丁螺环酮

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals

2.3

2.3

Breast Feeding; Lactation; Milk, Human; Anti-Anxiety Agents; Serotonin Agonists

Pharmaceuticals

201.5-202.5

201.5 - 202.5 °C

Positive

4.334729774

2.7

Thermo LTQ

Electrospray ionization

formic acid (5.3nM)

196.8 Ų [M]+ [CCS Type: DT; Buffer gas: N2; Ionization: APCI+; Dataset: TOXCAST; Source Identifier: DTXSID2022707]

195.97 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

199.3 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

Danger

H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]

P264, P270, P301+P316, P321, P330, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 4 reports by companies from 1 notifications to the ECHA C&L Inventory.

General symptomatic and supportive measures should be used along with immediate gastric lavage. Respiration, pulse, and blood pressure should be monitored as in all cases of drug overdosage. No specific antidote is known to buspirone, and dialyzability of buspirone has not been determined. (L1712)

Buspirone has been associated with infrequent serum aminotransferase elevations, but has not been linked to instances of clinically apparent liver injury in the published literature. Indeed, buspirone is often used as a control, noncytotoxic agent in assessment of other psychotropic drugs in vitro and in vivo. Buspirone is, nevertheless, metabolized in the liver by the P450 system (CYP 3A4) and has the potential of causing drug-drug interactions.

Relative to other anxiolytics, buspirone has low toxicity and potential for abuse. There have been no deaths reported from a buspirone overdose alone. In pharmacological trials, healthy male patients were given up to 375 mg daily and developed nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. While buspirone overdose typically resolves with complete recovery, high suspicion of other medication overdoses should be maintained and investigated. In a literature review, multiple reports of movement disorders, including dyskinesia, akathisia, myoclonus, parkinsonism, and dystonia, have been reported.

Buspirone binds to 5-HT type 1A serotonin receptors on presynaptic neurons in the dorsal raphe and on postsynaptic neurons in the hippocampus, thus inhibiting the firing rate of 5-HT-containing neurons in the dorsal raphe. Buspirone also binds at dopamine type 2 (DA2) receptors, blocking presynaptic dopamine receptors. Buspirone increases firing in the locus ceruleus, an area of brain where norepinephrine cell bodies are found in high concentration. The net result of buspirone actions is that serotonergic activity is suppressed while noradrenergic and dopaminergic cell firing is enhanced.

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

buspirone

BuSpar®

Anxiolytics

3

less-DILI-concern drugs

N - Nervous system

QN - Nervous system

The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT_1A receptors, or buspirone may induce adaptations of 5-HT_1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use.

The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT_1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT_1A receptors, or 5-HT_1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT_1A receptors expressed on hippocampus and cortex. 5-HT_1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT_1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT_1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT_1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist.

Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone.

Metabolized hepatically, primarily by oxidation by cytochrome P450 3A4 producing several hydroxylated derivatives and a pharmacologically active metabolite, 1-pyrimidinylpiperazine (1-PP) Route of Elimination: In a single-dose study using 14C-labeled buspirone, 29% to 63% of the dose was excreted in the urine within 24 hours, primarily as metabolites; fecal excretion accounted for 18% to 38% of the dose. Half Life: 2-3 hours (although the action of a single dose is much longer than the short halflife indicates).

Agents that alleviate ANXIETY, tension, and ANXIETY DISORDERS, promote sedation, and have a calming effect without affecting clarity of consciousness or neurologic conditions. ADRENERGIC BETA-ANTAGONISTS are commonly used in the symptomatic treatment of anxiety but are not included here.

Endogenous compounds and drugs that bind to and activate SEROTONIN RECEPTORS. Many serotonin receptor agonists are used as ANTIDEPRESSANTS; ANXIOLYTICS; and in the treatment of MIGRAINE DISORDERS.

Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes.

A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion.

In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg.

In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg.

Use (kg; approx.) in Germany (2009): >25

For the management of anxiety disorders or the short-term relief of the symptoms of anxiety, and also as an augmention of SSRI-treatment against depression.