Buspirone

Last updated

Buspirone
Buspirone 200.svg
Buspirone 3D structure.png
Clinical data
Pronunciation /ˈbjuːspɪroʊn/ (BEW-spi-rohn)
Trade names Buspar
Other namesMJ 9022-1 [1]
AHFS/Drugs.com Monograph
MedlinePlus a688005
License data
Pregnancy
category
  • AU:B1
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 3.9% [3]
Protein binding 86–95% [4]
Metabolism Liver (via CYP3A4) [5] [6]
Metabolites 5-OH-Buspirone; 6-OH-Buspirone; 8-OH-Buspirone; 1-PP Tooltip 1-(2-pyrimidinyl)piperazine [7] [8] [9]
Elimination half-life 2.5 hours [5]
Excretion Urine: 29–63% [4]
Feces: 18–38% [4]
Identifiers
  • 8-{4-[4-(Pyrimidin-2-yl)piperazin-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 InfoCard 100.048.232 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H31N5O2
Molar mass 385.512 g·mol−1
3D model (JSmol)
  • O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
  • 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 Yes check.svgY
  • Key:QWCRAEMEVRGPNT-UHFFFAOYSA-N Yes check.svgY
   (verify)

Buspirone, sold under the brand name Buspar, among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder. [10] [11] It is a serotonin 5-HT1A receptor agonist, increasing action at serotonin receptors in the brain. [3] It is taken orally, and takes two to six weeks to be fully effective. [10] [11]

Contents

Common side effects of buspirone include nausea, headaches, dizziness, and difficulty concentrating. [10] [12] Serious side effects may include movement disorders, serotonin syndrome, and seizures. [12] Its use in pregnancy appears to be safe but has not been well studied, and use during breastfeeding has not been well studied. [12] [13]

Buspirone was developed in 1968 and approved for medical use in the United States in 1986. [10] [11] It is available as a generic medication. [12] In 2021, it was the 53rd most-commonly prescribed medication in the United States, with more than 12 million prescriptions. [14] [15]

Medical uses

Anxiety

Buspirone is used for the short-term and long-term treatment of anxiety disorders or symptoms of anxiety. [16] [17] [18] [19] [20] It is generally preferred over benzodiazepines because it does not activate the receptors that make drugs like alprazolam addictive. [11]

Buspirone has no immediate anxiolytic effects, and hence has a delayed onset of action; its full clinical effectiveness may require 2–4 weeks to manifest itself. [21] The drug has been shown to be similarly effective in the treatment of generalized anxiety disorder (GAD) to benzodiazepines including diazepam, alprazolam, lorazepam, and clorazepate. [3] Buspirone is not known to be effective in the treatment of other anxiety disorders besides GAD. [22]

Other uses

Sexual dysfunction

There is some evidence that buspirone on its own may be useful in the treatment of hypoactive sexual desire disorder (HSDD) in women. [23] Buspirone may also be effective in treating antidepressant-induced sexual dysfunction. [11] [24] [25]

Miscellaneous

Buspirone is not effective as a treatment for benzodiazepine withdrawal, barbiturate withdrawal, or alcohol withdrawal/delirium tremens. [26]

SSRI and SNRI antidepressants such as paroxetine and venlafaxine may cause jaw pain/jaw spasm reversible syndrome (although it is not common), and buspirone appears to be successful in treating bruxism on SSRI/SNRI-induced jaw clenching. [27] [28]

Contraindications

Buspirone has these contraindications: [29] [30]

Side effects

Known side effects associated with buspirone include dizziness, headaches, nausea, tinnitus, and paresthesia. [3] Buspirone is relatively well tolerated, and is not associated with sedation, cognitive and psychomotor impairment, muscle relaxation, physical dependence, or anticonvulsant effects. [3] In addition, buspirone does not produce euphoria [21] and is not a drug of abuse. [17]

Overdose

Buspirone appears to be relatively benign in cases of single-drug overdose, although no definitive data on this subject appear to be available. [31] In one clinical trial, buspirone was administered to healthy male volunteers at a dosage of 375 mg/day, and produced side effects including nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. [16] [17] [19] In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, with akathisia, tremor, and muscle rigidity observed. [32] Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals. [32] One death has been reported in a co-ingestion of 450 mg buspirone with alprazolam, diltiazem, alcohol, cocaine. [32]

