Buspirone

The miscellaneous anxiolytics, sedatives and hypnotics are a diverse group of drugs mostly with unknown mechanisms of action that produce central nervous system depression in overdose. Most are older drugs(chloral hydrate was synthesised in 1832) that have been superseded in clinical practice by the benzodiazepines. In relatively small doses, the older agents can cause a profound, prolonged and occasionally cyclical coma, respiratory depression and death (especially when cardiac arrhythmias accompany the toxic profile). Toxicity is even more severe with sedative coingestants, especially alcohol and opiates, and advanced age is an additional risk factor for severe toxicity. These features have led to a questioning of their therapeutic role (1). Acute overdose toxicity and risk of death has been observed disproportionately with chloral hydrate but death has been reported after overdose with all the older agents.

In any discussion of toxic doses of sedative-hypnotic drugs, there will always be considerable variation due to interindividual differences in tolerance and the contribution or otherwise of active metabolites.

Serotonin toxicity has been seen when therapeutic doses of buspirone have been combined with serotonin uptake inhibitors (5–8), monoamine oxidase inhibitors (9;10) and possibly on its own (11) although it has been used successfully to treat serotonin uptake inhibitor adverse effects (12). Daily doses as high as 375 mg have been administered to healthy male volunteers; near this dosage, nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress occurred (13). Doses up to 2400 mg daily were administered during early trials where akathisia, tremor, and rigidity were observed (14). Deliberate self-poisoning with 250 mg (14) and up to 300 mg (15) resulted in drowsiness in about one half of patients. One fatality followed ingestion of 450 mg of buspirone with other drugs (alprazolam, diltiazem, alcohol, and cocaine) (16).

In most cases, it is the development of tolerance to sedative-hypnotics that determines the recovery of consciousness after overdose rather than the clearance of the drug. In general, because of tolerance and the active metabolites of these drugs, there is a poor correlation between concentration and effect.

Little or no information is available on the toxicokinetics/ toxicodynamics of buspirone.

Buspirone is a partial agonist at the 5-HT1A receptor. 5-HT1A receptor sites are located on both presynaptic and postsynaptic neurons. The net effect of the binding of buspirone to these 5-HT1A receptors is a reduction in serotonergic activity (implying greater effect on pre-synaptic autoreceptors than post-synaptic heteroceptors)(13). Buspirone has a direct antagonist effect on the presynaptic dopamine receptor, thus increasing dopaminergic transmission; it does not interact directly with noradrenergic receptors but decreased serotonergic activity may lead to a secondary increase in noradrenergic activity (13). Buspirone does not interact directly with either the benzodiazepine-GABA receptor complex or with GABA receptors (111), but there is some evidence that buspirone enhances benzodiazepine receptor binding in vivo (112). Nevertheless, benzodiazepine antagonists (e.g. flumazenil) do not reverse buspirone effects (113) and buspirone is ineffective in ameliorating features of benzodiazepine withdrawal in man (114). There is evidence for the development of tolerance to some of the effects of buspirone that does not seem to be due to a change in the binding properties of the 5-HT1A receptor itself but may be due to a change in its coupling mechanism (115). The abuse liability of buspirone appears lower than that of the benzodiazepines (116).

Only mild toxicity is to be expected even after very large doses of buspirone. Nausea, vomiting, dizziness, drowsiness (15), miosis and gastric distress may occur at lower doses (13) while akathisia, tremor and rigidity may occur at higher doses(14). Combined overdose with a serotonergic agent may produce features of serotonin toxicity (5–10). There is one case of buspirone overdose that resulted in a generalized tonic clonic seizure approximately 36 hours after ingestion(154). A combined overdose with fluvoxamine resulted in prolonged bradycardia (155). Death from buspirone alone has not been reported.

Withdrawal from central nervous system depressants is dealt with in more detail in the drug withdrawal monograph. Suddenly stopping treatment in dependent people may produce withdrawal symptoms and signs including anxiety, dysphoria, irritability, insomnia, nightmares, sweating, memory impairment, hallucinations, hypertension, tachycardia, psychosis, tremors and seizures (227). The withdrawal syndromes associated with the older agents are similar to those associated with barbiturates (228); they are severe and likely to be associated with life-threatening events such as seizures. Acute withdrawal from sedative-hypnotics may present solely as a confusional state due to non-convulsive status epilepticus (toxic ictal delirium) which can easily be missed (229).

Common adverse effects include dizziness, light-headedness, headache, nausea, nervousness and excitement. Rare adverse effects include tachycardia, palpitations, chest pain, confusion, drowsiness, dry mouth, sweating, dystonia, akathisia, tardive dyskinesia, serotonin toxicity and angioedema (230).

Routine quantitative drug estimation is not readily available for any of these agents and not indicated for routine management. Hepatic and renal function tests are indicated. Measurement of creatine kinase in cases of coma will help in the assessment of rhabdomyolysis. Core body temperature should be assessed as hypothermia is common. Chest X-ray is helpful to assess for noncardiogenic pulmonary oedema in a patient with oxygen desaturation. Measurement of partial pressure of carbon dioxide via expired air or arterial blood gases is the best way to assess respiratory compromise from sedation.

For many drugs, there is a postmortem diffusion of drugs along a concentration gradient, from sites of high concentration in solid organs, into the blood with resultant artifactual elevation of drug concentrations in blood (postmortem redistribution). Highest drug concentrations are found in central vessels such as pulmonary artery and vein, and lowest concentrations are found in peripheral vessels such as subclavian and femoral veins. This creates major difficulties in interpretation and undermines the reference value of data bases where the site of origin of postmortem blood samples is unknown (240). It is widely agreed, however, that the femoral vein site represents the optimum sampling site and this site is now standardised amongst forensic pathologists.

Oral activated charcoal is unlikely to be of value in pure buspirone poisoning. It may be given to patients who have recently (within 1 hour) ingested buspirone with other drugs that may benefit from decontamination.

The preferred treatment for buspirone poisoning is entirely supportive with IV access and fluids and maintenance of the airway and ventilation if required. Non-cardiogenic pulmonary oedema should be managed along conventional lines. In the face of continuing hypotension not responding to fluid resuscitation, inotropic agents may be required.

Patients with a significant sedative drug overdose should be advised not to drive until potential interference with psychomotor performance has resolved(260). For overdose of most of these agents this will be at least 48 hours after discharge.

Principles of elimination enhancement are discussed in the Treatment monograph. Based on their volumes of distribution and plasma protein binding (277), there is no indication for extracorporeal techniques in buspirone poisoning and there are no reports of their use in this poisoning.

Routine observation of vital signs, especially GCS airway patency and blood pressure, is indicated. For the older agents, continuous arterial blood pressure monitoring should be considered. Measurement of partial pressure of carbon dioxide via expired air or arterial blood gases is the best way to assess respiratory compromise from sedation.

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