Barbital became the first commercially available barbiturate in 1903. Although many other barbiturates were subsequently developed, their popularity has greatly waned since the introduction of benzodiazepines. Barbiturates are derivatives of barbituric acid (2,4,6-trioxo-hexa-hydropyrimidine), which itself has no CNS depressant properties. The addition of various side chains influences the pharmacologic properties. Barbiturates with long side chains tend to have increased lipophilicity, potency, and slower rates of elimination. However, the observed clinical effects also depend on absorption, redistribution, and the presence of active metabolites. For this reason, the duration of action of barbiturates (like those of benzodiazepines) may not correlate well with their biologic half-lives.
Oral barbiturates are preferentially absorbed in the small intestine and are eliminated by both hepatic and renal mechanisms. Longer-acting barbiturates tend to be more lipid soluble, more protein bound, have a higher pKa, and are metabolized almost completely by the liver. Renal excretion of unchanged drug is significant for phenobarbital, a long-acting barbiturate with a relatively low pKa (7.24). Alkalinizing the urine with sodium bicarbonate to a urinary pH of 7.5 to 8.0 can increase the amount of phenobarbital excreted by 5- to 10-fold. This procedure is not effective for the short-acting barbiturates because they have higher pKa values, are more protein bound, and are primarily metabolized by the liver with very little unchanged drug excreted by the kidneys (Antidotes in Depth: A5 and Chap. 10). Although several authors have questioned the clinical benefit of urinary alkanization,141 this practice is still recommended to enhance renal elimination of phenobarbital.
Barbiturates (especially the shorter-acting barbiturates) can accelerate their own hepatic metabolism by cytochrome P450 enzyme autoinduction. Phenobarbital is a nonselective inducer of hepatic cytochromes, the greatest effects being on CYP2B1, CYP2B2, and CYP2B10, although CYP3A4 is also affected.82,117,145,159,182 Not surprisingly, a variety of interactions are reported following the use of barbiturates. Clinically significant interactions as a result of enzyme induction lead to increased metabolism of β-adrenergic antagonists, corticosteroids, doxycycline, estrogens, phenothiazines, quinidine, theophylline, and many other xenobiotics.
Similar to other sedative-hypnotics, patients with significant barbiturate overdoses present with CNS and respiratory depression. Hypothermia and cutaneous bullous lesions are often present. These two signs are also described for other patients with sedative-hypnotic overdoses, but they may be more pronounced with barbiturates.14,44 Early deaths caused by barbiturate ingestions result from respiratory arrest and cardiovascular collapse. Delayed deaths result from acute kidney failure, pneumonia, acute respiratory distress syndrome, cerebral edema, and multiorgan system failure as a result of prolonged cardiorespiratory depression.3,58
The commercial use of benzodiazepines began with the introduction of chlordiazepoxide for anxiety in 1961 and diazepam for seizures in 1963. Benzodiazepines are used principally as sedatives and anxiolytics. Clonazepam is the only benzodiazepine approved for use as a chronic anticonvulsant. Benzodiazepines may rarely cause paradoxical psychological effects, including nightmares, delirium, psychosis, and transient global amnesia.84,103,106,203,206,215 The incidence and intensity of CNS adverse events increases with age.102
Similar to barbiturates, variations of the benzodiazepine side chains influence potency, duration of action, metabolites, and rate of elimination. Most benzodiazepines are highly protein bound and lipophilic. They passively diffuse into the CNS, their main site of action. Because of their lipophilicity, benzodiazepines are extensively metabolized via oxidation and conjugation in the liver prior to their renal elimination.
Benzodiazepines bind nonselectively to “central” benzodiazepine sites located throughout the brain. These sites contain the GABAAα and γ subunits.42,193 The binding of the benzodiazepine to its particular site changes the GABA receptor to “lock” into a position that promotes GABA binding to the GABA receptor. Benzodiazepines that are active at the α1 subunit are hypothesized to affect anxiety, sleep, and amnesia, whereas those that are active in the α2 and α3 subunits tend to have greater anxiolytic properties. “Peripheral” benzodiazepine sites are found throughout the body, with the greatest concentrations in steroid-producing cells in the adrenal gland, anterior pituitary gland, and reproductive organs. These sites are not affiliated with the GABA receptor (Antidotes in Depth: A23).
