Aspects of the Pharmacology of Phenytoin (Dilantin®) and Phenobarbital Relevant to their Dosage in the Treatment of Epilepsy

Abstract

SUMMARY AND CONCLUSIONS Findings are reviewed concerning the distribution and fate of phenytoin and pheno‐barbital in animals and in man. The serum concentration of these drugs can be considered an adequate expression of their concentration in the brain and hence of their anticonvulsant effect. The serum level increased approximately linearly with increasing dose, 1 mg/kg phenytoin by mouth giving about 3 μg/ml in the serum and 1 mg/kg phenobarbital giving about 10 μg/ml in the serum. The scatter of the ratio of level to dosage was greater for phenytoin than for phenobarbital. In most of the patients who had taken phenytoin for several years the serum level per mg/kg given was above 3 μg/ml per mg/kg. In the individual patient it may therefore be difficult to predict the serum concentration from the amount given and the determination of serum phenytoin has proved of considerable value for the institution and maintenance of therapy. In patients who were given only phenytoin, clinical and electroencephalographic improvement was not observed with serum concentrations below 10 μg/ml. Convulsions in most patients with severe grand mal epilepsy were controlled or significantly reduced in number when the dosage was adjusted so that the serum concentration was about 15 μg/ml (0.3–0.4 g daily to a 70 kg patient). For patients who were on phenobarbital only no information is available as to the correlation between serum level and anticonvulsant effect. In institutionalized patients who had been given combined phenytoin and phenobarbital medication for years serum levels averaged 18 μg/ml of phenytoin and 20 μg/ml of phenobarbital. In patients who had not previously received phenytoin it took about a week to reach a level of 10–15 μg/ml. The time required for the serum concentration to become at equilibrium increased with increasing dosage. With phenobarbital it took still longer, a level of 20 μg/ml being reached after about 1 month. The rate of fall after withdrawal of the drug was about proportional to the serum concentration, the rate of elimination being 35–55 % for phenytoin and 11–25 % for phenobarbital per 24 h. When a serum level had been attained the maximum variation between two daily doses given by mouth at twelve hour intervals did not exceed 10% for phenytoin and was still less for phenobarbital. Thus the administration of phenytoin more often than twice a day and of phenobarbital more often than once a day is unnecessary. Toxic side‐effects (fatigue and signs of incoordination) were not seen with phenytoin serum concentrations below 14 μg/ml. Half of the patients with phenytoin serum levels of 30 μg/ml showed side‐effects. Gum hyperplasia is not included in this compilation. Its occurrence was not correlated to the phenytoin concentration in saliva. The development of an increased tolerance to phenytoin is indicated by the more frequent occurrence of side‐effects in patients who had been given phenytoin treatment for less than six months as compared with those who had been given a longer treatment. With pheno...

Diphenylhydantoin And Phenobarbital

“…were complicated and thus readily interfered with. In rats some of the drug, administered intravenously, is excreted into the intestine and reabsorbed before being metabolized in the liver.3'4 In man the slow rate of accumu¬ lation 16 and the absence of a linear relation¬ ship between serum level and low doses 9 are consistent with a complex metabolism and excretion of the drug. This nonlinearity can¬ not be explained by insensitivity of the method.…”

Therapeutic Drug Monitoring of Classical and Newer Anticonvulsants

“…This type of information initially became available in the 1960s, when methods were first developed to measure serum concentrations of classical AEDs [9]. These drug levels are then compared to reference levels that have been derived from collective data from multiple studies.…”

Therapeutisches Drugmonitoring von Antiepileptika

“…Bereits in den fünfziger und sechziger Jahren des vergangenen Jahrhunderts gab es Bestrebungen von Buchthal u. Svensmark [1], Serumkonzentrationen von Phenytoin und Phenobarbital zu messen. Anfang der siebziger Jahre kamen kommerzielle Enzymimmunoassays in die Labore, deren methodische Spezifikationen jedoch noch sehr zu wünschen übrig ließen.…”