo_Ref = {{cascite|correct|CAS}} | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 151319-34-5 | ATC_prefix = N05 | ATC_suffix = CF03 | PubChem = 5719 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00962 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 5517 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = S62U433RMH | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00530 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 10102 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 1521 <!--Chemical data--> | C=17 | H=15 | N=5 | O=1 | molecular_weight = 305.34 | smiles = O=C(C)N(CC)C1=CC=CC(C2=CC=NC3=C(C=NN23)C#N)=C1 | InChI = 1/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 | InChIKey = HUNXMJYCHXQEGX-UHFFFAOYAO | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | 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_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = HUNXMJYCHXQEGX-UHFFFAOYSA-N }} '''Zaleplon''' (marketed under the brand names '''Sonata''', '''Starnoc''' and '''Andante''') is a [[sedative]]-[[hypnotic]], almost entirely used for the management/treatment of [[insomnia]]. It is a [[nonbenzodiazepine]] [[hypnotic]] from the [[pyrazolopyrimidine]] class.<ref>{{cite journal | doi=10.4088/JCP.v60n0806 | journal=J Clin Psychiatry |date=Aug 1999 | pages=536–44 | title=Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic. Zaleplon Clinical Study Group | author=Elie R | coauthors=Rüther E, Farr I, Emilien G, Salinas E | pmid=10485636 | volume=60 | issue=8 }}</ref> '''Sonata''' (US) is manufactured by [[King Pharmaceuticals]] of [[Bristol, TN]]. [[Gedeon Richter|Gedeon Richter Plc.]] manufactures zaleplon under the brand name '''Andante'''. '''Starnoc''' has been discontinued in [[Canada]]. It is prescribed rarely in the [[United Kingdom]]; with [[zopiclone]] being the preferred [[Z-drug]] by the [[National Health Service]] (NHS). ==Medical uses== Zaleplon is effective in the management/treatment of [[insomnia]],<ref name=TB2012>{{cite journal|last=Huedo-Medina|first=TB|coauthors=Kirsch, I; Middlemass, J; Klonizakis, M; Siriwardena, AN|title=Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration.|journal=BMJ (Clinical research ed.)|date=Dec 17, 2012|volume=345|pages=e8343|pmid=23248080|pmc=3544552|doi=10.1136/bmj.e8343}}</ref> primarily characterized by difficulty falling asleep. Due to its ultra-short elimination half-life, zaleplon may not be effective in premature awakenings. It may result in an impaired ability to drive the next day, though it has proven promising when compared to other sedative-hypnotics and next day residual sedation.<ref>{{cite journal |author=Verster JC, Veldhuijzen DS, Volkerts ER |title=Residual effects of sleep medication on driving ability |journal=Sleep Med Rev |volume=8 |issue=4 |pages=309–25 |date=August 2004 |pmid=15233958 |doi=10.1016/j.smrv.2004.02.001 |url=http://linkinghub.elsevier.com/retrieve/pii/S1087079204000073}}</ref> It may have advantages over [[benzodiazepines]] with less adverse effects.<ref name=Bar2005>{{cite journal |author=Barbera J, Shapiro C |title=Benefit-risk assessment of zaleplon in the treatment of insomnia |journal=Drug Saf |volume=28 |issue=4 |pages=301–18 |year=2005 |pmid=15783240 |doi= 10.2165/00002018-200528040-00003|url=}}</ref> Zaleplon or any [[nonbenzodiazepine]] should never be combined with any alcoholic beverage as both substances [[modulate]] [[GABAA receptor|GABA_A]] receptor sites, and in a [[synergistic]] manner increase the chances of fatal [[respiratory depression]] and [[asphyxiation]] from vomiting. ===Special populations=== Zaleplon is not recommended for chronic use in the elderly.