Interactions

Buspirone has been shown in vitro to be metabolized by the enzyme CYP3A4. [6] This finding is consistent with the in vivo interactions observed between buspirone and these inhibitors or inducers of cytochrome P450 3A4 (CYP3A4), among others: [29]

Elevated blood pressure has been reported when buspirone has been administered to patients taking monoamine oxidase inhibitors (MAOIs). [29]

Pharmacology

Pharmacodynamics

Buspirone [35]
SiteKi (nM)ActionSpeciesRef
5-HT1A 3.98–214
21 (median)		AgonistHuman [35] [36]
5-HT1B >100,000Agonist ? [37] Rat [38]
5-HT1D 22,000–42,700Agonist ? [37] Human [39] [40]
5-HT2C 1,100–6,026Antagonist ? [37] Rat/pig
[38]
5-HT7 375–381
840		Antagonist ? [37] Rat
Human		 [41] [42]
[43]
α1 1,000AntagonistRat [38]
α2 6,000AntagonistRat [44]
   α2A 7.3 (1-PP Tooltip 1-(2-Pyrimidinyl)piperazine)AntagonistHuman [38]
β 8,800AntagonistRat [38]
D1 33,000AntagonistRat [38]
D2 484
240		AntagonistHuman
Rat		 [45]
[38]
D3 98AntagonistHuman [45]
D4 29AntagonistHuman [45]
mACh Tooltip Muscarinic acetylcholine receptor38,000?Rat [38]
GABAA
(BDZ) 		>100,000-Rat [38]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Buspirone acts as an agonist of the serotonin 5-HT1A receptor with high affinity. [3] [38] It is a partial agonist of both presynaptic 5-HT1A receptors, which are inhibitory autoreceptors, and postsynaptic 5-HT1A receptors. [3] It is thought that the main effects of buspirone are mediated via its interaction with the presynaptic 5-HT1A receptor, thus reducing the firing of serotonin-producing neurons. [3] Buspirone also seems to have lower affinities for the serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, 5-HT7 receptors probably as an antagonist. [37]

In addition to binding to serotonin receptors, buspirone is an antagonist of the dopamine D2 receptor with weak affinity. [3] [38] It preferentially blocks inhibitory presynaptic D2 autoreceptors, and antagonizes postsynaptic D2 receptors only at higher doses. [3] In accordance, buspirone has been found to increase dopaminergic neurotransmission in the nigrostriatal pathway at low doses, whereas at higher doses, postsynaptic D2 receptors are blocked and antidopaminergic effects such as hypoactivity and reduced stereotypy, though notably not catalepsy, are observed in animals. [3] Buspirone has also been found to bind with much higher affinity to the dopamine D3 and D4 receptors, where it is similarly an antagonist. [45]

A major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP), occurs at higher circulating levels than buspirone itself and is known to act as a potent α2-adrenergic receptor antagonist. [44] [46] [47] This metabolite may be responsible for the increased noradrenergic and dopaminergic activity observed with buspirone in animals. [46] [48] Buspirone also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor. [38] [49] However, buspirone has been reported to have shown "significant and selective intrinsic efficacy" at the α1-adrenergic receptor expressed in a "tissue- and species-dependent manner". [49]

Unlike benzodiazepines, buspirone does not interact with the GABAA receptor complex. [3] [50]

Pharmacokinetics

Buspirone has a low oral bioavailability of 3.9% relative to intravenous injection due to extensive first-pass metabolism. [3] The time to peak plasma levels following ingestion is 0.9 to 1.5 hours. [3] It is reported to have an elimination half-life of 2.8 hours, [3] although a review of 14 studies found that the mean terminal half-life ranged between 2 and 11 hours, and one study even reported a terminal half-life of 33 hours. [7] Buspirone is metabolized primarily by CYP3A4, and prominent drug interactions with inhibitors and inducers of this enzyme have been observed. [5] [6] Major metabolites of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP. [51] [7] [8] [9] 6-Hydroxybuspirone has been identified as the predominant hepatic metabolite of buspirone, with plasma levels that are 40-fold greater than those of buspirone after oral administration of buspirone to humans. [8] The metabolite is a high-affinity partial agonist of the 5-HT1A receptor (Ki=25 nM) similarly to buspirone, and has demonstrated occupancy of the 5-HT1A receptor in vivo . [8] As such, it is likely to play an important role in the therapeutic effects of buspirone. [8] 1-PP has also been found to circulate at higher levels than those of buspirone itself and may similarly play a significant role in the clinical effects of buspirone. [46] [48]

Phase I Metabolism of buspirone in humans Buspirone metabolism.png
Phase I Metabolism of buspirone in humans

Chemistry

Buspirone is a member of the azapirone chemical class, and consists of azaspirodecanedione and pyrimidinylpiperazine components linked together by a butyl chain.

