The use of phenytoin in patients with epilepsy dates back to 1938. The main mechanism of action of phenytoin is believed to be inactivation of the voltage-dependent sodium channels, resulting in suppression of repetitive firing. The absorption occurs primarily in the duodenum, and its rate is highly variable, depending on the specific oral preparation, the amount ingested and on different factors affecting solubility of the drug in the gastrointestinal tract. For example, complete-nutrition formulas co-administered through nasogastric tube with phenytoin may cause a dramatic decrease in its serum concentrations. The bioavailability of both intramuscularly and rectally administered phenytoin is poor, therefore these routes are not recommended for use in clinical practice.
In healthy individuals, phenytoin is around 90% bound to plasma proteins, only the free portion being pharmacologically active. However, the percentage of binding varies according to changes in albumin concentration, in renal failure, hepatic failure, AIDS and in the presence of concomitant highly protein bounded medications (such as valproic acid).
Total phenytoin plasma concentrations (established therapeutic range of 10-20 mg/ml) may, therefore, be a misleading test in the above-mentioned conditions. Thus, measurement of unbound concentrations may be of clinical value, especially in patients experiencing toxic reactions despite therapeutic concentrations. Phenytoin is almost completely metabolized in the liver, 80% by the cytochrome p450 system, and has nonlinear pharmacokinetics due to enzyme saturation at the usual therapeutic plasma concentrations. Therefore age, genetic profile, pregnancy, concomitant illnesses and medications (enzyme inducers and inhibitors, such as many of the AEDs) may significantly affect the dose/concentration ratio of phenytoin. On the other hand, since phenytoin is an inducer of the liver enzymes, it may affect the concentration of other drugs (such as warfarin and many AEDs).
Phenytoin was proved to be effective in the acute treatment of SE and repetitive seizures and as a seizure-prevention agent against generalized tonic-clonic and partial seizures. However, only limited efficacy was observed in absence, myoclonic, tonic and atonic seizure types. The most common concentration-related side effects of phenytoin are drowsiness, ataxia, incoordination, diplopia and nystagmus. Serum concentrations above 30 mg/ml can cause encephalopathy (even as severe as coma), aggravation of seizures, more severe cerebellar symptoms and signs and movement disorders. Idiosyncratic reactions include rash, fever, lymphadenopathy, abnormal LFTs, blood dyscrasias and renal failure.
Long-term treatment with phenytoin has been associated with gingival hyperplasia, acne, hirsutism, cerebellar atrophy, peripheral neuropathy, enhanced osteopenia, decreased folate level, macrocytosis and changes in the concentration of thyroid hormones. When administred to pregnant women, phenytoin has been associated with an increase in the rate of birth defects. Intravenously administered, phenytoin can cause sometimes very severe local reactions, as well as cardiovascular adverse effects, such as arrhythmias and hypotention. Substituting phenytoin for an equivalent dose of phosphenytoin (a water-soluble phenytoin prodrug) may reduce the adverse events rate, especially for intravenous administration.
The recommended loading dose of phenytoin is 15-20 mg/kg. When given intravenously, phenytoin should be diluted in normal saline (not in dextrose-containing fluids), and the infusion should not exceed 50 mg/min or 25 mg/min in patients with history of cardiovascular disease. In cases of oral loading, it should be divided into three doses, given two to three hours apart for better absorption.
For maintenance therapy, the regimen should be individualized according to the plasma concentrations, which should be closely monitored. Due to the phenytoin nonlinear pharmacokinetics, especially low increments in the dose should be made once the minimal therapeutic level had been reached.
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