Benzodiazepines Chemische Eigenschaften,Einsatz,Produktion Methoden
Chemische Eigenschaften
The basic chemical structure of the benzodiazepines
consists of a benzene ring coupled to a seven-member
heterocyclic structure containing two nitrogens (diazepine)
at positions 1 and 4. Of the 2,000
benzodiazepines that have been synthesized, approximately
15 clinically useful compounds are on the market
in the United States.
Biologische Funktion
Benzodiazepines also possess muscle relaxant activity.
Their pharmacology is discussed in Chapter 30.
Diazepam (Valium) has been used for control of flexor
and extensor spasms, spinal spasticity, and multiple sclerosis.
The muscle relaxant effect of the benzodiazepines
may be mediated by an action on the primary afferents
in the spinal cord, resulting in an increased level of
presynaptic inhibition of muscle tone. Polysynaptic reflexes
are inhibited.The most troublesome side effect is
drowsiness, which is dose dependent. Tolerance to both
the therapeutic effects and the side effects develops.
Allgemeine Beschreibung
For details of the chemistry and SARs of the BZDs, see thediscussion of anxiolytic sedative–hypnotic drugs. Amongthe current clinically useful drugs, the structural features associatedwith anticonvulsant activity are identical with thoseassociated with anxiolytic sedative–hypnotic activity.
Pharmakologie
Although it is widely claimed that the benzodiazepine
drugs have a specific calming or anxiolytic effect, their
most prominent and easily quantifiable action is central
nervous system depression. In very low therapeutic
doses, this depression manifests as relief of anxiety that
is often accompanied by a feeling of sluggishness or
drowsiness. As the dose is increased, the degree of depression
is intensified such that muscle relaxation, hypnosis and a more intense central nervous system depression
occur. This depression is related to the ability
of these drugs to facilitate the inhibitory actions of
GABA.
A significant advantage of the benzodiazepines over
other central nervous system depressants (e.g., the barbiturates)
is that they possess a much greater separation
between the dose that produces sleep and the dose that
produces death. This increased margin of safety has
been one of the major reasons benzodiazepines have
largely replaced the barbiturates and other types of sedative–
hypnotics in the treatment of anxiety and insomnia.
In addition, benzodiazepine administration is associated
with few side effects.
Nebenwirkungen
Midazolam (Versed), diazepam (Valium), and lorazepam
(Ativan) are benzodiazepine derivatives that
are useful in anesthesia. Midazolam is the most popular
of these agents for the induction of anesthesia. Its popularity
is related to its aqueous solubility and to its short
duration of action, which permits a prompt return of
psychomotor competence. Unlike midazolam, lorazepam
and diazepam are not water soluble and must
be formulated in propylene glycol; the latter is irritating
to the vasculature on parenteral administration.
Benzodiazepines are useful as orally administered
premedications. They are also used intravenously in
doses that produce conscious sedation rather than hypnosis.
Sedated patients tolerate unpleasant procedures
(e.g., wound repair, bronchoscopy, angiography) while
maintaining cardiorespiratory function and the ability
to respond to tactile stimulation or verbal commands.
Midazolam has a shorter half-life (t
1/2β = 1.3–2.2
hours) than either diazepam (t
1/2β = 30 hours) or lorazepam
and is not converted in the liver to active
metabolites, as is diazepam. Thus, use of midazolam results
in a more rapid return to psychomotor competence.
Doses may need to be lowered by at least 30% in
older patients and in those premedicated with opioids
or other sedative drugs.
Arzneimittelwechselwirkung
When used with other sedative–hypnotics or alcohol,
the benzodiazepines will produce additive central nervous
system depression.
Many benzodiazepines are metabolized by the cytochrome
P450 (CYP) enzyme designated CYP3A4.
CYP3A4 is inhibited by grapefruit juice and by drugs
such as ketoconazole, itraconazole, nefazodone, erythromycin,
and ritonavir. Coadministration of these substances
along with a benzodiazepine may result in intensification
and prolongation of the benzodiazepine
effect. Conversely, rifampin, carbamazepine, and phenytoin
can induce the CYP3A4 enzyme, and therefore
their coadministration can reduce the therapeutic effect
of the benzodiazepines.
Benzodiazepines Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
