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Buspirone

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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
MedlinePlus
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability ~4%[1]
Protein binding 86-95%[1]
Metabolism Hepatic mostly via CYP3A4[1]
Biological half-life 2-3 hours[2]
Excretion Urine (29-63%), Faeces (18-38%)[1]
Identifiers
CAS Registry Number  Y
ATC code N05
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  Y
ChEMBL  Y
Chemical data
Formula C21H31N5O2
Molecular mass 385.50314 g/mol
 Y   

Buspirone ( ), trade name Buspar, is an anxiolytic psychotropic drug of the azapirone chemical class.[3]   It is primarily used to treat generalized anxiety disorder (GAD). Unlike most drugs predominantly used to treat anxiety, buspirone's pharmacology is not related to benzodiazepines or barbiturates, and so does not carry the risk of physical dependence and withdrawal symptoms for which those drug classes are known.

Buspirone was first identified by a team at Mead Johnson in 1972, but was not patented until 1975.[4][5]

In 1986, Bristol-Myers Squibb gained Food and Drug Administration (FDA) approval for buspirone in the treatment of GAD. The patent placed on buspirone expired in 2001 and buspirone is now available as a generic drug.

Contents

  • Medical uses 1
  • Dosage 2
  • Adverse effects 3
    • Contraindications 3.1
    • Interactions 3.2
    • Overdose 3.3
  • Pharmacology and mechanism 4
  • Research 5
  • Comparison to benzodiazepines 6
  • Synthesis 7
    • analogues 7.1
  • References 8

Medical uses

Buspirone is approved in the United States by the FDA for the treatment of anxiety disorders and the short-term relief of the symptoms of anxiety.[6] Likewise in Australia, buspirone is licensed for the treatment of anxiety disorders.[7][8] In the United Kingdom, buspirone is indicated only for the short-term treatment of anxiety.[9][10]

Although not approved for this indication, studies such as impotence) of the SSRI.[11][12][13][14]

Several clinical trials, most randomised double-blind trials (and in one buspirone was used as an adjunct to atomoxetine) and one open-label, have been conducted to evaluate the utility of buspirone in the treatment of attention deficit hyperactivity disorder with mostly positive results.[15][16][17][18]

Buspirone is also used in the treatment of mild to moderate cerebellar ataxia.[19]

Dosage

For generalized anxiety disorder (GAD): 15–60 mg. Starting dose is 5 mg, 3 times daily, average dosage being 20–30 mg a day. If symptoms still persist after several weeks then the dose may be titrated up to 60 mg. Due to Buspar's short half-life and linear pharmacokinetics,[20] dosage can be increased by 5 mg every two to three days.[21][22][23][24][25][26][27]

Adverse effects

Buspar (buspirone) 10-mg tablets.

Adverse effects by incidence[1][6][7][9] include:

Very common (>10% incidence)

  • Dizziness/light-headedness
  • Headache
  • Somnolence (sleepiness)
  • Premature ejaculation

Common (1-10% incidence)

  • Nervousness
  • Insomnia
  • Sleep disorder
  • Disturbance in attention
  • Depression
  • Confusional state
  • Anger
  • Tachycardia (fast heart rate)
  • Chest pain
  • Sinusitis (nasal congestion)
  • Pharyngolaryngeal pain
  • Paraesthesia (tingling skin)
  • Blurred vision
  • Abnormal coordination
  • Tremor
  • Cold sweat
  • Rash
  • Nausea
  • Abdominal pain
  • Dry mouth
  • Diarrhea
  • Constipation
  • Vomiting
  • Fatigue
  • Musculoskeletal pain

Uncommon (0.1-1%)

  • Syncope
  • Hypotension
  • Hypertension
  • Redness and itching of the eyes
  • Altered taste
  • Conjunctivitis
  • Flatulence
  • Anorexia
  • Increased appetite
  • Salivation
  • Rectal bleeding
  • Urinary frequency
  • Urinary hesitancy
  • Menstrual irregularity or spotting
  • Dysuria
  • Muscle cramps
  • Muscle spasms
  • Muscle rigidity/stiffness
  • Involuntary movements
  • Shortness of breath
  • Chest congestion
  • Changes in libido
  • Oedema
  • Pruritus
  • Flushing
  • Easy bruising
  • Dry skin
  • Facial oedema
  • Mild increases in hepatic aminotransferases (AST, ALT)
  • Weight gain
  • Fever
  • Roaring sensation in the head
  • Weight loss
  • Malaise
  • Depersonalisation
  • Noise intolerance
  • Euphoria
  • Akathisia
  • Fearfulness
  • Loss of interest
  • Dissociative reaction

Rare (<0.1% incidence)

Contraindications

Buspirone has these contraindications:[28][29]

Interactions

Buspirone has been shown in vitro to be metabolized by CYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and these inhibitors inducers of cytochrome P450 3A4 (CYP3A4), among others:[28]

