INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Barbiturates are the earliest known class of sedative-hypnotic agents and were once extremely popular drugs to abuse. Benzodiazepines largely have replaced barbiturates for outpatient medical therapy, which has created a decline in barbiturate abuse. Stricter guidelines dictating barbiturate use have led to decreased availability as well.

Pathophysiology: Barbiturates bind to specific sites on gamma-aminobutyric acid (GABA)-sensitive ion channels found in the central nervous system (CNS), where they allow an influx of chloride into cell membranes and, subsequently, hyperpolarize the postsynaptic neuron.

GABA and glycine are the major inhibitory neurotransmitter in the CNS. Barbiturates enhance GABA-mediated chloride currents by binding to the GABA A receptor-ionophore complex and increasing the duration of ionophore opening; barbiturates inhibit neuronal depolarization by potentiating and prolonging the actions of GABA. At high doses, barbiturates stimulate GABA A receptors directly in the absence of GABA. Barbiturates also block glutamate (excitatory neurotransmitter) receptors in the CNS.

Barbiturates may be grouped functionally into long-acting and short-acting agents (consisting of ultrashort, short, and intermediate-acting agents). Compared to long-acting agents, short-acting agents are more lipid soluble, more protein bound, have a higher pKa, a more rapid onset and shorter duration of action, and are metabolized almost entirely in the liver to inactive metabolites (which are excreted as glucuronides in the urine). Long-acting agents, which are less lipid soluble, accumulate more slowly in tissue and are excreted more readily by the kidney as active drug. For instance, urinary excretion accounts for 20-30% of phenobarbital and 15-42% of primidone elimination (both long-acting agents).

Short-acting agents have an elimination half-life less than 40 hours compared to long-acting agents, which have an elimination half-life longer than 40 hours.

An ultra–short-acting agent mainly used for procedural sedation, propofol, deserves mention here. It is barbiturate-like in its activity at the GABA receptor, its pharmacologic effects (respiratory depression and hypotension) and its lipophilic nature. However, its chemical structure is not analogous. Because of its short half-life of 3 minutes, it must be used in an intravenous infusion for long sedation. Additionally, its side effects, particularly respiratory depression, are compounded by benzodiazepines, opioids, and ethanol.

Propofol is only available in an intravenous formulation with a soy milk base and is not absorbed by the intramuscular, subcutaneous, or sublingual routes. Propofol is associated with a unique infusion syndrome that can last several hours after the intravenous formulation has stopped. This results from susceptible patients' inability to metabolize medium and long chain fatty acids that comprise the vehicle, soybean milk. Additionally, allergy to soy products is a relative contraindication to its use.

Barbiturates stimulate the hepatic cytochrome P-450 mixed function oxidase microsomal enzyme system; thus, barbiturates affect the drug levels of medications that are dependent on this system usually by increasing their metabolism (eg, Coumadin).

Central nervous system effects

Barbiturates mainly act in the CNS, though they may indirectly affect other organ systems. Direct effects include sedation and hypnosis at lower dosages. The lipophilic barbiturates, such as thiopental, cause rapid anesthesia because of their tendency to penetrate brain tissue quickly. Barbiturates all have anticonvulsant activity because they hyperpolarize cell membranes; therefore, they are effective adjuncts in the treatment of epilepsy.

Pulmonary effects

Barbiturates can cause a depression of the medullary respiratory center and induce a respiratory depression. Patients with underlying chronic obstructive pulmonary disease (COPD) are more susceptible to these effects, even at doses that would be considered therapeutic in healthy individuals. Barbiturate overdose fatality is usually secondary to respiratory depression.

Cardiovascular effects

Cardiovascular depression may occur following depression of the medullary vasomotor centers; patients with underlying congestive heart failure (CHF) are more susceptible to these effects. At higher doses, cardiac contractility and vascular tone are compromised, which may cause cardiovascular collapse.

Frequency:

• In the US: Barbiturate abuse was popular in the 1960s and 1970s. Since then, however, its popularity has waned because of stricter guidelines for use and the advent of benzodiazepines, which inherently have lower cardiorespiratory toxicity. These two factors have decreased barbiturate availability significantly and have led to less abuse. However, a recent gradual increase in barbiturate abuse has been observed among high school seniors.

Mortality/Morbidity: Fatality associated with barbiturate overdose is rare, but complications are abundant. Morbidity includes pneumonia, acute respiratory distress syndrome (ARDS), shock, hypoxia, and coma.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History:

• As with any overdose, make and effort to ascertain the exact substance and quantity ingested, the time of ingestion, and possible co-intoxicants, especially alcohol. Remember that some barbiturates are included in combination drugs (eg, Fioricet [butalbital, acetaminophen]; Donnatal [phenobarbital, hyoscyamine, scopolamine, atropine]) with components that also may have toxicity.

• Investigate to determine if the barbiturate overdose represents a suicide attempt.

• Do not overlook the patient's medical history. Most notably, a history of liver disease could suggest potential prolongation of toxic effects.

Physical: A full physical examination is warranted in any overdose. Record vital signs. The patient with barbiturate toxicity may present with any or all of the following symptoms:

• Neurologic
  • Lethargy

  • Coma

  • Hypothermia

  • Decreased pupillary light reflex

  • Nystagmus

• Strabismus

• Vertigo

• Slurred speech

• Ataxia

• Decreased deep tendon reflexes

• Psychiatric

• Impairment in thinking (eg, memory disturbances, poor judgment, limited attention span) (A delirium of any fashion is a cardinal feature.)

• Irritability

• Combativeness

• Paranoia

• Respiratory

• Respiratory depression

• Apnea

• Hypoxia

• Acute respiratory distress syndrome

• Cardiovascular

• Tachycardia

• Bradycardia

• Hypotension

• Diaphoresis

• Shock

• Gastrointestinal - Decreased bowel sounds

• Skin - Barbiturate blisters (ie, bullous lesions typically found on the hands, buttocks, and knees)

• Mutagenicity - Barbiturates cause craniofacial deformities and contribute to mental retardation.