Most of the commonly used antiepileptic drugs cause, to varying degrees, a decrease in bone density and an increased risk of fracture from osteoporosis in older patients, particularly in women. Several mechanisms are probably active, among them, induction of the cytochrome P450 system, which enzymatically degrades vitamin D. No specific recommendations have been offered to counteract this effect of bone loss, but many practitioners have advised patients to take calcium supplements, vitamin D, or one of the bisphosphonates if there is no contraindication, and to periodically check bone density.
Finally, several reports and meta-analyses over the past decades have suggested that antiepileptic drugs taken together as a class, increase the incidence of depression and suicide, both in individuals with epilepsy and psychiatric patients. The issue may never be entirely resolved because of confounding factors but a patient level-analysis performed by Arana and colleagues showed no such relationship in epilepsy once underlying depression was accounted for. However, this assessment was contrary to an earlier FDA meta-analysis and it may not hold for certain drugs, for example, levetiracetam.
Phenytoin This sodium channel blocker has been used for decades for focal and generalized seizures. Its advantages are low cost, wide availability, ease of monitoring of blood levels and ability to rapidly achieve therapeutic levels with, oral, intravenous, and intramuscular preparations. Rash, fever, lymphadenopathy, eosinophilia and other blood dyscrasias, and polyarteritis are manifestations of idiosyncratic phenytoin hypersensitivity; their occurrence calls for discontinuation of the medication. Overdose with phenytoin causes ataxia, diplopia, and stupor. The prolonged use of phenytoin leads to hirsutism, enlargement of gums from hyperplasia of connective tissue and epithelium with subsequent periodontal disease, and coarsening of facial features in children. A clinical trial conducted by Arya and colleagues suggested that folate supplementation may prevent gingival hyperplasia in children. Chronic phenytoin use over several decades may occasionally be associated with peripheral neuropathy and probably with a form of cerebellar degeneration (Lindvall and Nilsson); it is not clear if these are strictly dose-related effects or idiosyncratic reactions. An antifolate effect on blood and interference with vitamin K metabolism have also been reported, for which reason pregnant women taking phenytoin (and in fact most other antiepileptic drugs) should be given folate supplementation and vitamin K before delivery and the newborn infant also should receive vitamin K to prevent bleeding. Phenytoin should not be used together with disulfiram, chloramphenicol, sulfamethizole, or cyclophosphamide, and the use of either phenobarbital or phenytoin is not advisable in patients receiving warfarin because of the undesirable interactions already described. Choreoathetosis is a rare idiosyncratic side effect. Fosphenytoin for intramuscular and intravenous administration allows somewhat faster attainment of serum levels and may have minor advantages in special circumstances, especially the availability of the IM route. Intravenous phenytoin and fosphenytoin, including their risks, are discussed further in the section on status epilepticus.