Hepatic enzyme induction anticonvulsants

Oral absorption of carbamazepine is quite slow and often erratic. Its half-life is reported to vary from 12 to 60 hours in humans. The development of blood level assays has markedly improved the success of therapy with this drug, since serum concentration is only partially dose related. Carbamazepine is metabolized in the liver, and there is evidence that its continued administration leads to hepatic enzyme induction. Carbamazepine-10,11-epoxide is a pharmacologically active metabolite with significant anticonvulsant effects of its own. 

Barbiturates + phenytoin —> decreased anticonvulsant effect due to hepatic enzyme induction enhanced phenytoin toxicity on abruptly stopping barbiturate. 

Regarding the effect of anticonvulsants on calcium metabolism, the potential size of the problem was highlighted by Richens and Rowe (34 ) who showed that 22.5% of epileptic patients in an adult residential centre had decreased serum calcium levels, and 29% had increased alkaline phosphatase levels. Lemaire et al. (24 ) studied a case of osteomalacia due to anticonvulsants using tritium-labelled vitamin D. It was shown that its metabolism was accelerated in comparison with deficiency type osteomalacia. This supports the hypothesis that anticonvulsants, acting via hepatic enzyme induction processes, cause increased transformation of vitamin D into inactive metabolites. Richens states that it is likely that anticonvulsant osteomalacia is caused by a disturbance of the hepatic hydroxylation of vitamin D3 to... 

Pharmacokinetics. Carbamazepine is extensively metabolised one of the main products, an epoxide (a chemically reactive form), has anticonvulsant activity similar to that of the parent drug but may also cause some of its adverse effects. The t) of carbamazepine falls from 35 h to 20 h over the first few weeks of therapy due to induction of hepatic enzymes that metabolise it as well as other drugs, including corticosteroids (adrenal and contraceptive), theophylline and warfarin. Cimetidine and valproate inhibit its metabolism. There are complex interactions with other antiepilepsy drugs, which constitute a reason for monodrug therapy. 

Long-term anticonvulsive therapy with diphenylhydantoin or phenobarbital is known to cause osteomalacia by influencing calcium metabolism (24,25). Alteration in the metabolism of vitamin D, presumably secondary to induction of hepatic microsomal enzymes, leads to the calcium and bone abnormalities (26). Patients on anticonvulsive therapy with phenytoin exhibit a decrease in serum 25-hydroxyvitamin D (27). Adequate dietary amounts of vitamin precursors or microsomal enzyme stimulators might prevent these effects of long-term therapy. 

Stamp et al, (48 ) suggested that plasma calcium concentrations among epileptics may be regulated by effects of anticonvulsants on mechanisms other than those concerning vitamin D, i.e. that it is not related to hepatic induction of vitamin D-metabolizing enzymes as has been thought. 

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