Prazepam

Prazepam is a benzodiazepine derivative.

Recent evidence indicates that benzodiazepines exert their effects through enhancement of the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. GABA is an inhibitory neurotransmitter that exerts its effects at specific receptor subtypes designated GABA-A and GABA-B. GABA-A is the primary receptor subtype in the CNS and is thought to be involved in the actions of anxiolytics and sedatives.

Specific benzodiazepine (BNZ) receptor subtypes are thought to be coupled to GABA-A receptors. Three types of BNZ receptors are located in the CNS and other tissues; the BNZ1 receptors are located in the cerebellum and cerebral cortex, the BNZ₂ receptors in the cerebral cortex and spinal cord, and the BNZ₃ receptors in peripheral tissues. Activation of the BNZ₁ receptor is thought to mediate sleep while the BNZ₂ receptor affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. Benzodiazepines bind non-specifically to BNZ₁ and BNZ₂ which ultimately enhances the effects of GABA. Unlike barbiturates which augment GABA responses by increasing the length of time that chloride channels are open, benzodiazepines enhance the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.

The pharmacological effects of prazepam are mainly due to norprazepam, to which it is converted on first pass through the liver. Therefore, the drug has clinical activity similar to other benzodiazepines. It has anxiolytic, sedative, anticonvulsant and central muscle relaxant properties.

Studies in normal subjects have shown that prazepam has depressant effects on the central nervous system. Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the CNS and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, and anticonvulsant activity.

Prazepam is a long acting benzodiazepine. The mean half-life of the principal active metabolite, norprazepam, measured in subjects given 10 mg prazepam three times a day for one week was 63 (±15 SD) hours before and 70 (± 10 SD) hours after multiple dosing – a non-significant difference. Repeated dosage will lead to accumulation of drug metabolites.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Prazepam administered during pregnancy caused abortions in rabbits at >25mg/kg and death in rats and deaths and malformations in their foetuses at >1000 mg/kg. Teratogenic effects in rats and abortions in rabbits, occurred at 162-fold and 8-fold the human dose based on body surface area, respectively.

Prazepam decreased fertility in male rats at 1000mg/kg, possibly by retardation of spermatogenesis, and decreased fertility and mating was observed in female rats at >80mg/kg.

In a prenatal and postnatal study in rats, the administration of prazepam at >25mg/kg increased the mortality of offspring.