Clonazepam metabolism

Carbamazepine also can induce the enzymes that metabolize other anticonvulsant drugs, including phenytoin, primidone, phenobarbital, valproic acid, clonazepam, and ethosuximide, and metabolism of other drugs the patient may be taking. Similarly, other drugs may induce metabolism of carbamazepine the end result is the same as for autoinduction, and the dose of carbamazepine must be readjusted. A common drug-drug interaction is between carbamazepine and the macrolide antibiotics erythromycin and trolean-domycin. After a few days of antibiotic therapy, symptoms of carbamazepine toxicity develop this is readily reversible if either the antibiotic or carbamazepine is discontinued. 

Clonazepam reaches a peak plasma level in 1 to 4 hours. It is metabolized by acetylation, so the half-life ranges from 20 to 80 hours and is dependent on whether a person has a rapid or slow acetylatior phenotype (DeVane et ah, 1991). 

Most sedative drugs, including narcotics and alcohol, potentiate the sedative effects of benzodiazepines. In addition, medications that inhibit hepatic cytochrome P450 (CYP) 3A3/4 increase blood levels and hence side effects of clonazepam, alprazolam, midazolam, and triazolam. Lorazepam, oxazepam, and temazepam are not dependent on hepatic enzymes for metabolism. Therefore, they are not affected by hepatic disease or the inhibition of hepatic enzymes. 

Reduction Nitro Groups. Nitro reduction is catalyzed by the cytochrome P450 system in the presence of the NADPH cofactor it is a multistep process in which the reduction of the nitro group to a nitroso group is a rate-limiting step. The metabolic conversion of the nitro group in clonazepam to an amine is a representative example. 

Clonazepam is well absorbed orally and approximately 85 percent is bound with plasma proteins, completely metabolized in liver and excreted through kidney. 

Clonazepam As for diazepam >80% bioavailability extensively metabolized but no active metabolites fiy2 20-50 h Absence seizures, myoclonic seizures, infantile spasms Toxicity Similar to diazepam Interactions Minimal... 

Carbamazepine + phenytoin, tricyclic antidepressants, typical neuroleptics, valproate, clonazepam, warfarin, nefazodone and propoxyphene —> reduced plasma concentration of carbamazepine due to increased metabolism. 

A 41-year-old woman developed seizures that progressed to status epilepticus, and died from secondary rhabdomyolysis and disseminated intravascular coagulation (128). She had been taking olanzapine 10 mg/ day for 5 months. No other toxic, metabolic, or anatomical abnormalities were identified pre- or postmortem to explain the seizures. However, her medications also included levothyroxine 0.15 mg/day, clonazepam 1.0 mg qds, and propranolol 20 mg tds. 

The effects of concomitant carbamazepine, phenytoin, sodium valproate, and zonisamide on the steady-state serum concentrations of clonazepam have been investigated in 51 epileptic in-patients under 20 years of age (14). Serum concentrations of clonazepam correlated positively with the dose of clonazepam and negatively with the doses of carbamazepine and valproic acid, but not with phenytoin or zonisamide. These results confirm that as the oral doses of carbamazepine and sodium valproate increase, the serum concentration of clonazepam falls, but there is no interaction with either phenytoin or zonisamide. In the case of carbamazepine the mechanism of action is thought to be enzyme induction, increasing the metabolism of clonazepam. It is not known what the mechanism is with sodium valproate. In patients with epilepsy, the co-administration of either sodium valproate or carbamazepine will reduce the serum concentration of clonazepam and increase the risk of a seizure. When... 

BARBITURATES BZDs - clonazepam 1 barbiturate levels Induction of metabolism Watch for poor response to barbiturates... 

Anticonvulsants. Carbamazepine, phenobarbital and primidone accelerate warfarin metabolism (enzyme induction) the effect of phenytoin is variable. Clonazepam and sodium valproate are safe. 

Felbamate Clonazepam Diazepam Phenobarbital Phenytoin Valproate High risk of toxicity with phenytoin, phenobarbital, and valproate Inhibition of metabolism of the affected drug... 

Cimetidine Carbamazepine Clobazam Clonazepam Diazepam Phenytoin Valproate Risk of toxicity, particularly with phenytoin Inhibition of metabolism of the object drugs... 

Various aromatic nitro drugs undergo enzymatic reduction to the corresponding aromatic amines. For example, the 7-nitro benzodiazepine derivatives clonazepam and nitrazepam are metabolized extensively to their respective 7-amino meubolitcs in humans. Thc skeletal muscle relaxant dantrolene (Dantrium) also reportedly undergoes reduction to aminodantrolene in humans. ... 

Clonazepam, U5P. Clonazepam S-(2-chlorophenyl)-3-dihydro-7-nitro-2//-1,4-benzodiazpin-2-one (iCIonopin). partially selective at benzodiazepine allosteric binding sites on GABAa receptors, is useful in ab.sence seizures and in myoclonic seizures. Tolerance to the anticonvulsant effect often develops, a common problem with the benzodiazepines. Metabolism involves hydroxylation of the 3 position, followed by glucuronidation and nitro group reduction, followed by acetylation. 

Acetylation of drugs is also associated with genetically determined interindividual and interethnic differences. Differences in isoniazid toxicity between Asians and Caucasians are due to acetylation enzyme polymorphism. The majority (78%-93%) of Chinese and East Asians are fast acetylators, whereas only 50% of whites and African Americans are fast acetylators (Weber 1987). This is clinically important, because several psychoactive compounds (e.g., caffeine, clonazepam, nitrazepam, and phenelzine) are metabolized through acetylation (Sjoqvist et al. 1997). 

Nitrazepam. As indicated previously, nitrazepam (4e), is similar in structure to clonazepam. Absorption after oral administration occurred within 1 h however, in some cases relatively slow absorption (up to 4 h) has been reported (43-48). Rectal administration provided more rapid absorption (median peak time 18 min versus 38 min orally) (48). Although a good correlation was apparent between the volume of distribution and elimination half-life, when comparing the young, elderly, female, and male subjects, the differences observed in volume of distribution related to sex, age, and body weight seem to depend on the relative proportion of body adipose tissue (49). The metabolic pattern of nitrazepam is similar to that of clonazepam, with the principal formation of the inactive 7-amino (41) and 7-acetamido (4m) compounds. 

Clonazepam (8) is almost completely absorbed after oral dosing (96) with an average max of 2-4 h. As with other 7-nitro benzodiazepines, the major metabolic pathway for clonazepam is reduction of the nitro group, acetylation of the resulting amine, and elimination of the acetamide. Hydroxylation of clonazepam or of 7-amino clonazepam to give the 3-hydroxy derivatives represents minor metabolic pathways. The elimination half-life of clonazepam is 20-30 h (97), and no active metabolites are produced. 

Studies on the pharmacokinetics of flunltrazepam (lb) in man, clonazepam (Ih) in rhesus monkeys, and triazolam (9a) in dogs have appeared. The metabolism of bromazepam (li) in rodents has been studied, and the major metabolic pathway is cleavage of the benzodiazepine ring at the - 2 and bonds with subsequent reduction and hydroxy-... 

Convulsions are among the most severe symptoms of intoxication with high toxic OPC. The reduction of central convulsive syndrome exerts positive effect on both the course of OPC intoxication and the delayed consequences. For this, antidotic formulas are supplemented with anticonvulsants of different chemical structures (diazepam, clonazepam, phenazepam, etc ). Anticonvulsants facilitate normalization of metabolism of biogenic amines and CNS uptake of glucose, whose consumption grows up steeply in poisonings with soman [92]. 

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