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[top]Introduction to Buspirone

Buspirone is an anti-anxiety medication sold under the brand name of BuSpar and is also available under its generic name. It is chemically and pharmacologically unrelated to benzodiazepines or other sedative/hypnotic drugs used to treat anxiety, including barbiturates. It has not shown to be effective in the treatment of all anxiety related disorder, such as panic disorder.[1]
It has the advantage compared to benzodiazepines and other sedative/hypnotic drugs of not causing general depressant CNS effects. Buspirone does not cause the sedative effects and the cognitive impairment that are thought to be necessarily linked to anti-anxiety effects. As well, it does not impair motor co-ordination, enhance the effects of CNS-depressant drugs such as alcohol, or show cross-tolerance with CNS-depressants.[2]

Generalized Anxiety Disorder (GAD): characterized by the chronic presentation (at least one month) of fear or apprehension without a known cause and exemplified by at least three out of four psychomotor symptoms: motor tension, autonomic hyperactivity, apprehensive expectation and vigilance and scanning.


[top]Using Buspirone

[top]Ways of Administration

Buspirone comes in tablet form and is only taken orally. It has a relatively short half-life and therefore must be administered in two or three doses daily.[3] The usual therapeutic dose is 20 to 30 mg daily. The usual starting adult dose is 10-15 mg daily in 2 or 3 divided doses. The dose may be increased by 5 mg every 2 to 4 days until an effective dose is found.[4] The maximum adult dose is 60 mg daily, but most patients respond to 15-30 mg daily in 2 or 3 divided doses. Although food increases the amount of buspirone that is absorbed, the importance of this effect is not clear. Buspirone should be taken with or without food on a consistent basis.[4]

[top]Side Effects

The most common side effects of buspirone involve the nervous system. Ten percent of people may experience dizziness, drowsiness, and headache, and another 5% may experience fatigue, nervousness, insomnia, and light-headedness. [5] Those taking buspirone may also experience excitement, depression, anger, hostility, confusion, nightmares, or other sleep disorders, lack of coordination, tremor, and numbness of the extremities. Buspirone is non-sedating but at higher doses, drowsiness and a lack of mental alertness can be experienced at higher doses, especially early in therapy.[5] The side effects of buspirone decrease with time, and include:
  • Nausea (up to 8% of patients)
  • Dry mouth, abdominal distress, gastric distress, and diarrhea, constipation (up to 5% of users)
  • Rapid heart rate and palpitations (up to 2% of users)
  • Blurred vision (up to 2% of users)
  • Increased or decreased appetite
  • Flatulence
  • Non-specific chest pain
  • Rash
  • Irregular menstrual periods and/or breakthrough bleeding

[top]Interactions with Buspirone

Dangerously high blood pressure has resulted from the combination of buspirone and a class of antidepressants MAO Inhibitors.[4] As such, buspirone should not be taken in combination with MAO Inhibitors such as:
  • Isocarboxazid (Marplan)
  • Phenelzine (Nardil)
  • Tranylcypromine (Parnate)
  • Procarbazine (Matulane) [used in psychotic disorders]

The use of buspirone with these drugs can cause increased blood pressure. Any MAO inhibitors being taken should be stopped at least 10 days prior to taking buspirone, and the same is true when discontinuing buspirone before starting an MAO inhibitor.[4] The combination of buspirone and warfarin (Coumadin), a blood thinner, may accentuate the effects of warfarin and increase the risk of bleeding.[1]

Certain drugs may inhibit the enzyme system in the liver that breaks down buspirone. Also, the combination of buspirone and trazodone (Desyrel), an antidepressant, may cause abnormal liver enzymes in the blood. Examples of drugs that might inhibit this system are erythromycin, a broad-spectrum antibiotic, itraconazole, an oral antifungal agent, and nefazodone, an antidepressant. When these drugs are combined with buspirone, buspirone concentrations may increase to the point of toxicity (poisoning). These combinations should either be avoided or doses of buspirone decreased to compensate for this interaction. [1] Grapefruit juice should be avoided while taking buspirone since the juice (even long after a dose is taken) can increase the amount of buspirone in the blood, possibly leading to side effects.[1]

[top]Contraindications

MAO Inhibitors
The occurrence of elevated blood pressure in patients receiving both buspirone and a monoamine oxidase inhibitor (MAOI) has been reported. Therefore, it is recommended that buspirone should not be used alongside with an MAOI.[4]

Extrapyramidal Symptoms
Since buspirone can bind to central dopaminergic receptors, there is a possibility of acute and chronic changes in dopamine mediated neurological function (e.g. dystonia, pseudo-parkinsonism, akathisia and tardive dyskinesia.[4]

Convulsive Disorders
Those with a history of seizure disorders are not recommended to take buspirone.[4]

