Buspirone: Difference between revisions - Wikipedia
Line 1:
{{Short description|Medication used to treat anxiety disorders}}
{{Drugbox
{{Distinguish|Bupropion}}
| verifiedrevid = 443491260
{{Use dmy dates|date=January 2024}}
| IUPAC_name = 8-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-8-azaspiro[4.5]decane-7,9-dione
{{cs1 config|name-list-style=vanc|display-authors=6}}
| image = Buspirone.svg
{{Infobox drug
| width = 250px
| Watchedfields = changed
| verifiedrevid = 459522704
| image = Buspirone 200.svg
| width = 250
| alt =
| image2 = Buspirone 3D structure.png
| alt2 =
<!-- Clinical data -->
| pronounce = {{IPAc-en|ˈ|b|juː|s|p|ᵻ|r|oʊ|n}} ({{respell|BEW|spi-rohn}})
| tradename = Buspar
| tradename = Buspar
| Drugs.com = {{drugs.com|monograph|buspirone-hydrochloride}}
| Drugs.com = {{drugs.com|monograph|buspirone-hydrochloride}}
| MedlinePlus = a688005
| MedlinePlus = a688005
| pregnancy_US = B
| DailyMedID = Buspirone
| legal_status = Rx-only
| pregnancy_AU = B1
| routes_of_administration = Oral
| pregnancy_AU_comment =
| pregnancy_category =
| routes_of_administration = [[Oral administration|By mouth]]
| class =
| ATC_prefix = N05
| ATC_suffix = BE01
| ATC_supplemental =
<!--Pharmacokinetic dataLegal status -->
| bioavailabilitylegal_AU = 5%S4
| legal_AU_comment =
| protein_bound = 95%
| legal_BR = C1
| metabolism = Hepatic
| legal_BR_comment = <ref>{{cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control |url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=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 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>
| elimination_half-life = 2-3 hours
| legal_CA = Rx-only
| excretion = Urine (29-63%), Feces (18-38%)
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment =
| legal_EU =
| legal_EU_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->
<!--Identifiers Pharmacokinetic data -->
| bioavailability = 3.9%<ref name="pmid22608068">{{cite journal | vauthors=Loane C, Politis M | title=Buspirone: what is it all about? | journal=Brain Research | volume=1461 | pages=111–118 | date=June 2012 | pmid=22608068 | doi=10.1016/j.brainres.2012.04.032 | s2cid=11734819 }}</ref>
| CASNo_Ref = {{cascite|correct|CAS}}
| protein_bound = 86–95%<ref name=MSR>{{cite web|title=buspirone (Rx) - BuSpar, Buspirex, more..|work=Medscape Reference|publisher=WebMD|url=http://reference.medscape.com/drug/buspar-buspirone-342913|access-date=14 November 2013}}</ref>
| CAS_number_Ref = {{cascite|correct|??}}
| metabolism = [[Liver]] (via [[CYP3A4]])<ref name="pmid10320950" /><ref name="pmid15640381">{{cite journal | vauthors=Zhu M, Zhao W, Jimenez H, Zhang D, Yeola S, Dai R, Vachharajani N, Mitroka J | title=Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes | journal=Drug Metabolism and Disposition | volume=33 | issue=4 | pages=500–507 | date=April 2005 | pmid=15640381 | doi=10.1124/dmd.104.000836 | s2cid=10142905 }}</ref>
| CAS_number = 36505-84-7
| metabolites = 5-OH-Buspirone; 6-OH-Buspirone; 8-OH-Buspirone; {{abbrlink|1-PP|1-(2-pyrimidinyl)piperazine}}<ref name="pmid3515929" /><ref name="SchatzbergNemeroff2009" /><ref name="pmid17494642" />
| ATC_prefix = N05
| onset =
| ATC_suffix = BE01
| elimination_half-life = 2.5 hours<ref name="pmid10320950">{{cite journal | vauthors=Mahmood I, Sahajwalla C | title=Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug | journal=Clinical Pharmacokinetics | volume=36 | issue=4 | pages=277–287 | date=April 1999 | pmid=10320950 | doi=10.2165/00003088-199936040-00003 | s2cid=1102318 | url=https://zenodo.org/record/1236411 }}</ref>
| PubChem = 2477
| duration_of_action =
| IUPHAR_ligand = 36
| excretion = [[Urine]]: 29–63%<ref name=MSR/><br />[[Feces]]: 18–38%<ref name=MSR/>
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00490
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2383
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = TK65WKS8HL
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07593
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 3223
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 49
<!--Chemical dataIdentifiers -->
| index2_label = as HCl
| C=21 | H=31 | N=5 | O=2
| CAS_number_Ref = {{cascite|correct|??}}
| molecular_weight = 385.50314 g/mol
| CAS_number = 36505-84-7
| smiles = O=C1N(C(=O)CC2(C1)CCCC2)CCCCN4CCN(c3ncccn3)CC4
| CAS_number2 = 33386-08-2
| InChI = 1/C21H31N5O2/c27-18-16-21(6-1-2-7-21)17-19(28)26(18)11-4-3-10-24-12-14-25(15-13-24)20-22-8-5-9-23-20/h5,8-9H,1-4,6-7,10-17H2
| CAS_supplemental =
| InChIKey = QWCRAEMEVRGPNT-UHFFFAOYAL
| PubChem = 2477
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| IUPHAR_ligand = 36
| StdInChI = 1S/C21H31N5O2/c27-18-16-21(6-1-2-7-21)17-19(28)26(18)11-4-3-10-24-12-14-25(15-13-24)20-22-8-5-9-23-20/h5,8-9H,1-4,6-7,10-17H2
| StdInChIKey_RefDrugBank_Ref = {{stdinchicitedrugbankcite|correct|chemspiderdrugbank}}
| DrugBank = DB00490
| StdInChIKey = QWCRAEMEVRGPNT-UHFFFAOYSA-N
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2383
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = TK65WKS8HL
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07593
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 3223
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 49
| NIAID_ChemDB =
| PDB_ligand =
| synonyms = MJ 9022-1<ref name="Elks2014" />
<!-- Chemical and physical data -->
| IUPAC_name = 8-{4-[4-(Pyrimidin-2-yl)piperazin-1-yl]butyl}-8-azaspiro[4.5]decane-7,9-dione
| C = 21
| H = 31
| N = 5
| O = 2
| SMILES = O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C21H31N5O2/c27-18-16-21(6-1-2-7-21)17-19(28)26(18)11-4-3-10-24-12-14-25(15-13-24)20-22-8-5-9-23-20/h5,8-9H,1-4,6-7,10-17H2
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = QWCRAEMEVRGPNT-UHFFFAOYSA-N
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}}
<!-- Definition and medical uses -->
