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Benzodiazepines
The first benzodiazepine, chlordiazepoxide,
was synthesised by accident in 1961, the
unusual seven-membered ring having been
produced as a result of a reaction that went
wrong in the laboratories of Hoffman-la
Roche. Its unexpected pharmacological
activity was recognised in a routine screening
procedure, and benzodiazepines quite soon
became the most widely prescribed drugs in
the pharmacopoeia.
BENZODIAZEPINE INVERSE
AGONISTS AND ANTAGONISTS
The term inverse agonist is applied
to drugs that bind to benzodiazepine
receptors and exert the opposite
effect to that of conventional
benzodiazepines, producing signs of
increased anxiety and convulsions.
Diazepam-binding inhibitor is an
example, and some benzodiazepine
analogues act similarly.
PHARMACOKINETIC
ASPECTS
Benzodiazepines are well absorbed when given
orally, usually giving a peak plasma concentration
in about 1 hour. Some (e.g. oxazepam,
lorazepam) are absorbed more slowly. They bind
strongly to plasma protein, and their high lipid
solubility causes many of them to accumulate
gradually in body fat. They are normally given by
mouth but can be given intravenously (e.g.
diazepam in status epilepticus, midazolam in
anaesthesia). Intramuscular injection often results
in slow absorption.
UNWANTED EFFECTS
Toxic effects resulting from acute overdosage
Benzodiazepines in acute overdose are considerably less
dangerous than other anxiolytic/hypnotic drugs. Because
such agents are often used in attempted suicide, this is
an important advantage. In overdose, benzodiazepines
cause prolonged sleep, without serious depression of
respiration or cardiovascular function. However, in the
presence of other CNS depressants, particularly alcohol,
benzodiazepines can cause severe, even life-threatening,
respiratory depression. The availability of an effective
antagonist, flumazenil, means that the effects of an
acute overdose can be counteracted,3 which is not
possible for most CNS depressants.
BUSPIRONE
Buspirone is a partial agonist at 5-HT1A receptors
and is used to treat various anxiety disorders. It
also binds to dopamine receptors, but it is likely
that its 5-HT-related actions are important in
relation to anxiety suppression, because related
compounds (e.g. ipsapirone and gepirone,
neither of which are approved for clinical use,
which are highly specific for 5-HT1A receptors; show
similar anxiolytic activity in experimental animals.
5-HT1A receptors are inhibitory autoreceptors that
reduce the release of 5-HT and other mediators.
BARBITURATES
The sleep-inducing properties of barbiturates
were discovered early in the 20th century, and
hundreds of compounds were made and tested.
Until the 1960s, they formed the largest group of
hypnotics and sedatives in clinical use.
Barbiturates all have depressant activity on the
CNS, producing effects similar to those of
inhalation anaesthetics. They cause death from
respiratory and cardiovascular depression if given
in large doses, which is one of the main reasons
that they are now little used as anxiolytic and
hypnotic agents.