Adverse effect of phenytoin on mineralocorticoid replacement with fludrocortisone in adrenal insufficiency.

Two patients with longstanding adrenal insufficiency developed severe mineralocorticoid deficiency during concomitant phenytoin treatment. A 64-year-old man with primary adrenal insufficiency of 41 years duration was treated with phenytoin for an acute seizure disorder. He subsequently developed mineralocorticoid insufficiency despite taking his customary dosages of cortisone acetate and fludrocortisone. This responded to volume repletion and increased fludrocortisone requirement from 0.05 mg to 0.4 mg daily, which decreased to the former amount following discontinuation of phenytoin. A 42-year-old woman with primary adrenal insufficiency of 3 years duration and a lifelong seizure disorder treated with phenytoin incurred multiple, life-threatening episodes of mineralocorticoid insufficiency. Her fludrocortisone requirement was ultimately established as 2.0 mg daily with a normal hydrocortisone requirement and clearance rate. Fludrocortisone thus appears to be another synthetic steroid whose metabolism is sensitive to drugs that increase hepatic 6-beta-hydroxylation, such as phenytoin. Treatment with these inducing drugs may markedly alter mineralocorticoid requirements in patients with primary adrenal insufficiency.