'''Buspirone''', sold under the brand name '''Buspar''', among others, is an [[anxiolytic]], a [[medication]] primarily used to treat [[anxiety disorders]], particularly [[generalized anxiety disorder]] (GAD).<ref name="AHFS2019">{{cite web |title=Buspirone Hydrochloride Monograph for Professionals | url=https://www.drugs.com/monograph/buspirone.html |website=[[Drugs.com]]}}</ref><ref name=Wil2018/> It is a [[serotonin]] [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]] [[partial agonist]], increasing action at serotonin receptors in the brain.<ref name="pmid22608068" /> It is taken orally, and takes two to six weeks to be fully effective.<ref name=AHFS2019/><ref name=Wil2018/>
Common side effects of buspirone include [[nausea]], [[Headache|headaches]], [[dizziness]], and difficulty concentrating.<ref name=AHFS2019/><ref name=BNF76>{{cite book |title=British national formulary : BNF 76 |date=2018 |publisher=Pharmaceutical Press |isbn=9780857113382 |pages=338 |edition=76}}</ref> Serious side effects may include [[movement disorder]]s, [[serotonin syndrome]], and [[seizures]].<ref name=BNF76/> Its use in [[pregnancy]] appears to be safe but has not been well studied, and use during [[breastfeeding]] has not been well studied.<ref name=BNF76/><ref name=Preg2019>{{cite web |url=https://www.drugs.com/pregnancy/buspirone.html |title=Buspirone Pregnancy and Breastfeeding Warnings |website=[[Drugs.com]]}}</ref>
'''Buspirone''' (pronounced {{respell|BYOO|spur|OWN|'}} (trade name '''Buspar''', pronounced {{Respell|BYOO|spar}}) is an [[anxiolytic]] [[psychoactive drug]] of the [[azapirone]] [[chemical class]], and is primarily used to treat [[generalized anxiety disorder]] (GAD)
Buspirone was developed in 1968 and approved for medical use in the United States in 1986.<ref name=AHFS2019/><ref name=Wil2018>{{cite journal | title=Buspirone | journal=StatPearls | date=January 2018 | pmid=30285372 | url=https://www.ncbi.nlm.nih.gov/books/NBK531477/ | vauthors=Wilson TK, Tripp J }}</ref> It is available as a [[generic medication]].<ref name=BNF76/> In 2022, it was the 54th most commonly prescribed medication in the United States, with more than 12{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Buspirone Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Buspirone | access-date = 30 August 2024 }}</ref>
[[Bristol-Myers Squibb]] (BMS) gained [[Food and Drug Administration|FDA approval]] of buspirone in 1986 for treatment of GAD. The patent on Buspar by Bristol-Myers Squibb expired in 2001, and buspirone is available as a [[generic drug|generic]].
{{TOC limit}}
==Medical uses==
===Anxiety===
*[[Generalized anxiety disorder]] (GAD) of very mild to moderate intensity, without any [[panic attack]]s (it is not generally considered to be effective, nor does it have regulatory approval for other types of [[anxiety disorder]]s such as [[obsessive-compulsive disorder]] (OCD) and [[social anxiety disorder|social phobia]], with or without [[agoraphobia]]).<ref name=mono/>
Buspirone is used for the short-term and long-term treatment of [[anxiety disorder]]s or symptoms of anxiety.<ref name=DM>{{cite web|title=Buspirone HCL (buspirone hydrochloride) tablet [Watson Laboratories, Inc.]|work=DailyMed|publisher=Watson Laboratories, Inc.|date=July 2013|access-date=14 November 2013|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a3fe0ccd-565f-4d0a-a7ba-2fad7a819358}}</ref><ref name=TGA>{{cite web|title=Buspar (buspirone hydrochloride) Tablets 5 mg & 10 mg PRODUCT INFORMATION|work=TGA eBusiness Services|publisher=Aspen Pharma Pty Ltd|date=January 2010|access-date=14 November 2013|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03962-3|format=PDF}}</ref><ref name=AMH>{{cite book | title=Australian Medicines Handbook | year=2013 | publisher=The Australian Medicines Handbook Unit Trust | isbn=978-0-9805790-9-3 | edition=2013 | place=Adelaide | veditors=Rossi S }}</ref><ref name=EMC>{{cite web |title=Buspirone 10mg Tablets |work=electronic Medicines Compendium |publisher=Actavis UK Ltd |date=10 September 2012 |access-date=14 November 2013 |url=http://www.medicines.org.uk/emc/medicine/23859/SPC/Buspirone+10mg+Tablets/|archive-date=13 November 2013|archive-url=https://web.archive.org/web/20131113191142/http://www.medicines.org.uk/emc/medicine/23859/SPC/Buspirone+10mg+Tablets/|url-status=dead}}</ref><ref name=BNF>{{cite book | last1=Joint Formulary Committee | title=British National Formulary (BNF) | publisher=Pharmaceutical Press | pages=224 }}</ref> It is generally preferred over [[benzodiazepines]] because it does not activate the receptors that make drugs like [[alprazolam]] addictive.<ref name=Wil2018/>
* Although not FDA approved for the indication, it is sometimes used [[Off-label use|off-label]] for augmentation of [[selective serotonin reuptake inhibitor]] (SSRI) [[drug therapy|therapy]] against [[clinical depression|depression]].{{Citation needed|date=October 2011}}
Buspirone has no immediate anxiolytic effects, and hence has a delayed [[onset of action]]; its full clinical effectiveness may require 2–4 weeks to manifest itself.<ref name="SadockSadock2014">{{cite book| vauthors=Sadock BJ, Sadock VA, Ruiz P |title=Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry |url=https://books.google.com/books?id=IzGYBAAAQBAJ&pg=PT3211|date=22 September 2014|publisher=Wolters Kluwer Health |isbn=978-1-4698-8375-5|pages=3211–}}</ref> The drug has been shown to be similarly effective in the treatment of [[generalized anxiety disorder]] (GAD) to [[benzodiazepine]]s including [[diazepam]], [[alprazolam]], [[lorazepam]], and [[clorazepate]].<ref name="pmid22608068" /> Buspirone is not known to be effective in the treatment of other [[anxiety disorder]]s besides GAD.<ref name="pmid26535760">{{cite journal | vauthors=Howland RH | title=Buspirone: Back to the Future | journal=Journal of Psychosocial Nursing and Mental Health Services | volume=53 | issue=11 | pages=21–24 | date=November 2015 | pmid=26535760 | doi=10.3928/02793695-20151022-01 }}</ref>
