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 names Buspar
AHFS/Drugs.com monograph
MedlinePlus a688005
Pregnancy cat. B (US)
Legal status ℞ Prescription only
Routes Oral
Pharmacokinetic data
Bioavailability 5%
Protein binding 95%
Metabolism Hepatic
Half-life 2-3 hours
Excretion Urine (29-63%), Feces (18-38%)
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 /ˈbjuːspɨroʊn/ BEW-spi-rohn), trade name Buspar (pronounced BYOO-spar), is an anxiolytic psychoactive drug of the azapirone chemical class and is primarily used to treat generalized anxiety disorder (GAD).

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.

Contents

[edit] Medical uses

Although not approved for this indication, studies have shown buspirone to be an effective augmentation agent alongside treatment with SSRIs for clinical depression.[1][2][3]

[edit] Adverse effects

Buspar (buspirone) 10 mg tablets

Most common adverse effects:[4]

  • drowsiness
  • upset stomach
  • vomiting
  • constipation
  • diarrhea
  • stomach pain
  • headache
  • dry mouth
  • depression
  • excitement
  • fatigue
  • nervousness
  • insomnia
  • lightheadedness
  • weakness
  • numbness

[edit] Contraindications

Buspirone has the following contraindications:[5][6]

[edit] 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 the following inhibitors / inducers of Cytochrome P450 3A4 (CYP3A4), among others:[5]

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.[7]

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).[5]

[edit] Pharmacology

Buspirone functions as a serotonin 5-HT1A receptor partial agonist[5][8] (IA = 0.465).[9] It is this action that is thought to mediate its anxiolytic and antidepressant effects. Additionally, it functions as a presynaptic dopamine agonist D2,D3, dopamine antagonist D4,[5][10] as well as a partial α1 receptor agonist.

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.[11][12][13] 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.[14]

[edit] Research

  • 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.[15]
  • In a 1996 study, buspirone was shown to be effective as an augmentative agent for the treatment of alcohol dependence.[16]
  • Several studies have shown that administration of buspirone can improve spatial learning and memory function following a traumatic brain injury (TBI).[17][18]
  • 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.[10][19][20]
  • 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.[21]

[edit] Comparison to benzodiazepines

Buspirone's efficacy is comparable to that of members of the benzodiazepine family in treating GAD.[22][23]

Cross-tolerance to benzodiazepines, barbiturates, and alcohol, as well as other GABAergics, is not present.

In a study of diazepam and buspirone in GAD patients both drugs were effective, but buspirone took longer to take effect.

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.[24]

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.[5]

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.[25]

[edit] 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.[26]

Buspirone synthesis.png

[edit] See also

[edit] References

  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ Health, PubMed. "Buspirone - PubMed Health". The American Society of Health-System Pharmacists. Retrieved 1 September 2012. 
  5. ^ a b c d e f "Buspirone monograph". Drugs.com. Retrieved 2011-08-27. 
  6. ^ Geddes, John; Gelder, Michael G.; Mayou, Richard (2005). Psychiatry. Oxford [Oxfordshire]: Oxford University Press. p. 237. ISBN 0-19-852863-9. 
  7. ^ 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.  edit
  8. ^ 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.  edit
  9. ^ 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): 1130–7. doi:10.1124/jpet.102.036798. PMID 12438536.  edit
  10. ^ 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. 
  11. ^ Fava M, Targum SD, Nierenberg AA, Bleicher LS, Carter TA, Wedel PC, Hen R, Gage FH, Barlow C (December 2012). "An exploratory study of combination buspirone and melatonin SR in Major Depressive Disorder (MDD): a possible role for neurogenesis in drug discovery". J Psychiatr Res 46 (12): 1553–63. doi:10.1016/j.jpsychires.2012.08.013. PMID 22998742. 
  12. ^ Biotech, Xconomy. "BrainCells Inc. Maps Out Next Steps for Novel Depression Drug". Xconomy. Retrieved 21 September 2012. 
  13. ^ New Research Approaches for Mental Health Interventions, NCDEU. "A Pilot Study of a Novel Drug Combination in Major Depressive Disorder". NCDEU. Retrieved 21 September 2012. 
  14. ^ US patent 5431922, Nicklasson AGM, "Method for administration of buspirone", issued 1995-07-11, assigned to Bristol-Myers Squibb Company url=http://www.google.com/patents/US5431922 
  15. ^ "IU School of Medicine, Rehabilitation Hospital of Indiana selected for national brain injury research network". Retrieved 16 October 2012. 
  16. ^ 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.  edit
  17. ^ 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. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ "Effects of Chronic Buspirone Treatment on Cocaine Self-Administration". Neuropsychopharmacology. Harvard Medical School. Retrieved 5 March 2013. 
  21. ^ 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. 
  22. ^ Cohn JB, Rickels K, Steege JF (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.  edit
  23. ^ 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.  edit
  24. ^ 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.  edit
  25. ^ 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.  edit
  26. ^ Wu YH, Rayburn JW, 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): 477–9. 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 
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