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
Clinical data
Trade namesBuspar
AHFS/Drugs.commonograph
MedlinePlusa688005
Pregnancy cat.B1 (AU) B (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
RoutesOral
Pharmacokinetic data
Bioavailability~4%[1]
Protein binding86-95%[1]
MetabolismHepatic mostly via CYP3A4[1]
Half-life2-3 hours[1]
ExcretionUrine (29-63%), Faeces (18-38%)[1]
Identifiers
CAS number36505-84-7 YesY
ATC codeN05BE01
PubChemCID 2477
IUPHAR ligand36
DrugBankDB00490
ChemSpider2383 YesY
UNIITK65WKS8HL YesY
KEGGD07593 YesY
ChEBICHEBI:3223 YesY
ChEMBLCHEMBL49 YesY
Chemical data
FormulaC21H31N5O2 
Mol. mass385.50314 g/mol
 YesY (what is this?)  (verify)
 
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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
Clinical data
Trade namesBuspar
AHFS/Drugs.commonograph
MedlinePlusa688005
Pregnancy cat.B1 (AU) B (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
RoutesOral
Pharmacokinetic data
Bioavailability~4%[1]
Protein binding86-95%[1]
MetabolismHepatic mostly via CYP3A4[1]
Half-life2-3 hours[1]
ExcretionUrine (29-63%), Faeces (18-38%)[1]
Identifiers
CAS number36505-84-7 YesY
ATC codeN05BE01
PubChemCID 2477
IUPHAR ligand36
DrugBankDB00490
ChemSpider2383 YesY
UNIITK65WKS8HL YesY
KEGGD07593 YesY
ChEBICHEBI:3223 YesY
ChEMBLCHEMBL49 YesY
Chemical data
FormulaC21H31N5O2 
Mol. mass385.50314 g/mol
 YesY (what is this?)  (verify)

Buspirone (pronounced /ˈbjuːspɨrn/ BEW-spi-rohn), trade name Buspar (pronounced BYOO-spar), is an anxiolytic psychoactive drug of the azapirone chemical class is primarily used to treat generalized anxiety disorder (GAD). Unlike most drugs predominately used to treat anxiety, buspirone's pharmacology is not related to benzodiazepines or barbiturates, and so does not carry the risk of withdrawal symptoms those drug classes are known for when discontinued.

Buspirone was first identified by a team at Mead Johnson[2] but wasn't patented until 1975[3]

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

Medical uses[edit]

Buspirone is approved, in the US, by the FDA for the treatment of anxiety disorders and the short-term relief of the symptoms of anxiety.[4] Likewise in Australia buspirone is licensed for the treatment of anxiety disorders.[5][6] In the UK buspirone is indicated only for the short-term treatment of anxiety.[7][8]

Although not approved for this indication, studies have shown buspirone to be an effective augmentation agent alongside treatment with SSRIs (selective serotonin reuptake inhibitors) for clinical depression and is also used to counter the sexual side-effects (HSDD, anorgasmy, impotence...) of the SSRI.[9][10][11]

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.[12][13][14][15]

Adverse effects[edit]

Buspar (buspirone) 10 mg tablets

Adverse effects by incidence[1][4][5][7]

Very common (>10% incidence) adverse effects include:

Common (1-10% incidence) adverse effects include:

  • Nervousness
  • Insomnia
  • Disturbance in attention
  • Depression
  • Confusional state
  • Sleep disorder
  • Anger
  • Tachycardia
  • Chest pain
  • Nasal congestion
  • Pharyngolaryngeal pain
  • Blurred vision
  • Coordination abnormal
  • Tremor
  • Cold sweat
  • Rash
  • Nausea
  • Abdominal pain
  • Dry mouth
  • Diarrhoea
  • Constipation
  • Vomiting
  • Fatigue
  • Musculoskeletal pain

Uncommon (0.1-1%) adverse effects include:

  • 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) adverse effects include:

  • Enuresis
  • Nocturia
  • Hyperventilation
  • Epistaxis
  • Delayed ejaculation

Contraindications[edit]

Buspirone has the following contraindications:[16][17]

Interactions[edit]

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 inhibitors / inducers of Cytochrome P450 3A4 (CYP3A4), among others:[16]

The likely mechanism of the interaction caused by grapefruit juice is delayed gastric emptying / inhibition of cytochrome P450 3A4-mediated first-pass metabolism of buspirone.[18]

There have been reports of the occurrence of elevated blood pressure when Buspirone hydrochloride has been added to a regimen including an monoamine oxidase inhibitor (MAOI).[16]

Overdose[edit]

