Buspirone

Buspirone

Systematic (IUPAC) name
8-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-8-azaspiro[4.5]decane-7,9-dione
Clinical data
Trade names	Buspar
AHFS/Drugs.com	monograph
MedlinePlus	a688005
Pregnancy cat.	B(US)
Legal status	℞ Prescription only
Routes	Oral
Pharmacokinetic data
Bioavailability	5%
Protein binding	95%
Metabolism	Hepatic
Half-life	2-3 hours
Excretion	Urine (29-63%), Feces (18-38%)
Identifiers
CAS number	36505-84-7
ATC code	N05BE01
PubChem	CID 2477
IUPHAR ligand	36
DrugBank	APRD00222
ChemSpider	2383 Y
UNII	TK65WKS8HL Y
KEGG	D07593 Y
ChEBI	CHEBI:3223 Y
ChEMBL	CHEMBL49 Y
Chemical data
Formula	C21H31N5O2
Mol. mass	385.50314 g/mol
SMILES	eMolecules & PubChem
InChI 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 Y Key:QWCRAEMEVRGPNT-UHFFFAOYSA-N Y
Y(what is this?)  (verify)

Buspirone (brand name Buspar) is a psychoactive drug and pharmaceutical medication of the piperazine and azapirone chemical classes. It is used primarily as an anxiolytic, specifically for generalized anxiety disorder. Bristol-Myers Squibb (BMS) gained Food and Drug Administration (FDA) approval for buspirone in 1986 for generalized anxiety disorder only, and it became available as a generic in 2001.

[edit] Indications

• Generalized anxiety disorder (GAD) of very mild to moderate intensity, without any panic attacks (it is not generally considered to be effective, nor does it have regulatory approval for other types of anxiety disorders such as obsessive-compulsive disorder (OCD) and social phobia, with or without agoraphobia).
• Although not FDA approved for the indication, it is sometimes used off-label for augmentation of selective serotonin reuptake inhibitor (SSRI) therapy against depression.
• Although not related to clinical indications, it is interesting that in experimental trials with rodents, buspirone has been shown to improve spatial learning and memory after traumatic brain injury (TBI). Such findings may have clinical relevance to TBI patients.^[1][2]
• Buspirone is currently being investigated as a treatment for alcohol dependence^[3]

[edit] Comparison to benzodiazepines

Buspirone's chemical structure and mechanism of action are completely unrelated to those of the benzodiazepines, and its efficacy is not comparable to that of members of the benzodiazepine family, such as diazepam (Valium) in treating GAD.^[4][5] Unlike the benzodiazepines, buspirone shows no potential for addiction or dependence, and the development of tolerance has not been observed. Furthermore, cross-tolerance to benzodiazepines, barbiturates, and alcohol, as well as other GABAergics, is not present either.

It may take several weeks before its anxiolytic effects become noticeable, although it is "simply not true" that buspirone has a slower onset than benzodiazepines, according to Shatzberg et al. (2007) in the Sixth Edition of the Manual of Clinical Psychopharmacology (p. 373). Many patients may also require a higher dosage to adequately respond to treatment, which may also be increased in gradual increments of 5 mg every three days and up to 60 mg daily^[6] , which may be the dose required for adequate relief. This makes it particularly difficult to treat patients pre-treated with benzodiazepines, for they know the immediate effects of these anxiolytics. Often patients have to be initially co-treated with a benzodiazepine for an immediate anxiolytic effect.^{[citation needed]}

Regular use of benzodiazepines at prescribed levels for six weeks was found to produce a significant risk of dependence, with resultant withdrawal symptoms appearing on abrupt discontinuation in a study assessing diazepam and buspirone. However, with abrupt withdrawal after six weeks of treatment with buspirone, no withdrawal symptoms developed.^[7] However, buspirone is ineffective for benzodiazepine withdrawal; buspirone does not improve discontinuation rates and does not decrease the severity of withdrawal symptoms.^[8]

[edit] Pharmacology

Buspirone functions as a serotonin 5-HT_1A receptor partial agonist.^[9] It is this action that is thought to mediate its anxiolytic and antidepressant effects. Additionally, it functions as a dopamine D₂, as well as α₁, and α₂-adrenergic receptor antagonist to a lesser degree, though these properties are generally undesirable in an anxiolytic and likely only contribute to side effects.

[edit] Interactions

Buspar (buspirone) 10 mg tablets (AU)

• Carbamazepine: Increased plasma levels of buspirone.
• Grapefruit, grapefruit juice: Significantly increases the plasma levels of buspirone.^[10] The probable mechanism of this interaction is delayed gastric emptying and inhibition of the cytochrome P450 3A4-mediated first-pass metabolism of buspirone caused by grapefruit juice.
• Haloperidol: Increased plasma levels of buspirone.
• Rifampicin: Decreased plasma levels of buspirone.
• caffine: seizure with loss of memory of the event, with excessive caffine

[edit] Contraindications

• Acute, closed-angle glaucoma
• Asthma, history of bronchiospasm or obstructive airways disease ^[11]
• Epilepsy
• Pre-existing heart conditions (e.g., myocardial infarction)
• Severely compromised liver and/or renal function
• Metabolic acidosis, as in diabetes ^[11]
• Myasthenia gravis

[edit] Chemistry

Buspirone, 8-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-8-azaspiro [4,5] decan-7,9-dione, is synthesized by the reaction of 1-(2-pyrimidyl)-4- (4-aminobutyl)piperazine with 8-oxaspiro[4,5]decan-7,9-dione. In turn, 1- (2-pyrimidyl)-4-(4-aminobutyl)piperazine is synthesized by the reaction of 1-(2-pyrimidyl)piperazine with 4-chlorobutyronitrile, giving 4-(2-pyrimidyl)-1-(3-cyanopropyl)piperazine, which is hydrogenated over Raney nickel catalyst. The primary amine product of the last step is reacted with the depicted spirocyclic acid anhydride to yield buspirone.

• Y.H. Wu, R.J. Warren, DE 2057845  (1970).
• J.W. Rayburn, Y.H. Wu, U.S. Patent 3,976,776 (1976).
• J.W. Rayburn, Y.H. Wu, U.S. Patent 3,907,801 (1975).
• J. Rayburn, Y. Wu, U.S. Patent 3,717,634 (1973).
• Wu, Y. H.; Rayburn, J. W.; Allen, L. E.; Ferguson, H. C.; Kissel, J. W. (1972). "Psychosedative agents. 2. 8-(4-Substituted 1-piperazinylalkyl)-8-azaspiro[4.5]decane-7,9-diones". Journal of Medicinal Chemistry 15 (5): 477. doi:10.1021/jm00275a009. PMID 5035267.  edit

[edit] See also

• Gepirone
• Tandospirone

[edit] References