Diazepam

Diazepam is a psychotropic substance from the class of 1,4-benzodiazepines with marked properties of suppression of tension, agitation and anxiety as well as sedative and hypnotic effects. In addition, diazepam demonstrates muscle relaxant and anticonvulsive properties. It is used in the short-term treatment of anxiety and tension states, as a sedative and premedicant, in the control of muscle spasm and in the management of alcohol withdrawal symptoms.

Diazepam binds to specific receptors in the central nervous system and particular peripheral organs. The benzodiazepine receptors in the CNS have a close functional connection with receptors of the GABA-ergic transmitter system. After binding to the benzodiazepine receptor, diazepam augments the inhibitory effect of GABA-ergic transmission.

Absorption

Oral administration

Diazepam is readily and completely absorbed from the GI tract. Peak plasma concentrations occurring within about 30-90 minutes of oral administration, a steady plasma concentration is reached after 5-6 days and is directly related to dose.

IV administration

Diazepam is highly lipid soluble and crosses the blood brain barrier. These properties qualify it for intravenous use in short term anaesthetic procedures since it acts promptly on the brain, and its initial effects decrease rapidly as it is distributed into fat deposits and tissues. Following the administration of an adequate intravenous dose of diazepam, effective plasma concentrations are usually reached within 5 minutes (ca. 150-400 ng/ml).

Rectal administration

After rectal administration of the solution, diazepam is absorbed rapidly and almost completely from the rectum.

The onset of the therapeutic effect occurs within a few minutes of rectal administration. The rapidity of the rise in the serum level following rectal administration corresponds approximately to that following an intravenous dose but peak plasma concentrations are lower after rectal tubes than after intravenous administration. In adults maximal plasma concentrations following the administration of 10 mg diazepam in rectal solution are reached after about 10-30 minutes (ca. 150-400 ng/ml).

Distribution

Oral administration

Diazepam crosses the blood-brain barrier and is highly lipid soluble, this causes the initial effects to decrease rapidly as it is redistributed into fat deposits and tissues Diazepam is very extensively bound to plasma proteins (98-99%). Diazepam and its metabolites also enters breast milk and crosses the placenta freely, this may lead to accumulation in the infant or foetus.

IV administration / Rectal administration

Diazepam is extensively protein bound (95-99%). The volume of distribution is between 0.95 and 2 l/kg depending on age. Diazepam and its main metabolite, N-desmethyldiazepam, cross the placenta and are secreted in breast milk.

Biotransformation

Oral administration

Diazepam is extensively metabolised in the liver and, in addition to desmethyldiazepam, its active metabolites include oxazepam and temazepam. 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 2-5 days of its principle active metabolite, desmethyldiazepam (nordiazepam), the relative proportion of which increases in the body on long-term administration. The plasma half-life of diazepam is prolonged in neonates, in the elderly, and in patients with kidney or liver disease.

IV administration / Rectal administration

Diazepam is metabolised predominantly in the liver. Its metabolites, N-desmethyldiazepam (nordiazepam), temazepam and oxazepam, which appear in the urine as glucuronides, are also pharmacologically active substances. Only 20% of the metabolites are detected in the urine in the first 72 hours.

Diazepam has a biphasic half life with an initial rapid distribution phase followed by a prolonged terminal elimination phase of 1-2 days. For the active metabolites N-desmethyldiazepam, temazepam and oxazepam, the half lives are 30-100 hours, 10-20 hours and 5-15 hours, respectively.

Elimination

Oral administration

It is excreted in the urine, mainly in the form of its metabolites, either free or in conjugated form.

IV administration / Rectal administration

Excretion is mainly renal and also partly biliary. It is dependent on age as well as hepatic and renal function.

Metabolism and elimination in the neonate are markedly slower than in children and adults. In the elderly, elimination is prolonged by a factor of 2 to 4. In patients with impaired renal function, elimination is also prolonged. In patients with hepatic disorders (liver cirrhosis, hepatitis), elimination is prolonged by a factor of 2.

Chronic toxicity studies have demonstrated no evidence of drug induced changes. There are no long term animal studies to investigate the carcinogenic potential of diazepam. Several investigations pointed to a weakly mutagenic potential at doses far above the human therapeutic dose.

Local tolerability has been studied following single and repeat dose applications into the conjunctival sac of rabbits and the rectum of dogs. Only minimal irritation was observed. There were no systemic changes.

In humans it would appear that the risk of congenital abnormalities from the ingestion of therapeutic doses of benzodiazepines is slight, although a few epidemiological studies have pointed to an increased risk of cleft palate. There are case reports of congenital abnormalities and mental retardation in prenatally exposed children following overdosage and intoxication with benzodiazepines.