Barbiturate Toxicity

  • Author: Keith A Lafferty, MD; Chief Editor: Asim Tarabar, MD  more...
 
Updated: May 12, 2014
 

Background

Barbiturates are the earliest class of sedative-hypnotic agents to be developed and were first used in medicine in the early 1900s and remained widely prescribed prior to the development of the less toxic hypnosedative drug class known as benzodiazepines. Their popularity peaked in the 1960s and 1970s for treatment of insomnia, anxiety, and seizures. Also known by street names such as, “reds”, “downers”, “barbs”, “yellow jackets”, “blue heavens”, and “nenbies”, barbiturates’ owe their various effects to a combination of a pyrimidinetrione ring structure and the overall size and structure of the C-5 position substituents.

Barbiturates once enjoyed a central place in the world of recreational drugs at the beginning of the 20th century and were used for a wide range of conditions until their liability for abuse led to an extensive number of barbiturate poisoning cases in the 1950s and 1960s. 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 elderly persons were due to barbiturates.[1] Treatment for poisoning remains supportive as there is no specific antidote.

Interestingly, as abuse of phenobarbital wanes, cases of poisoning and abuse from other sedative-hypnotic drugs, such as propofol, ketamine, and γ -hydroxybutyrate (GHB), have been reported to be steadily increasing. The effects that limit the clinical use of these drugs make them appealing to recreational drug users. 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] Recent high school surveys suggest abuse has been rising over the last 10 years, perhaps to counter the excitement caused by today’s synthetic stimulants.

Despite the decline in barbiturate use, cases of acute poisoning with severe toxicity are still noted at staggering rates in developing countries, where resource limitations and the affordability of barbiturates lend to their increased use as anticonvulsants.

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.

Toxicity within the barbiturate drug class varies depending on the onset and duration of the agent. For instance, patients with significant poisoning by short-acting barbiturates recover quickly (within 24-48h) in a setting devoid of complications, as opposed to those poisoned with longer-acting agents, such as phenobarbital, which requires more aggressive interventions such as ventilatory support and admission to the ICU.

Benzodiazepines have largely replaced barbiturates both medically and recreationally due to their wider therapeutic window, lower drug tolerance, and lower propensity for abuse. Although tolerance to the sedative-hypnotic effects does occur, no tolerance appears to develop to the level at which lethal toxicity occurs. Stricter guidelines dictating barbiturate use have also contributed to its decreased availability.

Procedural sedation and analgesia are essential to ameliorating painful procedures for both adults and children in the emergency department. The favorable pharmacokinetics and adverse effect profile of propofol allows it to be used clinically for procedural sedation. However, propofol contains a relatively narrow therapeutic window and is associated with a dose-dependent risk of bradypnea and hypotension, especially in elderly persons.

While clinically barbiturate use has been largely replaced by benzodiazepines and propofol, there are two distinct scenarios in which their use may still be warranted: status epilepticus and elevated intracranial pressure (ICP).

Being that status epilepticus is the second most frequent neurological emergency and that refractory status epilepticus (RSE) carries a 25% mortality rate, studies indicate that barbiturates still may have a role in this scenario.[3] Supporting this, toxicological or withdraw seizures seem to be more amendable to GABA receptor activation, compared with idiopathic or traumatic seizures, which usually start with a focus of isolated abnormal neurons and are more amendable to blockade of voltage-dependent sodium channels.[4]

In a meta analysis of the use of barbiturates, propofol, or midazolam in RSE there was no difference in short-term mortality, although immediate effectiveness favored barbiturates.[3] In addition, pentobarbital’s activity at the GABA receptor is less dependent on the presence of adequate normal quantities of GABA, a theoretical benefit in treating of seizures induced by toxins that deplete GABA. In saying this, propofol has the advantage of a short half life which allows for rapid weaning; however, the risks of propofol infusion syndrome needs to be monitored. This has to be weighed against barbiturate long elimination time secondary to its lipophilic nature and high adipose storage (thiopental has a 36-hour elimination half life after continuous infusion).[3]

Although guidelines for management of traumatic brain injury (TBI) recommend that high-dose barbiturate therapy may be considered to lower ICP, the evidence for decreasing morbidity and mortality is lacking. In a recent study, high-dose barbiturate treatment caused a decrease in ICP in 69% of patients but also caused longer periods of a decreased mean arterial pressure (MAP) despite increased use of high-dose vasopressors. There was no significant effect on outcome.[5] Overall, there is no evidence that barbiturate therapy in patients with TBI improves outcome.[5] This probably is from the fact that cerebral perfusion pressure (CPP) remains unchanged as any benefit in decreasing ICP is offset by a decrease in MAP (CPP=MAP-ICP).

