Benzodiazepines are sedating drugs, which do not usually cause either profound CNS or respiratory depression or any non-sedative effects. Deaths may occur prior to hospital due to sedation (particularly if combined with other sedative drugs e.g. alcohol) but the course of patients reaching hospital is generally uncomplicated. Zopiclone is not a benzodiazepine but has similar toxicity in overdose and binds to a similar site adjacent to the GABA-A receptor in the central nervous system.

MECHANISM OF TOXIC EFFECTS

Benzodiazepines bind to the benzodiazepine receptor, which modifies the gamma amino benzoic acid (GABA) chloride channel complex. Benzodiazepines enhance the effects of GABA. GABA is an inhibitory neurotransmitter and thus central nervous system depression occurs. Benzodiazepines also cause muscle relaxation and are anticonvulsant.

KINETICS IN OVERDOSE

Absorption

All benzodiazepines are lipid soluble drugs that are absorbed fairly rapidly. The rate of absorption is an important variable in determining the clinical effects of benzodiazepines. Rapid rises in serum concentrations lead to greater depth of sedation than slow rises to the same concentrations. The most rapidly absorbed drugs are temazepam and flurazepam and less rapidly absorbed drugs include oxazepam. The extent of absorption of these drugs is high.

Distribution

All these drugs are highly protein bound and have volumes of distributions of about 1 L/kg. They distribute well into the central nervous system.

Metabolism - Elimination

All benzodiazepines are hepatically metabolised with a renal clearance accounting for less than 5%. The half-life of these drugs varies widely and a number of drugs have active metabolites. Drug with a shorter half-life (temazepam, triazolam) and drugs with a longer half-life (diazepam, clonazepam) still have very similar spectrums of clinical toxicity. This is due to the development of tolerance to the effects of benzodiazepines. It is actually the development of tolerance to the benzodiazepines that determines the recovery of consciousness rather than the clearance of the drug.

CLINICAL EFFECTS

The clinical effects of benzodiazepine poisoning are due entirely to central nervous system depression. Severe poisonings may develop hypothermia, bradycardia, and hypotension, however this is unusual. Respiratory depression and depression of consciousness may lead to aspiration pneumonia. However, deep coma is unusual. Most patients are stuporous or still responsive to painful stimuli unless they have coingested other sedating drugs.

DIFFERENCES IN TOXICITY

Rapidly absorbed drugs lead to greater degrees of CNS depression than slowly absorbed drugs. There are differences in fatal toxicity within this class with temazepam and flurazepam having much higher rates of fatal overdose per prescription than other drugs such as oxazepam (Serfaty and Masterton 1993). This appears to be due to sedation as temazepam has been found more sedating in overdose than oxazepam (Buckley et al 1995). However, in a patient who presents with benzodiazepine overdose, these differences do not require any change to management. Zopiclone is not a benzodiazepine but has similar toxicity in overdose and binds to a similar site adjacent to the GABA-A receptor in the central nervous system.

DETERMINATION OF SEVERITY

The severity of sedative drug overdose should be measured using the Glasgow Coma Score, a seven point scale of unconsciousness or the McCarron Score. These all measure the depth of coma and this should be the indication for whether patients require intubation and/or ventilation.

TREATMENT

The preferred treatment is entirely supportive with maintenance of the airway and ventilation, IV access and fluids.

GI Decontamination

Oral activated charcoal is of no value in pure benzodiazepine poisoning. It may be given to patients who have recently (within 1-2 hours) ingested benzodiazepines with other drugs that may benefit from decontamination. Gastric lavage is not indicated.

Flumazenil

Flumazenil is a benzodiazepine antagonist. It may be used for either diagnosis or treatment.

Diagnostic use
Flumazenil (0.1-2.0 mg IV) may be given to unconscious patients where the drug ingested is unknown. A rapid response within a minute or two is expected in pure benzodiazepine poisoning. The patient should have a dramatic improvement in the level of consciousness. Minor improvements may be seen with alcohol and other sedative drugs. Flumazenil should only be given if there is no evidence of proconvulsant drug ingestion as the removal of the effects of benzodiazepines that have been coingested may lead to seizures or cardiac arrest.

Contraindications to flumazenil administration
Indications that the patient may have ingested proconvulsant drug include:

widened QRS complex on the ECG
hyperreflexia and myoclonus
anticholinergic signs
marked tachycardia
hypokalaemia

Elimination enhancement

This is not indicated.

LATE COMPLICATIONS

Long term sequelae are unusual and patients usually recover consciousness within twelve hours although the elderly may take considerably longer. Patients who fail to regain consciousness within this time should have a search made for alternative causes of sedation including non toxicological causes.

REFERENCES

Meredith TJ, Jacobsen D, Haines JA, Berger J-C (eds). Naloxone, flumazenil and dantrolene as antidotes. IPCS/CEC evaluation of antidotes series Vol 1. Cambridge University Press 1993
Gaudreault P, Guay J, Thivierge RL, Verdy I. Benzodiazepine poisoning. Clinical and pharmacological considerations and treatment. Drug Safety 1991;6:247-265.
Hoffman RS, Goldfrank LR. The poisoned patient with altered consciousness. Controversies in the use of a 'coma cocktail'. JAMA 1995;274:562-569.
Buckley NA, Whyte IM, Dawson AH, O'Connell D. The relative toxicity of benzodiazepines in overdose. BMJ 1995;310:219-221. (see also