eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Barbiturate

Author: Keith A Lafferty, MD, Adjunct Assistant Professor of Emergency Medicine, Temple University; Consulting Staff, Department of Emergency Medicine, South West Regional Medical Center
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Updated: Oct 1, 2008

Introduction

Background

Barbiturates are the earliest class of sedative-hypnotic agents to be developed and were once extremely popular drugs of abuse. In general, sedative-hypnotic drugs are nonselective in their effects. At lower doses, a reduction in restlessness and emotional tension occurs. At increasingly higher doses, sedation is followed by increasing levels of anesthesia and eventually death.  

Benzodiazepines have largely replaced barbiturates for outpatient medical therapy, with a subsequent decline in barbiturate abuse. Stricter guidelines dictating barbiturate use have also contributed to their decreased availability.

Though tolerance occurs to the sedative-hypnotic effects, no tolerance appears to develop to the level at which lethal toxicity occurs.

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 neurotransmitters 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. This potentiates and prolongs the inhibitory 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 ultra-short-, short-, and intermediate-acting agents). All of the drugs in this class are derivatives of barbituric acid, which was the original compound developed in 1864. However, the structure of each barbiturate differs and can be related to its effective duration of action.

Compared with long-acting agents, short-acting agents are more lipid soluble, more protein bound, have a higher pKa, a more rapid onset, 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 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). Specifically, the duration of action depends mainly on the alkyl groups attached to carbon #5. The structure of these alkyl groups determine lipid solubility of the drug in that the duration of action decreases as the total number of carbons at carbon #5 increases.

An ultra–short-acting agent mainly used for procedural sedation, propofol, deserves mention. It is barbituratelike 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 has specific pharmacokinetics that make it attractive for use in ED procedures. Notably, its rapid onset and short duration of action make it an excellent choice for this purpose. Miner et al recently compared the efficacy and safety of propofol and etomidate for ED procedures.¹ The success rate was 10% higher in the group given propofol, as 20% of the etomidate group experienced myoclonus. No significant increase in clinical respiratory depression or hypotension occurred in either arm of the study. 

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 and typically increase their metabolism (eg, warfarin [Coumadin]). Note that barbiturates themselves are metabolized by this system, which may partially explain the drug tolerance often observed in chronic users.

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 CNS depressant effect mimics that of ethanol. 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. Fatality from barbiturate overdose is usually secondary to respiratory depression and subsequent pneumonia.

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

United States

Barbiturate abuse was popular in the 1960s and 1970s. Since then, however, its popularity has waned because of stricter guidelines for use and the introduction 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

History

• As with any overdose, it is important to attempt to ascertain the exact substance and quantity ingested, the time of ingestion and possible co-intoxicants, especially alcohol or other sedatives. Remember that some barbiturates are included in combination drugs (eg, Fioricet [butalbital, acetaminophen]; Donnatal [phenobarbital, hyoscyamine, scopolamine, atropine]) with components that have their own toxicity profile.
• 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 potentially result in 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) (Delirium of any kind 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 fetal craniofacial deformities and contribute to mental retardation.

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