Barbiturates are sedative and antiepileptic drugs. Poisonings have reduced significantly since the introduction of the less toxic benzodiazepines. Overdose causes dose-dependent sedation, with significant poisoning with long-acting agents resulting in prolonged coma.

Management includes supportive care and maintenance of airway, if coma is present. In large, ingestions of long-acting agent, enhanced elimination techniques can be employed to lessen the duration of toxicity.

Commonly encountered agents include phenobarbitone (phenobarbital) and thiopentone. Pentobarbital is used in veterinary medicine but has gained some popularity as an agent of self-harm, usually being sourced online for this purpose.

Barbiturates enhance the inhibitory effects of gamma-aminobutyric acid (GABA) at the GABA-A receptor. This effect leads to an increase in the duration of chloride channel opening, resulting in greater chloride influx and therefore a higher degree of hyperpolarisation.

At higher doses barbiturates can have a direct effect at the GABA-A receptor, without the need for the presence of GABA.

Other effects include inhibition of excitatory neurotransmitters and depression of the reticular activating system (RAS)

There is an additive effect of barbiturates with other CNS depressants.

Barbiturates have a narrow therapeutic index, and mild signs of intoxication can occur with any ingestion above the therapeutic range, particularly in patients naïve to the drugs.

Phenobarbitone is the most common agent encountered. Doses >0.5g are normally associated with symptoms whilst those greater than 3g are more likely to cause severe effects including coma.

Whilst barbiturates are well absorbed orally, concentrations may not peak until 2-6 hours post ingestion, particularly in overdose.

The volume of distribution varies between individual barbiturates based on their lipophilicity, ranging from 0.25-2.0L/kg.

The primary site of metabolism is the liver via cytochrome P450 (mainly CYP2C9, CYP2C19, CYP3A4). Highly lipophilic barbiturates (e.g. thiopental, pentobarbital) are metabolised more rapidly leading to shorter duration of action.

Phenobarbital is less lipophilic and is metabolised more slowly leading to a prolonged duration of toxicity. Whilst liver metabolism still predominates, renal clearance has a greater role for phenobarbital compared to other drugs in this class.

The elimination half-life varies widely for most barbiturates (10-40h), except for phenobarbital (80-120h).

• CNS Effects: Dose-dependent CNS depression, from mild sedation to deep coma, respiratory depression, hypotonia, areflexia
• Cardiovascular effects: Hypotension (vasodilatation and cardiac depression at higher doses).
• Other effects: Hypothermia

Phenobarbital (and in some centres pentobarbital) serum concentrations are available and can help confirm the extent and expected duration of poisoning and thus help guide treatment.

Barbiturate poisonings present similarly to many other sedative ingestions including benzodiazepines, baclofen, GHB.

Airway and Breathing
Loss of airway protection and adequate ventilation are the main threats following barbiturate overdose. Intubation and ventilation should be undertaken promptly if required.

Circulation
Hypotension is common and at least initially is mainly driven by vasodilation. Initial treatment should be with intravenous fluids. If hypotension is resistant to fluid resuscitation, start a vasopressor.

Use: Adults: Noradrenaline 3 to 50 mcg/minute titrated to desired blood pressure target
Children: Noradrenaline 0.05 to 1 mcg/kg/minute titrated to desired blood pressure target

Cardiac depression can also occur. If escalating vasopressor doses are required, then addition of an inotrope (e.g. adrenaline) may be needed. A beside ECHO to assess cardiac function is very helpful in determining how to escalate treatment.

Activated Charcoal
Offer activated charcoal to patients up to 2 hours after oral overdose of a barbiturate, if they are alert, co-operative and able to protect their airway.

Give: 50g Activated Charcoal (Child: 1g/kg, max 50g)

In the case of phenobarbital, where absorption can be delayed, consider giving, even if it has been longer than 2 hours as long as they are alert, co-operative and able to protect their airway.

Multi-dose activated charcoal

Evidence for multi-dose charcoal for barbiturate poisoning varies with the drug and dose taken. In mild to moderate poisonings without haemodynamic or respiratory compromise, it is not beneficial.

Following large phenobarbital or primidone ingestions with coma, respiratory depression or cardiovascular toxicity then MDAC is more likely to be of benefit in shortening the duration of toxicity. MDAC (link)

Haemodialysis

Haemodialysis is unlikely to be of benefit following ingestion of shorter acting agents. In those ingesting longer acting agents it may reduce the duration of toxicity and should be considered in those with severe toxicity (after use of MDAC).

There is no specific antidote for the treatment of barbiturate toxicity.

Patients requiring intubation should be admitted to an intensive care unit.

Other patients need a minimum of 6 hours observation post time of ingestion for the onset of toxicity. Discharge patients after this observation period once they are alert and asymptomatic.

Patients on long-term barbiturate therapy are at risk of withdrawal, which normally develops within 48-72hours. Restart a patients regular barbiturate therapy once toxicity has resolved.

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2. Pond SM, Olson KR, Osterloh JD, Tong TG. Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal. JAMA 1984;251(23):3104–8. PDF
3. Roberts DM, Buckley NA. Enhanced elimination in acute barbiturate poisoning - a systematic review. Clin Toxicol (Phila) 2011;49(1):2–12. PDF
4. Barbiturate withdrawal - case report and nomogram. Drug and Alcohol Review 1995;14(4):385-8. PDF