Clobazam

Clobazam belongs to the benzodiazepine class of drugs. As a long-acting benzodiazepine derivative it's primarily used as an adjunctive therapy in epilepsy. Benzodiazepines act as central nervous system depressants by enhancing the effects of gamma-Aminobutyric acid (GABA), a neurotransmitter, which in turn reduces neuronal electrical activity, throughout the entire central nervous system (CNS). It's also used as an anxiolytic (anti-anxiety agent) for short-term relief of severe and disabling anxiety. Clobazam is also sometimes used for sedation for preoperational anxiety. As an adjunctive therapy in epilepsy, it is used in patients who have not responded to first-line drugs and in children who are refractory to first-line drugs. It is unclear if there are any benefits to clobazam over other seizure medications for children with Rolandic epilepsy or other epileptic syndromes. It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need. Clobazam is sometimes used for refractory epilepsies. However, long-term prophylactic treatment of epilepsy may have considerable drawbacks, most importantly decreased anti-epileptic effects due to drug tolerance which may render long-term therapy less effective. Other anti-epileptic drugs may therefore be preferred for the long-term management of epilepsy. Furthermore, benzodiazepines may have the drawback, particularly after long-term use, of causing rebound seizures upon abrupt or over-rapid discontinuation of therapy causing benzodiazepine withdrawal syndrome. Clobazam is approved in Canada for add-on use in tonic-clonic, complex partial, and myoclonic seizures. Clobazam is approved for adjunctive therapy in complex partial seizures, certain types of status epilepticus, specifically the myoclonic, myoclonic-absent, simple partial, complex partial, and tonic varieties, and non-status absence seizures. It is also approved for the treatment of anxiety. In India, clobazam is approved for use as an adjunctive therapy in epilepsy, and in acute and chronic anxiety. In Japan, clobazam is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures. In New Zealand, clobazam is marketed as Frisium. In the United Kingdom clobazam (Frisium) is approved for short-term (2–4 weeks) relief of acute anxiety in patients who have not responded to other drugs, with or without insomnia and without uncontrolled clinical depression. It was not approved in the United States until October 2011, when it was approved for the adjunctive treatment of seizures associated with Lennox–Gastaut syndrome in people aged two years of age or older. In the United States, clobazam is indicated for use in combination with other medicines to control seizures in people aged two years of age and older who have a specific severe form of epilepsy called Lennox–Gastaut syndrome. ==Side effects==

In September 2020, the US Food and Drug Administration required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class. Common Common side effects include sedation, drooling, constipation, headaches, trembling hands, digestive problems, low blood pressure, dry mouth, nausea, addiction, physical and psychological dependence. Prescription Only: Clobazam requires a doctor's prescription and is available under brand names like Onfi (US) and Frisium (International). Habit-Forming: Clobazam has a high potential for misuse, abuse and can cause physical and psychological dependence. Overdose Overdose and intoxication with benzodiazepines, including clobazam, may lead to CNS depression, associated with drowsiness, confusion, and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol. Abuse potential and addiction Classic (non-anxioselective) benzodiazepines in animal studies have been shown to increase reward-seeking behaviours which may suggest an increased risk of addictive behavioural patterns. Clobazam abuse has been reported in some countries, according to a 1983 World Health Organization report. Dependence and withdrawal In humans, tolerance to the anticonvulsant effects of clobazam may occur and withdrawal seizures may occur during abrupt or over-rapid withdrawal. Clobazam as with other benzodiazepine drugs can lead to physical dependence, addiction, and what is known as benzodiazepine withdrawal syndrome. Withdrawal from clobazam or other benzodiazepines after regular use often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dosage and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Benzodiazepine treatment should only be discontinued via a slow and gradual dose reduction regimen. ==Pharmacology==

Clobazam is predominantly a positive allosteric modulator at the GABAA receptor to increase GABAergic transmission, particularly chloride conductance in neurons and with some speculated additional activity at sodium channels and voltage-sensitive calcium channels. The exact mechanism of action for clobazam, a 1,5-benzodiazepine, which has anticonvulsant and anxiolytic effects similar to those produced by other benzodiazepine derivatives. Clobazam is a potent partial agonist at the GABAA receptor. The anti-epileptic effects are related to binding to one or more specific GABA receptors, increasing GABA-mediated inhibition. Clobazam is thought to involve the potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABAA receptor. Like other 1,5-benzodiazepines (for example, arfendazam, lofendazam, triflubazam, and CP-1414S), clobazam and the active metabolite N-Desmethylclobazam have less affinity for the α1 subunit (sedative effects) of the GABAA receptor compared to the 1,4-benzodiazepines. They have a higher affinity for the α2 subunit (anxiolytic effects) and γ2 subunit of the GABAA receptor, which is essential for the anxiolytic and anticonvulsant effects of clobazam. It is generally considered less sedating and causes less tolerance than traditional 1,4-benzodiazepines, partially because it binds less to subunits that cause sedation. N-Desmethylclobazam, is the active metabolite of the benzodiazepine, clobazam. It works by enhancing GABA-activated chloride influx at GABAA receptor, At therapeutic dosages, plasma concentrations of N-Desmethylclobazam are approximately 3–5 times higher than those of clobazam. The primary active metabolite of clobazam, is crucial for its prolonged anti-epileptic and anti-anxiety effects, acting similarly on GABAA receptors but with potentially greater importance in long-term therapy, especially for epilepsy, and is largely responsible for the drug's overall clinical action. It was also reported that these effects were inhibited by the GABA antagonist flumazenil, and that clobazam acts more efficiently in GABA-deficient brain tissue. Metabolism Clobazam has three major metabolites: N-Desmethylclobazam, 4'-Hydroxy-N-desmethylclobazam, the former of which is active and 4'-Hydroxyclobazam The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4'-Hydroxyclobazam by CYP2C18 and CYP2C19. The half-life is approximately 36 to 42 hours for clobazam and 71 to 82 hours for N-Desmethylclobazam. ==Chemistry==

Clobazam is a 1,5-benzodiazepine, meaning that its diazepine ring has nitrogen atoms at the 1 and 5 positions (instead of the usual 1 and 4). ==History==

Clobazam was discovered at the Maestretti Research Laboratories in Milan and was first published in 1969. Maestretti was acquired by Roussel Uclaf which became part of Sanofi. ==Society and culture==

Legal status Internationally clobazam is a federally controlled Schedule IV Psychotropic Substance with potential for abuse, addiction, and severe withdrawal if stopped abruptly. ==See also==