Analogues

Structural analogues of buspirone include other azapirones like gepirone, ipsapirone, perospirone, and tandospirone. [55]

A number of analogues are recorded. [56]

Synthesis

A number of methods of synthesis have also been reported. [57] [58] [59] One method begins with alkylation of 1-(2-pyrimidyl)piperazine (1) with 3-chloro-1-cyanopropane (4-chlorobutyronitrile) (2) to give (3). Next, reduction of the nitrile group is performed either by catalytic hydrogenation or with lithium aluminium hydride (LAH) giving (4). The primary amine is then reacted with 3,3-tetramethyleneglutaric anhydride (5) in order to yield buspirone (6). [60] [61] [62] [63] [64]

Synthesis of buspirone Buspirone-synthesis.svg
Synthesis of buspirone

History

Buspirone was first synthesized by a team at Mead Johnson in 1968 [22] but was not patented until 1980. [65] [60] [66] It was initially developed as an antipsychotic acting on the D2 receptor but was found to be ineffective in the treatment of psychosis; it was then used as an anxiolytic instead. [3] In 1986, Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD. [22] [67] The patent expired in 2001, and buspirone is now available as a generic drug.

Society and culture

Buspar (buspirone) 10-mg tablets Buspar.jpg
Buspar (buspirone) 10-mg tablets

Generic names

Buspirone is the INN Tooltip International Nonproprietary Name, BAN Tooltip British Approved Name, DCF Tooltip Dénomination Commune Française, and DCIT Tooltip Denominazione Comune Italiana of buspirone, while buspirone hydrochloride is its USAN Tooltip United States Adopted Name, BANM Tooltip British Approved Name, and JAN Tooltip Japanese Accepted Name. [1] [68] [69] [70]

Brand names

Buspirone was primarily sold under the brand name Buspar. [68] [70] Buspar is currently listed as discontinued by the US Food and Drug Administration. [71] In 2010, in response to a citizen petition, the US FDA determined that Buspar was not withdrawn from sale for reasons of safety or effectiveness. [72]

Related Research Articles

An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.

<span class="mw-page-title-main">Fluvoxamine</span> SSRI antidepressant drug

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<span class="mw-page-title-main">Azapirone</span> Drug class of psycotropic drugs

Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).

<span class="mw-page-title-main">Trazodone</span> Antidepressant medication

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<span class="mw-page-title-main">Quazepam</span> Benzodiazipine

Quazepam, sold under brand name Doral among others, is a relatively long-acting benzodiazepine derivative drug developed by the Schering Corporation in the 1970s. Quazepam is used for the treatment of insomnia including sleep induction and sleep maintenance. Quazepam induces impairment of motor function and has relatively selective hypnotic and anticonvulsant properties with considerably less overdose potential than other benzodiazepines. Quazepam is an effective hypnotic which induces and maintains sleep without disruption of the sleep architecture.

<span class="mw-page-title-main">Clorazepate</span> Benzodiazepine medication

Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.

<span class="mw-page-title-main">Alpidem</span> Anxiolytic medication

Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was discontinued due to liver toxicity. Alpidem is taken by mouth.

<span class="mw-page-title-main">Camazepam</span> Chemical compound

Camazepam is a benzodiazepine psychoactive drug, marketed under the brand names Albego, Limpidon and Paxor. It is the dimethyl carbamate ester of temazepam, a metabolite of diazepam. While it possesses anxiolytic, anticonvulsant, skeletal muscle relaxant and hypnotic properties it differs from other benzodiazepines in that its anxiolytic properties are particularly prominent but has comparatively limited anticonvulsant, hypnotic and skeletal muscle relaxant properties.

<span class="mw-page-title-main">Etizolam</span> Benzodiazepine analog drug

Etizolam is a thienodiazepine derivative which is a benzodiazepine analog. The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine.

