Buspirone (BuSpar)
Buspirone
Brand Name: BuSpar®
Classification:
Psychotropic Agents
» Anxiolytics, Sedatives, and Hypnotics
Description: Buspirone is an orally administered anxiolytic that is structurally and pharmacologically distinct from all other anxiolytics including benzodiazepines and barbiturates. Buspirone also differs from other anxiolytics in that it does not possess anticonvulsant or muscle-relaxant properties, does not impair psychomotor function, and does not cause sedation or physical dependence. Thus, an advantage of buspirone over benzodiazepine anxiolytics is that buspirone does not impair state of arousal or attentiveness. Buspirone is not used for immediate relief because its onset of anxiolytic effects can be as long as 2 weeks. The clinical use of buspirone is for the treatment of generalized anxiety disorder (GAD). Buspirone was approved by the FDA in September 1986. A topical patch that would be changed daily began phase III investigation for ADHD February 1997.
Mechanism of Action: The mechanism of action of buspirone is not clearly understood since anxiety may be mediated by more than one neuropathway. In general, buspirone suppresses serotonergic activity while enhancing noradrenergic and dopaminergic cell firing. Buspirone does not inhibit monoamine oxidase. Buspirone does not have any significant activity at benzodiazepine receptors, nor does it affect GABA receptors, however buspirone has some inhibitory actions on GABAergic pathways. In vitro, buspirone exhibits highest affinity for serotonin (5-HT) type 1A receptors, moderate affinity for dopamine type 2 (DA2) receptors, and weak affinity for serotonin type 2 (5-HT2) receptors. Type 1A serotonin receptors are found in high quantities in the dorsal raphe and the hippocampus. Buspirone binding to type 1A serotonin receptors occurs on presynaptic neurons in the dorsal raphe and on postsynaptic neurons in the hippocampus. Animal studies reveal that buspirone inhibits the firing rate of 5-HT-containing neurons in the dorsal raphe. The dominant action of buspirone is partial agonism or mixed agonism/antagonism at 5-HT type 1A receptors.
Buspirone also binds at dopamine type 2 (DA2) receptors, displaying properties of both a dopamine agonist and an antagonist. Buspirone blocks presynaptic dopamine receptors, however, effects on postsynaptic receptors are conflicting. Affinity for dopamine receptors differentiates buspirone from gepirone, a related investigational agent which does not interact with dopamine receptors.
Buspirone increases firing in the locus ceruleus, an area of brain where norepinephrine cell bodies are found in high concentration. Benzodiazepines, in contrast, decrease firing in the locus ceruleus. This may explain why benzodiazepines cause drowsiness while buspirone does not.
The net result of buspirone actions at serotonin and dopamine receptors and related secondary messengers is inhibition of the synthesis and release of serotonin, however, since anxiety is thought to be mediated via multiple CNS pathways, the effects on serotonin do not totally explain the anxiolytic action of buspirone. Clinically, buspirone relieves the symptoms associated with generalized anxiety disorder such as motor tension (restlessness, twitching, and muscle tension); autonomic hyperactivity (sweating, palpitations, and tachycardia); and vigilance and scanning.
 Buspirone Tablets (Tab 15 mg)
The immunosuppressive action of buspirone appears to be distinct from its anxiolytic action. Buspirone has no muscle relaxant activity, anticonvulsant activity, and does not lead to dependence after chronic administration.
Pharmacokinetics: After oral administration, buspirone is rapidly and almost completely absorbed, but only about 4% of a dose reaches systemic circulation because of extensive first-pass metabolism in the liver. When given with food, the AUC and Cmax of buspirone increase by roughly 84% and 116%, respectively; food may decrease the presystemic clearance of buspirone. For this reason, buspirone should be taken in a consistent manner with regard to the timing of dosing; either always with or always without food. The onset of anxiolytic effect can take 3 - 6 weeks.
Distribution of buspirone in the human body has not been fully elucidated. An in vitro binding study inicated that approximately 86% of buspirone is bound to plasma proteins. Buspirone and its metabolites are found in breast milk. Metabolism of buspirone occurs in the liver primarily by oxidation, which in vitro has been shown to be mediated by cytochrome P450 3A4 (CYP3A4). Buspirone has a major active metabolite, 1-PP, whose anxiolytic effect in humans has not been established. There are other hydroxylated, inactive derivatives. In a single-dose study, 29 - 63% of a buspirone dose was excreted in the urine within 24 hours, primarily as metabolites; fecal excretion accounted for 18 - 38% of the dose. The average elimination half-life of buspirone is roughly 2 - 4 hours in healthy adults.
Special Populations: After single or multiple doses in adults, no significant differences in buspirone pharmacokinetics (AUC and Cmax ) were observed between elderly and younger subjects or between men and women. Pharmacokinetic studies have shown that, for identical doses (i.e., 7.5 - 30 mg), plasma exposure to buspirone and its active metabolite, 1-PP, are equal to or higher in pediatric patients (age 6 - 17 years) than adults. A pharmacokinetic study in patients with impaired hepatic or renal function demonstrated increased plasma levels and a lengthened half-life of buspirone. After multiple-dose administration to patients with hepatic impairment or renal impairment (i.e., CrCl 10 - 70 ml/min), steady-state AUC of buspirone increased 13-fold or 4-fold, respectively, compared with healthy adults. Therefore, the administration of buspirone to patients with severe hepatic or renal impairment cannot be recommended.
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References
. Eison AS, Temple DL. Buspirone: Review of its pharmacology and current perspectives on its mechanism of action. Am J Med 1986;80(suppl 3B):1 - 9.
[ Revised 3/1/2006 2:41:00 PM ]
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