🧬 Receptor activity
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| 5-hydroxytryptamine receptor 1A | — | Ki 12.59 nM | CHEMBL | Target5-hydroxytryptamine receptor 1A Action— AffinityKi 12.59 nM SourceCHEMBL |
| Adrenergic receptor alpha-2 | — | Ki 5011.87 nM | CHEMBL | TargetAdrenergic receptor alpha-2 Action— AffinityKi 5011.87 nM SourceCHEMBL |
Mechanism of action
The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT<sub>1A</sub> 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<sub>1A</sub> receptors, or 5-HT<sub>1A</sub> autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT<sub>1A</sub> receptors expressed on hippocampus and cortex. 5-HT<sub>1A</sub> 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<sub>1A</sub> 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<sub>1A</sub> 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<sub>1A</sub> 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.
Pharmacodynamics
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<sub>1A</sub> receptors, or buspirone may induce adaptations of 5-HT<sub>1A</sub> 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.
Pharmacokinetics
Half-life
In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours.
Absorption
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.
Metabolism
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).
Protein binding
Based on the findings of an _in vitro_ protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein.
External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.