<span class="mw-page-title-main">Gepirone</span> Medication used for major depressive disorder

Gepirone, sold under the brand name Exxua, is a medication used for the treatment of major depressive disorder. It is taken orally.

<span class="mw-page-title-main">Delorazepam</span> Benzodiazepine medication

Delorazepam, also known as chlordesmethyldiazepam and nordiclazepam, is a drug which is a benzodiazepine and a derivative of desmethyldiazepam. It is marketed in Italy, where it is available under the trade name EN and Dadumir. Delorazepam (chlordesmethyldiazepam) is also an active metabolite of the benzodiazepine drugs diclazepam and cloxazolam. Adverse effects may include hangover type effects, drowsiness, behavioural impairments and short-term memory impairments. Similar to other benzodiazepines delorazepam has anxiolytic, skeletal muscle relaxant, hypnotic and anticonvulsant properties.

<span class="mw-page-title-main">Tandospirone</span> Anxiolytic and antidepressant medication

Tandospirone, sold under the brand name Sediel, is an anxiolytic and antidepressant medication used in Japan and China, where it is marketed by Dainippon Sumitomo Pharma. It is a member of the azapirone class of drugs and is closely related to other azapirones like buspirone and gepirone.

5-HT<sub>1A</sub> receptor Serotonin receptor protein distributed in the cerebrum and raphe nucleus

The serotonin 1A receptor is a subtype of serotonin receptors, or 5-HT receptors, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarization and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.

<span class="mw-page-title-main">Premazepam</span> Chemical compound

Premazepam is a Pyrrolodiazepine class of drug. It is a partial agonist of benzodiazepine receptors and was shown in 1984 to possess both anxiolytic and sedative properties in humans but was never marketed.

<span class="mw-page-title-main">Cyamemazine</span> Antipsychotic medication

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<span class="mw-page-title-main">Deramciclane</span> Drug used to treat anxiety disorders

Deramciclane (EGIS-3886) is a non-benzodiazepine-type anxiolytic drug to treat various types of anxiety disorders. Deramciclane is a unique alternative to current anxiolytics on the market because it has a novel chemical structure and target. It acts as an antagonist at the 5-HT2A receptor, as an inverse agonist at the 5-HT2C receptor, and as a GABA reuptake inhibitor. The two serotonin receptors are G protein-coupled receptors and are two of the main excitatory serotonin receptor types. Their excitation has been implicated in anxiety and mood. Deramciclane does not affect CYP3A4 activity in metabolizing other drugs, but it is a weak inhibitor of CYP2D6. Some studies also show the drug to have moderate affinity to dopamine D2 receptors and low affinity to dopamine receptor D1. Researchers are looking for alternatives to benzodiazepines for anxiolytic use because benzodiazepine drugs have sedative and muscle relaxant side effects.

<span class="mw-page-title-main">Pyrimidinylpiperazine</span> Chemical compound

1-(2-Pyrimidinyl)piperazine (1-PP, 1-PmP) is a chemical compound and piperazine derivative. It is known to act as an antagonist of the α2-adrenergic receptor (Ki = 7.3–40 nM) and, to a much lesser extent, as a partial agonist of the 5-HT1A receptor (Ki = 414 nM; Emax = 54%). It has negligible affinity for the dopamine D2, D3, and D4 receptors (Ki > 10,000 nM) and does not appear to have significant affinity for the α1-adrenergic receptors. Its crystal structure has been determined.

<span class="mw-page-title-main">Eptapirone</span> Chemical compound

Eptapirone (F-11,440) is a very potent and highly selective 5-HT1A receptor full agonist of the azapirone family. Its affinity for the 5-HT1A receptor was reported to be 4.8 nM (Ki), and its intrinsic activity approximately equal to that of serotonin.

<span class="mw-page-title-main">Vortioxetine</span> Serotonin modulator antidepressant

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<span class="mw-page-title-main">Osemozotan</span> Pharmaceutical drug

Osemozotan (MKC-242) is a selective 5-HT1A receptor agonist with some functional selectivity, acting as a full agonist at presynaptic and a partial agonist at postsynaptic 5-HT1A receptors. 5-HT1A receptor stimulation influences the release of various neurotransmitters including serotonin, dopamine, norepinephrine, and acetylcholine. 5-HT1A receptors are inhibitory G protein-coupled receptor.

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