The term sedative-hypnotic refers to any drug designed to produce sedation and sleepiness. These drugs can be divided into the benzodiazepines (see chapter 183, Benzodiazepines) and nonbenzodiazepines (Table 184-1).

One is most likely to encounter toxicity from these sedative drugs as part of accidental or nonaccidental overdose, as well as after an assault or trauma. Many nonbenzodiazepines were developed and are marketed for the treatment of insomnia.¹ The sedative effect of other agents, including antihistamines (e.g., diphenhydramine, doxylamine), antidepressants (e.g., amitriptyline, trazodone, and mirtazapine), and antipsychotics (e.g., quetiapine), are also used to promote sleep.

Three sedative agents used in the past have been removed from the legal U.S. and Canadian markets: ethchlorvynol, glutethimide, and methaqualone. However, comments on the Internet suggest these drugs might be available to North American customers from locations in Eastern Europe, Africa, Asia, and South America.²

Buspirone is approved by the U.S. Food and Drug Administration for treatment of anxiety disorders.³ Other off-label uses include treatment of depression and nicotine dependence. Buspirone is a partial agonist at the serotonin-1A receptor and an antagonist of the dopamine-2 receptor. The resultant effect on serotonin and dopamine neurotransmitter levels is complex, depending on the concentration of the drug and specific brain location, but overall effects are primarily suppression of CNS serotoninergic activity and enhancement of dopaminergic and, possibly, noradrenergic activity.

The typical starting dose for buspirone is 5 milligrams PO three times daily, and the maximum recommended total daily dose is 60 milligrams. Following ingestion, absorption is rapid and nearly complete, with significant first-pass metabolism in the liver, primarily via oxidation, resulting in a low bioavailability. Metabolism of buspirone, by cytochrome P3A4, produces several metabolites, including one active metabolite. Primary elimination is renal, with additional substantial fecal elimination.

Common adverse effects with buspirone use include sedation, GI discomfort, vomiting, and dizziness. In therapeutic dosing, buspirone does not appear to cause psychomotor depression and has not been associated with any potential for abuse or withdrawal.⁴

The effects observed with a buspirone overdose would likely be an exaggeration of adverse effects observed during therapeutic dosing. In general, the drug is well tolerated in overdose, and the treatment is largely supportive.⁵ Animal toxicity studies indicate the potential for buspirone to provoke seizures, and one human case report noted the occurrence of a generalized tonic-clonic convulsion approximately 36 hours after a buspirone overdose (Table 184-2).⁶ Because of its serotoninergic properties, buspirone has been associated with serotonin syndrome.⁷

Carisoprodol and its primary active metabolite meprobamate have been used since the 1950s. Carisoprodol is marketed as a centrally acting muscle relaxant, whereas meprobamate is marketed as an anxiolytic drug.

The exact mechanism of action of carisoprodol is not known; animal data demonstrate its ability to block interneuronal activity within the spinal cord and descending reticular formation. Other evidence suggests that the primary mechanism of action is simply related to sedation.⁸ Carisoprodol may also have direct γ-aminobutyric acid activity, independent of its metabolite meprobamate.⁹

The recommended dose of carisoprodol is 200 to 350 milligrams PO up to four times daily. Following ingestion, carisoprodol is rapidly absorbed, with an onset of action within 30 minutes and a duration of action between 2 and 6 hours. Several formulations are marketed, sometimes combined with aspirin, caffeine, or codeine. Following metabolism in the liver, the carisoprodol metabolites are renally excreted.

The recommended dose of meprobamate is 400 milligrams PO three or four times daily, with a maximum total daily dose of 2400 milligrams. Following ingestion, meprobamate is rapidly absorbed, with a duration of action of 6 to 10 hours. Following metabolism in the liver, the metabolites and 10% to 20% of the unchanged drug are eliminated by the kidneys.

With a carisoprodol overdose, sedation, coma, cardiovascular collapse, and pulmonary edema have been reported. Myoclonic jerks are commonly observed and appear somewhat unique to carisoprodol; occasional jerking movements of the extremities in a sedated or comatose patient suggest carisoprodol toxicity. Serotoninergic features of carisoprodol intoxication have been noted, but the mechanism by which these symptoms and signs are produced is not understood.¹⁰ Treatment of carisoprodol overdose and toxicity is supportive.

With meprobamate overdose, sedation, coma, and cardiopulmonary depression are seen, but the myoclonic jerks described above are not. Ingestion of a large number of meprobamate tablets has been reported to form a gastric bezoar, and prolonged coma has been attributed to such retained drug within the stomach. If this occurs, endoscopic removal of the mass or multidose activated charcoal would appear useful.

Carisoprodol and meprobamate have significant potential for abuse and dependence.¹¹ A withdrawal syndrome has been described in which patients can develop tremor, anxiety, insomnia, and anorexia, usually within 12 to 48 hours of abstinence. Visual and auditory hallucinations and seizures have been described during withdrawal, although these later effects are observed less consistently.

Chloral hydrate was first marketed as a sedative in 1869, making it the oldest sedative hypnotic agent still available. It remained quite popular until the early 1900s, when barbiturates largely supplanted its use. Chloral hydrate is primarily used for procedural sedation in young children because of its relatively wide therapeutic index, the lack of significant respiratory depression, and the ability for oral administration,¹² although it is not without risk.¹³

The hypnotic dose in adults is 500 to 1000 milligrams PO. For children the hypnotic dose is 50 milligrams/kg PO and the sedation dose is 80 to 100 milligrams/kg PO.¹² Following ingestion, chloral hydrate is quickly absorbed and rapidly reduced to trichloroethanol, an active metabolite, via alcohol dehydrogenase. Trichloroethanol is further oxidized to trichloroacetic acid, which is an inactive compound. Renal excretion of chloral hydrate is minimal.

Co-ingested chloral hydrate and ethanol have a synergistic effect. The metabolism of ethanol results in increased amounts of the reduced form of nicotinamide adenine dinucleotide, which, in turn, promotes the conversion of chloral hydrate to trichloroethanol. In addition, because of competition by chloral hydrate for alcohol dehydrogenase, there is decreased metabolism of ethanol. These interactions result in more elevated levels of both trichloroethanol and ethanol than would be seen if either was ingested alone. The resultant profound sedation yields the terms “knock-out drops” or “Mickey Finn” for this combination.

At therapeutic doses, chloral hydrate results in mental status depression, but airway and respiratory reflexes are not impaired. Paradoxical hyperactivity occurs in 1% to 2% and vomiting is seen in 3% to 10% of children given doses of 50 to 100 milligrams/kg PO.

With an overdose, chloral hydrate can produce coma. An important feature of chloral hydrate overdose is cardiovascular instability, manifested by decreased cardiac contractility, myocardial electrical instability, and increased sensitivity to catecholamines.¹⁴ Commonly encountered cardiac dysrhythmias include premature ventricular contractions, ventricular fibrillation, torsade de pointes, and asystole. GI irritation, including nausea, vomiting, and hemorrhagic gastritis, has been observed. A diagnostic clue is the common presence of a pear-like odor.

Treatment of chloral hydrate overdose and toxicity is largely supportive. With coma, endotracheal intubation may be necessary. IV β-adrenergic blockers should be used to treat ventricular dysrhythmias seen with chloral hydrate overdose.¹⁵ Torsade de pointes should be managed with IV magnesium sulfate or ventricular overdrive pacing.

Chronic consumption of chloral hydrate can result in dependency and addiction. A withdrawal state, similar to ethanol, has been described.