indication

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.

pharmacology

Buspirone is used in the treatment of generalized anxiety where it has advantages over other antianxiety drugs because it does not cause sedation (drowsiness) and does not cause tolerance or physical dependence. Buspirone differs from typical benzodiazepine anxiolytics in that it does not exert anticonvulsant or muscle relaxant effects. It also lacks the prominent sedative effect that is associated with more typical anxiolytics. in vitro preclinical studies have shown that buspirone has a high affinity for serotonin (5-HT_1A) receptors. Buspirone has no significant affinity for benzodiazepine receptors and does not affect GABA binding in vitro or in vivo when tested in preclinical models. Buspirone has moderate affinity for brain D2-dopamine receptors. Some studies do suggest that buspirone may have indirect effects on other neurotransmitter systems.

mechanism of action

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.

toxicity

Oral, rat LD₅₀ = 136 mg/kg. Symptoms of overdose include dizziness, drowsiness, nausea or vomiting, severe stomach upset, and unusually small pupils.

biotransformation

Metabolized hepatically, primarily by oxidation by cytochrome P450 3A4 producing several hydroxylated derivatives and a pharmacologically active metabolite, 1-pyrimidinylpiperazine (1-PP)

absorption

Rapidly absorbed in man. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism.

half life

2-3 hours (although the action of a single dose is much longer than the short halflife indicates).

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.

drug interactions

Clarithromycin: Clarithromycin may increase the effect and toxicity of buspirone.

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Diltiazem: The calcium channel blocker, diltiazem, increases the effect and toxicity of buspirone.

Erythromycin: The macrolide, erythromycin, may increase the effect and toxicity of buspirone.

Isocarboxazid: Possible blood pressure elevation

Josamycin: The macrolide, josamycin, may increase the effect and toxicity of buspirone.

Nefazodone: Nefazodone increases the effect of buspirone

Phenelzine: Possible blood pressure elevation

Rasagiline: Possible blood pressure elevation

Rifabutin: Rifabutin decreases the effect of buspirone

Rifampin: Rifampin decreases the effect of buspirone

Ritonavir: Ritonavir increases the effect and toxicity of buspirone

Telithromycin: Telithromycin may reduce clearance of Buspirone. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Buspirone if Telithromycin is initiated, discontinued or dose changed.

Tranylcypromine: Buspirone may increase the adverse effects of Tranylcypromine. Elevation of blood pressure may occur. Concomitant therapy also may increase the risk of serotonin syndrome. Concomitant therapy should be avoided.

Trazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Trimipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Verapamil: Verapamil may increase the serum concentration of Buspirone. The likely occurs via Verapamil-mediated CYP3A4 inhibition resulting in decreased Buspirone metabolism. Monitor for changes in the therapeutic/adverse effects of Buspirone if Verpamil is initiated, discontinued or dose changed.

Voriconazole: Voriconazole may increase the serum concentration of buspirone likely by decreasing its metabolism via CYP3A4. Monitor for changes in the therapeutic and adverse effects of buspirone if voriconazole is initiated, discontinued or dose changed.

Zolmitriptan: Use of two serotonin modulators, such as zolmitriptan and buspirone, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.