Buspirone

Buspirone (trade name Buspar) is an anxiolytic psychoactive drug of the piperazine and azapirone chemical classes, 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 is available as a generic.

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.
 * Buspirone is currently being investigated as a treatment for alcohol dependence

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. 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. 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, which may be the dose required for adequate relief. This makes it particularly difficult to treat patients pre-treated with benzodiazepines, as these individuals are likely familiar with the relatively fast onset of action offered by the drugs. Often patients have to be initially co-treated with a benzodiazepine for an immediate anxiolytic effect.

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

Pharmacology
Buspirone functions as a serotonin 5-HT1A 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 to a lesser degree, though these properties are generally undesirable in an anxiolytic and likely only contribute to side effects.

Interactions



 * Carbamazepine: Increased plasma levels of buspirone.
 * 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.


 * Haloperidol: Increased plasma levels of buspirone.
 * Rifampicin: Decreased plasma levels of buspirone.
 * Caffeine: Possible increased risk of seizures with excessive caffeine intake.

Contraindications

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

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, (1970).
 * J.W. Rayburn, Y.H. Wu, (1976).
 * J.W. Rayburn, Y.H. Wu, (1975).
 * J. Rayburn, Y. Wu, (1973).