Buspirone

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Buspirone
Buspirone2DACS.svg
Buspirone3Dan.gif
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 monograph
MedlinePlus a688005
Pregnancy cat. B1 (AU) B (US)
Legal status Prescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability ~4%[1]
Protein binding 86-95%[1]
Metabolism Hepatic mostly via CYP3A4[1]
Half-life 2-3 hours[1]
Excretion Urine (29-63%), Faeces (18-38%)[1]
Identifiers
CAS number 36505-84-7 YesY
ATC code N05BE01
PubChem CID 2477
IUPHAR ligand 36
DrugBank DB00490
ChemSpider 2383 YesY
UNII TK65WKS8HL YesY
KEGG D07593 YesY
ChEBI CHEBI:3223 YesY
ChEMBL CHEMBL49 YesY
Chemical data
Formula C21H31N5O2 
Mol. mass 385.50314 g/mol
 YesY (what is this?)  (verify)

Buspirone (pronounced /ˈbjuːspɨrn/ BEW-spi-rohn), trade name Buspar (pronounced BYOO-spar), is an anxiolytic psychotropic drug[2] of the azapirone chemical class. It 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 physical dependence and withdrawal symptoms those drug classes are known for when discontinued.

Buspirone was first identified by a team at Mead Johnson[3] in 1972, but wasn't patented until 1975.[4]

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.[5] Likewise in Australia buspirone is licensed for the treatment of anxiety disorders.[6][7] In the UK buspirone is indicated only for the short-term treatment of anxiety.[8][9]

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.[10][11][12]

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.[13][14][15][16]

Adverse effects[edit]

Buspar (buspirone) 10 mg tablets

Adverse effects by incidence[1][5][6][8]

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

  • Dizziness/light-headedness
  • Headache
  • Premature Ejaculation

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
  • Diarrhea
  • 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:

  • Arthralgias
  • Amenorrhoea (cessation of menstrual cycles)
  • Enuresis
  • Nocturia
  • Hyperventilation
  • Epistaxis
  • Delayed ejaculation

Contraindications[edit]

Buspirone has the following contraindications:[17][18]

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:[17]

  • 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 / inhibition by a substance in grapefruit rind of cytochrome P450 3A4-mediated first-pass metabolism of buspirone.[19]

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).[17]

Overdose[edit]

Activated charcoal is believed to be an effective treatment for overdose, provided the patient is treated sufficiently promptly.[5][6][8] 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][6][8]

  • Nausea
  • Vomiting
  • Dizziness
  • Drowsiness
  • Gastric distress

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.[20]

Pharmacology and Mechanism[edit]

Buspirone functions as a serotonin 5-HT1A receptor partial agonist[17][21] (IA = 0.465).[22] 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 [17][23] receptors. Buspirone is also a partial α1 receptor agonist.

Binding Profile of Buspirone (towards cloned human receptors)[24]

Receptor Ki (nM)
5-HT1A 28.62
5-HT2A 138.03
5-HT2B 213.79
5-HT2C 489.77
D4 107

Research[edit]

  • In September 2012 a five-year $2,137,500 grant was given to the Indiana University School of Medicine and Rehabilitation Hospital of Indiana by the United States Federal Government. One of the major focuses of research will be to study the effectiveness of Buspirone as a treatment for symptoms resulting from traumatic brain injuries.[25]
  • In a 1996 study, buspirone was shown to be effective as an augmentative agent for the treatment of alcohol dependence.[27]
  • Several studies have shown that administration of buspirone can improve spatial learning and memory function following a traumatic brain injury (TBI).[28][29]
  • 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.[23][30][31]
  • In a 2007 study conducted on rats, buspirone showed a complete remission of haloperidol-induced tardive vacuous chewing symptoms when co-administered for five weeks.[32]

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.[33][34]

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.[35] 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.[17]

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.[36] Unlike benzodiazepines buspirone is not a drug of abuse.[6]

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.[37]

