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

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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 phenobarbital the increase in tolerance is still more pronounced and may obscure symptoms of accumulation of the drug. Phenobarbital addicts showed mild side‐effects with blood levels of 24–100 μg/ml.RÉSUMÉ ET CONCLUSIONS: Les auteurs passent en revue des résultats concernant la distribution et le sort de la phénytoïne et du phénobarbital chez l'homme et chez les animaux. Le taux sérique de ces médicaments est à considérer comme une expression adéquate de leur concentration dans le cerveau et, de là, de leur effet anticonvulsif.Le taux de concentration dans le sérum augmente à peu près proportionnellement à l'augmentation de la dose: 1 mg/kg de phénytoïne prise oralement donne environ 3 μg/ml dans le sérum, et 1 mg/kg de phénobarbital donne environ 10 μg/ml. La dispersion de la proportion entre le taux et la dose est plus élevée quant à la phénytoïne que quant au phénobarbital. Chez beaucoup des malades qui ont dû prendre de la phénytoïne pendant plusieurs années, le taux sérique par mg/kg administré a dépassé 3 μg/ml par mg/kg. C'est pour cela qu'il est difficile de déduire pour chaque malade individuellement la concentration sérique qui suivra la dose administrée; la détermination de la phénytoïne sérique s'est donc révélée de valeur considérable dans le début et le maintien de la thérapie.Chez les malades qui ne prenaient que de la phénytoïne, on n'a observé aucune amélioration clinique et électroencéphalographique quand le taux sérique était audessous de 10 μg/ml. Les convulsions de la plupart des malades souffrant du grand mal ont été contrôlées et leur nombre réduit de façon marquée quand le dosage a étéétabli de sorte que la concentration sérique atteigne à peu près 15 μg/ml (0.3–0.4 g par jour à un malade de 70 kg).Quant aux malades n'ayant eu que du phénobarbital, aucune information n'est disponible quant à la corrélation entre le taux sérique et l'effet anticonvulsif.Chez les malades hospitalisés ayant subi pendant des années un traitement par phénytoïne et phénobarbital combinés, la moyenne des niveaux sériques est 18 μg/ml de phénytoïne et 20 μg/ml de phénobarbital.Chez les malades n'ayant pas reçu d'abord de la phénytoïne, il a fallu une semaine à peu près pour que le niveau atteigne 10–15 μg/ml. Le temps nécessaire à la concentration sérique pour atteindre son...