Features
The symptoms of Apaurin overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, bradycardia, nystagmus) or paradoxical excitation. In most cases only observation of vital functions is required.
Extreme overdosage may lead to coma, areflexia, cardiorespiratory depression and apnoea, requiring appropriate countermeasures (ventilation, cardiovascular support). Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease. Severe effects in overdose also include rhabdomyolysis and hypothermia.
Management
Maintain a clear airway and adequate ventilation.
Consider activated charcoal (50g for an adult, 1g/kg for a child) in adults who have taken more than 100mg or children who have taken more than 1mg/kg within one hour, provided they are not too drowsy.
Monitoring level of consciousness, respiratory rate, pulse oximetry and blood pressure in symptomatic patients.
Consider arterial blood gas analysis in patients who have a reduced level of consciousness (GCS < 8; AVPU scale P or U) or have reduced oxygen saturations on pulse oximetry.
Correct hypotension by raising the foot of the bed and by giving an appropriate fluid challenge. Where hypotension is thought mainly due to decreased systemic vascular resistance, drugs with alpha-adrenergic activity such as noradrenaline or high dose dopamine (10-30 micrograms/kg/min) may be beneficial. The dose of inotrope should be titrated against blood pressure.
If severe hypotension persists despite the above measures, then central venous pressure monitoring should be considered.
Supportive measures are indicated depending on the patient's clinical state.
Benzodiazepines are not significantly removed from the body by dialysis.
Flumazenil, a benzodiazepine antagonist, is not advised as a routine diagnostic test in patients with reduced conscious level. It may sometimes be used as an alternative to ventilation in children who are naive to benzodiazepines, or in patients with COPD to avoid the need for ventilation. It is not necessary or appropriate in cases of poisoning to fully reverse the benzodiazepine effect. Flumazenil has a short half-life (about an hour) and in this situation an infusion may therefore be required. Flumazenil is contraindicated when patients have ingested multiple medicines, especially after co-ingestion of a benzodiazepine and a tricyclic antidepressant or any other drug that causes seizures. This is because the benzodiazepine may be suppressing seizures induced by the second drug; its antagonism by flumazenil can reveal severe status epilepticus that is very difficult to control.
Contraindications to the use of flumazenil include features suggestive of a tricyclic antidepressant ingestion including a wide QRS, or large pupils. Use in patients postcardiac arrest is also contraindicated.
It should be used with caution in patients with a history of seizures, head injury, or chronic benzodiazepine use.
Occasionally a respirator may be required but generally few problems are encountered, although behavioral changes are likely in children.
If excitation occurs, barbiturates should not be used.
Effects of overdose are more severe when taken with centrally-acting drugs, especially alcohol, and in the absence of supportive measures, may prove fatal.
None known.
Not applicable.
ATC code: N05B A01
Pharmacotherapeutic group: Apaurin is a benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant and amnesic properties.
Absorption
Apaurin is readily and completely absorbed from the GI tract.
Distribution
Peak plasma concentration occurring within 30-90 minutes of oral administration; the rate of absorption is age related and tends to be delayed in the elderly. Apaurin crosses the blood-brain barrier and is highly lipid soluble. Apaurin is very extensively bound to plasma proteins.
Apaurin and its metabolites cross the placental barrier and are excreted in breast milk.
Biotransformation
It has a biphasic half-life with an initial rapid distribution phase followed by a prolonged terminal elimination phase of 1-2 days; its action is further prolonged by the even longer half-life of 2-5 days of its active principle metabolite, desmethylApaurin, the relative proportion of which increases in the body on long-term administration.
Apaurin is extensively metabolised in the liver and, in addition to desmethylApaurin, its active metabolites include oxazepam and temazepam.
The half-life of Apaurin is prolonged in neonates, in the elderly and in patients with kidney or liver disease.
Elimination
It is excreted in the urine, mainly in the form of its metabolites, either free or in conjugated forms.
Not applicable.
Administrative data