One unique property of the benzodiazepines is their relative safety even after substantial ingestion, which probably results from their GABA receptor properties.42,119 Unlike many other sedative-hypnotics, benzodiazepines do not open GABA channels independently at high concentrations. Benzodiazepines are not known to cause any specific systemic injury, and their long-term use is not associated with specific organ toxicity. Deaths resulting from isolated benzodiazepine ingestions alone are extremely rare. Most often deaths are secondary to a combination of alcohol or other sedative-hypnotics.156,203,206 Supportive care is the mainstay of treatment.
Tolerance to the sedative effects of benzodiazepines occurs more rapidly than does tolerance to the antianxiety effects.93,137 Abrupt discontinuation following long-term use of benzodiazepines may precipitate benzodiazepine withdrawal. This is characterized by autonomic instability, changes in perception, paresthesias, headaches, tremors, and seizures. Withdrawal from benzodiazepines is common, manifested by almost one-third of long-term users.84 Alprazolam and lorazepam are associated with more severe withdrawal syndromes compared with chlordiazepoxide and diazepam.84,85 This is likely due to the fact that both chlordiazepoxide and diazepam have active metabolites. Withdrawal may also occur when a chronic user of a particular benzodiazepine is switched to another benzodiazepine with different receptor activity.96
First introduced in 1832, chloral hydrate belongs to one of the oldest classes of pharmaceutical hypnotics, the chloral derivatives. Although still used sporadically in children, its use has substantially decreased.1,95,125 Chloral hydrate is well absorbed but is irritating to the GI tract. It has a wide tissue distribution, rapid onset of action, and rapid hepatic metabolism by alcohol and aldehyde dehydrogenases. Trichloroethanol is a lipid soluble, active metabolite that is responsible for the hypnotic effects of chloral hydrate. It has a serum half-life of 4 to 12 hours and is metabolized to inactive trichloroacetic acid by alcohol dehydrogenases. It is also conjugated with glucuronide and excreted by the kidney as urochloralic acid. Less than 10% of trichloroethanol is excreted unchanged.
Metabolic rates in children vary widely because of variable development and function of hepatic enzymes, in particular glucuronidation.18,101 The elimination half-life of chloral hydrate and trichloroethanol is markedly increased in children younger than 2 years. This may be especially of concern in neonates and in infants exposed to repetitive doses.
Acute chloral hydrate poisoning is unique compared with that of other sedative-hypnotics. Cardiac dysrhythmias are believed to be the major cause of death.57 Chloral hydrate and its metabolites reduce myocardial contractility, shorten the refractory period, and increase myocardial sensitivity to catecholamines. Persistent cardiac dysrhythmias (ventricular fibrillation, ventricular tachycardia, torsade de pointes) are common terminal events.100 Standard antidysrhythmics often are ineffective, and β-adrenergic antagonists are considered the treatment of choice.17,19,24,94,179,200,212 In addition to cardiotoxicity, chloral hydrate toxicity may cause vomiting, hemorrhagic gastritis, and rarely gastric and intestinal necrosis, leading to perforation and esophagitis with stricture formation.88,188 Chloral hydrate is radiopaque and may be detected on radiographs; however, a negative radiograph should not be used to exclude chloral hydrate ingestion. Few hospital-based laboratories have the ability to rapidly detect chloral hydrate or its metabolites.
