Buspirone

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	CID 2477
IUPHAR ligand	36
DrugBank	APRD00222
ChemSpider	2383
Chemical data
Formula	C21H31N5O2
Mol. mass	385.50314 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	5%
Protein binding	95%
Metabolism	Hepatic
Half-life	2-3 hours
Excretion	Urine (29-63%), Feces (18-38%)
Therapeutic considerations
Pregnancy cat.	B(US)
Legal status	℞ Prescription only
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, 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.

Indications

• Generalized anxiety disorder (GAD) of very mild to moderate intensity, without 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 and/or anxiety.
• 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]

Comparison to benzodiazepines

Buspirone's chemical structure and mechanism of action are completely unrelated to those of the benzodiazepines, nor does it have an efficacy comparable to that of members of the benzodiazepine family, such as 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.

The two main disadvantages of buspirone are that it provides little symptomatic relief for even moderate anxiety and 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). This statement by Shatzberg contrasts clinical experience that benzodiazepines generally provide symptomatic relief within hours. 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. 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.

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, 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.

Pharmacokinetics

The action of a single dose of buspirone is much longer than its short half-life of 2–3 hours actually indicates. Buspirone's bioavailability is very low and variable due to extensive first-pass metabolism; it is quickly absorbed, and is 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.

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), ataxia (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.

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.

Interactions

• 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.
• Carbamazepine: Increased plasma levels of buspirone.

Contraindications

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

Misuse and dependence

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

See also

• Gepirone
• Tandospirone

References