Phenytoin serum concentrations

One author suggested that if the phenytoin serum concentration is less than 7 mcg/mL, the daily dose should be increased by 100 mg if the concentration is 7 to 12 mcg/mL, the daily dose can be increased by 50 mg and if the concentration is greater than 12 mcg/mL, the daily dose can be increased by 30 mg or less. 

A suggestion to minimize interaction is to hold tube feeding 1-2 hours before and after phenytoin, but this has no proven benefit Adjust tube feeding rate to account for time held for phenytoin administration Monitor phenytoin serum concentrations and clinical response closely Consider switching to IV phenytoin route if unable to reach therapeutic serum concentration Consider holding tube feeding before and after administration... 

Several case reports and one in vitro study have suggested that combined administration of fluoxetine with phenytoin can significantly increase phenytoin serum concentrations, leading to toxicity (19,39,40). 

Sands CD, Robinson JD, Salem RB, Stewart RB, Muniz C. Effect of thioridazine on phenytoin serum concentration a retrospective study. Drug Intell Clin Pharm 1987 21(3) 267-72. 

A lower than expected phenytoin serum concentration has been measured in a 78-year-old white woman with a grade III astrocytoma of the right parieto-occipital region treated with ciprofloxacin (500 mg bd) (78). 

CL Dougherty, J Kres, H Davoudi. Bio availability studies of drugs with nonlinear pharmacokinetics. II. absolute bioavailability of intravenous phenytoin prodrug at therapeutic phenytoin serum concentrations determined by doublestable isotope technique. J Clin Pharmacol 33 89-94, 1993. 

Job ML, Am SK, Strom JG, Jacobs NF,D Souza Ml. Effect of ciprofloxacin on tiie pharmacokinetics of multiple-dose phenytoin serum concentrations. Ther Drug Monit (1994) 16, 427-31. 

Browne TR, Szabo GK, Evans JE, Evans BA, GreenblattDJ, Mkati MA Carbamazepine increases phenytoin serum concentration and reduces phenytoin clearance. Neurology (1988) 38,1146-50. 

HYDANTOINS Fhenytoin is the most commonly prescribed anticonvulsant because of its effectiveness and relatively low toxicity. However, a genetically linked inability to metabolize phenytoin has been identified. For this reason, it is important to monitor serum concentrations of the drug on a regular basis to detect signs of toxicity Fhenytoin is administered orally and parenterally. If the drug is administered parenterally, the IV route is preferred over the intramuscular route because erratic absorption of phenytoin causes pain and muscle damage at the injection site... 

Additive bone marrow depressive effects occur when the miotic inhibitor drugs are administered with other anti-neoplastic dragp or radiation therapy. Administration of vincristine with digoxin results in a decreased therapeutic effect of tlie digoxin and decreased plasma digoxin levels. There is a decrease in serum concentrations of phenytoin when administered widi vinblastine... 

Assess the AED serum concentration and adjust therapy as needed for agents with a defined therapeutic range (e.g., phenytoin, carbamazepine, valproic acid, and phenobarbital). Drug levels can also be used to determine adherence to medication regimens for agents that do not have defined ranges. 

Instruct patients receiving phenytoin about the symptoms of elevated serum concentrations (e.g., nystagmus, blurred vision, dizziness, drowsiness, and lethargy). 

Phenytoin is metabolized in the liver mainly by CYP2C9, but CYP2C19 is also involved. Zero-order kinetics occurs within the usual therapeutic range, so any change in dose may produce disproportional changes in serum concentrations. 

Absorption/Distrlbutlon - Phenytoin is slowly absorbed from the small intestine. Rate and extent of absorption varies and is dependent on the product formulation. Bioavailability may differ among products of different manufacturers. Administration IM results in precipitation of phenytoin at the injection site, resulting in slow and erratic absorption, which may continue for up to 5 days or more. Plasma protein binding is 87% to 93% and is lower in uremic patients and neonates. Volume of distribution averages 0.6 L/kg. Phenytoin s therapeutic plasma concentration is 10 to 20 mcg/mL, although many patients achieve complete seizure control at lower serum concentrations. 