<ref>{{cite journal|last=American Geriatrics Society 2012 Beers Criteria Update Expert|first=Panel|title=American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults.|journal=Journal of the American Geriatrics Society|date=April 2012|volume=60|issue=4|pages=616–31|pmid=22376048|doi=10.1111/j.1532-5415.2012.03923.x|pmc=3571677}}</ref> 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.<ref>{{cite journal |author=Antai-Otong D |title=The art of prescribing. Risks and benefits of non-benzodiazepine receptor agonists in the treatment of acute primary insomnia in older adults|journal=Perspect Psychiatr Care |volume=42 |issue=3 |pages=196–200 |date=August 2006 |pmid=16916422|doi=10.1111/j.1744-6163.2006.00070.x |url=http://www3.interscience.wiley.com/journal/118727940/abstract}}</ref> When compared with [[benzodiazepines]], nonbenzodiazepines (including zaleplon) appear to offer few significant advantages in efficacy or tolerability among elderly individuals. Long-term use of [[sedative]]-[[hypnotics]] for [[insomnia]] has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment, [[anterograde amnesia]], daytime sedation, musculo-skeletal impairment, and subsequently an increased risk of harm to oneself (e.g. falling) and to others (e.g. automotive accidents). Though, quite obviously as the body and brain age, these aforementioned phenomena are expected events, as they occur daily regardless of ingestion of a sedative-hypnotic. Thus, statistically significant and empirical evidence are arguably still absent as dramatic precautions and conclusions are drawn irrespective of the debilitating realities that accompany insomnia and the fact that these medicines do indeed provide assistance to millions of elderly individuals. It is important to distinguish between the extrapolation of potential side effects relative to the vast number of examples, wherein the sedative-hypnotic has proven therapeutically beneficial and appropriate. In addition, some contend the efficacy and safety of long-term use of these agents remains to be enumerated, but there is nothing concrete to suggest that long term use poses any direct harm to a person.<ref name="Bain KT 2006 168–92">{{cite journal | journal = Am J Geriatr Pharmacother |date=June 2006 | volume = 4 | issue = 2 | pages = 168–92 | title = Management of chronic insomnia in elderly persons | author = Bain KT | pmid = 16860264 | doi = 10.1016/j.amjopharm.2006.06.006}}</ref> ==Adverse effects== The side effects of zaleplon are similar to the side effects of benzodiazepines, although with less next-day sedation,<ref name="Wagner J 1998 680–91">{{cite journal | doi =10.1345/aph.17111 | journal =Ann Pharmacother |date=June 1998 | pages =680–91 | title =Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia | author =Wagner J | coauthors =Wagner ML, Hening WA | pmid =9640488 | volume =32 | issue =6 }}</ref> and in two studies zaleplon use was found to not cause an increase in road traffic accidents, as compared to other [[hypnotics]] currently on the market.<ref>{{cite journal |author=Menzin J, Lang KM, Levy P, Levy E |title=A general model of the effects of sleep medications on the risk and cost of [[motor vehicle accidents]] and its application to France |journal=PharmacoEconomics |volume=19 |issue=1 |pages=69–78 |date=January 2001 |pmid=11252547 |doi= 10.2165/00019053-200119010-00005|url=}}</ref><ref>{{cite journal |author=Vermeeren A, Riedel WJ, van Boxtel MP, Darwish M, Paty I, Patat A |title=Differential residual effects of zaleplon and zopiclone on actual driving: a comparison with a low dose of alcohol |journal=Sleep |volume=25 |issue=2 |pages=224–31 |date=March 2002 |pmid=11905433 |doi= |url=}}</ref> Zaleplon may prompt day-time or next-day residual sedation. Available data cannot provide a reliable estimate of the