Barbiturate toxicity has historically been associated with the highest risk of morbidity and mortality among all sedative-hypnotics. Barbiturates are still the most common class of antiepileptic drugs used in developing countries, but their use is declining due to the introduction of safer, less toxic sedative-hypnotics, such as benzodiazepines, and second-generation anticonvulsants.¹ Status epilepticus,² severe ethanol and sedative withdrawal syndromes,^3,4,5 and toxicologic seizures⁶ are typically managed with benzodiazepines, but barbiturates have a useful role as a second-line agent. They are still used in combination drugs (i.e., butalbital) and alone (i.e., secobarbital) for the treatment of tension and migraine headaches,^7,8 although the efficacy of either is controversial.⁹ Barbiturates are used in the pharmacologic management of refractory intracranial hypertension from focal and diffuse brain injury, but evidence of improved outcomes has been modest.¹⁰

Barbiturates are generally classified according to their duration of action, which is primarily dependent on lipid solubility and tissue distribution rather than the elimination half-life (Table 182-1).

Barbiturates readily distribute throughout the body to most tissues, crossing the blood–brain barrier and placenta, and are excreted in breast milk. Fetal blood barbiturate concentrations closely reflect maternal plasma levels, creating the potential for fetal withdrawal syndrome.¹¹ Most barbiturates are metabolized in the liver to inactive metabolites primarily through routes involving the cytochrome P450 system. The elimination half-life of barbiturates can be greatly shortened in infants and children and very prolonged in the elderly and in patients with liver or renal disease. Chronic barbiturate use induces activity of the cytochrome P450 enzymes and may accelerate the metabolism of other therapeutic drugs, such as oral contraceptives, anticoagulants, and corticosteroids, when taken concurrently.

Barbiturates’ main action is the depression of activity in the CNS and musculoskeletal system. In the CNS, this is accomplished by enhancing the action of the primary inhibitory neurotransmitter γ-aminobutyric acid at its receptor.¹² When γ-aminobutyric acid binds to its chloride channel receptor, it causes it to open, resulting in depolarization, which temporarily stabilizes the resting membrane potential and inhibits the firing of new action potentials. Barbiturates bind to the α subunit of the γ-aminobutyric acid receptor, causing an increase in the duration of time that the cell membrane chloride channel is open, resulting in prolonged depolarization and prolonged inactivity.

Benzodiazepines bind to a different site on the α subunit of the γ-aminobutyric acid receptor and increase the frequency with which the chloride channel opens. Increased duration, as opposed to increased frequency, is one of the reasons cited for increased morbidity and mortality with barbiturate overdoses compared to benzodiazepines.

Barbiturates inhibit both the activity of the excitatory neurotransmitter, glutamate, at the glutamate receptor and calcium-mediated excitatory neurotransmitter release at the presynaptic terminal. Blockade of the calcium channel may contribute to the cardiac contractility impairment seen with barbiturate overdoses. Barbiturates also have effects on voltage-dependent sodium and potassium channels, but in concentrations typically far above the therapeutic range.¹³ These effects may contribute to the toxicity or paradoxical actions seen with some barbiturate drugs in overdoses.

Mild to moderate barbiturate intoxication closely resembles alcohol intoxication and toxicity of other sedative-hypnotics; drowsiness, disinhibition, ataxia, slurred speech, and mental confusion are common features that escalate with increasing dose. The progressive neurologic depression seen with severe barbiturate intoxication predictably manifests as a range from stupor to coma to complete neurologic unresponsiveness, including the absence of a corneal reflex and deep tendon reflexes.

The most common vital sign abnormalities seen in overdose are respiratory depression, hypothermia, and hypotension, with respiratory depression usually occurring first. Abnormal temperature control and respiratory depression are centrally mediated phenomena, whereas hypotension is primarily a result of decreased vascular tone. Pulse rate, pupil size, light reactivity, and nystagmus are variable. GI tract motility is slowed, resulting in delayed gastric emptying and ileus. Skin bullae, sometimes referred to as “barb blisters” or “coma blisters,” are uncommon and may indicate nothing more than the effects of local skin pressure, although hypoxia has been implicated as well.¹⁴ Coma blisters are not specific to sedative-induced coma; they have been reported after surgery,¹⁵ from other causes of coma,¹⁶ and even without coma.¹⁷