155 Sedative-Hypnotic Agents
Key Points• Benzodiazepines account for the majority of overdoses with sedative-hypnotic drugs.
• Benzodiazepines can induce cardiovascular and pulmonary toxicity, but fatalities resulting from pure benzodiazepine overdoses are rare.
• Central nervous system depression is the primary symptom of sedative-hypnotic toxicity.
• Treatment should focus on supportive care, with particular attention to airway patency and respiratory function.
• Urinary alkalinization and multiple doses of activated charcoal can enhance the elimination of phenobarbital.
• Flumazenil is a reversal agent for benzodiazepine toxicity, but it should be used cautiously, to avoid the risk of seizures.
• Other possible causes of altered mental status should always be considered.
Epidemiology
Sedative-hypnotic agents are a heterogeneous group of agents that have tranquilizing (sedative) or sleep induction (hypnotic) properties. Grouped with antipsychotics, they comprise the fourth leading class of substances reported to poison centers, and they are the leading cause of reported fatalities.1 These drugs are widely used in clinical settings but are also used for suicide, illicit recreational activities, and facilitation of sexual assault (“date rape”). Several high-profile deaths have been attributed to sedative-hypnotic overdoses.
Benzodiazepines have largely supplanted older agents and have become the most widely used sedative-hypnotics in clinical settings. However, given their prevalence, benzodiazepines also account for the majority of sedative-hypnotic overdoses.1 Flunitrazepam, sometimes referred to as “roofies,”2 is a potent benzodiazepine that has been popularized as a street drug of abuse and has been implicated as a date-rape drug.3
Barbiturates were formerly the primary sedative-hypnotic agents used clinically. Currently, they are most often encountered as anticonvulsants, induction agents for anesthesia, and agents used for procedural sedation. Because the barbiturates have largely been replaced clinically by benzodiazepines due to safety concerns, their prevalence in overdoses has drastically decreased when compared with previous decades.1 The reported use of barbiturates among high school seniors experienced a slow but steady surge throughout the 1990s and reached a peak in 2005, only to experience a decline since then.4 Barbiturates accounted for only two single-substance deaths reported to poison centers in 2009.1
Gamma-hydroxybutyrate (GHB) was synthesized in 1960 as an anesthetic agent. Although it found limited use in this arena, GHB gained widespread acceptance in the body-building community in the 1990s as a purported anabolic agent. More recently, it has been used as a recreational drug for its euphoric and intoxicating effects.5 It has also been implicated in date rape because of its “knockout” and amnestic properties.
Several nonbenzodiazepine sedatives have been introduced for sleep induction. Examples include zolpidem (Ambien), zaleplon (Sonata), and eszopiclone (Lunesta). Cases of abuse and dependence have been reported, albeit with much less frequency compared with benzodiazepines.6 Nonbenzodiazepine sedatives have been implicated in cases of impaired driving.7
Chloral hydrate has been used as a sedative since the nineteenth century. In the early 1900s, chloral hydrate was used maliciously, added to alcoholic drinks consumed by unwary individuals to facilitate robberies. The drug-laced drink was referred to as a “Mickey Finn,” named after the owner of a Chicago bar who used these drinks to rob unsuspecting patrons.8 Currently, chloral hydrate is used primarily for procedural sedation.
Propofol is a short-acting sedative-hypnotic that has become widely used clinically for induction of anesthesia and procedural sedation. Despite its abuse potential, the literature is limited to case reports of toxicity from recreational use because of its limited availability to the general public.9 Most reported cases involve self-administration by medical personnel.10–12 Propofol is covered in greater detail elsewhere in this text.
Pathophysiology
Benzodiazepines
Benzodiazepines vary in onset and duration of action according to their lipid solubility and the presence or absence of active metabolites (Box 155.1). The more lipid soluble the agent is, the more rapidly it crosses the blood-brain barrier, thus yielding a faster onset of action. The duration of action depends largely on the elimination half-life of specific agents, which can range from hours to days. The duration of action is also affected by the metabolism of certain benzodiazepines because their active metabolites extend the duration of symptoms.
Barbiturates
The barbiturates are often classified according to their therapeutic duration of action: ultrashort-acting, short-acting, intermediate-acting, and long-acting agents (Box 155.2). In overdoses, however, the duration of action varies with dose, rate of absorption, and rate of distribution and elimination. The ultrashort-acting and short-acting agents are highly lipid soluble and rapidly penetrate the CNS, so the onset of symptoms is also rapid. In addition, the ultrashort-acting barbiturates are more highly protein bound, have higher acid-dissociation constant (pKa), values, and have larger volumes of distribution. Long-acting agents such as phenobarbital are metabolized more slowly in the liver, with a greater fraction of unchanged drug excreted in the kidney. These factors help explain why enhanced renal elimination through alkalinization may be more effective with phenobarbital, which also has a lower pKa than the other barbiturates, thus making it more sensitive to alkalinization. In addition, phenobarbital undergoes enterohepatic recirculation, which makes repeated use of activated charcoal potentially advantageous.
The reticular activating system and the cerebellum appear to be the most susceptible to the depressant effects of barbiturates. Toxicity can lead to suppression of skeletal, smooth, and cardiac muscles, with resulting depressed myocardial contractility, bradycardia, vasodilation, and hypotension (Table 155.1).
Gamma-Hydroxybutyrate
GHB is a metabolite of GABA that occurs naturally in the human brain.5 It is highly lipophilic and rapidly absorbed, and, unlike GABA, it readily crosses the blood-brain barrier. Presentation in a coma state and subsequent rapid recovery is characteristic of GHB overdose.
Chloral Hydrate
Although chloral hydrate has been used for more than a century to induce sedation, its mechanism of action is still largely unknown. It probably works through effects at the GABA receptor, similar to the other sedative-hypnotic agents discussed. Chloral hydrate can also induce cardiac dysrhythmias, most likely by increasing the sensitivity of the myocardium to catecholamines.13
Other Agents
Buspirone is a nonbenzodiazepine used to treat generalized anxiety. Its mechanism of action involves serotonin, rather than GABA. Although buspirone is one of the more commonly reported miscellaneous sedative-hypnotic exposures, significant toxicity from overdose is extremely rare.1