==Adverse effects==
* Common: dizziness, nausea, headache, nervousness, lightheadedness, and excitement.<ref name=mono/>
===ContraindicationsOther uses===
* Hypersensitivity to buspirone.<ref name=mono/>
* not to be used with MAO inhibitors.<ref name=mono/>
*Severely compromised [[liver]] and/or [[renal]] function.<ref name=mono/>
*[[Asthma]], history of bronchiospasm or obstructive airways disease.<ref name="Gelder">{{cite book | author = Geddes, John; Gelder, Michael G.; Mayou, Richard | title = Psychiatry | publisher = Oxford University Press | location = Oxford [Oxfordshire] | year = 2005 | page = 237 | isbn = 0-19-852863-9 | oclc = | doi = | accessdate = }}</ref>
*[[Metabolic acidosis]], as in [[diabetes]].<ref name="Gelder" />
====Sexual dysfunction====
*Epilepsy{{Citation needed|date=October 2011}}
There is some evidence that buspirone on its own may be useful in the treatment of [[hypoactive sexual desire disorder]] (HSDD) in women.<ref name="pmid27916394">{{cite journal |vauthors=Goldstein I, Kim NN, Clayton AH, DeRogatis LR, Giraldi A, Parish SJ, Pfaus J, Simon JA, Kingsberg SA, Meston C, Stahl SM, Wallen K, Worsley R |title=Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review |journal=Mayo Clinic Proceedings |volume=92 |issue=1 |pages=114–128 |date=January 2017 |pmid=27916394 |doi=10.1016/j.mayocp.2016.09.018 |doi-access=free }}</ref> Buspirone may also be effective in treating antidepressant-induced [[sexual dysfunction]].<ref name=Wil2018/><ref name="pmid34247952">{{cite journal |vauthors=Trinchieri M, Trinchieri M, Perletti G, Magri V, Stamatiou K, Cai T, Montanari E, Trinchieri A |title=Erectile and Ejaculatory Dysfunction Associated with Use of Psychotropic Drugs: A Systematic Review |journal=The Journal of Sexual Medicine |volume=18 |issue=8 |pages=1354–1363 |date=August 2021 |pmid=34247952 |doi=10.1016/j.jsxm.2021.05.016 |s2cid=235798526 |quote=Buspirone, a non-benzodiazepine anxiolytic, have even demonstrated enhancement of sexual function in certain individuals. For this reason, they have been proposed as augmentation agents (antidotes) or substitution agents in patients with emerging sexual dysfunction after treatment with antidepressants.}}</ref><ref name="pmid31591339">{{cite journal |vauthors=Montejo AL, Prieto N, de Alarcón R, Casado-Espada N, de la Iglesia J, Montejo L |title=Management Strategies for Antidepressant-Related Sexual Dysfunction: A Clinical Approach |journal=Journal of Clinical Medicine |volume=8 |issue=10 |date=October 2019 |page=1640 |pmid=31591339 |pmc=6832699 |doi=10.3390/jcm8101640 |doi-access=free }}</ref>
*Pre-existing [[heart disease|heart conditions]] (e.g., [[myocardial infarction]]){{Citation needed|date=October 2011}}
*Acute, [[closed-angle glaucoma]]{{Citation needed|date=October 2011}}
*[[Myasthenia gravis]]{{Citation needed|date=October 2011}}
===Interactions=Miscellaneous====
Buspirone is not effective as a treatment for [[benzodiazepine withdrawal syndrome|benzodiazepine withdrawal]], [[barbiturate withdrawal]], or [[alcohol withdrawal]]/[[delirium tremens]].<ref>{{cite journal | vauthors=Sontheimer DL, Ables AZ | title=Is imipramine or buspirone treatment effective in patients wishing to discontinue long-term benzodiazepine use? | journal=The Journal of Family Practice | volume=50 | issue=3 | pages=203 | date=March 2001 | pmid=11252203 }}</ref>
[[File:Buspar.jpg|thumb|Buspar (buspirone) 10 mg tablets ([[Australia|AU]])]]
Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4): Buspirone has been shown in vitro to be metabolized by CYP3A4. This finding is consistent with the in vivo interactions observed between Buspirone and the following
*[[Itraconazole]]: Increased plasma level of buspirone.<ref name=mono/>
*[[Nefazodone]]: Increased plasma levels of buspirone.<ref name=mono/>
*[[Rifampicin]]: Decreased plasma levels of buspirone.<ref name=mono/>
*[[Carbamazepine]]: Reduced plasma levels of buspirone.<ref name=mono/>
*[[Haloperidol]]: Increased plasma levels of haloperidol.<ref name=mono/>
*[[Grapefruit|Grapefruit or grapefruit juice]]: Significantly increases the plasma levels of buspirone. The probable mechanism of this interaction caused by grapefruit juice is delayed gastric emptying and inhibition of the cytochrome P450 3A4-mediated first-pass metabolism of buspirone.<ref>{{cite pmid|9871430}}</ref><ref name=mono/>
* other inhibitors or inducers of P450 3A4: accordingly.<ref name=mono/>
SSRI and SNRI antidepressants such as [[paroxetine]] and [[venlafaxine]] may cause jaw pain/jaw spasm reversible syndrome (although it is not common), and buspirone appears to be successful in treating [[bruxism]] on SSRI/SNRI-induced jaw clenching.<ref>{{cite journal | vauthors=Garrett AR, Hawley JS | title=SSRI-associated bruxism: A systematic review of published case reports | journal=Neurology. Clinical Practice | volume=8 | issue=2 | pages=135–141 | date=April 2018 | pmid=29708207 | pmc=5914744 | doi=10.1212/CPJ.0000000000000433 }}</ref><ref>{{cite journal| vauthors=Prisco V, Iannaccone T, Di Grezia G |date=1 April 2017 |title=Use of buspirone in selective serotonin reuptake inhibitor-induced sleep bruxism|journal=European Psychiatry|series=Abstract of the 25th European Congress of Psychiatry|volume=41 |pages=S855 |doi=10.1016/j.eurpsy.2017.01.1701 |s2cid=148816505 }}</ref>
MAO inhibitors: There have been reports of the occurrence of elevated blood pressure when Buspirone hydrochloride has been added to a regimen including an MAOI.<ref name=mono/>
==Contraindications==
