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Buspirone

( 1968 In Science )

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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). It is a serotonin 5-HT_1A receptor partial agonist, increasing action at serotonin receptors in the brain. It is taken orally and takes two to six weeks to be fully effective.

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

(2025). 9780857113382, Pharmaceutical Press. ISBN 9780857113382

Serious side effects may include movement disorders, serotonin syndrome, and seizures. Its use in pregnancy appears to be safe but has not been well studied, and use during breastfeeding has not been well studied either.

Buspirone was developed in 1968 and approved for medical use in the United States in 1986. It is available as a generic medication. In 2022, it was the 54th most commonly prescribed medication in the United States, with more than 12million prescriptions.

Medical uses

Anxiety

Buspirone is used for the short-term and long-term treatment of or symptoms of anxiety.

(2025). 9780980579093, The Australian Medicines Handbook Unit Trust. ISBN 9780980579093

It is generally preferred over benzodiazepines because it does not activate the receptors that make drugs like alprazolam addictive.

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.

(2014). 9781469883755, Wolters Kluwer Health. . ISBN 9781469883755

The drug is similarly effective in the treatment of generalized anxiety disorder (GAD) to including diazepam, alprazolam, lorazepam, and clorazepate. Buspirone is not known to be effective in the treatment of other besides GAD.

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. Buspirone may also be effective in treating antidepressant-induced sexual dysfunction.

Miscellaneous

Buspirone is not effective as a treatment for benzodiazepine withdrawal, barbiturate withdrawal, or alcohol withdrawal.

SSRI and SNRI antidepressants such as paroxetine and venlafaxine, respectively, may cause jaw pain/jaw spasm reversible syndrome, although it is not common, and buspirone appears to be successful in treating antidepressant-induced bruxism.

Contraindications

Buspirone has these contraindications:

(2025). 9780198528630, Oxford University Press. . ISBN 9780198528630

Hypersensitivity to buspirone
Metabolic acidosis, as in diabetes
Should not be used with
Severely compromised liver and/or kidney function

Side effects

Known side effects associated with buspirone include dizziness, , nausea, tinnitus, and paresthesia. Buspirone is relatively tolerability and is not associated with sedation, cognitive and psychomotor impairment, muscle relaxation, physical dependence, or anticonvulsant effects. In addition, buspirone does not produce euphoria and is not a drug of abuse.

Overdose

Buspirone appears to be relatively benign in cases of single-drug overdose, although no definitive data on this subject appear to be available. 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. In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, with akathisia, tremor, and muscle rigidity observed.

(2025). 9780781728454, Lippincott Williams & Wilkins. . ISBN 9780781728454

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

Interactions

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

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. See grapefruit–drug interactions.
Fluvoxamine: Moderately increased plasma levels of buspirone.

Hypertension has been reported when buspirone has been administered to patients taking monoamine oxidase inhibitors (MAOIs).

Buspirone has been found to markedly reduce the effects of the serotonergic psychedelic psilocybin in humans. This parallels findings in which serotonin 5-HT_1A receptor agonists like 8-OH-DPAT attenuate the head-twitch response, a behavioral proxy of psychedelic effects, induced by serotonergic psychedelics in rodents.

(2025). 9780444641250, Elsevier. ISBN 9780444641250

Paradoxically however, buspirone enhances the head-twitch response, a behavioral proxy of psychedelic effects, induced by 5-hydroxytryptophan (5-HTP) plus pargyline in rodents.

Pharmacology

Pharmacodynamics

+ Buspirone
3.98–214 21 (median)
>100,000
22,000–42,700
5-HT_2A	138–3,240	Antagonist	Human
5-HT_2B	214	?	Human
490
375–381 840
1,000
6,000
7.3 ()
8,800
33,000
484 240
98
29
38,000
>100,000
Values are K_i (nM). The smaller the value, the more strongly the drug binds to the site.

