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== Dosage ==
== Dosage ==
For [[generalized anxiety disorder]] (GAD): 15-60mg. Starting dose is 5mg, 3 times daily, average dosage being between 20-30mg a day. If symptoms still persist after several weeks then the dose may be titrated up to 60mg. Due to Buspar's short [[half-life]] and linear {{clarify|date=September 2014}} [[pharmacokinetics]], dosage can be increased by 5mg every two to three days.<ref>{{cite web|last1=List|first1=RX|title=Buspar Dosage|url=http://www.rxlist.com/buspar-drug/indications-dosage.htm|website=RX List|accessdate=25 August 2014}}</ref><ref>{{cite web|title=Clinical Effects of the 5-HT1A Partial Agonists in Depression: A Composite Analysis of Buspirone in the Treatment of Depression.|url=http://journals.lww.com/psychopharmacology/Abstract/1990/06001/Clinical_Effects_of_the_5_HT1A_Partial_Agonists_in.13.aspx|publisher=Journal of Clinical Psychopharmacology:}}</ref><ref>{{cite web|title=Buspirone, a novel nonbenzodiazepine anxiolytic.|url=http://europepmc.org/abstract/MED/6150781|publisher=Clinical Pharmacy}}</ref><ref>{{cite web|title=Clinical Studies of Buspirone|url=http://www.karger.com/Article/Abstract/284132|publisher=Psychopathology}}</ref><ref>{{cite web|title=Effects of Buspirone on Agitation Associated With Dementia|url=http://www.sciencedirect.com/science/article/pii/S1064748112617035|publisher=The American Journal of Geriatric Psychiatry}}</ref><ref>{{cite web|title=Metabolism and disposition of buspirone|url=http://onlinelibrary.wiley.com/doi/10.1002/bdd.2510060205/abstract;jsessionid=C820FC16EE1EC58C98E246B590C52B3C.f03t03?deniedAccessCustomisedMessage=&userIsAuthenticated=false|publisher=The American Journal of Medicine}}</ref><ref>{{cite web|title=The comparative efficacy of buspirone and diazepam in the treatment of anxiety.|url=http://psycnet.apa.org/psycinfo/1980-06003-001|publisher=The American Journal of Psychiatry}}</ref>
For [[generalized anxiety disorder]] (GAD): 15-60mg. Starting dose is 5mg, 3 times daily, average dosage being between 20-30mg a day. If symptoms still persist after several weeks then the dose may be titrated up to 60mg. Due to Buspar's short [[half-life]] and linear {{elucidate|date=September 2014}} [[pharmacokinetics]], dosage can be increased by 5mg every two to three days.<ref>
{{cite web
|last1=List
|first1=RX
|title=Buspar Dosage
|url=http://www.rxlist.com/buspar-drug/indications-dosage.htm
|website=RX List
|accessdate=25 August 2014}}
</ref><ref>
{{cite web
|title=Clinical Effects of the 5-HT1A Partial Agonists in Depression: A Composite Analysis of Buspirone in the Treatment of Depression.
|url=http://journals.lww.com/psychopharmacology/Abstract/1990/06001/Clinical_Effects_of_the_5_HT1A_Partial_Agonists_in.13.aspx
|publisher=Journal of Clinical Psychopharmacology:}}
</ref><ref>
{{cite web
|title=Buspirone, a novel nonbenzodiazepine anxiolytic.
|url=http://europepmc.org/abstract/MED/6150781|publisher=Clinical Pharmacy}}
</ref><ref>
{{cite web
|title=Clinical Studies of Buspirone
|url=http://www.karger.com/Article/Abstract/284132
|publisher=Psychopathology}}
</ref><ref>
{{cite web
|title=Effects of Buspirone on Agitation Associated With Dementia
|url=http://www.sciencedirect.com/science/article/pii/S1064748112617035
|publisher=The American Journal of Geriatric Psychiatry}}
</ref><ref>
{{cite web
|title=Metabolism and disposition of buspirone
|url=http://onlinelibrary.wiley.com/doi/10.1002/bdd.2510060205/abstract;jsessionid=C820FC16EE1EC58C98E246B590C52B3C.f03t03?deniedAccessCustomisedMessage=&userIsAuthenticated=false
|publisher=The American Journal of Medicine}}
</ref><ref>
{{cite web
|title=The comparative efficacy of buspirone and diazepam in the treatment of anxiety.
|url=http://psycnet.apa.org/psycinfo/1980-06003-001
|publisher=The American Journal of Psychiatry}}</ref>


