Buspirone

Source: Wikipedia, the free encyclopedia.
Not to be confused with Bupropion.

Buspirone
Clinical data
Pronunciation/ˈbjuːspɪroʊn/ (BEW-spi-rohn)
Trade namesBuspar, Namanspin
Other namesMJ 9022-1[1]
AHFS/Drugs.comMonograph
MedlinePlusa688005
License data
Pregnancy
category
  • AU: B1
Routes of
administration		By mouth
ATC code
Legal status
Legal status
1-PPTooltip 1-(2-pyrimidinyl)piperazine[5][6][7]
Elimination half-life2.5 hours[8]
ExcretionUrine: 29–63%[4]
Feces: 18–38%[4]
Identifiers
  • 8-{4-[4-(Pyrimidin-2-yl)piperazin-1-yl]butyl}-8-azaspiro[4.5]decane-7,9-dione
JSmol)
  • O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
  • InChI=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 checkY
  • Key:QWCRAEMEVRGPNT-UHFFFAOYSA-N checkY
  (verify)

Buspirone, sold under the brand name Buspar, among others, is an

anxiety disorders, particularly generalized anxiety disorder.[10][11] It is a serotonin 5-HT1A receptor agonist, increasing action at serotonin receptors in the brain.[3] It is taken orally, and takes two to six weeks to be fully effective.[10][11]

Common side effects of buspirone include nausea, headaches, dizziness, and difficulty concentrating.

seizures.[12] Its use in pregnancy appears to be safe but has not been well studied, and use during breastfeeding has not been well studied.[12][13]

Buspirone was developed in 1968 and approved for medical use in the United States in 1986.

generic medication.[12] In 2021, it was the 53rd most-commonly prescribed medication in the United States, with more than 12 million prescriptions.[14][15]

Medical uses

Anxiety

Buspirone is used for the short-term and long-term treatment of

benzodiazepines because it does not activate the receptors that make drugs like alprazolam addictive.[11]

Buspirone has no immediate anxiolytic effects, and hence has a delayed

social phobia as an adjunct to selective serotonin reuptake inhibitors (SSRIs).[3][23]

Other uses

Sexual dysfunction

There is some evidence that buspirone on its own may be useful in the treatment of hypoactive sexual desire disorder (HSDD) in women.[24] Buspirone may also be effective in treating antidepressant-induced sexual dysfunction.[11][25][26]

Miscellaneous

Buspirone is not effective as a treatment for

alcohol withdrawal/delirium tremens.[27]

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.[28][29]

Contraindications

Buspirone has these contraindications:[30][31]

Side effects

Main article: List of side effects of buspirone

Known

drug of abuse.[17]

Overdose

Buspirone appears to be relatively benign in cases of single-drug

muscle rigidity observed.[33] Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals.[33] One death has been reported in a co-ingestion of 450 mg buspirone with alprazolam, diltiazem, alcohol, cocaine.[33]

Interactions

Buspirone has been shown in vitro to be metabolized by the enzyme CYP3A4.[9] This finding is consistent with the in vivo interactions observed between buspirone and these inhibitors or inducers of cytochrome P450 3A4 (CYP3A4), among others:[30]

Elevated blood pressure has been reported when buspirone has been administered to patients taking monoamine oxidase inhibitors (MAOIs).[30]

Pharmacology

Pharmacodynamics

Buspirone[36]
Site Ki (nM) Action Species Ref
5-HT1A 3.98–214
21 (median) 		Agonist Human [36][37]
5-HT1B >100,000 Agonist ? [38] Rat [39]
5-HT1D 22,000–42,700 Agonist ? [38] Human [40][41]
5-HT2C 1,100–6,026 Antagonist ? [38] Rat/pig
[39]
5-HT7 375–381
840 		Antagonist ? [38] Rat
Human		 [42][43]
[44]
α1 1,000 Antagonist Rat [39]
α2 6,000 Antagonist Rat [45]
  α2A 7.3 (
1-PP
Tooltip 1-(2-Pyrimidinyl)piperazine) 		Antagonist Human [39]
β
 8,800 Antagonist Rat [39]
D1
 33,000 Antagonist Rat [39]
D2
 484
240 		Antagonist Human
Rat		 [46]
[39]
D3
 98 Antagonist Human [46]
D4
 29 Antagonist Human [46]
mAChTooltip Muscarinic acetylcholine receptor 38,000 ? Rat [39]
GABAA
(BDZ)		 >100,000 - Rat [39]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Buspirone acts as an

postsynaptic 5-HT1A receptors.[3] It is thought that the main effects of buspirone are mediated via its interaction with the presynaptic 5-HT1A receptor, thus reducing the firing of serotonin-producing neurons.[3] Buspirone also seems to have lower affinities for the serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, 5-HT7 receptors probably as an antagonist.[38]

In addition to binding to serotonin receptors, buspirone is an antagonist of the

D4 receptors, where it is similarly an antagonist.[46]

A major

noradrenergic and dopaminergic activity observed with buspirone in animals.[47][49] In addition, 1-PP may play an important role in the antidepressant effects of buspirone.[49] Buspirone also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor.[39][50] However, buspirone has been reported to have shown "significant and selective intrinsic efficacy" at the α1-adrenergic receptor expressed in a "tissue- and species-dependent manner".[50]

Unlike benzodiazepines, buspirone does not interact with the GABAA receptor complex.[3][51]

Pharmacokinetics

Buspirone has a low

elimination half-life of 2.8 hours,[3] 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.[5] Buspirone is metabolized primarily by CYP3A4, and prominent drug interactions with inhibitors and inducers of this enzyme have been observed.[8][9] Major metabolites of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP.[52][5][6][7] 6-Hydroxybuspirone has been identified as the predominant hepatic metabolite of buspirone, with plasma levels that are 40-fold greater than those of buspirone after oral administration of buspirone to humans.[6] The metabolite is a high-affinity partial agonist of the 5-HT1A receptor (Ki=25 nM) similarly to buspirone, and has demonstrated occupancy of the 5-HT1A receptor in vivo.[6] As such, it is likely to play an important role in the therapeutic effects of buspirone.[6] 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.[47][49]

Phase I Metabolism of buspirone in humans[53][54][55][9]

Chemistry

Buspirone is a member of the

chemical class, and consists of azaspirodecanedione and pyrimidinylpiperazine components linked together by a butyl chain
.

Analogues

Structural analogues of buspirone include other azapirones like gepirone, ipsapirone, perospirone, and tandospirone.[56]

A number of analogues are recorded.[57]

Synthesis

A number of methods of synthesis have also been reported.

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).[61][62][63][64][65]

Synthesis of buspirone

History

Buspirone was first

Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD.[22][68] The patent expired in 2001, and buspirone is now available as a generic drug
.

Society and culture

Buspar (buspirone) 10-mg tablets

Generic names

Buspirone is the

INNTooltip International Nonproprietary Name, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and DCITTooltip Denominazione Comune Italiana of buspirone, while buspirone hydrochloride is its USANTooltip United States Adopted Name, BANMTooltip British Approved Name, and JANTooltip Japanese Accepted Name.[1][69][70][71]

Brand names

Buspirone was primarily sold under the brand name Buspar.[69][71] Buspar is currently listed as discontinued by the US Food and Drug Administration.[72] In 2010, in response to a citizen petition, the US FDA determined that Buspar was not withdrawn from sale for reasons of safety or effectiveness.[73]

2019 shortage

Due to interrupted production at a

Mylan Pharmaceuticals plant in Morgantown, West Virginia, the United States experienced a shortage of buspirone in 2019.[74]

References

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External links

  • Media related to Buspirone at Wikimedia Commons