Chapter 72: Sedative–Hypnotics

HISTORY AND EPIDEMIOLOGY

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–hypnotic 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.

Barbiturates were introduced in 1903 and quickly supplanted older xenobiotics. Barbiturates dominated the sedative–hypnotic market for the first half of the 20th century. Because of 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.¹⁹ After their introduction in the early 1960s, benzodiazepines quickly became the most 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. 130). 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. Compared with barbiturate overdoses, overdoses of benzodiazepines alone account for relatively few deaths.^29,36,43 Most deaths associated with benzodiazepines result from mixed overdoses with other respiratory depressants.^36,112

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. Although the benzodiazepines remain the most popular prescribed anxiolytics, several benzodiazepine-receptor agonists were developed in 1989 in an attempt to circumvent some of the side effects of benzodiazepines. These drugs include zolpidem, as zaleplon, zopiclone, and eszopiclone.^6,107 Newer formulations of zolpidem tartrate such as Intermezzo are now available, which is a low-dose sublingual tablet form (1.75 mg and 3.5 mg compared with 5 mg and 10 mg). Ramelteon and tasimelteon are newer sleep aids that function as melatonin receptor (MT₁ and MT₂) agonists rather than benzodiazepine-receptor agonists.^112,134 Dexmedetomidine, a central α₂-adrenergic agonist, is now increasingly used in the hospital setting for short-term sedation.¹⁴³ An additional medication is suvorexant, a dual orexin receptor antagonist that inhibits the action of orexin, a neuropeptide that promotes wakefulness.³⁰

This chapter focuses primarily on pharmaceuticals prescribed for their sedative–hypnotic effects, many of which interact with the γ-aminobutyric acid-A (GABA_A) receptor (Table 72–1). Specific sedative–hypnotics such as ethanol and γ-hydroxybutyric acid (GHB) are discussed in more depth in their respective chapters (Chaps. ...