Source: Υπουργείο Υγείας (CY) Revision Year: 2014 Publisher: Medochemie Ltd, p.o box 51409, Limassol, CY – 3505, Cyprus
Diazepam is thought to specifically interfere with interneuronal transmission. Polysynaptic spindle reflexes are inhibited producing skeletal muscle relaxation. Tranquilization is achieved by inhibition of the limbic system.
The mechanism of action of the benzodiazepines has not been fully elucidated in humans. The most promising hypothesis involves GABA transmission. GABA is a major inhibitory transmitter in the CNS. Benzodiazepines exert their pharmacological effect at the site of the GABA synapse, increasing the affinity of the receptor for GABA, thus reducing GABA turnover.
It is speculated that an endogenous protein ligand exists which normally binds to the benzodiazepine receptor and serves to produce anxiety for survival purposes. This endogenous ligand also may serve as a natural inhibitor for the regulatory site of GABA receptors. When benzodiazepines occupy the sites, the affinity of GABA receptors is increased. When the natural ligand occupies the site, GABA affinity is decreased.
Increased GABA activity can explain most of the pharmacologic effects of benzodiazepines. Increased presynaptic inhibition at the spinal level may be one site of skeletal muscle relaxation. There also appears to be a direct peripheral action on the contractile process of muscle. Enhancement of GABA activity in the limbic area and mesencephalic reticular formation is responsible for anticonvulsant properties.
Diazepam is readily and completely absorbed from the gastrointestinal tract, peak plasma concentrations occurring within about 30 to 90 minutes of oral administration.
Diazepam is highly lipid soluble and crosses the blood-brain barrier; it acts promptly on the brain, and its initial effects decrease rapidly as it is redistributed into fat depots and tissues.
Diazepam has a biphasic half-life with an initial rapid distribution phase followed by a prolonged terminal elimination phase of 1 or 2 days; its action is further prolonged by the even longer half-life of 2 to 5 days of its principal active metabolite, desmethyldiazepam (nordazepam). Diazepam and desmethyldiazepam accumulate on repeated administration and the relative proportion of desmethyldiazepam in the body increases on long-term administration.
Diazepam is extensively metabolised in the liver and, in addition to desmethyldiazepam, its active metabolites include oxazepam, and temazepam. It is excreted in the urine, mainly in the form of free or conjugated metabolites. Diazepam is 98 to 99% bound to plasma proteins.
The plasma elimination half-life of diazepam and/or its metabolites is prolonged in neonates, in the elderly, and in patients with liver disease. In addition to crossing the blood-brain barrier, diazepam and its metabolites also cross the placental barrier and are distributed into breast milk.
For most other benzodiazepines the lack of human studies meant that the carcinogenic risk to humans was not classifiable.
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