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. ^ "Commonly Prescribed Psychotropic Medications". NAMI. Retrieved 25 June 2014. 
  3. ^ 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
  4. ^ US Patent 3907801 N-(8 (4-pyridyl-piperazino)-alkyl(9 -azaspiroalkanediones
  5. ^ a b c d "BUSPIRONE HCL (buspirone hydrochloride) tablet [Watson Laboratories, Inc.]". DailyMed. Watson Laboratories, Inc. July 2013. Retrieved 14 November 2013. 
  6. ^ 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. 
  7. ^ Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. 
  8. ^ a b c d "Buspirone 10mg Tablets". electronic Medicines Compendium. Actavis UK Ltd. 10 September 2012. Retrieved 14 November 2013. 
  9. ^ Joint Formulary Committee. British National Formulary (BNF). Pharmaceutical Press. p. 224. 
  10. ^ National Institute Of Health. "Questions and Answers about the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study — All Medication Levels". Retrieved 12 August 2012. 
  11. ^ 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. 
  12. ^ Appelberg BG, Syvälahti EK, Koskinen TE, Mehtonen OP, Muhonen TT, Naukkarinen HH (June 2001). "Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors and in a Class of Drugs called Benzodiazepines and effects similar if not idenical to Alprazelam,Lorazepam etc : results from a placebo-controlled, randomized, double-blind, placebo wash-in study". J Clin Psychiatry 62 (6): 448–52. doi:10.4088/JCP.v62n0608. PMID 11465522. 
  13. ^ Malhotra S, Santosh PJ (April 1998). "An open clinical trial of buspirone in children with attention- deficit/hyperactivity disorder". Journal of the American Academy of Child and Adolescent Psychiatry 37 (4): 364–371. doi:10.1097/00004583-199804000-00013. PMID 9549956. 
  14. ^ Mohammadi MR, Hafezi P, Galeiha A, Hajiaghaee R, Akhondzadeh S (November 2012). "Buspirone versus Methylphenidate in the Treatment of Children with Attention- Deficit/ Hyperactivity Disorder: Randomized Double-Blind Study". Acta Medica Iranica 50 (11): 723–728. PMID 23292622. 
  15. ^ Sutherland SM, Adler LA, Chen C, Smith MD, Feltner DE. "An 8-Week, Randomized Controlled Trial of Atomoxetine, Atomoxetine Plus Buspirone, or Placebo in Adults With ADHD". The Journal of Clinical Psychiatry 73 (4): 445–450. doi:10.4088/JCP.10m06788. PMID 22313788. 
  16. ^ Davari-Ashtiani R, Shahrbabaki ME, Razjouyan K, Amini H, Mazhabdar H. "Buspirone Versus Methylphenidate in the Treatment of Attention Deficit Hyperactivity Disorder: A Double-Blind and Randomized Trial" (PDF). Child Psychiatry and Human Development 41 (6): 641–648. doi:10.1007/s10578-010-0193-2. PMID 20517641. 
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  18. ^ Geddes, John; Gelder, Michael G.; Mayou, Richard (2005). Psychiatry. Oxford [Oxfordshire]: Oxford University Press. p. 237. ISBN 0-19-852863-9. 
  19. ^ Lilja JJ, Kivistö KT, Backman JT, Lamberg TS, Neuvonen PJ (1998). "Grapefruit juice substantially increases plasma concentrations of buspirone*". Clinical Pharmacology & Therapeutics 64 (6): 655–660. doi:10.1016/S0009-9236(98)90056-X. PMID 9871430. 
  20. ^ Fulton B, Brogden RN (January 1997). "Buspirone" (PDF). CNS Drugs 7 (1): 68–88. doi:10.2165/00023210-199707010-00007. 
  21. ^ Blier P, Bergeron R, de Montigny C (1997). "Selective Activation of Postsynaptic 5-HT1A Receptors Induces Rapid Antidepressant Response". Neuropsychopharmacology 16 (5): 333–338. doi:10.1016/S0893-133X(96)00242-4. PMID 9109104. 
