Buspirone

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Buspirone

Systematic (IUPAC) name
8-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]- 8-azaspiro[4.5]decane-7,9-dione
Identifiers
CAS number	36505-84-7
ATC code	N05BE01
PubChem	2477
DrugBank	APRD00222
ChemSpider	2383
Chemical data
Formula	C21H31N5O2
Mol. mass	385.50314 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	low and variable (approx. 5%), due to high first pass metabolism
Protein binding	95% bound to plasma proteins
Metabolism	mainly hepatic, active metabolite 1-Pyrimidylpiperazin (1-PP)
Half life	2-3hr
Excretion	urine (29-63%) and feces (18-38%) in the form of metabolites
Therapeutic considerations
Pregnancy cat.	B(US)
Legal status	Rx-only, not a controlled substance
Routes	oral
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Buspirone (Buspar) is a psychoactive drug and pharmaceutical medication of the piperazine and azapirone chemical classes. It is used primarily as an anxiolytic, but also to a lesser extent as an antidepressant. Bristol-Myers Squibb (BMS) gained Food and Drug Administration (FDA) approval for buspirone in 1986, and it went generic in 2001.

[edit] Indications

• Generalized anxiety disorder (GAD) of mild to moderate intensity, with or without panic attacks (it is not generally considered to be effective against other types of anxiety disorders such as obsessive-compulsive disorder (OCD) and social phobia, with or without agoraphobia).
• Augmentation of selective serotonin reuptake inhibitor (SSRI) therapy against depression and/or anxiety.
• 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]

[edit] Comparison to benzodiazepines

Buspirone's chemical structure and mechanism of action are completely unrelated to those of the benzodiazepines, but it purportedly has an efficacy comparable to that of diazepam (Valium) in treating GAD.^[2][3] 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. Additionally, it is non-sedating^{[citation needed]}, non-cognitive/memory impairing, and has a generally very favorable side effect profile.

The main disadvantage of buspirone is that 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 slow 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, 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.

Therefore, benzodiazepines are often the first approach in treating anxiety disorders and panic attacks. Although buspirone may be a consideration for patients whose benzodiazepine therapy is becoming extensive beyond weeks, buspirone must not be assumed to counteract the withdrawal effects of benzodiazepines, which, in severe, chronic, and high dose cases, can include seizures, coma and death.

Benzodiazepines should be gradually withdrawn, for example alprazolam (Xanax) may safely be withdrawn by 0.25 mg every two weeks in some patients who’ve been taking large chronic doses.^{[citation needed]} As the mechanism of action in the brain between benzodiazepines, which act as GABA_A receptor positive allosteric modulators (PAMs), and buspirone, which acts as a serotonin receptor agonist is uncorrelated, it is essential that buspirone is not considered an anxiolytic agent which may shorten the benzodiazepine withdrawal syndrome or help prevent or lessen the severity of benzodiazepine withdrawal symptoms.

[edit] Pharmacology

Buspar 10 mg tablets (AU)

Buspirone functions as a serotonin 5-HT_1A receptor partial agonist.^[4] It is this action that is thought to mediate its anxiolytic and antidepressant effects. Additionally, it functions as a dopamine D₂, 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] Pharmacokinetics

The action of a single dose of buspirone is much longer than its short half-life of 2–3 hours actually indicates.^{[citation needed]} Buspirone's bioavailability is very low and variable due to extensive first-pass metabolism, it's quickly absorbed, and it's highly plasma bound (95%). Taking it together with food may significantly increase its bioavailability. Buspirone's active metabolite 1-pyrimidinylpiperazine (1-PP) is also a 5-HT_1A partial agonist with anxiolytic properties, but weaker so than the parent compound. It may account for buspirone's extended duration of action.

[edit] Side effects

Buspirone's side effects may include:

• Frequent: vertigo, headache, nervousness, agitation, light-headedness, nausea, vomiting.
• Often (>1%): Drowsiness, insomnia, impaired concentration, confusion, depression, gastrointestinal disturbance, paresthesia (pins and needles), impaired coordination, tremors, visual impairment, tinnitus (ear ringing), fatigue, weakness, angina pectoris, sore throat, tachycardia, palpitations, dry mouth, muscle pain and/or joint pain.
• Seldom: Allergic reaction, subdermal bleeding, extrapyramidal symptoms, hallucinations, psychosis, ataxia, seizures, syncope, tunnel vision, urinary retention, alopecia, pruritus, hot flashes.

Other side effects have been reported, but are not more frequent than those encountered with placebo. An unusual side effect reported by patients is an enhanced sense of smell and a taste of pepper in the mouth. The structure of buspirone is similar to the active molecules of black pepper, piperine and chavicine.

Rarely, buspirone's side effects may have a dangerous nature or intensity. Some tend to disappear with continued therapy, or are less frequent if the initial dose is low and increased gradually.

[edit] Interactions

• Alcohol: Sedative properties are slightly increased.^{[citation needed]}
• Grapefruit, grapefruit juice, grapefruit extract: Drastically increased plasma levels of buspirone.^[5] Grapefruit juice considerably increased plasma buspirone concentrations. 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 haloperidol.
• Rifampicin: Decreased plasma levels of buspirone.

[edit] Contraindications

• Myasthenia gravis.
• Acute, closed-angle glaucoma.
• Severely compromised liver and/or renal function.
• Pre-existing heart conditions (e.g., myocardial infarction).

[edit] Abuse and dependence

Buspirone has no known potential for abuse or psychological or physiological dependence.^[6]

[edit] See also

• Gepirone
• Tandospirone

[edit] References