View source for Category:Sedative-hypnotics

The sedative-hypnotics are the broad class of medicines that calm and induce sleep, "sedative" referring to the calming of agitation and anxiety, "hypnotic" to the bringing on of sleep, the two effects being, for most of these medicines, the same action at different doses. The class is best understood through its history, which is one of the clearest examples in all of medicine of a single recurring pattern: each generation of sedative was introduced as the safe answer to the dangers of the one before it, was used widely, and was in time found to carry serious problems of its own.

== Before the sedatives: alcohol and opium ==
For most of history the only substances available to calm or to induce sleep were alcohol and the preparations of [[opium]]. Both worked, and both were freely used; neither was safe, and neither was reliable in dose. The history of the sedative-hypnotics proper begins in the nineteenth century, when chemistry first made it possible to produce specific medicines for the purpose.

== The nineteenth century: bromide, chloral, paraldehyde ==
The first medicine introduced specifically as a sedative was potassium bromide, brought into use from 1857. It genuinely reduced agitation and was also the first useful treatment for epilepsy, but it was slow, and prolonged use caused a syndrome of skin eruptions and dulled mental state. Chloral hydrate followed in 1869, the first synthetic hypnotic, fast-acting, and notorious as the "knockout drops" of popular legend. Paraldehyde, introduced in the 1880s, was effective and relatively safe but had a powerful, lasting smell that made it unpopular with patients. Sulphonal and other agents followed. Each of these filled a real need, and each had drawbacks that left room for something better.<ref name="ban">Ban TA. Sedatives in the second part of the 19th century. International Network for the History of Neuropsychopharmacology, educational series.</ref>

== The barbiturate era ==
The something better, for half a century, was the barbiturates. From the introduction of the first, Veronal, in 1903, the barbiturates rapidly displaced the older sedatives; dozens were developed, and from the 1930s they were among the most widely used medicines in the world. They were more effective and more predictable than bromide or chloral, but they too carried a high risk of dependence, and, most seriously, a narrow margin between an effective dose and a fatal one. The barbiturates are covered fully under [[:Category:Barbiturates|barbiturates]].

A number of non-barbiturate sedatives, among them [[meprobamate]], [[glutethimide]], [[methaqualone]], and [[ethchlorvynol]], were introduced in the 1940s and 1950s and for a time rivalled the barbiturates. Marketed as improvements, they were generally found to share the same essential problems, and most are now little used.

== The benzodiazepine era ==
The next generation was the benzodiazepines, introduced from 1960. They produced the same calming and sleep-inducing effects but were far less likely to cause death by overdose, and they rapidly displaced the barbiturates for the treatment of anxiety and insomnia. They became, in their turn, among the most prescribed medicines in the world, and were in their turn found to carry a serious risk of dependence, with a difficult withdrawal syndrome. The benzodiazepines are covered fully under [[:Category:Benzodiazepines|benzodiazepines]].

== The Z-drugs and after ==
From the late 1980s a further group appeared: the non-benzodiazepine hypnotics, widely known as the "Z-drugs", among them [[zolpidem]], [[zaleplon]], [[zopiclone]], and [[eszopiclone]]. Chemically unrelated to the benzodiazepines, they act at the same receptor but more selectively, and were introduced as a better-targeted treatment for insomnia. They are now very widely used; the familiar pattern has recurred to some degree, with concerns about dependence and about unusual sleep-related behaviours.

More recent medicines for insomnia work in entirely different ways, the melatonin receptor agonists, which act on the body's sleep-timing system, and the orexin receptor antagonists, which block a signal that promotes wakefulness. These represent a move away from the GABA-based sedation that every generation from the barbiturates onward had relied upon. Alongside the medicines, non-drug treatment, particularly cognitive behavioural therapy for insomnia, is now generally recommended as the first-line approach for chronic insomnia.

== Mechanisms ==
The sedative-hypnotics do not all work the same way, but a large majority of them, the barbiturates, the benzodiazepines, and the Z-drugs, are understood to act at the GABA-A receptor, the receptor for the brain's principal inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). Broadly, these medicines enhance GABA's inhibitory effect, increasing the damping of activity in the nervous system; the barbiturates, benzodiazepines, and Z-drugs do this in characteristically different ways and with different consequences for safety, as described on their own pages. The newer agents act outside the GABA system altogether, on the melatonin or the orexin signalling systems. That these medicines have these actions is well established; the fuller relationship between a given action and the experience of sedation or sleep is more complex and remains a subject of research.

== Members ==
The sedative-hypnotics include several groups. The [[:Category:Barbiturates|barbiturates]] and the [[:Category:Benzodiazepines|benzodiazepines]] are each covered as classes in their own right. The non-benzodiazepine "Z-drugs" include [[zolpidem]], [[zaleplon]], [[zopiclone]], and [[eszopiclone]]. The older non-barbiturate sedatives include [[meprobamate]], [[glutethimide]], [[methaqualone]], and [[ethchlorvynol]]. Newer agents for insomnia include the melatonin receptor agonists and the orexin receptor antagonists. The classical sedatives, bromide, chloral hydrate, paraldehyde, are now largely of historical interest. The list is not exhaustive.

== Safety ==
Because the sedative-hypnotics span many distinct medicines, their risks differ considerably, and the safety information for each is best read on its own page. Some points apply broadly. As a group these medicines cause drowsiness and impair coordination and alertness, effects that contribute to falls and injuries, particularly in older adults. Many carry a risk of tolerance and of dependence, with a withdrawal syndrome on stopping, so that they are generally intended for short-term use and are often reduced gradually rather than stopped abruptly. The danger of any sedative rises sharply when it is combined with another, or with alcohol or opioids, because the depressant effects add together, and combined use is an important cause of fatal overdose. Figures for these risks are population estimates that vary between studies, and individual response varies considerably between people.

== References ==

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