Sedative-hypnotics are xenobiotics that limit excitability (sedation) and or induce drowsiness and sleep (hypnosis). Anxiolytics (formerly known as minor tranquilizers) are medications prescribed for their sedative-hypnotic properties. Mythology of ancient cultures is replete with stories of xenobiotics that cause sleep or unconsciousness (Chap. 1). Sedative-hypnotics overdoses were described in the medical literature soon after the commercial introduction of bromide preparations in 1853. Other commercial xenobiotics that subsequently were developed include chloral hydrate, paraldehyde, sulfonyl, and urethane.
The barbiturates were introduced in 1903 and quickly supplanted the older xenobiotics. Barbiturates dominated the sedative-hypnotic market for the first half of the twentieth century. Due to their narrow therapeutic index and substantial potential for abuse, they quickly became a major health problem. By the 1950s, barbiturates were frequently implicated in overdoses and were responsible for the majority of drug-related suicides. As fatalities from barbiturates increased, attention shifted toward preventing their abuse and finding less toxic alternatives.23 The “safer” drugs of that era included methyprylon, glutethimide, ethchlorvynol, bromides, and methaqualone. Unfortunately, many of these sedative hypnotics also had significant adverse drug reactions. After the introduction of benzodiazepines in the early 1960s, barbiturates and the other alternatives were quickly replaced as commonly used sedatives in the United States.
Intentional and unintentional overdoses with sedative-hypnotics occur frequently. According to the American Association of Poison Control Centers, sedative-hypnotics is consistently one of the top five classes of xenobiotics associated with overdose fatalities (Chap. 136). With the ubiquitous worldwide use of sedative-hypnotics, they may be associated with a substantially higher number of overdoses and deaths than are officially reported.
Chlordiazepoxide, the first commercially available benzodiazepine, was initially marketed in 1960. Since then, more than 50 benzodiazepines have been marketed, and more are being developed. Compared with barbiturate overdoses, overdoses of benzodiazepines alone account for relatively few deaths.37,48,59 Most deaths associated with benzodiazepines result from mixed overdoses with other respiratory depressants.48,134
Benzodiazepines remain the most popular prescribed anxiolytics. However, newer hypnotic pharmaceuticals zolpidem, zaleplon, zopiclone, and eszopiclone have replaced benzodiazepines as the most commonly prescribed pharmaceutical sleep aids. Melatonin and ramelteon are emerging as popular sleep aids whose effects are mediated through melatonin receptor subtypes MT1 and MT2 specifically.134,140,160 Dexmedetomidine, a central α2-adrenergic agonist, is now increasingly used in the hospital setting for short-term sedation.30,37,40,121,129,139,160,170,173,176,177,210
This chapter focuses primarily on pharmaceuticals prescribed for their sedative-hypnotic effects, many of which interact with the γ-aminobutyric acid-A (GABAA) receptor (Table 74–1). Specific sedative-hypnotics such as ethanol and γ-hydroxybutyric acid are discussed in more depth in their respective chapters (Chaps. 80 and 83).
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