incidence of [[dependence]] during treatment at recommended doses of zaleplon (typically 5–20&nbsp;mg before bed). Other [[sedative]]-[[hypnotic]]s have been associated with various signs and symptoms of a withdrawal syndrome, following abrupt [[discontinuation]], ranging from mild [[dysphoria]] and insomnia to more serious cases that include abdominal and [[muscle cramps]], [[vomiting]], [[sweating]], [[tremors]], and [[convulsions]]. Following, abrupt cessation, the [[seizure threshold]] is further lowered, wherein [[coma]] and death are possible outcomes if untreated. Some evidence suggests that zaleplon is not as chemically reinforcing and exhibits far less [[rebound effects]] when compared with other [[nonbenzodiazepines]], or Z-drugs.<ref>{{cite journal |author=Lader MH |title=Implications of hypnotic flexibility on patterns of clinical use |journal=Int J Clin Pract Suppl |volume= |issue=116 |pages=14–9 |date=January 2001 |pmid=11219327 |doi= |url=}}</ref> ==Mechanism== Zaleplon, like [[zolpidem]], [[zopiclone]] or [[eszopiclone]] are all specific agonists at the benzodiazepine [[Gamma-aminobutyric acid receptor subunit alpha-1|GABA_A α₁ sub-receptor site]]. It also modulates the GABA_A sub-sites, α₂ and α₃, to a lesser degree. It has no [[statistical significance]] as an [[anticonvulsant]]. However, as a [[pyrazolopyrimidine]], zaleplon has served as a novel chemical platform, from which new [[anxiolytics]], will hopefully arise. Much like zolpidem, as an [[imidazopyridine]] and also a full [[agonist]] at the GABA_A α₁ sub-receptor site, has been reviewed considerably with some novel contributions. See also: [[alpidem]]. ==Pharmacology== Zaleplon selectively binds with high efficacy to the [[benzodiazepine site]] (ω₁) on the α₁-containing [[GABA-A receptors]] which help produce the primary therapeutic [[hypnotic]] properties. The ultra-short [[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.<ref>{{cite journal |author=Patat A, Paty I, Hindmarch I |title=Pharmacodynamic profile of Zaleplon, a new non-benzodiazepine hypnotic agent |journal=Hum Psychopharmacol |volume=16 |issue=5 |pages=369–392 |date=July 2001 |pmid=12404558 |doi=10.1002/hup.310}}</ref><ref>{{cite journal |author=Rowlett JK, Spealman RD, Lelas S, Cook JM, Yin W |title=Discriminative stimulus effects of zolpidem in squirrel monkeys: role of GABA(A)/alpha1 receptors |journal=Psychopharmacology (Berl.) |volume=165 |issue=3 |pages=209–15 |date=January 2003 |pmid=12420154 |doi=10.1007/s00213-002-1275-z |url=http://www.springerlink.com/content/392vkmeej4at9yuy/fulltext.pdf |format=PDF}}</ref> Unlike [[non-selective]] [[benzodiazepine]] drugs and [[zopiclone]] which distort the [[sleep pattern]], zaleplon appears to induce sleep without disrupting the natural [[sleep architecture]].<ref>{{cite journal |author=Noguchi H, Kitazumi K, Mori M, Shiba T |title=Binding and neuropharmacological profile of zaleplon, a novel nonbenzodiazepine sedative/hypnotic |journal=Eur. J. Pharmacol. |volume=434 |issue=1-2 |pages=21–8 |date=January 2002 |pmid=11755161 |doi= 10.1016/S0014-2999(01)01502-3|url=http://linkinghub.elsevier.com/retrieve/pii/S0014299901015023}}</ref> A [[meta-analysis]] of randomised controlled [[clinical trials]] which compared benzodiazepines against zaleplon or other Z-drugs such as [[zolpidem]], [[zopiclone]] and [[eszopiclone]] has found that there are 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, [[Drug tolerance|tolerance]], [[rebound insomnia]] and daytime [[alertness]].