  22. ^ Zuideveld KP, Rusiç-Pavletiç J, Maas HJ, Peletier LA, Van der Graaf PH, Danhof M (December 2002). "Pharmacokinetic-pharmacodynamic modeling of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in rats". J. Pharmacol. Exp. Ther. 303 (3): 1130–1137. doi:10.1124/jpet.102.036798. PMID 12438536. 
  23. ^ a b "Efficacy of buspirone for attenuating cocaine and methamphetamine reinstatement in rats.". Drug Alcohol Dependence. Virginia Commonwealth University School of Medicine. Retrieved 5 March 2013. 
  24. ^ Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 November 2013. 
  25. ^ "IU School of Medicine, Rehabilitation Hospital of Indiana selected for national brain injury research network". Retrieved 16 October 2012. 
  26. ^ "Buspirone Ameliorates the Morphine Withdrawal-Induced Anxiety through Synaptic Ultrastructural Changes in Hippocampus of Rat". Jialin Gao, Gang Qian, Suyuan Luo, Yan Tian, Mingsong Wu, Zhongxiang Yao. Retrieved 23 February 2014. 
  27. ^ Malec TS, Malec EA, Dongier M (1996). "Efficacy of buspirone in alcohol dependence: A review". Alcoholism, clinical and experimental research 20 (5): 853–858. doi:10.1111/j.1530-0277.1996.tb05263.x. PMID 8865960. 
  28. ^ Olsen AS, Sozda CN, Cheng JP, Hoffman AN, Kline AE (July 2012). "Traumatic Brain Injury-Induced Cognitive and Histological Deficits Are Attenuated by Delayed and Chronic Treatment with the 5-HT(1A)-Receptor Agonist Buspirone". J. Neurotrauma 29 (10): 1898–907. doi:10.1089/neu.2012.2358. PMID 22416854. 
  29. ^ Cheng JP, Hoffman AN, Zafonte RD, Kline AE (December 2008). "A delayed and chronic treatment regimen with the 5-HT1A receptor agonist 8-OH-DPAT after cortical impact injury facilitates motor recovery and acquisition of spatial learning". Behav. Brain Res. 194 (1): 79–85. doi:10.1016/j.bbr.2008.06.025. PMC 2568997. PMID 18638506. 
  30. ^ Bergman J, Roof RA, Furman CA, Conroy JL, Mello NK, Sibley DR, Skolnick P (July 2012). "Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors". Int J Neuropsychopharmacol: 1–14. doi:10.1017/S1461145712000661. PMID 22827916. 
  31. ^ "Effects of Chronic Buspirone Treatment on Cocaine Self-Administration". Neuropsychopharmacology. Harvard Medical School. Retrieved 5 March 2013. 
  32. ^ Haleem DJ, Samad N, Haleem MA (May 2007). "Reversal of haloperidol-induced tardive vacuous chewing movements and supersensitive somatodendritic serotonergic response by buspirone in rats". Pharmacol. Biochem. Behav. 87 (1): 115–21. doi:10.1016/j.pbb.2007.04.007. PMID 17498786. 
  33. ^ Cohn JB, Rickels K (1989). "A pooled, double-blind comparison of the effects of buspirone, diazepam and placebo in women with chronic anxiety". Current Medical Research and Opinion 11 (5): 304–320. doi:10.1185/03007998909115213. PMID 2649317. 
  34. ^ Goldberg HL, Finnerty RJ (1979). "The comparative efficacy of buspirone and diazepam in the treatment of anxiety". The American Journal of Psychiatry 136 (9): 1184–1187. PMID 382878. 
  35. ^ Murphy SM, Owen R, Tyrer P (1989). "Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks' treatment with diazepam or buspirone". The British journal of psychiatry : the journal of mental science 154: 529–534. doi:10.1192/bjp.154.4.529. PMID 2686797. 
  36. ^ Sontheimer DL, Ables AZ (2001). "Is imipramine or buspirone treatment effective in patients wishing to discontinue long-term benzodiazepine use?". The Journal of family practice 50 (3): 203. PMID 11252203. 
  37. ^ 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. ;
    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