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 Y
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
N(what is this?)  (verify)

Buspirone (pronounced byoo-spur-own (trade name Buspar, pronounced byoo-spar) is an anxiolytic psychoactive drug of the azapirone chemical class, and is primarily used to treat generalized anxiety disorder (GAD)

Bristol-Myers Squibb (BMS) gained 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.

Medical uses

• 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.^{citation needed}

Adverse effects

• Common: dizziness, nausea, headache, nervousness, lightheadedness, and excitement.

Contraindications

• Hypersensitivity to buspirone.
• not to be used with MAO inhibitors.
• Severely compromised liver and/or renal function.
• Asthma, history of bronchiospasm or obstructive airways disease.
• Metabolic acidosis, as in diabetes.

• Epilepsy^{citation needed}
• Pre-existing heart conditions (e.g., myocardial infarction)^{citation needed}
• Acute, closed-angle glaucoma^{citation needed}
• Myasthenia gravis^{citation needed}

Interactions

Buspar (buspirone) 10 mg tablets (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.
• Nefazodone: Increased plasma levels of buspirone.
• Rifampicin: Decreased plasma levels of buspirone.
• Carbamazepine: Reduced plasma levels of buspirone.
• Haloperidol: Increased plasma levels of haloperidol.
• 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.
• other inhibitors or inducers of P450 3A4: accordingly.

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.

Pharmacology

Buspirone functions as a serotonin 5-HT_1A receptor partial agonist. 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^{citation needed} to a lesser degree, though these properties are generally undesirable in an anxiolytic and likely only contribute to side effects.^{citation needed}

Research

• In a 1996 study buspirone has been investigated and found useful as an adjoint treatment for alcohol dependence
• Although not related to clinical indications, it is interesting that in a study in rats buspirone has been found to improve spatial learning and memory after traumatic brain injury (TBI). Such findings may have clinical relevance to TBI patients.

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 in treating GAD.

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. Many patients may also require a higher dosage to adequately respond to treatment.

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.

Buspirone is ineffective for benzodiazepine withdrawal, does not improve discontinuation rates and does not decrease the severity of withdrawal symptoms.

Chemistry

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.

See also

• Gepirone
• Tandospirone