Buspirone has these contraindications:<ref name=mono>{{cite web | url= https://www.drugs.com/pro/buspirone.html | title=Buspirone monograph | publisher=Drugs.com | access-date=27 August 2011}}</ref><ref name="Gelder">{{cite book | vauthors=Geddes J, Gelder MG, Mayou R | title=Psychiatry | publisher=Oxford University Press | location=Oxford [Oxfordshire] | year=2005 | page=[https://archive.org/details/psychiatry0000geld/page/237 237] | isbn=978-0-19-852863-0 | url=https://archive.org/details/psychiatry0000geld/page/237 }}</ref>
* Hypersensitivity to buspirone
*[[Metabolic acidosis]], as in [[diabetes]]
* Should not be used with [[MAO inhibitor]]s
* Severely compromised [[liver]] and/or [[kidney]] function
==Side effects==
{{Main|List of side effects of buspirone}}
Known [[side effect]]s associated with buspirone include [[dizziness]], [[headache]]s, [[nausea]], [[tinnitus]], and [[paresthesia]].<ref name="pmid22608068" /> Buspirone is relatively [[tolerability|well tolerated]] and is not associated with [[sedation]], [[cognitive impairment|cognitive]] and [[psychomotor retardation|psychomotor impairment]], [[muscle relaxation]], [[physical dependence]], or [[anticonvulsant]] effects.<ref name="pmid22608068" /> In addition, buspirone does not produce [[euphoria]]<ref name="SadockSadock2014" /> and is not a [[drug of abuse]].<ref name=TGA/>
==Overdose==
Buspirone appears to be relatively benign in cases of single-drug [[overdose]], although no definitive data on this subject appear to be available.<ref name="FultonBrogden1997">{{cite journal| vauthors=Fulton B, Brogden RN |title=Buspirone|journal=CNS Drugs|volume=7|issue=1|year=1997|pages=68–88|issn=1172-7047|doi=10.2165/00023210-199707010-00007|s2cid=57668523 }}</ref> In one [[clinical trial]], buspirone was administered to healthy male volunteers at a dosage of 375 mg/day, and produced side effects including [[nausea]], [[vomiting]], [[dizziness]], [[drowsiness]], [[miosis]], and [[gastric distress]].<ref name=DM/><ref name=TGA/><ref name=EMC/> In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, with [[akathisia]], [[tremor]], and [[muscle rigidity]] observed.<ref name="Dart2004">{{cite book| vauthors=Dart RC |title=Medical Toxicology |url= https://books.google.com/books?id=BfdighlyGiwC&pg=PA886 |year=2004 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-2845-4 |pages=886– }}</ref> Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals.<ref name="Dart2004" /> One death has been reported in a co-ingestion of 450 mg buspirone with [[alprazolam]], [[diltiazem]], [[alcohol (drug)|alcohol]], and [[cocaine]].<ref name="Dart2004" />
== Interactions ==
Buspirone has been shown ''[[in vitro]]'' to be [[metabolism|metabolized]] by the [[enzyme]] [[CYP3A4]].<ref name="pmid15640381" /> This finding is consistent with the ''[[in vivo]]'' interactions observed between buspirone and these inhibitors or inducers of [[cytochrome P450]] 3A4 (CYP3A4), among others:<ref name=mono/>
* [[Itraconazole]]: Increased plasma level of buspirone
* [[Rifampicin]]: Decreased plasma levels of buspirone
* [[Nefazodone]]: Increased plasma levels of buspirone
* [[Haloperidol]]: Increased plasma levels of buspirone
* [[Carbamazepine]]: Decreased plasma levels of buspirone
* Grapefruit: Significantly increases the plasma levels of buspirone.<ref>{{cite journal | vauthors=Lilja JJ, Kivistö KT, Backman JT, Lamberg TS, Neuvonen PJ | title=Grapefruit juice substantially increases plasma concentrations of buspirone | journal=Clinical Pharmacology and Therapeutics | volume=64 | issue=6 | pages=655–660 | date=December 1998 | pmid=9871430 | doi=10.1016/S0009-9236(98)90056-X | s2cid=22009095 }}</ref> See [[grapefruit–drug interactions]].
*[[Fluvoxamine]]: Moderately increase plasma levels of buspirone.<ref>{{cite journal | vauthors=Lamberg TS, Kivistö KT, Laitila J, Mårtensson K, Neuvonen PJ | title=The effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of buspirone | journal=European Journal of Clinical Pharmacology | volume=54 | issue=9–10 | pages=761–766 | date=1998 | pmid=9923581 | doi=10.1007/s002280050548 | s2cid=21939719 }}</ref>
[[Hypertension|Elevated blood pressure]] has been reported when buspirone has been administered to patients taking monoamine oxidase inhibitors (MAOIs).<ref name=mono/>
==Pharmacology==
Buspirone functions as a [[serotonin]] [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]] [[partial agonist]].<ref>{{cite pmid|9109104}}</ref><ref name=mono/> It is this action that is thought to mediate its anxiolytic and antidepressant effects. Additionally, it functions as a [[dopamine]] [[D2 receptor|D<sub>2</sub>]]<ref name=mono/>, as well as [[α1-adrenergic|α<sub>1</sub>]], and [[α2-adrenergic|α<sub>2</sub>-adrenergic]] [[receptor antagonist]]{{Citation needed|date=October 2011}} to a lesser degree, though these properties are generally undesirable in an anxiolytic and likely only contribute to side effects.{{Citation needed|date=October 2011}}
===Pharmacodynamics===
==Research==
{| class="wikitable floatright"
* In a 1996 study buspirone has been investigated and found useful as an adjoint treatment for [[alcoholism|alcohol dependence]]<ref>{{cite pmid|8865960}}</ref>
|+ Buspirone<ref name="PDSP">{{cite web | title=PDSP K<sub>i</sub> Database | work=Psychoactive Drug Screening Program (PDSP)|author1-link=Bryan Roth | vauthors=Roth BL, Driscol J | publisher=University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date=14 August 2017 | url=https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=buspirone&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}</ref>
* Although not related to clinical indications, it is interesting that in a study in rats buspirone has been found to improve [[spatial learning]] and [[spatial memory|memory]] after [[traumatic brain injury]] (TBI). Such findings may have clinical relevance to TBI patients.<ref>{{cite doi|10.1016/j.bbr.2008.06.025}}</ref>
|-
! Site !! K<sub>i</sub> (nM)
!Action!! Species !! Ref
|-