Use of Buspirone in Patients Previously Treated with a Benzodiazepine
Patients who have previously taken benzodiazepines may be less likely to respond to buspirone than those who have not. In two clinical studies to date, substitution of buspirone did not improve or prevent withdrawal symptoms in either abrupt or gradual withdrawal from various benzodiazepines following long term use. Therefore, if it is considered desirable to switch from benzodiazepines to buspirone, the benzodiazepine should be gradually withdrawn from first. Also, a drug-free interval is recommended in the time period between the withdrawal effects of benzodiazepines and the beginning of buspirone, as this will increase the likelihood of being to distinguish between benzodiazepine withdrawal effects and unrelieved anxiety due to possible failure of buspirone in this category of patients. Buspirone should not be used be used to detox patients addicted to benzodiazepines.[4]

Use in Pregnancy, Lactation, Labor and Delivery
The safety of buspirone during pregnancy and lactation has not been established and, therefore, it should not be used in women of childbearing potential or nursing mothers. The potential benefits to the patient outweigh the possible hazards to the fetus. Buspirone and its metabolites are excreted in milk in rats. The extent of excretion in human milk has not yet been determined. The effect of Buspirone on labor and delivery is unknown.[4]


[top]Different Uses for Buspirone

Initially developed for use in the treatment of generalized anxiety disorder, it appears that buspirone may be useful in various other neurological and psychiatric disorders, such as attenuating side effects of Parkinson's disease therapy, ataxia, depression, social phobia, and behaviour disturbances following brain injury, and those accompanying Alzheimer's disease, dementia and attention deficit disorder.[6] Considering the potential of this drug to be included in the management of many conditions, thorough and controlled studies are required to elucidate the exact mechanism of action.

Although Buspirone has been developed for use in the treatment of generalized anxiety disorder, it may be useful in other neurological and psychiatric disorders. It can be taken as a prophylactic in a subset of migraine patients suffering from concurrent anxiety disorders.[7], as well as a treatment aid to alcoholics who have co-morbid anxiety disorders. It is also useful to treat agitation and anxiety in brain injury patients.[7] In a review of buspirone in June 2012 by Loana and Politis, Department of Medicine at Imperial College London, the following conditions were reported as responding positively to buspirone therapy:[6]
  1. L-dopa-induced dyskinesia in PD: buspirone may be effective in the treatment of TD. TD causes abnormal, involuntary, and irregular motor movements of muscles in the head, limbs, or trunk. However, the exact mechanisms underlying the reported reduction of TD after using buspirone therapy are not clear. Regardless, buspirone’s therapeutic effects in the treatment of the L-dopa induced dyskinesia (LID) are notable and have been observed in PD patients following long-term use of L-dopa.[6]
  2. Graft-induced dyskinesia in PD: treatment of PD requires restorative approaches that correct the main chemical defect in the PD brain and must also overcome the resulting complications from long-term use of L-dopa. Cell therapy is an example of one restorative approach. However, graft-induced dyskinesias (GIDs) occur with some types of treatment such as fetal ventral mesencephalic tissue grafts.[6] GIDs occur because of an underlying dysfunction in serotonergic neurotransmission. When patients with PD affected by GID were given buspirone, a significant reduction was reported.[6]
  3. Spinocerebellar ataxias: The spinocerebellar ataxias (SCA) are a heterogeneous group of hereditary disorders resulting in ataxia and other variable neurological and systemic disorder[8] Following studies evaluating the use of buspirone for the treatment of ataxia, it is suggested that buspirone may subjectively influence performance via noradrenergic pathways. [8]
  4. Major depression: many reviews exist that have evaluated the potential benefit buspirone may have for the treatment of major depression, where the general conclusion to date is that buspirone does provide some useful benefit as both a primary and adjunctive treatment. Its antidepressant effects are independent of its anxiolytic effects.[6]
  5. SSRI-induced adverse events: Buspirone has shown to be effective in the resolution of some common SSRI side-effects when added to SSRI therapy.[6] It has been reported that the addition of 15–60 mg/day of buspirone to SSRIs created a noticeable improvement in sexual dysfunction originating from SSRI therapy.[9]


[top]Pharmacology of Buspirone


LD50 (mg/kg) [1] :
Rat : 136 intraperitoneally

Buspirone is a novel anxiolytic drug which belongs to the azaspirondecandione class of compounds. It is unrelated to the structure and pharmacologic properties of benzodiazepines. It exhibits a unique pharmacological profile in that it alleviates anxiety without causing sedation or functional impairment. [4] It has a complex interaction with neurotransmitters systems including the noradrenergic, serotonergic, dopaminergic, and gamma-aminobutric acid-benzodiazepine systems, not acting through the traditional mechanisms that benzodiazepines do.[1]