Meprobamate was introduced in 1950 and was used for its muscle-relaxant and anxiolytic characteristics. Carisoprodol, which was introduced in 1955, is metabolized to meprobamate. Both drugs have pharmacologic effects on the GABAA receptor similar to those of the barbiturates. Like barbiturates, meprobamate can directly open the GABA-mediated chloride channel and may inhibit NMDA receptor currents.135 Both are rapidly absorbed from the GI tract. Meprobamate is metabolized in the liver to inactive hydroxyl and glucuronide metabolites that are excreted almost exclusively by the kidney. Of all the nonbarbiturate tranquilizers, meprobamate is most likely to produce euphoria.73,74 Unlike most sedative-hypnotics, meprobamate causes profound hypotension from direct myocardial depression.27 Adherent masses or bezoars of pills have been discovered in the stomach at autopsy after large meprobamate ingestions.150 Orogastric lavage with a large-bore tube and MDAC may be indicated for patients with significant meprobamate ingestion. However, the potential benefits of orogastric lavage must be weighed against the risks of aspiration. Whole-bowel irrigation may be helpful if multiple pills or small concretions are suspected. Patients can experience recurrent toxic manifestations as a result of concretion formation with delayed drug release and absorption. Careful monitoring of the clinical course is essential even after the patient shows initial improvement because recurrent and cyclical CNS depression can occur.150
Bromides were used in the past as “nerve tonics,” headache remedies, and anticonvulsants. Although medicinal bromides have largely disappeared from the US pharmaceutical market, bromide toxicity still occurs through the availability of bromide salts of common drugs, such as dextromethorphan.112 Poisoning also may occur in immigrants and travelers from other countries where bromides are still therapeutically used.49 An epidemic of more than 400 cases of mass bromide poisoning occurred in the Cacuaco municipality of Luanda Province, Angola, in 2007. According to a World Health Organization report, the etiology of the bromide exposure in these cases was believed to be table salt contaminated with sodium bromide. Although the majority of persons affected were children, no actual deaths were attributed to bromide poisoning in this epidemic.201
Bromides tend to have long half-lives, and toxicity typically occurs overtime as concentrations accumulate in tissue. Bromide and chloride ions have a similar distribution pattern in the extracellular fluid. It is postulated that because the bromide ion moves across membranes slightly more rapidly than the chloride ion, it is more quickly reabsorbed in the tubules from the glomerular filtrate than the chloride ion. Although osmolar equilibrium persists, CNS function is progressively impaired by a poorly understood mechanism, with resulting inappropriateness of behavior, headache, apathy, irritability, confusion, muscle weakness, anorexia, weight loss, thickened speech, psychotic behavior, tremulousness, ataxia, and, eventually, coma. Delusions and hallucinations can occur. Bromide can lead to hypertension, increased intracranial pressure, and papilledema.6,25,49,68,174,180,214 Chronic use of bromides also produces dermatologic changes called bromoderma, with the hallmark characteristic of a facial acneiform rash.64,180 Toxicity with bromides during pregnancy may lead to accumulation of bromide in the fetus.126 A spurious laboratory result of hyperchloremia with decreased anion gap may result from the interference of bromide with the chloride assay on older analyzers208 (Chap. 19). Thus, an isolated elevated serum chloride concentration with neurologic symptoms should raise suspicion of possible bromide poisoning.