  • Itraconazole: Increased plasma level of buspirone
  • Rifampicin: Decreased plasma levels of buspirone
  • Nefazodone: Increased plasma levels of buspirone
  • Haloperidol: Increased plasma levels of haloperidol
  • Carbamazepine: Decreased plasma levels of buspirone
  • Commercial grapefruit juice: contains rind, the source of the competing compound: Significantly increases the plasma levels of buspirone

The likely mechanism of the interaction caused by grapefruit juice is delayed gastric emptying or inhibition by a substance in grapefruit rind of cytochrome P450 3A4-mediated first-pass metabolism of buspirone.[30]

The occurrence of elevated blood pressure has been reported when buspirone hydrochloride has been added to a regimen including a monoamine oxidase inhibitor (MAOI).[28]

Overdose

Activated charcoal is believed to be an effective treatment for overdose, provided the patient is treated promptly.  Expected symptoms (based on symptoms in male healthy volunteers treated with 375 mg/day — compared to the maximum daily licensed dosage in Australia, the UK, and the US):[6][7][9]

  • Nausea
  • Vomiting
  • Dizziness
  • Drowsiness
  • Miosis
  • Gastric distress

Buspirone appears to be relatively benign in cases of single-drug overdose, although no definitive data on this subject appear to be available.[31]

Pharmacology and mechanism

Buspirone functions as a serotonin 5-HT1A receptor partial agonist (IA = 0.465).[28][32][33]  It is this action that is thought to mediate its anxiolytic and antidepressant effects.  Additionally, it functions as a presynaptic dopamine antagonist at the D2, D3 and D4 receptors.[28][34] [35]   Buspirone is also a partial α1 receptor agonist.[36][37][38]  Buspirone also appears to produce some oxytocin stimulation via 5-HT1A receptor-induced action. Buspirone binds to 5-HT type 1A serotonin receptors on presynaptic neurons in the dorsal raphe and on postsynaptic neurons in the hippocampus, thus inhibiting the firing rate of 5-HT-containing neurons in the dorsal raphe. Buspirone also binds at dopamine type 2 (DA2) receptors, blocking presynaptic dopamine receptors. Buspirone increases firing in the locus ceruleus, an area of brain where norepinephrine cell bodies are found in high concentration. The net result of buspirone actions is that serotonergic activity is suppressed while noradrenergic and dopaminergic cell firing is enhanced. [39][40]

Binding Profile of Buspirone (towards cloned human receptors) [41]
 Receptor   Binding Affinity (Ki [nM])  Action
5-HT1A 28.62 Agonist
5-HT2A 138.03 Agonist
5-HT2B 213.79 Agonist
5-HT2C 489.77 Agonist
D2 484 Antagonist
D3 98 Antagonist
D4 29 Antagonist
α1 Agonist
α1D Agonist

Research

  • In a 1996 study, buspirone was shown to be effective as an augmentative agent for the treatment of alcohol dependence.[43]
  • Several studies have shown the administration of buspirone can improve spatial learning and memory function following a traumatic brain injury.[44][45]
  • New research is being conducted to test the antagonist properties of buspirone at both D3 and D4 receptors as a pharmacological treatment for cocaine dependence.[34][46][47]
  • In a 2007 study conducted on rats, buspirone showed a complete remission of haloperidol-induced tardive vacuous chewing symptoms when coadministered for five weeks.[48]
  • Positive results for the treatment of depression when buspirone was combined with melatonin has been shown. It is suspected that the method of action differs from SSRI medications. Preliminary research suggests that the combination of buspirone and melatonin stimulates the growth of new neurons in the brain, also known as neurogenesis.[49][50][51]
  • Buspirone has been studied as an adjunct in schizophrenia. Some neuroleptic drugs also act on 5-HT1A receptors and effects on the prefrontal cortex have been connected to clinical outcomes.[52]

Comparison to benzodiazepines

Buspirone's efficacy is comparable to that of members of the benzodiazepine family in treating GAD, although it tends to have a delayed onset of action.[53][54]

Abrupt discontinuation of diazepam after six weeks of continuous administration resulted in withdrawal symptoms. This was not the case when administration of buspirone was ceased after six weeks.[55] It may take several weeks before buspirone's anxiolytic effects become noticeable, and many patients may also need a higher dosage to adequately respond to treatment.[28]

Buspirone's chemical structure and mechanism of action are completely unrelated to those of benzodiazepines and is not effective as a treatment for benzodiazepine withdrawal.[56] Unlike benzodiazepines, buspirone is not a drug of abuse.[7] However, when snorted, buspirone is hallucinogenic, and is used this way in places such as prisons.

Synthesis

Buspirone synthesis:[57] DE 2057845  U.S. Patent 3,717,634 U.S. Patent 3,907,801 U.S. Patent 3,976,776

Alkylation of 1-(2-pyrimidyl)piperazine (1) with 3-chloro-1-cyanopropane (2, 4-chlorobutyronitrile) gives 3, which is reduced either by hydrogenation over Raney nickel catalyst, or with LAH. The resulting 1° amine (4) from the previous step is then reacted with 3,3-Tetramethyleneglutaric anhydride (5, 8-Oxaspiro[4.5]decane-7,9-dione) in order to yield buspirone (6).

analogues

References

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