Toxicity, Barbiturate

Background

Barbiturates are a class of organic compounds that were developed in the late 19th century for the treatment of anxiety and insomnia. These agents were originally touted as safer alternatives to bromides, but soon after their introduction, their toxic effects and their low therapeutic index became clear, eventually leading to their replacement by the much safer benzodiazepines.

Barbiturates are used mainly as intravenous (IV) anesthetics, as anticonvulsants, and in the resuscitation of patients with cerebral injuries. Barbiturates are also used commonly in combination with other substances for the treatment of gastrointestinal illness and migraine. Their use as sedative-hypnotics is limited because of the availability of safer agents but may be encountered in the drug-using community, where barbiturates may be used to counteract the unpleasant effects of stimulants. Barbiturates traditionally have been classified into 4 categories according to their duration of action, as follows:

• Ultra–short-acting barbiturates (eg, thiopental, thiamylal, methohexital) are highly lipid soluble and penetrate the CNS within minutes of an IV injection. Their effects generally last less than 30 minutes; these agents are used mainly for the induction of anesthesia.
• Short-acting barbiturates (eg, secobarbital, pentobarbital) cross the blood-brain barrier and affect the CNS within 10-15 minutes of ingestion. Their effects generally last 3 hours. Traditionally, they have been prescribed as sedative-hypnotics, but their abuse potential precludes their use as first-line agents.
• Intermediate-acting barbiturates (eg, amobarbital, butalbital, butabarbital, aprobarbital) cross the blood-brain barrier and affect the CNS within 30-60 minutes of ingestion. Their effects generally last as long as 6 hours. These barbiturates traditionally were prescribed as sedative-hypnotics, but their abuse potential precludes their use as first-line agents. Butalbital is commonly used in combination with acetylsalicylic acid and acetaminophen for the treatment of migraine headaches.
• Long-acting barbiturates (eg, phenobarbital, mephobarbital) are much less lipid soluble, have virtually no acute mood-altering effects, and have the least potential for abuse. They are used mainly as anticonvulsants, and their effects last as long as 12 hours.

Pathophysiology

Barbiturates suppress the activity of all excitable tissue, including the CNS, the peripheral nervous system, and the cardiovascular system. They also depress gastrointestinal function and have a number of effects on hepatic function. Their effects on the respiratory system are mainly due to CNS inhibition.

Central nervous system effects

Although all excitable tissues are depressed, CNS depression is most important and is generally responsible for most of the observed effects of barbiturates. Virtually all levels of the neural axis, including the cerebral cortex, the cerebellum, the thalamus, the striated nucleus, and the spinal cord, are affected. Specifically, barbiturates facilitate the binding of gamma-aminobutyric acid (GABA) to its receptor in the postsynaptic membrane and inhibit the function of alpha-amino-3-hydroxy-5-methylisoxazole (AMPA) cationophores. Their effects on GABA result in prolongation of the duration of opening of GABA-gated chloride channels, leading to hyperpolarization of the membrane and suppression of neurotransmission.

At high concentrations, barbiturates may also stimulate the GABA receptor directly to open the chloride channels. Their effects on AMPA, a subunit of the excitatory glutamate receptor, result in the sequential reduction in conductance of sodium-gated channels and inhibition of the voltage-dependent potassium channels.

Additional mechanisms by which barbiturates cause CNS depression include enhancement of chloride conductance without GABA, inhibition of calcium-dependent release of neurotransmitters, and inhibition of calcium-dependent action potentials.

Clinically, CNS depression occurs in a graded fashion, progressing from sedation to hypnosis, anesthesia, coma, and death due to respiratory arrest. Respiratory depression also occurs in a graded, dose-dependent fashion, starting with mild inhibition of the neurogenic respiratory drive and progressing to loss of the hypoxic drive. The dose at which CNS depression occurs varies among individuals and depends on a number of factors, including the prior use of barbiturates, the concomitant use of other substances and drugs, and the presence of preexisting cardiovascular or hepatic disease, among others.

Peripheral nervous system effects

The effects of barbiturates on the peripheral nervous system include inhibition of nicotinic receptors of the autonomic ganglia, leading to hypotension and reduced cardiac function. At anesthetic doses, they also inhibit the nicotinic receptors of skeletal muscle, leading to impaired neuromuscular transmission.

Cardiovascular effects

Through their effects on the nicotinic receptors of autonomic ganglia, barbiturates may cause hypotension, which is generally mild, unless the patient has preexisting congestive heart failure, dehydration, and hypovolemia. Massive barbiturate overdose may result in shock, leading to renal failure and death. Other cardiovascular effects include decreased cardiac output, decreased cerebral blood flow, and direct impairment of myocardial contractility.

