Chemistry:Buspirone

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Buspirone, sold under the name Buspar among others, is an anxiolytic medication primarily used for the treatment of generalized anxiety disorder. Unlike benzodiazepines, buspirone does not produce significant sedation, dependence, or withdrawal effects. Its principal mechanism of action involves partial agonism at postsynaptic serotonin 5-HT1A receptor and full agonism at presynaptic 5-HT1A autoreceptors, which initially reduces serotonergic neuron firing. Over time, autoreceptor desensitization occurs, leading to increased serotonin release and enhanced serotonergic tone, which may contribute to its clinical efficacy. Buspirone also has weak antagonistic effects at dopamine D2, D3, and D4 receptors and α1- and α2-adrenergic receptors.

Buspirone is approved for the management of generalized anxiety disorder. It is sometimes used off-label for other anxiety disorders, depression augmentation, and certain behavioral conditions. Buspirone is not effective as a sedative-hypnotic or muscle relaxant and does not have anticonvulsant properties.

Common side effects of buspirone include nausea, headaches, dizziness, and difficulty concentrating.[1][2] Serious side effects may include movement disorders, serotonin syndrome, and seizures.[2] Its use in pregnancy appears to be safe but has not been well studied, and use during breastfeeding has not been well studied either.[2][3]

Buspirone was developed in 1968 and approved for medical use in the United States in 1986.[1][4] It is available as a generic medication.[2] In 2023, it was the 40th most commonly prescribed medication in the United States, with more than 15 million prescriptions.[5][6]

Medical uses

Anxiety

Buspirone is used for the short-term and long-term treatment of anxiety disorders or symptoms of anxiety.[7][8][9][10][11] It is generally preferred over benzodiazepines because it does not activate the receptors that make drugs like alprazolam addictive.[4]

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.[12] The drug is effective in the treatment of generalized anxiety disorder (GAD) similar to benzodiazepines including diazepam, alprazolam, lorazepam, and clorazepate.[13] Buspirone is not known to be effective in the treatment of anxiety disorders other than GAD.[14]

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.[15] Buspirone may also be effective in treating antidepressant-induced sexual dysfunction.[4][16][17]

Miscellaneous

Buspirone is not effective as a treatment for benzodiazepine withdrawal, barbiturate withdrawal, or alcohol withdrawal.[18]

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.[19][20]

Contraindications

Buspirone has these contraindications:[21][22]

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

Side effects

Known side effects associated with buspirone include dizziness, headaches, nausea, tinnitus, and paresthesia.[13] Buspirone is relatively well tolerated and is not associated with sedation, cognitive and psychomotor impairment, muscle relaxation, physical dependence, or anticonvulsant effects.[13] In addition, buspirone does not produce euphoria[12] and is not a drug of abuse.[8]

Overdose

Buspirone appears to be relatively benign in cases of single-drug overdose, although no definitive data on this subject appear to be available.[23] 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.[7][8][10] In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, with akathisia, tremor, and muscle rigidity observed.[24] Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals.[24] One death has been reported in a co-ingestion of 450 mg buspirone with alprazolam, diltiazem, alcohol, and cocaine.[24]

Interactions

Buspirone has been shown in vitro to be metabolized by the enzyme CYP3A4.[25] This finding is consistent with the in vivo interactions observed between buspirone and these inhibitors or inducers of cytochrome P450 3A4 (CYP3A4), among others:[21]

Elevated blood pressure has been reported when buspirone has been administered to patients taking monoamine oxidase inhibitors (MAOIs).[21]

Buspirone has been found to markedly reduce the hallucinogenic effects of the serotonergic psychedelic psilocybin in humans.[28][29][30] This parallels findings in which serotonin 5-HT1A receptor agonists like 8-OH-DPAT attenuate the head-twitch response, a behavioral proxy of psychedelic effects, induced by serotonergic psychedelics in rodents.[31] Paradoxically however, buspirone enhances the head-twitch response, a behavioral proxy of psychedelic effects, induced by 5-hydroxytryptophan (5-HTP) plus pargyline in rodents.[32][33]

Pharmacology

Pharmacodynamics

Site Ki (nM) Action Species Ref
5-HT1A 3.98–214
21 (median) 		Agonist Human [34][35]
5-HT1B >100,000 Agonist ?[36] Rat [37]
5-HT1D 22,000–42,700 Agonist ?[36] Human [38][39]
5-HT2A 138–3,240 Antagonist Human
5-HT2B 214 ? Human
5-HT2C 490 Antagonist ?[36] Human
5-HT7 375–381
840 		Antagonist ?[36] Rat
Human		 [40][41]
[42]
α1 1,000 Antagonist Rat [37]
α2 6,000 Antagonist Rat [43]
α2A 7.3 (1-PP) Antagonist Human [37]
β 8,800 Antagonist Rat [37]
D1 33,000 Antagonist Rat [37]
D2 484
240 		Antagonist Human
Rat		 [44]
[37]
D3 98 Antagonist Human [44]
D4 29 Antagonist Human [44]
mACh 38,000 ? Rat [37]
GABAA
(BDZ)		 >100,000 - Rat [37]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Buspirone acts primarily on the serotonin 5-HT1A receptor. It behaves as a full agonist at presynaptic 5-HT1A autoreceptors in the dorsal raphe, reducing the firing of serotonin-producing neurons, and as a partial agonist at postsynaptic 5-HT1A receptors in forebrain regions. This difference in activity between presynaptic and postsynaptic sites is thought to result from variations in receptor density and coupling efficiency.[45][46][47][48][49][50]