CYP 450 Drugs that induce liver enzymes (eg, phenytoin, carbamazepine, phenobarbital) increase the metabolism and clearance of zonisamide and decrease its half-life. Concurrent medication with drugs that induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. 

Distribution - Valproic acid is rapidly distributed. Volume of distribution of total or free valproic acid is 11 or 92 L/1.73 m, respectively. Valproic acid has been detected in CSF (approximately 10% of total concentrations) and milk (about 1% to 10% of serum concentrations). Therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate. The plasma protein binding of valproate is concentration-dependent. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (eg, aspirin). Conversely, valproate may displace certain protein-bound drugs (eg, phenytoin, carbamazepine, warfarin, tolbutamide). 

High isoniazid plasma levels inhibit phenytoin metabolism and potentiate phenytoin toxicity when the two drugs are coadministered. The serum concentrations of phenytoin should be monitored, and the dose should be adjusted if necessary. 

Phenytoin serum levels should be monitored closely when ketoconazole is prescribed. Ketoconazole causes increases in serum concentrations of warfarin, cyclosporine, and sulfonylureas. Because of its ability to increase serum cyclosporine levels, ketoconazole has been given to cyclosporine-dependent cardiac transplant recipients to reduce the dose of cyclosporine needed and as a cost-saving measure. 

Clozapine is metabolized by hepatic CYP 1A2 and, to a lesser degree, CYP 3A3/4 therefore, the drug is subject to changes in serum concentration when combined with medications that inhibit or induce these enzymes. Serum clozapine levels increase with coadministration of fluvoxamine or erythromycin and decrease with coadministration of phenobarbital or phenytoin and with cigarette smoking (Byerly and DeVane 1996). These pharmacokinetic interactions are particularly important because of the dose-dependent risk of seizures. 

Nonlinear relationship of phenytoin dosage and plasma concentrations. Five patients (identified by different symbols) received increasing dosages of phenytoin by mouth, and the steady-state serum concentration was measured at each dosage. The curves are not linear, since, as the dosage increases, the metabolism is saturable. Note also the marked variation among patients in the serum levels achieved at any dosage. 

Chloramphenicol inhibits hepatic microsomal enzymes that metabolize several drugs. Half-lives are prolonged, and the serum concentrations of phenytoin, tolbutamide, chlorpropamide, and warfarin are increased. Like other bacteriostatic inhibitors of microbial protein synthesis, chloramphenicol can antagonize bactericidal drugs such as penicillins or aminoglycosides. 

Praziquantel is a synthetic isoquinoline-pyrazine derivative. It is rapidly absorbed, with a bioavailability of about 80% after oral administration. Peak serum concentrations are reached 1-3 hours after a therapeutic dose. Cerebrospinal fluid concentrations of praziquantel reach 14-20% of the drug s plasma concentration. About 80% of the drug is bound to plasma proteins. Most of the drug is rapidly metabolized to inactive mono- and polyhydroxylated products after a first pass in the liver. The half-life is 0.8-1.5 hours. Excretion is mainly via the kidneys (60-80%) and bile (15-35%). Plasma concentrations of praziquantel increase when the drug is taken with a high-carbohydrate meal or with cimetidine bioavailability is markedly reduced with some antiepileptics (phenytoin, carbamazepine) or with corticosteroids. 

General supportive care should be provided. Aggressive gut decontamination should be carried out using repeated doses of activated charcoal and whole bowel irrigation. Propranolol or other blockers (eg, esmolol) are useful antidotes for B-mediated hypotension and tachycardia. Phenobarbital is preferred over phenytoin for convulsions most anticonvulsants are ineffective. Hemodialysis is indicated for serum concentrations greater than 100 mg/L and for intractable seizures in patients with lower levels. 

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