BENZODIAZEPINES
History
Benzodiazepines were accidentally discovered to be effective sedative-hypnotic
drugs.[352]
Sternbach synthesized chlordiazepoxide
(Librium) in 1955, but it was discarded without testing because it was considered
inert. However, in 1957 the drug was discovered to have entirely unexpected "hypnotic,
sedative, and antistrychnine effects in mice."[353]
This first benzodiazepine was released for oral use in 1960, and in that year it
was clear that in sufficiently large doses, chlordiazepoxide possessed profound hypnotic
and amnestic properties, although it was not available in parenteral form for use
in anesthesia. However, a patient who was taking chlordiazepoxide was reported to
have fallen and fractured her sacrum accidentally[354]
;
this accident, which was not remembered or painful, suggested the use of benzodiazepines
as anesthetics during trauma (surgery). Diazepam (Valium) was synthesized by Sternbach
in 1959 while searching for a new and better compound. It was first described for
use as an intravenous anesthetic induction agent in 1965.[355]
Oxazepam (Serax), a metabolite of diazepam, was synthesized in 1961 by Bell and
was marketed by a different pharmaceutical company. Lorazepam (Ativan), a 2'-chloro
substitution product of oxazepam, was synthesized in 1971 in an attempt to produce
a more potent benzodiazepine. The next major achievement was Walser and colleagues'
1976 synthesis of midazolam (Versed), the first clinically used water-soluble benzodiazepine.
[356]
It is not
Figure 10-10
The structures of four benzodiazepines used in clinical
anesthesia practice.
certain when benzodiazepines were initially used to induce anesthesia, but in 1966
several groups reported the use of diazepam for anesthesia.[357]
[358]
Midazolam was the first benzodiazepine that
was produced primarily for use in anesthesia.[359]
Benzodiazepines possess many of the characteristics sought by
anesthesiologists. They produce their actions by occupying the benzodiazepine receptor,
which was first discussed in December 1971 in Milan.[360]
Barnett and Fiore[361]
postulated a benzodiazepine
receptor, and in 1977, specific benzodiazepine receptors were described when ligands
were found to interact with a central receptor.[362]
Discovery and understanding of the mechanism of the benzodiazepine receptor have
enabled chemists to develop many agonist compounds and to even produce a specific
antagonist for clinical use.