Hepatic effects

Long-term use of barbiturates induces the activity of the mixed-function oxidase-microsomal enzyme/cytochrome P-450 system, leading to a more rapid biotransformation of compounds using the same pathway for detoxification, which include the barbiturates themselves. This leads to reduced blood concentrations of the parent compounds and contributes to the development of tolerance. The experienced barbiturate user may require doses that might otherwise be toxic to achieve a specific therapeutic effect. Other enzymes induced by barbiturates include delta-aminolevulinic acid (ALA) synthetase and aldehyde dehydrogenase. Their effect on ALA synthetase leads to the accumulation of ALA, which can lead to exacerbations of acute intermittent porphyria and porphyria variegata.

Pharmacokinetics

Barbiturates are weak acids that are absorbed rapidly from the gastrointestinal tract and are distributed to all tissues and fluids.

Ultra–short-acting barbiturates have the highest lipid solubility. Once in the blood stream, they rapidly and freely diffuse into the brain, causing a rapid CNS depression followed by a fairly rapid redistribution out of the CNS and into all other tissues, leading to termination of their CNS effects. These barbiturates bind extensively to plasma proteins and are metabolized by the liver, where they are converted to water-soluble glucuronide products before excretion by the kidneys. Their onset of action is within minutes, and their duration of action is usually less than 30 minutes but may extend as long as 1 hour. They are commonly used in anesthesia as induction agents and for the rapid control of convulsive status epilepticus.

The short-acting and intermediate-acting barbiturates have an intermediate lipid solubility and protein binding and an intermediate duration of action. They are used as sedative-hypnotics and have the highest abuse potential of all barbiturates. They are generally well absorbed from the gastrointestinal tract and easily diffuse into the brain, causing CNS depression and sleep. Their onset of action varies from 10-60 minutes and may last as long as 3 hours (short-acting agents) and as long as 6 hours (intermediate-acting barbiturates). The presence of food in the stomach delays, but does not alter, their bioavailability.

Short-acting barbiturates are metabolized entirely by the liver into water-soluble glucuronide compounds, with only 3-6% remaining active before excretion by the kidneys. Before 1980, this group of barbiturates was responsible for a significant number of overdose fatalities. Similarly, more than 90% of intermediate-acting barbiturates undergo inactivation by the liver, with only 10-12% remaining active until excretion by the kidneys. In the case of aprobarbital, as much as 17.5% may be excreted unchanged.

Long-acting barbiturates have low lipid solubility, low plasma protein binding, low brain protein binding, a delayed onset of action, and a longer duration of action. They have virtually no abuse potential and are used mainly in the treatment of epilepsy. They penetrate the brain slowly and redistribute to the periphery slowly. Their effects usually last for 6-12 hours and are only partially inactivated by the liver. Most long-acting barbiturates have active metabolites that are excreted by the kidneys. Renal dysfunction results in prolonged effects and toxicity of these barbiturates.

Conditions that reduce the hepatic metabolism of barbiturates include old age, infancy, and pregnancy. The effect of hepatic disease on the metabolism of barbiturates varies. Drugs that potentiate the CNS depressant effects of barbiturates include other CNS depressants (eg, ethanol, benzodiazepines, antihistamines, tricyclic antidepressants, monoamine oxidase inhibitors). Methylphenidate and isoniazid may also potentiate the CNS depression.

Patients with impaired respiratory function, such as those with chronic obstructive pulmonary disease (COPD), those with cardiac and renal dysfunction, and those with myasthenia gravis and hypothyroidism, may be sensitive to the effects of barbiturates.

Frequency

United States

In the 1970s, barbiturates were commonly used in suicide attempts and were implicated in most lethal intentional overdoses in adults. As the use of barbiturates declined after the introduction of benzodiazepines, the incidence of deaths due to barbiturate poisoning also declined. The illicit use of short-acting barbiturates to antagonize the unpleasant effects of stimulants has recently increased in the drug community.

Mortality/Morbidity

Over the last several years, mortality rates from barbiturate poisoning declined markedly from 10% in the 1970s to 1% in the 1990s, largely because of improved supportive care. In 2004, 3149 barbiturate overdoses were reported to US poison control centers, with 11 deaths.¹ Most deaths (10 out of 11) were due to poisoning with long-acting agents.

Fatal poisonings have occurred with the ingestion of as little as 6 g of phenobarbital and 2-3 g of short-acting barbiturates. The presence of co-ingestants (eg, alcohol, tricyclic antidepressants) may increase the lethality of barbiturates.

The most common cause of death early in the course of barbiturate poisoning is respiratory failure. Cardiovascular collapse due to CNS depression may also contribute to death early in the course of barbiturate poisoning. Aspiration pneumonia, bronchopneumonia, pulmonary edema, renal failure, and cerebral edema are the most commonly cited fatal late complications of barbiturate poisoning.

Race

According to the Drug Abuse Warning Network (DAWN), whites are most likely to abuse barbiturates and are, therefore, at highest risk for barbiturate poisoning.

Sex

According to DAWN, males and females abuse barbiturates in equal numbers; therefore, they are poisoned with equal frequency. Pregnant women may be at higher risk of toxicity because pregnancy increases the protein binding of barbiturates, thereby increasing their half-life and increasing their toxicity. Barbiturates cross the placenta and are excreted in milk.