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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. Although the clinical effects of barbiturates and benzodiazepines are similar and result as a sequelae to hyperpolarizing the neuron, there are subtle differences in terms of receptor binding. Barbiturates increase the duration of Cl ion channel opening at the GABA receptor, which, in turn, increases the efficacy of GABA. Benzodiazepines, on the other hand, increase the frequency of Cl ion channel openings at the GABA receptor, which, in turn, increases the potency of GABA.[6]

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 at the beta subunit is distinct from the GABA and benzodiazepine binding site and increases 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 (principle excitatory neurotransmitter) receptors (AMPA) in the CNS.

Barbiturates may be grouped functionally into long- and short-acting agents (consisting of ultrashort-, short-, and intermediate-acting agents). However, the relevance of this classification system in terms of prognosis remains to be well defined as the agents’ duration of action is only partially correlated with half-life (the remaining differences are accounted for with tissue binding and distribution).[7] 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.

Chemical compounds of barbiturates. Chemical compounds of barbiturates.

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 barbiturate-like 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.[8] 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.[9] 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 as it is a derivative of PCP. It also binds to opioid receptors. At low doses (0.1-0.5 mg/kg/h), ketamine induces distortion of time and space, hallucinations, and mild dissociative effects. At larger doses, it induces a more severe dissociation wherein users experience intense detachment, such that their perceptions are completely disconnected from reality.[10] 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.

GHB interacts with GHB-specific receptors and GABA B receptors. GHB also affects dopamine, opioid, serotonin, acetylcholine, and glutamate neurotransmitter systems. Additional GABA-like effects occur at high doses through the conversion of GHB to GABA. When consumed in oral doses as low as 25 mg/kg, confusion, sedation, respiratory depression, and dizziness have been shown to result. At higher dosages of 50-63 mg/kg, loss of consciousness and profound coma has been documented.[11] 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. Elderly people have proportionally more adipose tissue and therefore are more susceptible to this narrow therapeutic index. Barbiturates all have anticonvulsant activity because they hyperpolarize cell membranes. Therefore, they are effective adjuncts in the treatment of epilepsy.

The high doses of barbiturates used in the care of neurocritical patients have in recent years been reported to possibly lead to the accumulation of propylene glycol. Propylene glycol is a commonly used vehicle in the intravenous formulations of many medications, including phenobarbital and pentobarbital. Increased levels of propylene glycol may yield a less recognized complication of therapy, as propylene glycol may exacerbate existing complications associated with large doses of barbiturates, to include hypotension and respiratory depression. In addition, propylene glycol toxicity, ironically, may induce seizures that the barbiturates are intended to treat.[12]

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 and one must respect its narrow therapeutic index as even a slight overdose can cause coma or death.

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. The combination of the decreased vascular resistance by means of peripheral dilation and inherent negative ionotropic properties of barbiturates yields to the development of another recognized complication, hypotension.

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Epidemiology

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 immunosuppression with frequent nosocomial infections such as pneumonia, acute respiratory distress syndrome (ARDS), shock, hypoxic damage secondary to prolonged hypotension, and coma. Other complications include those iatrogenic in nature from forced dieresis, gastric lavage, and central venous access.

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.[13] 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%.

Over recent years, multiple cases have been reported in the literature concerning the presentation of ketamine-related bladder dysfunction and lower urinary tract destruction in association with chronic abuse of a new entity of street ketamine. However, there are no current studies that demonstrate a statistically significant difference in urinary system presentations between ketamine and a control group.[8]

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Contributor Information and Disclosures
Author

Keith A Lafferty, MD Adjunct Assistant Professor of Emergency Medicine, Temple University School of Medicine; Medical Student Director, Department of Emergency Medicine, Gulf Coast Medical Center

Keith A Lafferty, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Medical Association, Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Coauthor(s)

Rehab Abdel-Kariem, MD Resident Physician, Department of Emergency Medicine, Temple University Hospital

Rehab Abdel-Kariem, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Physicians, American Medical Student Association/Foundation, Society for Academic Emergency Medicine, Physicians for Human Rights

Disclosure: Nothing to disclose.

Keisha Bonhomme, MD Resident Physician, Department of Internal Medicine, St Vincent’s Medical Center

Disclosure: Nothing to disclose.

Specialty Editor Board

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Michael J Burns, MD Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center

Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Additional Contributors

David C Lee, MD Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

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