<ref>{{cite journal | last = Dündar | first = Y | coauthors = Dodd S, Strobl J, Boland A, Dickson R, Walley T. |date=July 2004 | title = Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis | journal = Hum Psychopharmacol. | volume = 19 | issue = 5 | pages = 305–22 | pmid = 15252823 | doi = 10.1002/hup.594 }}</ref> Zaleplon has a pharmacological profile similar to benzodiazepines, that is characterized by an increase in slow wave deep sleep (SWDS) with rapid onset of hypnotic action. Zaleplon is a full [[agonist]] for the benzodiazepine [[Gamma-aminobutyric acid receptor subunit alpha-1|α₁ receptor]] located on the [[GABAA receptor|GABA_A receptor]] complex in the body, with lower affinity for the α₂ and α₃ sub-sites. It selectively enhances the action of [[gamma-Aminobutyric acid|GABA]] similar to, but more selectively than benzodiazepines. Zaleplon, although not a benzodiazepine, maintains a very similar [[chemical structure]] nonetheless; known for inducing [[hypnotic]] effects via α₁ sub-receptor sites, anxiolytic and [[muscle relaxant]] effects via α₂ and α₃ sub-sites, with negligible [[anticonvulsant]] properties (via α₅ sub-site), as zaleplon action is [[modulated]] at benzodiazepine receptor sites. The [[elimination half-life]] of zaleplon is about 1–1.5 hour. The absorption rate of zaleplon is rapid and the onset of therapeutic effects is typically breached within 5–15 minutes following ingestion. Zaleplon should be understood as an ultra short acting sedative-hypnotic drug for the treatment of insomnia. Zaleplon increases [[EEG]] power density in the delta frequency band and a decrease in the energy of the theta frequency band <ref>{{cite journal | author = Noguchi H | coauthors = Kitazumi K, Mori M, Shiba T. |date=March 2004 | title = Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats | journal = J Pharmacol Sci. | volume = 94 | issue = 3 | pages = 246–51 | pmid = 15037809 | url = http://www.jstage.jst.go.jp/article/jphs/94/3/246/_pdf | format = pdf | doi = 10.1254/jphs.94.246 }}</ref><ref>{{cite journal |author=Petroski RE, Pomeroy JE, Das R, ''et al.'' |title=Indiplon is a high-affinity positive allosteric modulator with selectivity for α1 subunit-containing GABA-A benzodiazepine receptor sites. |journal=J. Pharmacol. Exp. Ther. |volume=317 |issue=1 |pages=369–77 |date=April 2006 |pmid=16399882 |doi=10.1124/jpet.105.096701 |url=http://jpet.aspetjournals.org/cgi/content/full/317/1/369 |format=PDF}}</ref> ==Chemistry== Pure zaleplon in its solid state is a white to off-white powder that has very low [[solubility]] in water as well as low solubility in [[ethanol]] and [[propylene glycol]]. It has a partition coefficient in octanol/water that is constant (log PC = 1.23) when the [[pH]] range is between 1 and 7. ==Pharmacokinetics== Zaleplon is primarily metabolised by [[aldehyde oxidase]], and its half-life can be affected by substances which inhibit or induce aldehyde oxidase. Taken orally, zaleplon reaches full concentration in approximately one hour. It is extensively metabolised into 5-oxozaleplon and 5-oxodesethylzaleplon (the latter via desethylzaleplon), with less than 1% of it excreted intact in urine. ==Interactions== Cimetidine, [[rifampicin]] and [[thioridazine]] cause interactions with zaleplon.<ref>{{cite journal |author=Wang JS, DeVane CL |title=Pharmacokinetics and drug interactions of the sedative hypnotics |journal=Psychopharmacol Bull |volume=37 |issue=1 |pages=10–29 |year=2003 |pmid=14561946 |doi= 10.1007/BF01990373|url=http://www.medworksmedia.com/psychopharmbulletin/pdf/12/010-029_PB%20W03_Wang_final.pdf |format=PDF}}</ref> [[Cimetidine]] alongside [[Grapefruit drug interactions|grapefruit]], are known to increase [[blood plasma]] concentrations of benzodiazepines metabolized by the P450 [[CYP3A4]] [[liver enzyme]] (e.g. [[alprazolam]]), as well as increasing the time by which the drug leaves the body, effectively extending the [[half-life]] and enhancing effects to