==Adverse effects==
==Adverse effects==

Revision as of 20:09, 18 September 2014

Buspirone
Clinical data
Trade namesBuspar
AHFS/Drugs.comMonograph
MedlinePlusa688005
Pregnancy
category
  • AU: B1
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability~4%[1]
Protein binding86-95%[1]
MetabolismHepatic mostly via CYP3A4[1]
Elimination half-life2-3 hours[2]
ExcretionUrine (29-63%), Faeces (18-38%)[1]
Identifiers
  • 8-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-8-azaspiro[4.5]decane-7,9-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.048.232 Edit this at Wikidata
Chemical and physical data
FormulaC21H31N5O2
Molar mass385.50314 g/mol g·mol−1
3D model (JSmol)
  • O=C1N(CCCCN2CCN(CC2)C3=NC=CC=N3)C(CC4(CCCC4)C1)=O
  • InChI=1S/C21H31N5O2/c27-18-16-21(6-1-2-7-21)17-19(28)26(18)11-4-3-10-24-12-14-25(15-13-24)20-22-8-5-9-23-20/h5,8-9H,1-4,6-7,10-17H2 checkY
  • Key:QWCRAEMEVRGPNT-UHFFFAOYSA-N checkY
  (verify)

Buspirone (/ˈb[invalid input: 'ew']sp[invalid input: 'i-']r[invalid input: 'oh']n/ BEW-spi-rohn), 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, 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.

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 STAR*D have shown buspirone to be an effective augmentation agent alongside treatment with selective serotonin reuptake inhibitors (SSRIs) for clinical depression and is also used to counter the sexual side effects ( anorgasmy, 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): 15-60mg. Starting dose is 5mg, 3 times daily, average dosage being between 20-30mg a day. If symptoms still persist after several weeks then the dose may be titrated up to 60mg. Due to Buspar's short half-life and linear [further explanation needed] pharmacokinetics, dosage can be increased by 5mg every two to three days.[20][21][22][23][24][25][26]

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:[27][28]

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:[27]

  • 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.[29]

The occurrence of elevated blood pressure has been reported when buspirone hydrochloride has been added to a regimen including a monoamine oxidase inhibitor (MAOI).[27]

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. [30]

Pharmacology and mechanism

Buspirone functions as a serotonin 5-HT1A receptor partial agonist (IA = 0.465).[27][31][32]  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.[33][27]   Buspirone is also a partial α1 receptor agonist.[34][35][36]  Buspirone also appears to produce some oxytocin stimulation via 5-HT1A receptor-induced action. [37][38]

Binding Profile of Buspirone (towards cloned human receptors) [39]

 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 moderate Antagonist
D3 Antagonist
D4 107 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.[41]
  • Several studies have shown the administration of buspirone can improve spatial learning and memory function following a traumatic brain injury.[42][43]
  • 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.[33][44][45]
  • In a 2007 study conducted on rats, buspirone showed a complete remission of haloperidol-induced tardive vacuous chewing symptoms when coadministered for five weeks.[46]
  • 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.[47][48][49]

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.[50][51]

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.[52] 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.[27]

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.[53] Unlike benzodiazepines buspirone is not a drug of abuse.[7]

Chemistry

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.[54]

See also

References

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  2. ^ http://www.rxlist.com/script/main/mobileart-rx.asp?drug=buspar&monotype=rx-cp&monopage=10
  3. ^ "Commonly Prescribed Psychotropic Medications". NAMI. Retrieved 25 June 2014.
  4. ^ 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
  5. ^ US Patent 3907801 N-(8 (4-pyridyl-piperazino)-alkyl(9 -azaspiroalkanediones
  6. ^ a b c "BUSPIRONE HCL (buspirone hydrochloride) tablet [Watson Laboratories, Inc.]". DailyMed. Watson Laboratories, Inc. July 2013. Retrieved 14 November 2013.
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  54. ^ Allen LE, Ferguson HC, Kissel JW (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.{{cite journal}}: CS1 maint: multiple names: authors list (link);
    DE 2057845, Rayburn JW, Wu YH, "Heterocyclische Azaspirodecandione und Verfahren zu ihrer Herstellung", published 1971-06-09 ;
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