Phenytoin megaloblastic anemia with

Folic acid deficiency can be caused by drugs. Methotrexate and, to a lesser extent, trimethoprim and pyrimethamine, inhibit dihydrofolate reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia. Long-term therapy with phenytoin can also cause folate deficiency, but only rarely causes megaloblastic anemia. 

A small fraction of epileptics treated with anticonvulsants dilantin, phenytoin, diphenylhydantoin) develop folate deficiency. Epilepsy is not a rare disease. Hence, there is an awareness of the possibility of the occurrence of megaloblastic anemia in epileptics treated with the aforementioned anticonvulsant. Supplementing epileptics with folate can alleviate the deficiency however, the supplements may also result in an increase in Ihe seizure rate. Thus, physicians must be prepared to halt folate supplementation of epileptics beuig treated for anemia. 

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). 

Megaloblastic anemia and pancytopenia have been rarely attributed to phenytoin (27,28), whereas aplastic anemia has been observed with mephenytoin (29). 

Phenytoin may induce a megaloblastic anemia, as the levels of serum fohc acid decrease up to 40% in about half of aU patients treated with the anticonvulsant. The progression to overt megaloblastic anemia occurs in less than 1% of patients. Since folic acid doses as low as 1 mg/day may affect serum phenytoin levels, routine supplementation is not generally advised. This decline in phenytoin concentration is usually evidenced within the first 10 days and may diminish the phenytoin levels by 15% to 50%. ... 

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