potentially toxic levels. Thus, given the similarities between zaleplon and benzodiazepines, particularly in effect, and not just chemical structure, it is reasonable to take precautions (e.g. inquire at a pharmacy) before one consumes [[cimetidine]] (or [[grapefruit]]) while also taking zaleplon. Smoking [[tobacco]]/ingesting [[nicotine]] as well as [[caffeine]] likely reduces [[blood plasma]] concentrations of zaleplon, as sedative-hypnotic efficacy is diminished. This impact is shared by all [[GABA]]ergics, whether [[nonbenzodiazepine]]s, [[benzodiazepines]], [[barbiturates]], [[carbamates]], [[quinazolines]] or [[alcohol]]. ==Recreational use== Zaleplon has the potential to be a drug of abuse, and has been found to have an abuse potential similar to benzodiazepine and benzodiazepine-like hypnotics.<ref>http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=6299</ref> The mind and judgment altering effects of zaleplon are similar to those of many other benzodiazepines, but the fast-acting nature and short half-life of the chemical mean that high dosages set on much more quickly and last for short periods of time (usually from 45 to 60 minutes). Some individuals use a different delivery method than prescribed, such as [[Insufflation (medicine)|insufflation]], to induce effects faster.<ref>{{cite journal |author=Paparrigopoulos T, Tzavellas E, Karaiskos D, Liappas I. |title=Intranasal Zaleplon Abuse |journal=Am J Psychiatry |volume=165 |issue=11 |pages=1489–1490 |year=2008 |pmid=18981079 |doi=10.1176/appi.ajp.2008.08030452 |url=http://ajp.psychiatryonline.org/cgi/content/full/165/11/1489-a}}</ref> [[Image:Sonata10mg.JPG|thumb|right|180px|A one month's supply of Sonata 10mg capsules.]] Insufflation of the drug causes loss of yield, as zaleplon is not entirely water soluble, and may cause damage to the nasal passageways as well as sinuses.{{Citation needed|date = |date = August 2013}} A common effect of zaleplon abuse is the occurrence of (typically short-lived) [[hallucinations]]. Fewer visual and auditory hallucinations/disruptions with the use of zaleplon than with other drugs in the nonbenzodiazepine class (e.g. [[zolpidem]] and the “Ambien Walrus”). {{Citation needed|date=February 2013}} [[Anterograde amnesia]] can occur and can cause one to lose track of the amount of zaleplon already ingested, prompting one to ingest more than originally planned.<ref>{{cite journal | journal=Psychopharmacology (Berl) |date=Jul 1999 | pages=39–51 | title=Zaleplon and triazolam in humans: acute behavioral effects and abuse potential | author=Rush CR | coauthors=Frey JM, Griffiths RR | pmid=10445371 | doi=10.1007/s002130051030 | volume=145 | issue=1 }}</ref><ref>{{cite journal | journal=Drug Alcohol Depend | year=2000 | pages=55–68 | title=Zaleplon and triazolam: drug discrimination, plasma levels, and self-administration in baboons | author=Ator NA | pmid=11064184 | doi=10.1016/S0376-8716(00)00123-X | volume=61 | issue=1 }}</ref> However, continuous ingestion is extremely unlikely precisely because of zaleplon's quick onset of action. The combination of alcohol and zaleplon can result in fatal [[respiratory depression]] and [[asphyxiation]] from vomiting.{{Citation needed|date = |reason = |date = August 2013}} ==See also== *[[Nonbenzodiazepines]] *[[Z-drug]]s *[[Pyrazolopyrimidines]] :*[[Indiplon]] *[[Imidazopyridines]] :*[[Alpidem]] :*[[Necopidem]] :*[[Zolpidem]] (Ambien CR, Intermezzo, Stilnox) *[[Cyclopyrrolones]] :*[[Eszopiclone]] (Lunesta) :*[[Pagoclone]] :*[[Zopiclone]] (Imovane, Zimovane) bitchhhhhhh ==References== {{Reflist}} {{-}} {{Hypnotics and sedatives}} {{Hallucinogens}} [[Category:Acetanilides]] [[Category:Nitriles]] [[Category:Nonbenzodiazepines]] [[Category:Pyrazolopyrimidines]]'