|[[5-HT1A receptor|5-HT<sub>1A</sub>]]|| '''3.98–214<br />21 (median)'''
|Agonist|| Human ||<ref name="PDSP" /><ref name="pmid7984267">{{cite journal | vauthors=Boess FG, Martin IL | title=Molecular biology of 5-HT receptors | journal=Neuropharmacology | volume=33 | issue=3–4 | pages=275–317 | year=1994 | pmid=7984267 | doi=10.1016/0028-3908(94)90059-0 | s2cid=35553281 }}</ref><br />
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]] || >100,000
|Agonist ? <ref name="Sato_2010">{{cite journal | vauthors=Sato H, Skelin I, Diksic M | title=Chronic buspirone treatment decreases 5-HT1B receptor densities and the serotonin transporter but increases the density of 5-HT2A receptors in the bulbectomized rat model of depression: an autoradiographic study | journal=Brain Research | volume=1345 | pages=28–44 | date=July 2010 | pmid=20501324 | doi=10.1016/j.brainres.2010.05.054 | s2cid=22979155 }}</ref> || Rat || <ref name="pmid1974152">{{cite journal | vauthors=Hamik A, Oksenberg D, Fischette C, Peroutka SJ | title=Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites | journal=Biological Psychiatry | volume=28 | issue=2 | pages=99–109 | date=July 1990 | pmid=1974152 | doi=10.1016/0006-3223(90)90627-e | s2cid=25608914 | doi-access=free }}</ref>
|-
| [[5-HT1D receptor|5-HT<sub>1D</sub>]] || 22,000–42,700
|Agonist ? <ref name="Sato_2010" />|| Human || <ref name="pmid2521959">{{cite journal | vauthors=Peroutka SJ, Switzer JA, Hamik A | title=Identification of 5-hydroxytryptamine1D binding sites in human brain membranes | journal=Synapse | volume=3 | issue=1 | pages=61–66 | year=1989 | pmid=2521959 | doi=10.1002/syn.890030109 | s2cid=23503235 }}</ref><ref name="pmid2975354">{{cite journal | vauthors=Waeber C, Schoeffter P, Palacios JM, Hoyer D | title=Molecular pharmacology of 5-HT1D recognition sites: radioligand binding studies in human, pig and calf brain membranes | journal=Naunyn-Schmiedeberg's Archives of Pharmacology | volume=337 | issue=6 | pages=595–601 | date=June 1988 | pmid=2975354 | doi=10.1007/bf00175783 | s2cid=21344978 }}</ref>
|-
|5-HT2A
|
|Antagonist
|Human
|
|-
|[[5-HT2C receptor|5-HT<sub>2C</sub>]]|| 1,100–6,026
|Antagonist ? <ref name="Sato_2010" />|| Rat/pig ||<br /><ref name="pmid1974152" />
|-
|[[5-HT7 receptor|5-HT<sub>7</sub>]]|| 375–381<br />840
|Antagonist ? <ref name="Sato_2010" />|| Rat<br />Human ||<ref name="pmid8398139">{{cite journal | vauthors=Lovenberg TW, Baron BM, de Lecea L, Miller JD, Prosser RA, Rea MA, Foye PE, Racke M, Slone AL, Siegel BW | title=A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms | journal=Neuron | volume=11 | issue=3 | pages=449–458 | date=September 1993 | pmid=8398139 | doi=10.1016/0896-6273(93)90149-l | s2cid=28729004 }}</ref><ref name="pmid8397408">{{cite journal | vauthors=Ruat M, Traiffort E, Leurs R, Tardivel-Lacombe J, Diaz J, Arrang JM, Schwartz JC | title=Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation | journal=Proceedings of the National Academy of Sciences of the United States of America | volume=90 | issue=18 | pages=8547–8551 | date=September 1993 | pmid=8397408 | pmc=47394 | doi=10.1073/pnas.90.18.8547 | doi-access=free | bibcode=1993PNAS...90.8547R }}</ref><br /><ref name="pmid31882369">{{cite journal | vauthors=Perry CK, Casey AB, Felsing DE, Vemula R, Zaka M, Herrington NB, Cui M, Kellogg GE, Canal CE, Booth RG | title=Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT<sub>1A</sub> and 5-HT<sub>7</sub> G protein-coupled receptor affinity, 3D-QSAR and molecular modeling | journal=Bioorganic & Medicinal Chemistry | volume=28 | issue=3 | pages=115262 | date=February 2020 | pmid=31882369 | doi=10.1016/j.bmc.2019.115262 | s2cid=209498915 | doi-access=free }}</ref>
|-
| [[Alpha-1 adrenergic receptor|α<sub>1</sub>]] || 1,000
|Antagonist|| Rat || <ref name="pmid1974152" />
|-
| [[Alpha-2 adrenergic receptor|α<sub>2</sub>]] || 6,000
|Antagonist|| Rat || <ref name="pmid1681447">{{cite journal | vauthors=Blier P, Curet O, Chaput Y, de Montigny C | title=Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine--II. Effects of acute administration of 1-PP and long-term administration of tandospirone on noradrenergic neurotransmission | journal=Neuropharmacology | volume=30 | issue=7 | pages=691–701 | date=July 1991 | pmid=1681447 | doi=10.1016/0028-3908(91)90176-c | s2cid=44297577 }}</ref>
|-
|''' '''[[Alpha-2A adrenergic receptor|α<sub>2A</sub>]]|| '''7.3''' ({{abbrlink|1-PP|1-(2-Pyrimidinyl)piperazine}})
|Antagonist|| Human ||<ref name="pmid1974152" />
|-
| [[Beta-adrenergic receptor|β]] || 8,800
|Antagonist|| Rat || <ref name="pmid1974152" />
|-
| [[D1 receptor|D<sub>1</sub>]] || 33,000
|Antagonist|| Rat || <ref name="pmid1974152" />
|-
|[[D2 receptor|D<sub>2</sub>]]|| 484<br />240
|Antagonist|| Human<br />Rat ||<ref name="pmid22827916">{{cite journal | vauthors=Bergman J, Roof RA, Furman CA, Conroy JL, Mello NK, Sibley DR, Skolnick P | title=Modification of cocaine self-administration by buspirone (Buspar): potential involvement of D3 and D4 dopamine receptors | journal=The International Journal of Neuropsychopharmacology | volume=16 | issue=2 | pages=445–458 | date=March 2013 | pmid=22827916 | pmc=5100812 | doi=10.1017/S1461145712000661 }}</ref><br /><ref name="pmid1974152" />
|-
|[[D3 receptor|D<sub>3</sub>]]|| '''98'''
|Antagonist|| Human ||<ref name="pmid22827916" />
|-
|[[D4 receptor|D<sub>4</sub>]]|| '''29'''
|Antagonist|| Human ||<ref name="pmid22827916" />
|-
| {{abbrlink|mACh|Muscarinic acetylcholine receptor}} || 38,000
|?|| Rat || <ref name="pmid1974152" />
|-
|[[GABAA receptor#Benzodiazepine site|GABA<sub>A</sub><br />({{abbr|BDZ|Benzodiazepine site}})]] || >100,000
| -|| Rat || <ref name="pmid1974152" />
|- class="sortbottom"
| colspan="5" style="width: 1px;" | Values are K<sub>i</sub> (nM). The smaller the value, the more strongly the drug binds to the site.
