Carbamazepine enzymes

Newer AEDs do have some advantages in that they tend to have fewer effects on the metabolism of each other or other drugs. By contrast, phenobarbitone is one of the most potent inducers of the microsomal enzyme system (cytochrone T 450) responsible for the metabolism of drugs. Phenytoin and carbamazepine have a similar but less marked effect while valproate inhibits the system. 

Carbamazepine is a potent inducer of hepatic microsomal enzymes. Not only does it increase the rate of metabolism for many other drugs, it increases the rate of its own metabolism. Hepatic enzymes become maximally induced over several weeks, necessitating a small initial dose of carbamazepine that... 

Conversely, the metabolism of divalproex can be increased by enzyme-inducing drugs such as carbamazepine and phenytoin, while divalproex may simultaneously slow metabolism of the other agents.35... 

Commonly used drugs that induce liver enzymes (rifampin, phenytoin, carbamazepine, barbiturates, primidone, topiramate) and reduce efficacy of CHC... 

Phenobarbital, phenytoin, primidone, and carbamazepine are potent inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine diphosphate glucuronosyltransferase enzyme systems. Valproic acid inhibits many hepatic enzyme systems and displaces some drugs from plasma albumin. 

Valproic acid is an enzyme inhibitor that increases serum concentrations of concurrently administered phenobarbital and may increase concentrations of carbamazepine 10,11-epoxide without affecting concentrations of the parent drug. It also inhibits the metabolism of lamotrigine. 

Oxcarbazepine has mood-stabilizing effects similar to those of carbamaz-epine, but with milder side effects, no autoinduction of metabolizing enzymes, and potentially fewer drug interactions. There are fewer data supporting its efficacy than there are for carbamazepine s efficacy. 

Interestingly, there is a marked species difference in the in vitro hydrolysis of carbamazepine 10,11-epoxide, such that the reaction was observed only in liver microsomes from humans but not in liver microsomal or cytosolic preparations from dogs, rabbits, hamsters, rats, or mice [181][196], Thus, carbamazepine appears to be a very poor substrate for EH, in analogy with the simpler analogues 10.129 (X = RN, RCH, or RCH=C). The human enzyme is exceptional in this respect, but not, however, in the steric course of the reaction. The diol formed (10.131, X = H2NCON) is mostly the trans-(10.S, 11. S )-enaniiomer [196], In other words, the product enantioselectivity of the hydration of carbamazepine epoxide catalyzed by human EH is the same as that of di benzol a,oxide catalyzed by rabbit microsomal EH, discussed above. 

Drug-drug interactions are often more problematic with carbamazepine than other mood stabilizers. Carbamazepine increases the activity of certain liver enzymes. Because these enzymes metabolize and eliminate medications and other substances introduced to the body, carbamazepine therapy can decrease the blood level and thereby reduce the effectiveness of itself (a phenomenon called autoinduction) and other medications that are metabolized by these enzymes. It is not unusual to find that the dose of carbamazepine must be increased after several weeks, because it has increased its own elimination. Other medications may likewise be less effective. Of particular concern are the oral contraceptives, Depo-Provera, and protease inhibitors used for the treatment of HI V+ patients. Oral contraceptives often require an increase in dose. 

Carbamazepine, phenytoin, pheno-barbital, and other anticonvulsants (except for gabapentin) induce hepatic enzymes responsible for drug biotransformation. Combinations between anticonvulsants or with other drugs may result in clinically important interactions (plasma level monitoring ). 

Tolerability" should not be confused with the term "tolerance", which describes the diminution in effects of a drug on prolonged exposure. Tolerance may be due to increased clearance because of autoinduction of the enzymes that metabolise the drug, such as occurs with some antiepileptic drugs, for example, carbamazepine. Tolerance may also result from altered pharmacodynamics, which is common with drugs acting on the CNS. 

CYP 450 Drugs that induce liver enzymes (eg, phenytoin, carbamazepine, phenobarbital) increase the metabolism and clearance of zonisamide and decrease its half-life. Concurrent medication with drugs that induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. 

The apparent clearance of lamotrigine is affected by the coadministration of AEDs. Lamotrigine is eliminated more rapidly in patients who have been taking hepatic enzyme inducing antiepileptic drugs (ElAEDs), including carbamazepine, phenytoin, phenobarbital, and primidone. 

Dosage regimen for bipolar disorder The target dose of lamotrigine is 200 mg/day (100 mg/day in combination with valproate and 400 mg/day in combination with carbamazepine or other enzyme-inducing drugs). Doses above 200 mg/day are not recommended. 

Discontinuation of psychotropic drugs excluding valproic acid, carbamazepine, or other enzyme-inducing drugs After discontinuation of valproic acid After discontinuation of carbamazepine or other enzyme-inducing drugs... 

Strong inducers of cytochrome P450 enzymes (ie, carbamazepine, phenytoin, phenobarbital) have been shown to decrease the plasma levels of MHD (29% to 40%). 

Rifampicin, the anti-convulsants phenytoin, phe-nobarbitone and carbamazepine, and the steroid dex-amethasone, are amongst the best recognized inducers of enzyme function, and their action nearly... 

The macrolide antibacterials (including erythromycin, clarithromycin and telithromycin) are often implicated in interactions, most frequently as a result of inhibition of the CYP3A4 enzyme system in the liver and enterocytes. Erythromycin inhibits the metabolism of carbamazepine, ciclosporin and theophylline significant increases in serum levels and features of toxicity have been documented. Careful clinical and pharmacokinetic monitoring are required in a patient taking any of these drugs who requires concomitant erythromycin. 

Phenobarbital, primidone, phenytoin and also carbamazepine are inducers of cytochrome P450 enzymes and in combination the effects of substrates... 

Phenobarbital is still used for the management of partial seizures, generalized tonic-clonic seizures and for the control of status epilepticus. However because of its low therapeutic index and the possibility of dependence, phenobarbital has largely been displaced by other anticonvulsants. For newborns phenobarbital is often the drug of first choice. If given together with sodium valproate the metabolism of phenobarbital may be inhibited while in combination with carbamazepine the serum concentrations of carbamazepine will be reduced due to enzyme induction by phenobarbital. 

Carbamazepine stimulates antidiuretic hormone activity and has been used for the treatment of neurohypophyseal diabetes insipidus. Carbamazepine induces microsomal enzymes and its metabolism is subject to auto-induction. Frequently occurring adverse effects are sedation, dry mouth, dizziness and gastrointestinal disturbances. Photosensitivity reactions, urticaria and Stevens-Johnson syndrome have been described. The elderly are more prone to mental confusion, cardiac abnormalities and problems due to inappropriate ADH secretion. 

Oxcarbazepine is a derivative of carbamazepine and although its precise mechanism of action is unknown it has similar properties as carbamazepine and is also used for the treatment of primary generalized tonic-clonic seizures and partial seizures. Also the adverse effects are similar to those of carbamazepine. However the drug interaction profile is different as oxcarbazepine has hardly any enzyme-inducing capacity. 

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