Phenobarbital Folic acid

Folic acid Phenobarbital Phenytoin Reduced effect of the object drug Accelerated metabolism of the object drugs... 

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. 

These can interfere with vitamin processing in the intestinal tract, tie up the vitamin preventing it from being used, or possibly promote elimination of the vitamin. Examples include isoniazid-pyridoxine, phenobarbital-cholecalciferol, methotrexate-folic acid, phenytoin-folicacid. 

When drug-induced megaloblastic anemia is related to chemotherapy, no real therapeutic option is available, and the anemia becomes an accepted side effect of therapy. If drug-induced megaloblastic anemia results from cotrimoxazole, a trial course of folinic acid, 5 to 10 mg up to four times a day, may correct the anemia. Folic acid supplementation of 1 mg every day often corrects the drug-induced megaloblastic anemia produced by either phenytoin or phenobarbital, but some clinicians suggest that supplementation of folic acid may decrease the effectiveness of the antiepileptic medications. ... 

The treatment of folate deficiency in patients receiving anticonvulsant drugs is not without difiiculties. Chanarin (C3) described an epileptic patient who had developed a megaloblastic anemia due to folate deficiency. Treatment with folic acid apparently precipitated convulsions. Up to this time the patient had been free of seizures while on phenobarbital for 4 years. There have since been a number of reports of treatment with folic acid precipitating seizures in patients with epilepsy (D6, R3, W8). 

As with phenobarbital, serious toxicity for primidone is rare, although it may cause disabling sedation. Irritability, and decreased mental functioning In a number of persons. Ataxia, dysphoria, idiosyncratic rash, leukopenia, agranulocytosis, lymphadenopathy, hepatitis, and a systemic lupus erythematosus-like syndrome have been reported adverse effects for primidone. Deficiencies of folic acid and of vitamins D and K are possible with long-term therapy of primidone, as Is a folate-responsive megaloblastic anemia. Measurement of the complete blood cell count should be performed at 6-month intervals (40). 

Another long-term study was conducted in 26 patients with folic acid deficiency (serum folate less than 5 nanograms/mL), and treated with two or more drugs (phenytoin, phenobarbital, primidone). The mental state of 22 of them (as shown by increased alertness, concentration, sociability etc.) improved to a variable degree when they were given folic acid 5 mg three times daily. However, the frequency and severity of seizures in 13 patients (50%) increased to such an extent that the vitamin had to be withdrawn from 9 of them. ... 

A very well documented and clinically important interaction, which has been the subject of review." Reductions in serum phenytoin levels of 16 to 50% have been described in patients taking 5 to 15 mg folic acid daily for 2 to 4 weeks. If folic acid supplements are given to folate-deficient epileptics taking phenytoin, phenobarbital, primidone and possibly pheneturide, their serum antiepileptic levels should be well monitored so that suitable dosage increases can be made. 

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