Enzyme induction phenytoin

CYP450 enzyme induction from phenytoin, fosphenytoin, or barbiturates may decrease effect... 

Urinary D-glucaric acid levels have been shown to be a sensitive indicator of microsomal enzyme induction in workers exposed to chlordecone (Guzelian 1985). However, other substances such as barbiturates, phenytoin, chlorbutanol, aminopyrine, phenylbutazone, and contraceptive steroids as well as other organochlorinated pesticides also cause microsomal enzyme induction and cause changes in urinary D-glucaric acid (Morgan and Roan 1974). 

II.e. 5.2. Interactions between first and second generation AEDs. Felbamate raises plasma concentrations of phenytoin, valproic acid and carbamazepine. Clearance of tiagabine, topiramate and zon-isamide is increased in the presence of an enzyme inducer. Vigabatrin reduces phenytoin concentrations after 4-5 weeks of comedication (via an unknown mechanism). For tiagabine, the elimination half-life may be reduced by 2-3 hours in the presence of an enzyme-induction AED. Lamotrigine elimination is slower if given with valproic acid. Topiramate reduces elimination of phenytoin. 

Cyclosporin is metabolised by the hepatic cytochrome P-450 enzyme system, and enzyme induction by phenobarbital, phenytoin, carbamazepine, or rifampicin will drastically increase the clearance of cyclosporin. Concurrent administration of these drugs has caused rejection of transplanted organs. Conversely, the use of enzyme inhibitors, such as erythromycin or the azole antifungal agents, e.g. ketoconazole, will increase the blood concentrations of cyclosporin leading to an increased risk of toxic side effects. 

Phenytoin [NE] Enzyme induction anticoagulant effect may increase transiently at start of phenytoin therapy due to protein-binding displacement. 

Total and free (unbound) thyroxine can be reduced by phenytoin and carbamazepine, but free triiodothyronine is normal or only slightly reduced. Thyroid-stimulating hormone is normal or only slightly altered and patients remain clinically euthyroid (94,108). Reductions in the concentrations of some thyroid hormones are probably related to enzyme induction the concentrations return to normal after substituting carbamazepine with oxcarbaze-pine, a less potent enzyme inducer (109). Hypothyroidism has been rarely described in patients taking phenytoin or carbamazepine (110). In contrast to earlier reports, there were no changes in thyroid hormones during treatment with valproate in a later study (111). 

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

Enzyme induction can be problematic with co-administration of benzodiazepines and rifampicin or certain anticonvulsants (phenobarbital, phenytoin, carbamaze-pine). However, despite enzyme stimulation, the net effect of adding these anticonvulsants can be augmentation of benzodiazepine-induced sedation. 

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... 

Interactions. Drugs that lower gastric acidity, e.g. antacids, histamine H2 receptor antagonists, impair the absorption of ketoconazole from the gastrointestinal tract. Like all imidazoles, ketoconazole binds strongly to several cytochrome P450 isoenzymes and thus inhibits the metabolism (and increases effects of) oral anticoagulants, phenytoin and cyclosporin, and increases the risk of cardiac arrhythmias with terfenadine. A disulfiram-like reaction occurs with alcohol. Concurrent use of rifampicin, by enzyme induction of CYP 3A, markedly reduces the plasma concentration of ketoconazole. 

Interactions. Enzyme induction of CYP 3A, e.g. by rifampicin, reduces the plasma concentration of itraconazole. Additionally, its affinity for several P450 isoforms, notably CYP 3A4, causes it to inhibit the oxidation of a number of drugs, including phenytoin, warfarin, cyclosporine, tacrolimus, midazolam, triazolam, cisapride and terfenidine (see above), increasing their intensity and/or duration of effect. 

Adverse effects include CNS symptoms (reversible blurring of vision, diplopia, dizziness and ataxia) and depression of cardiac AV conduction. Alimentary symptoms, skin rashes, blood disorders and liver and kidney dysfunction also occur. Osteomalacia by enhanced metabolism of vitamin D (enzyme induction) occurs over years so also does folate deficiency. Enzyme induction reduces the efficacy of combined and progestogen-only contraceptives. Carbamazepine impairs cognitive function less than phenytoin. 

Other effects include Dupu5dren s contracture and pseudolymphoma. Some degree of macrocyto-sis is common but anaemia probably occurs only when dietary folate is inadequate. This responds to folate supplement (the requirement for folate is increased, as it is a cofactor in some hydroxylation reactions that are accelerated by enzyme induction by phenytoin). Osteomalacia due to increased metabolism of vitamin D occurs after years of therapy. 

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

Drugs. Antiepilepsy drugs, particularly phenytoin, primidone and phenobarbital, occasionally cause a macrocytic anaemia that responds to folic acid. This may be due to enzyme induction by the antiepileptics increasing the need for folic acid to perform hydroxylation reactions (see Epilepsy) but other factors such as reduced absorption may be involved. Administration of folic acid causes a recurrence of seizures in some patients. Some anti-malarials, e.g. pyrimethamine, may interfere with conversion of folates to the active tetrahydrofolic acid, causing macrocytic anaemia. Methotrexate, another folate antagonist, may cause a megaloblastic anaemia especially when used long-term for leukaemia, rheumatoid arthritis or psoriasis. 

Chronic treatment with phenobarbital, phenytoin, and carbamazepine is associated with reduced serum folate concentrations. Although megaloblastic anemia is rare, macrocytic changes in red cells are common in these patients. The fact that serum folate is not reduced by valproate and zonisamide, which do not induce liver enzymes, is consistent with the hypothesis that enzyme induction plays a role in the pathogenesis of folate deficiency (99). 

In addition to enzyme induction, phenytoin can reduce digoxin absorption. 

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