Chlordiazepoxide

Chlordiazepoxide has anxiolytic and central muscle relaxant properties. It has little autonomic activity.

Chlordiazepoxide acts as depressant of the central nervous system producing all levels of CNS depression, from mild sedation to hypnosis, to coma depending on the dose. The precise sites and mechanisms of action have not been fully established but various mechanisms have been proposed. It is believed that chlordiazepoxide enhances or facilitates the inhibitory neurotransmitter action of gama-aminobutyric acid (GABA) which mediates both pre- and postsynaptic inhibition in all regions of the CNS following interaction between chlordiazepoxide and a specific neuronal membrane receptor. Anti-anxiety action of chlordiazepoxide is believed to result from stimulation of GABA receptors in the ascending reticular activating system, since GABA in inhibitory receptor stimulation increases inhibition and blocks both cortical and limbic arousal following stimulation of the brainstem reticular formation.

The exact mechanism of action of chlordiazepoxide is not fully established. Skeletal muscle relaxation primarily occurs by inhibiting spinal polysynaptic afferent pathways but it may also inhibit monosynaptic afferent pathways.

Absorption

Chlordiazepoxide is well absorbed with peak blood levels being achieved one or two hours after administration. Rate of absorption is age-related and tends to be delayed in the elderly. After absorption it is highly bound to plasma proteins. The drug has a half-life of 6-30 hours.

Steady state levels are usually reached within 3 days.

Distribution

Chlordiazepoxide is extensively metabolised in the liver by hepatic microsomal enzymes and exhibits capacity limited, protein binding sensitive, hepatic clearance.

Chlordiazepoxide is metabolised to desmethyl-chlordiazepoxide. Pharmacologically active metabolites of chlordiazepoxide include desmethylchlordiazepoxide, demoxepam, desmethyldiazepam and oxazepam.

Demoxepam and desmethyldiazepam are also found in the plasma of patients on continuous treatment. The active metabolite desmethylchlordiazepoxide has an accumulation half-life of 10-18 hours and Demoxepam has an accumulation half-life of approximately 21-78 hours.

Steady state levels of these active metabolites are reached after 10-15 days with metabolite concentrations which are similar to those of the parent drug.

Chlordiazepoxide is distributed in the CSF corresponding to the free fraction of chlordiazepoxide. It enters the brain following a rapid distribution phase in grey matter with its high blood flow, followed by a longer accumulation phase of chlordiazepoxide and its metabolites in the white matter. The accumulation is more marked following repeated dosage. Chlordiazepoxide has a high affinity for lipids.

Elimination

Chlordiazepoxide is excreted mainly in the urine mainly in the form of its metabolites; only a small percent of this is in free form most being excreted as conjugates with glucuronide or sulphate. There is no biliary excretion.

Pharmacokinetic/pharmacodynamic relationship

No clear correlation has been demonstrated between the blood levels of Chlordiazepoxide and its clinical effects.

Reproductive effects

Toxicity data

(Registry of Toxic Effects of Chemical Substances 1985-86)

Mutagenic and tumourigenic potential

In in-vivo and in-vitro studies with chlordiazepoxide, there are indications for a mutagenic effect. Nevertheless, in similar test systems results are negative. The relevance of the positive findings is currently unclear.

In carcinogenicity studies in mice an increase of liver tumours was seen at high doses, especially in males, whereas no increase of tumour incidence was seen in rats.

Reproductive toxicity

In animal studies increased resorption rates, increased incidence of stillbirth and neonatal death, malformation of the scull (exencephaly, cleft palate), lung anomalies and changes in the urogenital tract as well as behavioural disorders and neurochemical changes have been observed in the offspring.