Buspirone acts as a partial agonist of the serotonin 5-HT_1A receptor with high affinity. It is a partial agonist of both presynaptic 5-HT_1A receptors, which are inhibitory , and postsynaptic 5-HT_1A receptors. It is thought that the main effects of buspirone are mediated via its interaction with the presynaptic 5-HT_1A receptor, thus reducing the firing of serotonin-producing neurons. Buspirone also seems to have lower affinities for the serotonin 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT₆, 5-HT₇ receptors where it probably acts as an antagonist.

In addition to binding to serotonin receptors, buspirone is an antagonist of the dopamine D₂ receptor with weak affinity. It preferentially blocks inhibitory presynaptic D₂ autoreceptors, and antagonizes postsynaptic D₂ receptors only at higher doses. In accordance, buspirone has been found to increase dopaminergic neurotransmission in the nigrostriatal pathway at low doses, whereas at higher doses, postsynaptic D₂ receptors are blocked and antidopaminergic effects such as hypoactivity and reduced stereotypy, though notably not catalepsy, are observed in animals. Buspirone has also been found to bind with much higher affinity to the dopamine D₃ and D₄ receptors, where it is similarly an antagonist.

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 α₂-adrenergic receptor antagonist. This metabolite may be responsible for the increased noradrenergic and dopaminergic activity observed with buspirone in animals. Buspirone also has very weak and probably clinically unimportant affinity for the α₁-adrenergic receptor.

(2015). 9780323413237, Elsevier Health Sciences. . ISBN 9780323413237

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".

Unlike benzodiazepines, buspirone does not interact with the GABAA receptor complex.

(2008). 9780470986837, John Wiley & Sons. . ISBN 9780470986837

Pharmacokinetics

Buspirone has a low oral bioavailability of 3.9% relative to intravenous injection due to extensive first-pass metabolism. The time to peak plasma levels following ingestion is 0.9 to 1.5 hours. It is reported to have an elimination half-life of 2.8 hours, 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. Buspirone is metabolism primarily by CYP3A4, and prominent with enzyme inhibitor and enzyme inducer of this enzyme have been observed. Major of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP. 6-Hydroxybuspirone has been identified as the predominant liver metabolite of buspirone, with plasma levels that are 40-fold greater than those of buspirone after oral administration of buspirone to humans.

(2025). 9781585623099, American Psychiatric Pub. . ISBN 9781585623099

The metabolite is a high-affinity partial agonist of the 5-HT_1A receptor (K_i=25 nM) similarly to buspirone, and has demonstrated occupancy of the 5-HT_1A receptor in vivo. As such, it is likely to play an important role in the therapeutic effects of buspirone. 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.

Chemistry

Buspirone is a member of the azapirone chemical class, and consists of azaspirodecanedione and pyrimidinylpiperazine components linked together by a butyl group side chain.

Analogues

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

A number of analogues are recorded.

Synthesis

A number of methods of synthesis have also been reported. 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).DE2057845 idem Y Wu, J Rayburn, (1973 to Mead Johnson).

History

Buspirone was first synthesized by a team at Mead Johnson in 1968 but was not patented until 1980. It was initially developed as an antipsychotic acting on the D₂ receptor but was found to be ineffective in the treatment of psychosis; it was then used as an anxiolytic instead. In 1986, Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD. The patent expired in 2001, and buspirone is now available as a generic drug.

Society and culture

Generic names

Buspirone is the , , , and of buspirone, while buspirone hydrochloride is its , , and .

(2014). 9781475720853, Springer. . ISBN 9781475720853

(2000). 9783887630751, Taylor & Francis. . ISBN 9783887630751

(2012). 9789401144391, Springer Science & Business Media. . ISBN 9789401144391

Brand names

Buspirone was primarily sold under the brand name Buspar. Buspar is currently listed as discontinued by the U.S. Food and Drug Administration (FDA). In 2010, in response to a citizen petition, the FDA determined that Buspar was not withdrawn from sale for reasons of safety or effectiveness.

External links

Categories: 1968 In Science, 5-ht1a Agonists, Alpha-2 Blockers, Aminopyrimidines, Antidepressants, Anxiolytics, Azapirones, Cyclopentanes, D2 Antagonists, D3 Antagonists, D4 Antagonists, Glutarimides, 1-piperazines, Wikipedia Medicine Articles Ready To Translate

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