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 [].
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TABLE 184-1Sedative-Hypnotics
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TABLE 184-1 Sedative-Hypnotics
NameTime to Peak Plasma LevelsOral BioavailabilityElimination Half-LifeBuspirone40–90 min6 hours after ingestion and is virtually nondetecTable >12 hours after ingestion. GHB has minimal protein binding and readily crosses the blood–brain barrier and placenta.
++The body produces some endogenous GHB, both as a precursor and a breakdown product of γ-aminobutyric acid. At physiologic concentrations, GHB binds to a unique receptor, which is distinct from γ-aminobutyric acid receptors. When the concentration of GHB in the brain exceeds the physiologic micromolar concentration, GHB can bind to [and activate] the γ-aminobutyric acid subunit B receptors.
++GHB has a steep dose–response curve with a narrow therapeutic ratio; doses of 10 milligrams/kg result in short-term amnesia, doses of 20 to 30 milligrams/kg result in sedation and drowsiness, and doses exceeding 50 milligrams/kg result in seizure, coma, respiratory depression, and cardiac depression. Bradycardia, hypothermia, and either miosis or mydriasis can occur. During recovery, the patients often wake up surprisingly quickly as opposed to the more prolonged awakening phase seen after an overdose with other sedatives. Despite co-ingestants being commonly encountered, most patients fully regain consciousness within 6 hours. The co-ingestion of ethanol can worsen hypoxia and possibly result in a longer elimination half-life of GHB.
++Treatment is largely supportive. Intubation is generally unnecessary, even in patients with severely depressed consciousness [Glasgow Coma Scale score ≤8] because patients are usually able to protect their airway and maintain ventilation. Once the patient is awake and alert, assuming no co-ingestants or secondary complications such as aspiration, the patient can be medically discharged or transferred. Physostigmine or neostigmine is not recommended for reversal of known or suspected GHB intoxication. Fomepizole [a competitive antagonist of alcohol dehydrogenase] has little benefit in 1,4-butanediol overdoses because preventing metabolism of the ingested drug into GHB is of little benefit due to the short expected duration of symptoms.
Chronic GHB use is associated with a withdrawal syndrome characterized by two often distinct phases., The first phase is typified by insomnia, confusion, GI distress, anxiety, and tremor. This first stage can be observed as soon as 2 hours after the last dose in patients who habitually use GHB. The second stage, which can occur in 2 to 3 days after the last dose, is characterized by tachycardia, hypertension, diaphoresis, tremor, confusion, hallucinations, and paranoia. The withdrawal state can last anywhere from 3 days to 2 weeks. The short latency period between the last dose and the onset of symptoms is helpful in distinguishing ethanol withdrawal from GHB withdrawal.
++Toxicologic detection of GHB can be difficult because of its short half-life, the complexity of assay methodology, and the presence of the endogenous compound. If needed, toxicologic confirmation should be performed with blood or urine collected as soon as the individual arrives in the ED.
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MELATONIN
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++Melatonin is an endogenous hormone that is normally secreted by the pineal gland and is believed to be involved with the circadian sleep–wake cycle. Melatonin is available without prescription in tablets or capsules at doses ranging from a physiologic dose of 0.3 milligram up to a pharmacologic dose of 10 milligrams.
++Two primary melatonin receptor subtypes are found in the human CNS. The MT1 receptor is located primarily in the hypothalamic suprachiasmatic nucleus and is involved in the effect melatonin has on circadian rhythm. The MT2 receptor is found primarily in the retina, presumably involved in the interaction between incoming light, melatonin, and the circadian cycle. The MT2 receptor is also found in the hypophysial pars tuberalis and is possibly responsible for the effects of melatonin on reproduction.
++Following ingestion, peak plasma melatonin concentrations occur within 40 to 50 minutes. Melatonin has a short plasma half-life and a short duration of action in therapeutic doses. Melatonin is metabolized by initial conversion to O-desmethylmelatonin and 6-hydroxymelatonin. Both are subsequently conjugated as either a glucuronide or a sulfate and then excreted by the kidneys.
++At therapeutic dosing, side effects from melatonin include fatigue, headache, dizziness, and irritability. Data on melatonin overdoses are limited, but overdose would be expected to result in an exaggeration of therapeutic effects, primarily sedation and disorientation without any significant life-threatening effects.
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RAMELTEON
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++Ramelteon is a highly selective agonist at the melatonin MT1 and MT2 receptors, marketed for the treatment of insomnia. Ramelteon has no significant activity at the γ-aminobutyric acid, dopamine, serotonin, norepinephrine, or opiate receptor sites. An active metabolite does have weak activity at the serotonin-2B receptor, but is thought to be clinically insignificant.
++Ramelteon is rapidly absorbed following oral administration, but oral bioavailability is