Rivotril Mechanism of Action

Therapeutic / Pharmacologic Class of Drug: Antiepileptic agent.
Pharmacology: Pharmacodynamics: Mechanism of Action: Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle-relaxing and anxiolytic effects. As with other benzodiazepines, these effects are thought to be mediated mainly by post-synaptic GABA-mediated inhibition, although there are animal data showing in addition an effect of clonazepam on serotonin. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absences seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations as well as irregular spikes and waves.
Generalized EEG abnormalities are more regularly suppressed than focal abnormalities. According to these findings, clonazepam has beneficial effects in generalized and focal epilepsies.
Pharmacokinetics: Absorption: Clonazepam is rapidly and almost completely absorbed after oral administration of Rivotril tablets. Peak plasma concentrations of clonazepam are reached in 1-4 hours. The absorption half-life is around 25 mins. The absolute bioavailability is 90%. Rivotril tablets are bioequivalent to an oral solution with respect to the extent of clonazepam absorption, whereas the rate of absorption is slightly slower for the tablet.
Plasma concentrations of clonazepam at steady-state for a once-daily dosage regimen are 3-fold higher than those after a single oral dose; the predicted accumulation ratios for two times and three times daily regimens are 5 and 7, respectively. Following multiple oral doses of 2 mg three times daily steady-state pre-dose plasma concentrations of clonazepam averaged 55 ng/ml. The plasma concentration-dose relationship of clonazepam is linear. The target anticonvulsant plasma concentrations of clonazepam range from 20 to 70 ng/ml. The threshold plasma concentration of clonazepam in patients with panic disorders is about 17 ng/ml.
Distribution: Clonazepam distributes very rapidly to various organs and body tissues with preferential uptake by brain structures.
The distribution half-life is approximately 0.5-1 hour. The volume of distribution is 3 l/kg. The plasma protein binding is 82-86%.
Metabolism: Clonazepam is extensively metabolized by reduction to 7-amino-clonazepam and by N-acetylation to 7-acetamino-clonazepam. Hydroxylation at the C-3 position also occurs. Hepatic cytochrome P450 3A4 is implicated in the nitroreduction of clonazepam to pharmacologically inactive metabolites.
The metabolites are present in urine both as free and conjugated (glucuronide and sulphate) compounds.
Elimination: The mean elimination half-life is 30-40 hours. The clearance is 55 ml/min.
50-70% of the dose is excreted in the urine and 10-30% in faeces as metabolites. The urinary excretion of unchanged clonazepam is usually less than 2% of the administered dose.
The elimination kinetics in children are similar to those observed in adults.
Pharmacokinetics in Special Populations: Renal Failure: Renal disease does not affect the pharmacokinetics of clonazepam. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal disease.
Hepatic Failure: The influence of hepatic disease on clonazepam pharmacokinetics has not been investigated.
Elderly: The pharmacokinetics of clonazepam in the old age has not been established.
Neonates: The elimination half-life and clearance values in neonates are of the same order of magnitude of those reported in adults.
Toxicology: Preclinical Safety: Carcinogenicity: No 2-year carcinogenicity studies have been conducted with clonazepam. However, in an 18-month chronic study in rats, no treatment-related histopathological changes were seen up to the highest tested dose of 300 mg/kg/day.
Mutagenicity: Genotoxicity tests using bacterial systems with in vitro or host-mediated metabolic activation did not indicate a genotoxic liability for clonazepam.
Impairment of Fertility: Studies assessing fertility and general reproductive performance in rats showed a reduced pregnancy rate and impaired pup survival at doses of 10 and 100 mg/kg/day.
Teratogenicity: No adverse maternal or embryo-fetal effects were observed in either mice or rats following administration of oral clonazepam during organogenesis, at doses of up to 20 or 40 mg/kg/day, respectively.
In several rabbit studies following doses of clonazepam of up to 20 mg/kg/day, a low, non-dose-related incidence of a similar pattern of malformations (cleft palate, open eyelids, fused sternebrae and limb defects) was observed (see Pregnancy under Use in Pregnancy & Lactation).