The underlying mechanism of Buspirone is unclear, however it is thought that its main pharmacology is mediated via the 5-HT1A receptors. It also binds at dopamine type 2 (DA2) receptors, blocking presynaptic dopamine receptors. The 5-HT receptors are divided into seven main types, with further sub-divisions for the 5-HT1, 5-HT2, and 5-HT3 receptors into A, B, and D subtypes found in the central nervous system and blood in vessels.[6] Coupled to inhibitory G-proteins, the 5-HT1A receptors have an inhibitory effect on neurotransmission when bound by an agonist.[10] It had been previously suggested that buspirone has a high affinity for the DA agonist and a low affinity for antagonist binding sites, concluding that the drug acts as a presynaptic DA agonist. However, it has since been confirmed that buspirone is without presynaptic agonist activity.[11], but that it does possess antagonist activity at the DA autoreceptors.

Benzodiazepines inhibit the neuronal activity of dopaminergic neurons in the substantianigra.[2] Antipsychotics, on the other hand, enhance firing in this region of the brain. Buspirone also enhances firing in this region. In the locus coeruleus, which is an area of the brain where norepinephrine cell bodies are located in high concentration, buspirone moderately increases firing in noradrenergic neurons. In the same region, benzodiazepines inhibit firing. The end result of buspirone’s actions is the suppression of serotonergic activity while the noradrenergic and dopaminergic cell firing is boosted.[2]


[top]Chemistry of Buspirone[1]

Systematic (IUPAC) name:8-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-8-azaspiro[4.5]decane-7,9-dione
Synonyms:Ansial, Anxut, Bespar, Buspar (hydrochloride)
Molecular Formula:C21H31N5O2, C21H31N5O2.HCl (hydrochloride)
Molar mass:385.51 g/mol, 421.97 g/mol (hydrochloride)
CAS Registry Number:36505-84-7, 33386-08-2 (hydrochloride)
Melting Point:201.5-202.5 °C (hydrochloride)
Boiling Point:no data
Flash Point:no data
Solubility:Hydrochloride very soluble in water; freely soluble in methanol, dichloromethane; sparingly soluble in ethanol, acetonitrile; very slightly soluble in ethyl acetate; practically insoluble in hexanes
Additionnal data:pKa1 4.12, pKa2 7.32
Notes:Hydrochloride crystallized from absolute ethanol
[1]


[top]The Dangers of Buspirone

[top]Buspirone Overdose

Emergency medical care should be notified if too much of the drug has been taken by an individual. Overdose symptoms include nausea, vomiting, dizziness, drowsiness, blurred vision, and stomach pain.[3]

[top]Addiction

Buspirone's potential for abuse has been extensively assessed through clinical trials and controlled studies, and unlike agents such pentobarbital or oxazepam, the preclinical pharmacology of buspirone as an “anxioselective” profile of action, defined as the relief of anxiety in the absence of muscle relaxation, seizure control, significant interaction with central nervous system depressants, physical dependence and the propensity to promote abuse.[2]

[top]Physical Addiction

Buspirone does not cause physical dependence. The safety of buspirone has been evaluated in depth and no indications of dependence or withdrawal symptoms are documented, including in the case of abrupt cessation of the drug. In a long term clinical study where more than 100 patients received buspirone continuously for one year at which treatment ceased, no drug dependence or withdrawal symptoms were reported.[12] Also, any benefits achieved during buspirone treatment are not reversed by the development of drug dependence or withdrawal symptoms when the drug is no longer taken. In this regard, buspirone may be superior to benzodiazepines in the treatment of GAD.[12] In comparison to patients treated with benzodiazepines such as diazepam, those who take buspirone do not experience withdrawal symptoms. The symptoms seen in patients after stopping benzodiazepine therapy constitute a true pharmacologic dependence and not a return to the state prior to treatment.[12]

In a study by Lader and Olajide, buspirone and benzodiazepines were chronically administered at 200 mg/kg per day to rats. After 21 days of treatment, the drug was withdrawn and changes in body weight were checked. With diazepam, as previously seen with dependence-producing drugs such as morphine and barbiturates, body weight dropped on two days of withdrawal. When drug treatment was started again 2 days later, changes in body weight returned to their normal weight. In contrast, stopping buspirone treatment resulted in an increase in body weight, which returned to the base line rate of gain when drug treatment was reinstituted. Secondly, chronic treatment with barbiturates followed by withdrawal can lead to convulsions. Benzodiazepines, such as diazepam, block these withdrawal-induced convulsions, whereas buspirone is inactive. Users do not appear to develop a tolerance to the drug's effects, and no withdrawal syndrome occurs after long-term use is abruptly stopped.[12] It was also found that buspirone is not cross-tolerant and does not suppress benzodiazepine withdrawal symptoms.[12]