These oral xenobiotics have supplanted benzodiazepines as the most commonly prescribed sleep aid medications.46 Although they are structurally unrelated to the benzodiazepines, they bind preferentially to the benzodiazepine site subtype in the brain that containes the GABAAα1 subunit.42 They have a lower affinity for benzodiazepine sites that contain the other α isoforms, therefore they have potent hypnotic effects with less potential for dependence and anticonvulsant properties.63 Each of these xenobiotics has a relatively short half-life (≤ 6 hours), with zaleplon exhibiting the shortest half-life (1 hour). Unlike benzodiazepines that prolong the first two stages of sleep and shorten stages 3 and 4 of rapid eye movement sleep, zolpidem and its congeners all decrease sleep latency with little effect on sleep architecture. Because of their receptor selectivity, they appear to have minimal effect at other sites on the GABAA receptor that mediate anxiolytic, anticonvulsant, or muscle-relaxant effects.86,190
They are hepatically metabolized by various CYP450 enzymes. Zolpidem is mainly metabolized by CYP3A4. Zaleplon is primarily metabolized by aldehyde oxidase, but CYP3A4 is also involved in parent compound oxidation. Zopiclone is primarily metabolized by CYP3A4 and CYP2C8, whereas eszopiclone is metabolized mainly by CYP3A4 and CYP2E1. Various pharmacokinetic interactions with inhibitors or inducers of CYP450 enzymes and these medications are reported.62
In isolated overdoses, drowsiness and CNS depression are common. However, prolonged coma with respiratory depression is exceptionally rare. Isolated overdoses usually manifest with depressed level of consciousness without respiratory depression. For example, even at 40 times the therapeutic dose of zolpidem, no biologic or electrocardiographic abnormalities were reported.52 Zoplicone overdoses are rarely associated with methemoglobinemia.51 Tolerance to zolpidem and its congeners occurs, and as expected, withdrawal follows abrupt discontinuation of chronic use. The withdrawal syndrome is typically mild.61,197 Flumazenil may reverse the hypnotic or cognitive effects of these xenobiotics (Antidotes in Depth: A22).90,209 Due to increasing prevalence of these xenobiotics, they have been associated with increasing hospitalizations especially when ingested with other sedative hypnotics.218 Deaths have resulted when zolpidem was taken in large amounts with other CNS depressants.52
Propofol is a rapidly acting intravenous sedative-hypnotic that is both a postsynaptic GABAA agonist and induces presynaptic release of GABA.115,181 Propofol is also an antagonist at NMDA receptors.80,165,217 In addition, propofol interacts with dopamine, promotes nigral dopamine release possibly via GABAB receptors,120,151 and has partial agonist properties at dopamine (D2) receptors.149 Propofol is used for procedural sedation and either induction or maintenance of general anesthesia. It is highly lipid soluble, so it crosses the blood–brain barrier rapidly. The onset of anesthesia usually occurs in less than one minute. The duration of action after short-term dosing is usually less than 8 minutes due to its rapid redistribution from the CNS.
Propofol use is associated with various adverse events. Acutely, propofol causes dose-related respiratory depression. Propofol may decrease systemic arterial pressure and cause myocardial depression. Although short-term use of propofol does not typically cause dysrhythmias or myocardial ischemia, atropine-sensitive bradydysrhythmias are noted, specifically sinus bradycardia and Mobitz type 1 atrioventricular block.178,196,211 Short-term use of propofol in the perioperative setting is associated with a myoclonic syndrome manifesting as opisthotonus, myoclonus, and sometimes myoclonic seizurelike activity.104,113
Prolonged propofol infusions, typically more than 48 hours at rates of 4 to 5 mg/kg/h or greater, are associated with a life-threatening propofol-infusion syndrome involving metabolic acidosis, cardiac dysrhythmias, and skeletal muscle injury.77,78 The clinical signs of propofol infusion syndrome often begin with the development of a new right bundle branch block and ST segment convex elevations in the electrocardiogram precordial leads.77 Predisposing factors to the development include young age, severe brain injury (especially in the setting of trauma), respiratory compromise, concurrent exogenous administration of catecholamines or glucocorticoids, inadequate carbohydrate intake, and undiagnosed mitochondrial myopathy. Some authors propose a “priming” and “triggering” mechanism for propofol infusion syndrome with endogenous glucocorticoids, catecholamines, and possibly cytokines as “priming” agents, and exogenous catecholamines and glucocorticoids in the setting of high-dose propofol infusion as “triggering” stimuli.186 Propofol is suggested to induce disruption of mitochondrial free fatty acid utilization and metabolism, causing a syndrome of energy imbalance and myonecrosis similar to mitochondrial myopathies.29,158,187 Case reports associate propofol with metabolic acidosis, elevated lactate concentration, and fatal myocardial failure in both children and young adults. However, this syndrome is also reported in older adults.122 Cases of metabolic acidosis may be associated with an inborn disorder of acylcarnitine metabolism.205 Prolonged propofol infusions may unmask previously undiagnosed myopathy that would cause them to be at increased risk for propofol infusion syndrome, especially in children. Despite the increasing number of reports of propofol infusion syndrome in the literature, a direct cause and effect relationship remains to be fully elucidated.