Buspirone also has lower affinity for other serotonin receptors, including 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7, where it is thought to act primarily as an antagonist.[51] In addition, buspirone has weak antagonistic activity at dopamine D2, D3, and D4 receptors, with preferential blockade of presynaptic D2 autoreceptors at low doses and postsynaptic D2 receptors only at higher doses.[52]

A major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP), circulates at higher levels than buspirone itself and is a potent α_2-adrenergic receptor antagonist, which may contribute to some of buspirone's noradrenergic and dopaminergic effects.[53][54][55] Buspirone has very weak affinity for α_1-adrenergic receptors, and does not interact with the GABA_A receptor complex, unlike benzodiazepines.[56][57]

Pharmacokinetics

Buspirone has a low oral bioavailability of 3.9% relative to intravenous injection due to extensive first-pass metabolism.[13] The time to peak plasma levels following ingestion is 0.9 to 1.5 hours.[13] It is reported to have an elimination half-life of 2.8 hours,[13] 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.[58] Buspirone is metabolized primarily by CYP3A4, and prominent drug interactions with inhibitors and inducers of this enzyme have been observed.[59][25] Major metabolites of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP.[60][58][61][62] 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.[61] 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.[61] As such, it is likely to play an important role in the therapeutic effects of buspirone.[61] 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.[63][64]

Phase I Metabolism of buspirone in humans[65][66][67][25]

Chemistry

Buspirone is a member of the azapirone 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.[68]

A number of analogues are recorded.[69]

Synthesis

A number of methods of synthesis have also been reported.[70][71][72] 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).[73][74][75][76][77]

Synthesis of buspirone

History

Buspirone was first synthesized by a team at Mead Johnson in 1968[14] but was not patented until 1980.[78][73][79] 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.[13] In 1986, Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD.[14][80] The patent expired in 2001, and buspirone is available as a generic drug.

Society and culture

Buspar (buspirone) 10-mg tablets

Generic names

Buspirone is the INN, BAN, DCF, and DCIT of buspirone, while buspirone hydrochloride is its USAN, BANM, and JAN.[81][82][83][84]

Brand names

Buspirone was primarily sold under the brand name Buspar.[82][84] Buspar is currently listed as discontinued by the U.S. Food and Drug Administration (FDA).[85] In 2010, in response to a citizen petition, the FDA determined that Buspar was not withdrawn from sale for reasons of safety or effectiveness.[86]

References

  1. ↑ 1.0 1.1 "Buspirone Hydrochloride Monograph for Professionals". https://www.drugs.com/monograph/buspirone.html. 
  2. ↑ 2.0 2.1 2.2 2.3 British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 338. ISBN 978-0-85711-338-2. 
  3. ↑ "Buspirone Pregnancy and Breastfeeding Warnings". https://www.drugs.com/pregnancy/buspirone.html. 
  4. ↑ 4.0 4.1 4.2 "Buspirone". StatPearls. January 2018. PMID 30285372. https://www.ncbi.nlm.nih.gov/books/NBK531477/. 
  5. ↑ "Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  6. ↑ "Buspirone Drug Usage Statistics, United States, 2013 - 2023". https://clincalc.com/DrugStats/Drugs/Buspirone. 
  7. ↑ 7.0 7.1 "Buspirone HCL (buspirone hydrochloride) tablet [Watson Laboratories, Inc."]. DailyMed. Watson Laboratories, Inc.. July 2013. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a3fe0ccd-565f-4d0a-a7ba-2fad7a819358. 
  8. ↑ 8.0 8.1 8.2 "Buspar (buspirone hydrochloride) Tablets 5 mg & 10 mg PRODUCT INFORMATION" (PDF). TGA eBusiness Services. Aspen Pharma Pty Ltd. January 2010. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03962-3. 
  9. ↑ Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. 2013. ISBN 978-0-9805790-9-3. 
  10. ↑ 10.0 10.1 "Buspirone 10mg Tablets". electronic Medicines Compendium. Actavis UK Ltd. 10 September 2012. http://www.medicines.org.uk/emc/medicine/23859/SPC/Buspirone+10mg+Tablets/. 
  11. ↑ Joint Formulary Committee. British National Formulary (BNF). Pharmaceutical Press. p. 224. 
  12. ↑ 12.0 12.1 Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. Wolters Kluwer Health. 22 September 2014. pp. 3211–. ISBN 978-1-4698-8375-5. https://books.google.com/books?id=IzGYBAAAQBAJ&pg=PT3211. 
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  15. ↑ "Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review". Mayo Clinic Proceedings 92 (1): 114–128. January 2017. doi:10.1016/j.mayocp.2016.09.018. PMID 27916394. 
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  83. ↑ Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 6 December 2012. pp. 57–. ISBN 978-94-011-4439-1. https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA57. 
  84. ↑ 84.0 84.1 "Buspirone". Drugs.com. https://www.drugs.com/international/buspirone.html. 
  85. ↑ "Drugs@FDA: FDA Approved Drug Products". Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=018731. 
  86. ↑ "Determination That Buspar (Buspirone Hydrochloride) Tablets, 10 Milligrams, 15 Milligrams, and 30 Milligrams, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness". 19 October 2010. https://www.federalregister.gov/documents/2010/10/19/2010-26214/determination-that-buspar-buspirone-hydrochloride-tablets-10-milligrams-15-milligrams-and-30. 

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