Barbiturate Toxicity 

Barbiturates are the earliest class of sedative-hypnotic agents to be developed and were once extremely popular drugs of abuse. Today, barbiturates are commonly used in geriatric suicide involving medication overdose. In one New York City study, 27.2% of fatal overdose suicide cases in the elderly were due to barbiturates.^[1] Interestingly enough, two other popular sedative-hypnotic drugs, propofol and ketamine, have had a rise in their abuse. In fact, 18% of academic anesthesiology departments surveyed have reported a case of propofol abuse or diversion in the past 10 years, a 5-fold increase from prior studies.^[2] Ketamine has become one of the mainstream club drugs, rising from 25% use among nightclub goers in the United Kingdom in 1999 to 40% in 2003.

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.

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.

Chemical compounds of barbiturates

See image below.

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

Although technically not a barbiturate, the barbituratelike sedative propofol deserves special mention. It is an ultra – short-acting agent usually used for general anesthesia, procedural sedation, or reduction of intracranial pressure after traumatic brain injury. Propofol binds to GABA A receptors directly and inhibits calcium flow through slow calcium ion channels.^[3] Both barbiturates and propofol also interact with N -methyl-D-aspartate (NMDA) and α -amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainite receptors.

Propofol is highly lipid soluble with an onset of less than 1 minute and a quick offset of action. 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 compared the efficacy and safety of propofol and etomidate for ED procedures.^[4] 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.

Another agent widely used for procedural sedation and increasingly as a drug of abuse is ketamine. Ketamine acts primarily on the NMDA receptor by noncompetitive antagonism that decreases the effect of the excitatory neurotransmitter glutamate. It also binds to opioid receptors. Ketamine causes a sympatheticlike response by inducing bronchodilatation and increasing heart rate and blood pressure. Increased salivation and minimal transient respiratory depression followed by respiratory stimulation may also occur.

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. Street names for phenobarbital include "purple hearts" and "golfballs", while pentobarbital is called "nembies", "yellow jackets", "abbots", or "Mexican yellows".

Since 1965, ketamine has emerged as a common recreational drug among young people and adolescents. Often used in combination with other so-called club drugs such as gamma-hydroxybutyric acid, lysergic acid diethylamide (LSD), and ecstasy, ketamine is commonly called "special K", "kit kat", or "vitamin K".

Propofol abuse has been highlighted by the fatal case of the mega pop star Michael Jackson; however, propofol dependence has been a known problem, especially amongst anesthesiologists whom have constant access to it. Nearly 1 in 5 of all anesthesiology departments in the United States have reported a case of propofol abuse or diversion in their midst. Due to the drug's narrow therapeutic window, at least 7 physician fatalities were reported in 10 years. The trade name for propofol is Diprivan.

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.

Although propofol is generally considered a safe agent, a new entity called propofol infusion syndrome (PRIS) has been recognized, describing acute onset of metabolic acidosis with refractory bradycardia progressing to asystole associated with propofol infusions greater than 48 hours.^[5] More than 40 cases have been identified in the literature since 1992 with wide-varied clinical manifestations including rhabdomyolysis, myocardial failure, acute renal failure, cardiac arrest, dyslipidemias, and hypotension. Risk factors for development of PRIS appear to be doses greater than 83 mcg/kg/min, age older than 18 years, duration of infusion greater than 48 hours, and use of propofol with catecholamine vasopressors or glucocorticoids. Mortality rates exceed 80%.