The unique nature of the carrier base of propofol, a milky soybean emulsion formulation, is associated with multiple adverse drug events. It is a fertile medium for many organisms, such as enterococcal, pseudomonal, staphylococcal, streptococcal, and candidal strains. In 1990, the US Centers for Disease Control and Prevention reported an outbreak of Staphylococcus aureus associated with contaminated propofol. This carrier base also impairs macrophage function,29 causes hypertriglyceridemia41,83,91,158,187 and histamine-mediated anaphylactoid reactions,43,79,187 and impairs platelet and coagulation function.5,39
Etomidate is an intravenous nonbarbiturate, hypnotic primarily used as an anesthesia induction agent. It is active at the GABAA receptor, specifically the β2 and β3 subunits.32,114 Only the intravenous formulation is available in the United States. The onset of action is less than 1 minute and its duration of action is less than 5 minutes.
Etomidate is commercially available as a 2 mg/mL solution in a 35% propylene glycol solution. Propylene glycol toxicity from prolonged etomidate infusions is implicated in the development of hyperosmolar metabolic acidosis (Chap. 55).89,98,183,185 Etomidate has minimal effect on cardiac function, but rare cases of hypotension are reported.53, 54, and 55,169 Etomidate has both proconvulsant and anticonvulsant properties.33,130 Involuntary muscle movements are common during induction and may be caused by etomidate interaction with glycine receptors at the spinal cord level.36,107,108
Etomidate depresses adrenal production of cortisol and aldosterone; therefore, it is associated with adrenocortical suppression, usually after prolonged infusions.147,191,192 Etomidate has been associated with increased morbidity and mortality in critically ill and trauma patients.35,65 However, other authors question the clinical significance of adrenal suppression from etomidate administration and dispute its association with adverse outcomes.66,171,172 In the appropriate setting, etomidate does not appear to have any greater risk of significant adverse events compared with its counterparts.
Dexmedetomidine is a central α2-adrenergic agonist that decreases central presynaptic catecholamine release, primarily in the locus coeruleus. It has a terminal half-life of 1.8 hours and its volume of distribution is less than 1 L/kg.When dexmedetomidine is used to help wean patients from ventilators, sedation is achieved with less associated delirium as compared with other agents.121,170 It is also used for procedural sedation in certain settings such as interventional radiology procedures and awake fiberoptic intubations. When compared with propofol, dexmedetomidine sedation may lessen opioid requirements in postoperative patients. Dexmedetomidine has been used as an adjunctive agent in benzodiazepine, opioid, or ethanol withdrawal.37,40,47,138,144,176,177
Dexmedetomidine has minimal effect at the GABAA receptor. Unlike other sedative-hypnotics, it is not associated with significant respiratory depression. Although mechanistically similar to clonidine, dexmedetomidine does not appear to cause as much respiratory depression as clonidine. Dexmedetomidine is said to induce a state of “cooperative sedation,” in which a patient is sedated but yet able to interact with health care providers. Dexmedetomidine may also have analgesic effects.31
Dexmedetomidine is currently only approved for use for less than 24 hours. Extensive safety trials have not yet explored its use beyond 24 hours. Unlike clonidine, rebound hypertension and tachycardia have not been described upon cessation. Because dexmedetomidine decreases central sympathetic outflow, its use should probably be avoided in patients whose clinical stability is dependent on high resting sympathetic tone. The most common adverse effects from its use are nausea, dry mouth, bradycardia, and varying effects on blood pressure (usually hypertension followed by hypotension). Slowing of the continuous infusion may help to prevent or lessen the hypotensive effects.31 In one case, a 60-fold overdose in a child was associated with hypoglycemia.13