Age

According to DAWN, young adults aged 20-40 years are most likely to abuse barbiturates. Elderly patients and infants are at higher risk for barbiturate toxicity because they metabolize and eliminate barbiturates more slowly than young adults. On the other hand, children may eliminate phenobarbital twice as fast as young adults.

Clinical

History

Patients with barbiturate toxicity or barbiturate poisoning present with coma accompanied by cardiorespiratory collapse and are unable to provide their history. Other substances are often used concomitantly. Every effort should be made to identify the ingested substance and the circumstances of ingestion. This may be accomplished by examining the patient's prior medical record and questioning prehospital personnel and family regarding the patient's psychiatric history, medical conditions, and the signs and symptoms immediately preceding presentation to the hospital. Additionally, patients receiving large doses of intravenous barbiturates for the treatment of status epilepticus and other neurologic conditions may be at risk for toxicity from the solvent used for injectable barbiturate solutions (propylene glycol).

The symptoms of short-acting barbiturate poisoning usually begin less than 1 hour after ingestion and peak 4-6 hours after ingestion. Symptoms of long-acting barbiturates usually begin within 2 hours after ingestion but may not peak until 12 hours after ingestion. In the absence of hypoxia, acute respiratory distress syndrome (ARDS), hypotension, and structural brain injury, CNS depression gradually improves over 2 days for short-acting barbiturates and over 4-7 days for long-acting agents.

Physical

• Temperature: Hypothermia with a temperature as low as 31°C often occurs and is due to depression of the thermoregulation center and reduced muscle activity. Exposure to a cold environment may worsen the extent of the hypothermia.
• Respiration: Barbiturates depress the medullary respiratory center. With moderate intoxications, the PaCO₂ -dependent ventilatory drive is depressed, and, at high doses, the hypoxic drive is eliminated, resulting in bradypnea and apnea. In the presence of hypoxia and acidosis, respirations may become rapid and shallow, or they may follow a Cheyne-Stokes pattern. The pulmonary examination may reveal evidence of bronchopneumonia, atelectasis, or pulmonary edema.
• Cardiovascular system: Barbiturates depress the vasomotor centers of the medulla, resulting in arteriolar and venous dilatation and hypotension, progressing to shock. Barbiturates also depress the sympathetic ganglia, cardiac contractility, and smooth muscle and vascular tone, resulting in bradycardia, pulmonary edema, cardiovascular collapse, and shock. Tachycardia may be observed in patients with hypoxia and in patients with co-ingestions. The presence of hypotension indicates a significant ingestion. Hypotension due to significant ingestion is most pronounced in patients with congestive heart failure and in those with hypovolemia because barbiturates partially inhibit ganglionic transmission and suppress cardiovascular reflexes. Hypoxia may compound these effects and may result in shock, which is manifested by hypotension with a rapid, weak, and thready pulse; cold and sweaty skin; and renal failure.
• Central nervous system: In the absence of co-ingestions and structural brain disease, barbiturates depress the CNS in a predictable manner, and the patient's clinical status may, therefore, be monitored clinically. Mild toxicity manifests as disorders of mentation, slurred speech, loss of coordination, and ataxia. Severe intoxication manifests as stupor and additional neurologic dysfunction. In massive overdoses, the patient becomes deeply comatose, hypotonic, and areflexic. The brainstem reflexes, including the corneal and oculovestibular reflexes, may be obliterated, and the electroencephalogram (EEG) may exhibit periods of electrical silence.
• Eyes: The ocular examination reveals nystagmus and a dysconjugate gaze. The pupils usually appear normal but may be small and reactive to light. In the presence of co-ingestants and anoxia, however, the pupils may be dilated and paralyzed.
• Gastrointestinal system: Barbiturates reduce gastrointestinal muscle tone and peristaltic function, resulting in gastric dilatation with delayed gastric emptying and ileus with bowel distention. Bowel distention may become so severe as to cause bowel necrosis. Physical examination findings include a succussion splash, decreased bowel sounds, and abdominal distention.
• Renal system: Barbiturate overdose may result in urinary retention. Poisoning with short-acting barbiturates may result in high output of dilute urine, much like that of diabetes insipidus. Additionally, hemodynamic instability and shock may lead to acute tubular necrosis, which is manifested by azotemia, volume overload, hyperkalemia, and acidosis.
• Skin: Approximately 6% of patients with barbiturate poisoning and 50% of patients with lethal poisoning develop tense, clear, bullous skin lesions of unclear etiology. These lesions commonly occur on the hands, knees, and buttocks within 24 hours of ingestion and heal very slowly. The lesions are not specific to barbiturates and occur with other CNS depressant overdoses and with carbon monoxide poisoning.

Causes

The most common scenario for a massive barbiturate poisoning is an intentional overdose of barbiturate-based anticonvulsants or barbiturate-containing combination medications (eg, Fioricet, Fiorinal, Donnatal).

Source : http://emedicine.medscape.com/article/165514-overview