[top]Buspirone and Alcohol Withdrawal Management[13]

Benzodiazepines have often been a choice drug for the treatment of alcohol withdrawal syndrome because of their anticonvulsant properties. However, problematic side-effects can occur. Repeated daily doses of benzodiazepines even for short periods results in accumulations of parent compounds or metabolites in the body. These unwanted effects may not be seen until sometime after discontinuation of the benzodiazepines. Early in the use of benzodiazepine treatment, excessive drowsiness is experienced that is frequent and not desirable. Other unwanted effects are lethargy, ataxia, diplopia, and confusion. Other pharmacologic agents have also been used with certain degrees of success, such as phenobarbital, beta blockers, magnesium sulphate, and clonidine. Buspirone’s low side-effects and profile that differs from benzodiazepines in both chemical and pharmacologic properties make it a good alternative to benzodiazepines. It does not have the sedating side-effects or psychomotor impairment common with benzodiazepines, and has no addiction or abuse potential. In a study where buspirone was administered to 118 patients for alcohol withdrawal, staff working with the patients reported higher satisfaction with patients using buspirone compared to patients with benzodiazepines. The study participants on buspirone were more alert after 24 hours of taking the drug compared to those on benzodiazepines as they were not sedated and able to attend AA meetings. As well, comments and reviews from the participants themselves were extremely positive. Some comments included enjoying the non-sedative properties of buspirone while still experiencing feelings of calmness and relaxation, and also the peace of mind about using a non-addictive substance compared to one that is.[13]

[top]Mental Addiction

Buspirone has no reinforcing effects as a drug for recreational purposes and as such, is not considered a drug of abuse. One of the major benefits Buspirone has over other drugs used to treat anxiety such as benzodiazepines is its lack of recreational properties. In a study with the Addiction Research Center, buspirone’s potential for recreational abuse was assessed in the laboratory of Cole and colleagues. [14] The study used participants who were recreational sedative abusers, and were given doses of various drugs and asked to indicate their impression of the drug recently consumed. A sixteen centimeter linear scale was used, where a score of zero would reflect extreme dislike and a score of 16 would reflect an extremely favourable impression. The benzodiazepine diazepam at 20 mg produced a score of 10.6, while 10 mg produced a neutral. On par with a placebo, buspirone produced liking scores of 3 and 4.[14]


[top]Legal Status of Buspirone

The FDA approved buspirone in 10 mg strength September 1986.[15] In April 1996, tablet strength 15 and 30 mg was approved.[15]

[top]History of Buspirone

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. It was initially developed as antipsychotic drug acting on dopamine (DS) D2 receptors, but it was soon discovered that while administration of the drug alleviated aggressive behaviour and anxiety, it was ineffective for the targeted psychotic symptoms.[4] Buspirone became the first nonbenzodiazepine approved by the Food and Drug Administration for the treatment of GAD in 1986[4]


[top]The Latest Buspirone Threads


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[top]References

  1. ^ a b c d e f http://www.drugbank.ca/drugs/DB00490
  2. ^ a b c d http://www.sciencedirect.com/science/article/pii/0002934386903256
  3. ^ a b http://www.drugs.com/buspirone.html
  4. ^ a b c d e f g h i j k l http://www.bmscanada.ca/static/products/en/pm_pdf/Buspar_EN_PM.pdf
  5. ^ a b http://www.minddisorders.com/Br-Del/Buspirone.html#b#ixzz2DANG8O8J
  6. ^ a b c d e f g h http://www.sciencedirect.com/science/article/pii/S0006899312007263
  7. ^ a b http://iospress.metapress.com/content/9LPP72UV9FNW4F54
  8. ^ a b http://www.ncbi.nlm.nih.gov/pubmed/15895552
  9. ^ http://www.ncbi.nlm.nih.gov/pubmed/1035004
  10. ^ http://www.sciencedirect.com/science/article/pii/0006295283906275
  11. ^ http://www.sciencedirect.com/science/article/pii/0091305782905081
  12. ^ a b c d e http://www.ncbi.nlm.nih.gov/pubmed/2880872
  13. ^ a b http://www.sciencedirect.com/science/article/pii/074054729090021H
  14. ^ a b http://www.sciencedirect.com/science/article/pii/0002934387901999
  15. ^ a b https://www.federalregister.gov/articles/2010/10/19/2010-26214/determination-that-buspar-buspirone-hydrochloride-tablets-10-milligrams-15-milligrams-and-30#h-5

[1]Merck Index, fifteenth edition (2013)


Contributors: John_bob, Docta, BitterSweet
Created by BitterSweet, 26-11-2012 at 05:34
Last edited by John_bob, 28-04-2014 at 20:40
Last comment by BitterSweet on 27-11-2012 at 12:31
1 Comments, 13,179 Views

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