|}
Buspirone acts as a [[partial agonist]] of the [[serotonin]] [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]] with high [[affinity (pharmacology)|affinity]].<ref name="pmid22608068"/><ref name="pmid1974152" /> It is a partial agonist of both [[presynaptic]] 5-HT<sub>1A</sub> receptors, which are inhibitory [[autoreceptor]]s, and [[postsynaptic]] 5-HT<sub>1A</sub> receptors.<ref name="pmid22608068" /> It is thought that the main effects of buspirone are mediated via its interaction with the presynaptic 5-HT<sub>1A</sub> receptor, thus reducing the firing of serotonin-producing neurons.<ref name="pmid22608068" /> Buspirone also seems to have lower affinities for the serotonin [[5-HT2A receptor|5-HT<sub>2A</sub>]], [[5-HT2B receptor|5-HT<sub>2B</sub>]], [[5-HT2C receptor|5-HT<sub>2C</sub>]], [[5-HT6 receptor|5-HT<sub>6</sub>]], [[5-HT7 receptor|5-HT<sub>7</sub>]] receptors where it probably acts as an antagonist.<ref name="Sato_2010" />
==Comparison to benzodiazepines==
Buspirone's [[chemical structure]] and [[mechanism of action]] are completely unrelated to those of the [[benzodiazepine]]s, and its [[efficacy]] is not comparable to that of members of the benzodiazepine family in treating GAD.<ref>{{cite pmid|2649317}}</ref><ref>{{cite pmid|382878}}</ref>
In addition to binding to serotonin receptors, buspirone is an antagonist of the [[dopamine]] [[D2 receptor|D<sub>2</sub> receptor]] with weak affinity.<ref name="pmid22608068"/><ref name="pmid1974152" /> It preferentially blocks inhibitory presynaptic D<sub>2</sub> autoreceptors, and antagonizes postsynaptic D<sub>2</sub> receptors only at higher doses.<ref name="pmid22608068" /> In accordance, buspirone has been found to increase [[dopaminergic]] [[neurotransmission]] in the [[nigrostriatal pathway]] at low doses, whereas at higher doses, postsynaptic D<sub>2</sub> receptors are blocked and [[dopamine antagonist|antidopaminergic]] effects such as [[hypoactivity]] and reduced [[stereotypy]], though notably not [[catalepsy]], are observed in animals.<ref name="pmid22608068" /> Buspirone has also been found to bind with much higher affinity to the dopamine [[D3 receptor|D<sub>3</sub>]] and [[D4 receptor|D<sub>4</sub> receptor]]s, where it is similarly an antagonist.<ref name="pmid22827916" />
Buspirone shows no potential for [[drug addiction|addiction]] or [[physical dependence|dependence]], and the development of [[Drug tolerance|tolerance]] has not been observed. Furthermore, [[cross-tolerance]] to benzodiazepines, [[barbiturate]]s, and [[ethanol|alcohol]], as well as other [[GABAergic]]s, is not present either.It may take several weeks before its anxiolytic effects become noticeable. Many patients may also require a higher dosage to adequately respond to treatment.<ref name=mono>{{cite web | url=http://www.drugs.com/pro/buspirone.html | title=Buspirone monograph | publisher=Drugs.com | accessdate=2011-08-27}}</ref>
A major [[metabolite]] of buspirone, [[1-(2-pyrimidinyl)piperazine]] (1-PP), occurs at higher circulating levels than buspirone itself and is known to act as a potent [[alpha-2 adrenergic receptor|α<sub>2</sub>-adrenergic receptor]] antagonist.<ref name="pmid1681447" /><ref name="pmid1796057">{{cite journal | vauthors=Tunnicliff G | title=Molecular basis of buspirone's anxiolytic action | journal=Pharmacology & Toxicology | volume=69 | issue=3 | pages=149–156 | date=September 1991 | pmid=1796057 | doi=10.1111/j.1600-0773.1991.tb01289.x }}</ref><ref name="pmid12438536">{{cite journal | vauthors=Zuideveld KP, Rusiç-Pavletiç J, Maas HJ, Peletier LA, Van der Graaf PH, Danhof M | title=Pharmacokinetic-pharmacodynamic modeling of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in rats | journal=The Journal of Pharmacology and Experimental Therapeutics | volume=303 | issue=3 | pages=1130–1137 | date=December 2002 | pmid=12438536 | doi=10.1124/jpet.102.036798 | s2cid=14139919 }}</ref> This metabolite may be responsible for the increased [[noradrenergic]] and [[dopaminergic]] activity observed with buspirone in animals.<ref name="pmid1796057" /><ref name="pmid17700052">{{cite journal |vauthors=Fava M |year=2007 |title=The combination of buspirone and bupropion in the treatment of depression |journal=Psychotherapy and Psychosomatics |volume=76 |issue=5 |pages=311–312 |doi=10.1159/000104708 |pmid=17700052 |s2cid=46284917}}</ref> Buspirone also has very weak and probably clinically unimportant affinity for the [[alpha-1 adrenergic receptor|α<sub>1</sub>-adrenergic receptor]].<ref name="pmid1974152" /><ref name="SternFava2015">{{cite book | vauthors=Stern TA, Fava M, Wilens TE, Rosenbaum JF |title= Massachusetts General Hospital Psychopharmacology and Neurotherapeutics E-Book |url= https://books.google.com/books?id=CCZ1CQAAQBAJ&pg=PA29|date=27 April 2015 |publisher= Elsevier Health Sciences |isbn= 978-0-323-41323-7 |pages=29–}}</ref> However, buspirone has been reported to have shown "significant and selective intrinsic efficacy" at the α<sub>1</sub>-adrenergic receptor expressed in a "tissue- and species-dependent manner".<ref name="SternFava2015" />
In a study of diazepam and buspirone in GAD patients both drugs were effective, but buspirone took longer to take effect. Abrupt discontinuation after 6 weeks resulted in withdrawal symptoms in diazepam, which were not present with buspirone. This indicated a risk of physical dependence with diazepam, which is not present with buspirone.<ref>{{cite pmid|2686797}}</ref>
Unlike benzodiazepines, buspirone does not interact with the [[GABAA receptor|GABA<sub>A</sub> receptor]] complex.<ref name="pmid22608068" /><ref name="NuttBallenger2008">{{cite book| vauthors=Nutt DJ, Ballenger JC |title=Anxiety Disorders|url=https://books.google.com/books?id=swAE2bRjV8UC&pg=PT395|date=15 April 2008|publisher=John Wiley & Sons|isbn=978-0-470-98683-7|pages=395–}}</ref>
Buspirone is ineffective for benzodiazepine withdrawal, does not improve discontinuation rates and does not decrease the severity of withdrawal symptoms.<ref>{{Cite pmid|11252203}}</ref>
===Pharmacokinetics===