Activated charcoal is believed to be an effective treatment for overdose, provided the patient is treated sufficiently promptly.[5][4][7] 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):[5][4][7]

It is likely (although no definitive data on this subject appears to be available) that buspirone is relatively benign in cases of single-drug overdose.[19]

Pharmacology[edit]

Buspirone functions as a serotonin 5-HT1A receptor partial agonist[16][20] (IA = 0.465).[21] 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 [16][22] receptors. Buspirone it is also a partial α1 receptor agonist. The ability of buspirone to selectively block presynaptic mesolimbic D2 autoreceptors in lower doses appears to result in increased dopamine synthesis and release.[23][24]

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.[25][26][27] Although never commercially produced, Bristol-Myers Squibb applied for a patent on Oct 28, 1993 and received the patent on Jul 11, 1995 for an extended release formulation of buspirone.[28] It also appears to produce some oxytocin stimulation via 5-HT1A receptor-induced action.[29][30]

Binding Profile of Buspirone (towards cloned human receptors)[31]

ReceptorKi (nM)
5-HT1A28.62
5-HT2A138.03
5-HT2B213.79
5-HT2C489.77
D4107

Research[edit]

Comparison to benzodiazepines[edit]

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.[39][40]

Abrupt discontinuation of diazepam after 6 weeks of continuous administration resulted in withdrawal symptoms. This was not the case when administration of buspirone was ceased after six weeks.[41] 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.[16]

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.[42] Unlike benzodiazepines buspirone is not a drug of abuse.[5]

Chemistry[edit]

Synthesis begins with N-alkylation 1-(2-pyrimidyl)piperazine w/ 4-chlorobutyronitrile followed by hydrogenation nitrile over Raney nickel catalyst.

The primary amine product of the previous step is reacted with the graphically represented spirocyclic acid anhydride in order to yield buspirone.[43]

Buspirone synthesis.png

See also[edit]

References[edit]

  1. ^ a b c d e f "buspirone (Rx) - BuSpar, Buspirex, more..". Medscape Reference. WebMD. Retrieved 14 November 2013. 
  2. ^ Psychosedative agents. 2. 8-(4-Substituted 1-piperazinylalkyl)-8-azaspiro[4.5]decane-7,9-diones Yao-Hua Wu, J.W.Rayburn, L.E.Allen, H.C.Ferguson, J.W.Kissel J.Med.Chem., 1972, 15 (5) pages 477–479
  3. ^ US Patent 3907801 N-{8 (4-pyridyl-piperazino)-alkyl{9 -azaspiroalkanediones
  4. ^ a b c d "BUSPIRONE HCL (buspirone hydrochloride) tablet [Watson Laboratories, Inc.]". DailyMed. Watson Laboratories, Inc. July 2013. Retrieved 14 November 2013. 
  5. ^ a b c d e "BUSPAR® (buspirone hydrochloride) Tablets 5 mg & 10 mg PRODUCT INFORMATION" (PDF). TGA eBusiness Services. Aspen Pharma Pty Ltd. January 2010. Retrieved 14 November 2013. 
  6. ^ Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. 2013. ISBN 9780980579093.  edit
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  10. ^ Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA, Lebowitz BD, Biggs MM, Luther JF, Shores-Wilson K, Rush AJ (March 2006). "Medication augmentation after the failure of SSRIs for depression". N. Engl. J. Med. 354 (12): 1243–52. doi:10.1056/NEJMoa052964. PMID 16554526. 
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  43. ^ Wu, Y. H.; Ferguson, J. W.; Kissel, L. E.; Ferguson, H. C.; Kissel, J. W. (May 1972). "Psychosedative agents. 2. 8-(4-Substituted 1-piperazinylalkyl)-8-azaspiro(4.5)decane-7,9-diones". J. Med. Chem. 15 (5): 477–479. doi:10.1021/jm00275a009. PMID 5035267.  edit;
    DE 2057845, Rayburn JW, Wu YH, "Heterocyclische Azaspirodecandione und Verfahren zu ihrer Herstellung", published 1971-06-09 ;
    US 3717634, Rayburn JW, Wu YH, "N-(heteroarcyclic)piperazinylalkyl-azaspiroalkanediones", published 1973-02-20 ;
    US 3907801, Rayburn JW, Wu YH, "N-{8 (4-pyridyl-piperazino)-alkyl}-9-azaspiroalkanediones", published 1975-09-23 ;
    US 3976776, Rayburn JW, Wu YH, "Tranquilizer process employing N-(heteroarcyclic)piperazinylalkylazaspiroalkanediones", published 1976-08-24