Barbiturates have been used as hypnotic and sedative agents, for the induction of anesthesia, and for the treatment of epilepsy and status epilepticus. They have been largely replaced by newer drugs and calls to poison control centers have decreased significantly. They often are divided into four major groups according to their pharmacologic activity and clinical use: ultra-short-acting, short-acting, intermediate-acting, and long-acting (Table II-13); and combination products containing barbiturates plus aspirin and caffeine or barbiturates plus belladonna alkaloids. Veterinary euthanasia products often contain barbiturates such as pentobarbital.

1. All barbiturates cause generalized depression of neuronal activity in the brain. Interaction with a barbiturate receptor leads to enhanced gamma-aminobutyric acid (GABA)-mediated chloride currents and results in synaptic inhibition. Hypotension that occurs with large doses is caused by depression of central sympathetic tone as well as by direct depression of cardiac contractility.
2. Pharmacokinetics vary by agent and group (see Table II-13 and Table II-63).
   1. Ultra-short-acting barbiturates are highly lipid soluble and rapidly penetrate the brain to induce anesthesia, then are quickly redistributed to other tissues. For this reason, the clinical duration of effect is much shorter than the elimination half-life for these compounds.
   2. Long-acting barbiturates like phenobarbital are distributed more evenly and have long elimination half-lives, making them useful for once-daily treatment of epilepsy. Primidone is metabolized to phenobarbital and phenylethylmalonamide (PEMA); although the longer-acting phenobarbital accounts for only about 25% of the metabolites, it has the greatest anticonvulsant activity.

The toxic dose of barbiturates varies widely and depends on the drug, the route and rate of administration, and individual patient tolerance. In general, toxicity is likely when the dose exceeds 5-10 times the hypnotic dose. Chronic users or abusers may have striking tolerance to depressant effects.

1. The potentially fatal oral dose of the shorter-acting agents such as pentobarbital is 2-3 g, compared with 6-10 g for phenobarbital.
2. Several deaths were reported in young women undergoing therapeutic abortion after they received rapid IV injections of as little as 1-3 mg of methohexital per kilogram.

The onset of symptoms depends on the drug and the route of administration.

1. Lethargy, slurred speech, nystagmus, and ataxia are common with mild-to-moderate intoxication. With higher doses, hypotension, coma, and respiratory arrest commonly occur. With deep coma, the pupils are usually small or midposition but as the dose increases the patient may lose all reflex activity and can neurologically appear dead.
2. Hypothermia is common in patients with deep coma, especially if the victim has been exposed to a cool environment. Hypotension and bradycardia commonly accompany hypothermia.

Is usually based on a history of ingestion and should be suspected in any epileptic patient with stupor or coma. Although skin bullae sometimes are seen with barbiturate overdose, they are not specific for barbiturates. Other causes of coma should also be considered.

1. Specific levels of phenobarbital are usually readily available from hospital clinical laboratories; concentrations greater than 60-80 mg/L are usually associated with coma, and those greater than 150-200 mg/L with severe hypotension. For short- and intermediate-acting barbiturates, coma is likely when the serum concentration exceeds 20-30 mg/L.
2. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, arterial blood gases or pulse oximetry, and chest radiography.

1. Emergency and supportive measures
   1. Protect the airway and assist ventilation if necessary.
   2. Treat coma, hypothermia, and hypotension if they occur.
2. Specific drugs and antidotes. There is no specific antidote.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
4. Enhanced elimination
   1. Alkalinization of the urine increases the urinary elimination of phenobarbital (a weak acid) but not other barbiturates. Its value in acute overdose is unproven, and it may potentially contribute to fluid overload and pulmonary edema.
   2. Repeat-dose activated charcoal has been shown to decrease the half-life of phenobarbital and its metabolites, but data are conflicting regarding its effects on the duration of coma, time on mechanical ventilation, and time to extubation.
   3. Hemodialysis may be necessary for severely intoxicated patients who are not responding to supportive care (ie, with intractable hypotension). Continuous venovenous hemodiafiltration has been reported to accelerate elimination.