Buspirone has a low [[oral administration|oral]] [[bioavailability]] of 3.9% relative to [[intravenous injection]] due to extensive [[first-pass metabolism]].<ref name="pmid22608068" /> The [[Tmax (pharmacology)|time to peak plasma levels]] following ingestion is 0.9 to 1.5 hours.<ref name="pmid22608068" /> It is reported to have an [[elimination half-life]] of 2.8 hours,<ref name="pmid22608068" /> although a review of 14 studies found that the mean terminal half-life ranged between 2 and 11 hours, and one study even reported a terminal half-life of 33 hours.<ref name="pmid3515929">{{cite journal | vauthors=Gammans RE, Mayol RF, LaBudde JA | title=Metabolism and disposition of buspirone | journal=The American Journal of Medicine | volume=80 | issue=3B | pages=41–51 | date=March 1986 | pmid=3515929 | doi=10.1016/0002-9343(86)90331-1 }}</ref> Buspirone is [[metabolism|metabolized]] primarily by [[CYP3A4]], and prominent [[drug interaction]]s with [[enzyme inhibitor|inhibitor]]s and [[enzyme inducer|inducer]]s of this [[enzyme]] have been observed.<ref name="pmid10320950" /><ref name="pmid15640381" /> Major [[metabolite]]s of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP.<ref>{{cite journal | vauthors=Zhu Y, Chen G, Zhang K, Chen C, Chen W, Zhu M, Jiang H | title=High-Throughput Metabolic Soft-Spot Identification in Liver Microsomes by LC/UV/MS: Application of a Single Variable Incubation Time Approach | journal=Molecules | volume=27 | issue=22 | pages=8058 | date=November 2022 | pmid=36432161 | pmc=9693510 | doi=10.3390/molecules27228058 | doi-access=free }}</ref><ref name="pmid3515929" /><ref name="SchatzbergNemeroff2009" /><ref name="pmid17494642">{{cite journal | vauthors=Wong H, Dockens RC, Pajor L, Yeola S, Grace JE, Stark AD, Taub RA, Yocca FD, Zaczek RC, Li YW | title=6-Hydroxybuspirone is a major active metabolite of buspirone: assessment of pharmacokinetics and 5-hydroxytryptamine1A receptor occupancy in rats | journal=Drug Metabolism and Disposition | volume=35 | issue=8 | pages=1387–1392 | date=August 2007 | pmid=17494642 | doi=10.1124/dmd.107.015768 | s2cid=25558546 }}</ref> 6-Hydroxybuspirone has been identified as the predominant [[liver|hepatic]] metabolite of buspirone, with plasma levels that are 40-fold greater than those of buspirone after oral administration of buspirone to humans.<ref name="SchatzbergNemeroff2009">{{cite book| vauthors=Schatzberg AF, Nemeroff CB |title=The American Psychiatric Publishing Textbook of Psychopharmacology |url=https://books.google.com/books?id=Xx7iNGdV25IC&pg=PA490 |year=2009 |publisher=American Psychiatric Pub |isbn=978-1-58562-309-9 |pages=490–}}</ref> The metabolite is a high-affinity partial agonist of the 5-HT<sub>1A</sub> receptor (K<sub>i</sub>=25 nM) similarly to buspirone, and has demonstrated occupancy of the 5-HT<sub>1A</sub> receptor ''[[in vivo]]''.<ref name="SchatzbergNemeroff2009" /> As such, it is likely to play an important role in the therapeutic effects of buspirone.<ref name="SchatzbergNemeroff2009" /> 1-PP has also been found to circulate at higher levels than those of buspirone itself and may similarly play a significant role in the clinical effects of buspirone.<ref name="pmid1796057" /><ref name="pmid17700052" />
[[File:Buspirone metabolism.png|800px|thumb|center|[[Drug metabolism|Phase I Metabolism]] of buspirone in humans<ref>{{cite journal | vauthors=Zhu Y, Chen G, Zhang K, Chen C, Chen W, Zhu M, Jiang H | title=High-Throughput Metabolic Soft-Spot Identification in Liver Microsomes by LC/UV/MS: Application of a Single Variable Incubation Time Approach | journal=Molecules | volume=27 | issue=22 | pages=8058 | date=November 2022 | pmid=36432161 | pmc=9693510 | doi=10.3390/molecules27228058 | doi-access=free }}</ref><ref>{{cite journal | vauthors=Dockens RC, Salazar DE, Fulmor IE, Wehling M, Arnold ME, Croop R | title=Pharmacokinetics of a newly identified active metabolite of buspirone after administration of buspirone over its therapeutic dose range | journal=Journal of Clinical Pharmacology | volume=46 | issue=11 | pages=1308–1312 | date=November 2006 | pmid=17050795 | doi=10.1177/0091270006292250 | s2cid=25050964 }}</ref><ref>{{cite journal | vauthors=Jajoo HK, Mayol RF, LaBudde JA, Blair IA | title=Metabolism of the antianxiety drug buspirone in human subjects | journal=Drug Metabolism and Disposition | volume=17 | issue=6 | pages=634–640 | year=1989 | pmid=2575499 }}</ref><ref name="pmid15640381"/>]]
==Chemistry==
Buspirone is a member of the [[azapirone]] [[chemical class]], and consists of [[azaspirodecanedione]] and [[pyrimidinylpiperazine]] components linked together by a [[butyl group|butyl]] [[side chain|chain]].
The synthesis of buspirone starts with the N-alkylation of 1-(2-pyrimidyl)piperazine with 4-chlorobutyronitrile followed by [[hydrogenation]] of the [[nitrile]] over [[Raney nickel]] catalyst. The primary amine product of the previous step is reacted with the depicted [[spirocyclic]] [[acid anhydride]] to yield buspirone.<ref>{{Cite doi|10.1021/jm00275a009}};<br/>{{cite patent | title = Heterocyclische Azaspirodecandione und Verfahren zu ihrer Herstellung | country=DE | number=2057845 | inventor=Rayburn JW, Wu YH | pubdate = 1971-06-09 }};<br/>{{cite patent | title = N-(heteroarcyclic)piperazinylalkyl-azaspiroalkanediones | country=US | number=3717634 | inventor=Rayburn JW, Wu YH | pubdate = 1973-02-20 }};<br/>{{cite patent | title = N-{8 (4-pyridyl-piperazino)-alkyl}-9-azaspiroalkanediones | country=US | number=3907801 | inventor=Rayburn JW, Wu YH | pubdate = 1975-09-23 }};<br/> {{cite patent | title = Tranquilizer process employing N-(heteroarcyclic)piperazinylalkylazaspiroalkanediones | country=US | number=3976776 | inventor=Rayburn JW, Wu YH | pubdate = 1976-08-24 }}</ref>
===Analogues===
[[File:Buspirone synthesis.png|800px]]
[[Structural analogue]]s of buspirone include other azapirones like [[gepirone]], [[ipsapirone]], [[perospirone]], and [[tandospirone]].<ref name="pmid1679210">{{cite journal | vauthors=Taylor DP, Moon SL | title=Buspirone and related compounds as alternative anxiolytics | journal=Neuropeptides | volume=19 | issue=Suppl | pages=15–19 | date=July 1991 | pmid=1679210 | doi=10.1016/0143-4179(91)90078-w | s2cid=13730683 }}</ref>
A number of analogues are recorded.<ref>{{cite journal | vauthors=Yevich JP, Temple DL, New JS, Taylor DP, Riblet LA | title=Buspirone analogues. 1. Structure-activity relationships in a series of N-aryl- and heteroarylpiperazine derivatives | journal=Journal of Medicinal Chemistry | volume=26 | issue=2 | pages=194–203 | date=February 1983 | pmid=6131130 | doi=10.1021/jm00356a014 | s2cid=28619843 }}</ref>
==See also==
*[[Gepirone]]
*[[Tandospirone]]
==References=Synthesis===
A number of methods of synthesis have also been reported.<ref>{{cite journal | vauthors=Cybulski J, Chilmonczyk Z, Szelejewski W, Wojtasiewicz K, Wróbel JT | date=1992 | title=An Efficient Synthesis of Buspirone and its Analogues. | journal=Archiv der Pharmazie | volume=325 | issue=5 | pages=313–315 | doi=10.1002/ardp.19923250513 | s2cid=83676454 }}</ref><ref>{{cite journal | vauthors=Kuo DL | date=1993 | title=Pd(0)-catalysed Synthesis of Buspirone and Gepirone. | journal=Heterocycles | volume=36 | issue=7 | pages=1463–1469 | doi= 10.3987/COM-93-6357 }}</ref><ref>{{cite journal | vauthors=Mou J, Zong ZM, Wei XY |title=Facile Synthesis of Anxiolytic Buspirone |date=August 2008 |journal=Organic Preparations and Procedures International |volume=40 |issue=4 |pages=391–394 |doi=10.1080/00304940809458099 |s2cid=95124245 |issn=0030-4948 |eissn=1945-5453}}</ref> One method begins with [[alkylation]] of 1-(2-pyrimidyl)piperazine ('''1''') with 3-chloro-1-cyanopropane (4-chlorobutyronitrile) ('''2''') to give ('''3'''). Next, reduction of the nitrile group is performed either by [[catalytic hydrogenation]] or with [[lithium aluminium hydride]] (LAH) giving ('''4'''). The primary amine is then reacted with 3,3-tetramethyleneglutaric anhydride ('''5''') in order to yield buspirone ('''6''').<ref name="Psychosedative agents. 2. 8-4-Subs">{{cite journal | vauthors=Allen LE, Ferguson HC, Kissel JW | title=Psychosedative agents. 2. 8-(4-Substituted 1-piperazinylalkyl)-8-azaspiro(4.5)decane-7,9-diones | journal=Journal of Medicinal Chemistry | volume=15 | issue=5 | pages=477–479 | date=May 1972 | pmid=5035267 | doi=10.1021/jm00275a009 }}</ref><ref>DE2057845 idem Y Wu, J Rayburn, {{US patent|3717634}} (1973 to [[Mead Johnson]]).</ref><ref>{{cite patent | inventor=Wu YH, Rayburn JW | country=US | number=3907801 | gdate=1975 | assign1=[[Mead Johnson]]}}</ref><ref>{{cite patent | inventor=Wu YH, Rayburn JW | country=US | number=3976776 | gdate=1976 | assign1=[[Mead Johnson]]}}</ref><ref>{{cite patent | inventor=Behme RJ, Kensler TT, Mikolasek DG | country=US | number=4810789 | gdate=1989 | assign1=[[Bristol Myers]]}}</ref>
[[File:Buspirone-synthesis.svg|701px|thumb|center|Synthesis of buspirone]] {{clear-left}}
==History==
Buspirone was first [[chemical synthesis|synthesized]] by a team at [[Mead Johnson]] in 1968<ref name="pmid26535760" /> but was not patented until 1980.<ref>{{cite patent|country=US |number=4182763 |title=Buspirone anti-anxiety method |pubdate=1980-01-08 |inventor=Casten GP, McKinney GR, Newton RE, Tompkins EC, Weikel Jr JH |assign1=[[Mead_Johnson|Mead Johnson & Co.]]|assign2=[[Bristol_Myers_Squibb#Bristol-Myers|Bristol-Meyers Co.]]}}</ref><ref name="Psychosedative agents. 2. 8-4-Subs"/><ref>{{cite patent |country=US |number=3907801| pubdate=1975-09-23 |title=N-[(4-pyridyl-piperazino)-alkyl]-azaspiroalkanediones |assign=[[Mead_Johnson]]| inventor=Hua WY, Warren RJ }}</ref> It was initially developed as an [[antipsychotic]] acting on the D<sub>2</sub> receptor but was found to be ineffective in the treatment of [[psychosis]]; it was then used as an anxiolytic instead.<ref name="pmid22608068" /> In 1986, [[Bristol-Myers Squibb]] gained FDA approval for buspirone in the treatment of GAD.<ref name="pmid26535760" /><ref>{{cite web | publisher=United States Federal Drug Administration | date=9 September 1986 | title=Approval Type-1 New Molecular Entry. | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/018731Orig1s000rev.pdf }}</ref> The [[patent]] expired in 2001, and buspirone is now available as a [[generic drug]].
==Society and culture==
[[File:Buspar.jpg|thumb|Buspar (buspirone) 10-mg tablets]]
===Generic names===
Buspirone is the {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|BAN|British Approved Name}}, {{abbrlink|DCF|Dénomination Commune Française}}, and {{abbrlink|DCIT|Denominazione Comune Italiana}} of buspirone, while buspirone hydrochloride is its {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BANM|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Elks2014">{{cite book| vauthors=Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies |url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA192 |date=14 November 2014 |publisher=Springer |isbn=978-1-4757-2085-3 |pages=192–}}</ref><ref name="IndexNominum2000">{{cite book |title=Index Nominum 2000: International Drug Directory |url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA149|date=January 2000|publisher=Taylor & Francis | isbn=978-3-88763-075-1|pages=149–}}</ref><ref name="MortonHall2012">{{cite book| vauthors=Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms |url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA57|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=57–}}</ref><ref name="Drugs.com">{{cite web | url=https://www.drugs.com/international/buspirone.html |title=Buspirone | work=Drugs.com }}</ref>
===Brand names===
Buspirone was primarily sold under the brand name Buspar.<ref name="IndexNominum2000" /><ref name="Drugs.com" /> Buspar is currently listed as discontinued by the U.S. [[Food and Drug Administration]] (FDA).<ref>{{cite web | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=018731 |title=Drugs@FDA: FDA Approved Drug Products| publisher=[[Food and Drug Administration]]}}</ref> In 2010, in response to a citizen petition, the FDA determined that Buspar was not withdrawn from sale for reasons of safety or effectiveness.<ref>{{cite web|url=https://www.federalregister.gov/documents/2010/10/19/2010-26214/determination-that-buspar-buspirone-hydrochloride-tablets-10-milligrams-15-milligrams-and-30|title=Determination That Buspar (Buspirone Hydrochloride) Tablets, 10 Milligrams, 15 Milligrams, and 30 Milligrams, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness|date=19 October 2010|website=Federal Register|access-date=20 September 2019}}</ref>
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