Anticonvulsant drugs: Their therapeutic and biochemical effects in epileptic patients

摘要

Satisfactory seizure control in epileptic patients may be difficult to achieve when anticonvulsant drug dosage is adjusted empirically. This may be due, in part, to individual variations in metabolism or distribution. Section 1 of this thesis includes studies of how serum concentrations of anticonvulsants may vary in different patients and the relationship between serum concentrations and therapeutic effects. As shown in Chapter 3, serum concentrations of phenytoin show wide variations between different patients. Chapter 4 describes a study to investigate the value of a nomogram (Richens and Dunlop, 1975) in adjusting serum concentrations. Control of major seizures, but not minor seizures, improved when the serum concentrations were raised into the postulated therapeutic range in patients on multiple drug therapy. The nomogram was found to be of only limited value in predicting serum concentrations, apparently because the phenobarbitone that these patients were receiving inhibits phenytoin metabolism and may alter the relationship between dose and serum concentration. The interactions between phenytoin and phenobarbitone are complex since, as shown in Chapter 3, administration of phenytoin inhibits phenobarbitone metabolism and increases phenobarbitone serum concentrations in patients receiving phenobarbitone as the drug itself or as a metabolic product of primidone. In addition, in the study described in Chapter 5, phenytoin was found to lower serum concentrations of primidone by inducing its conversion to phenylethyl- malonamide (PEMA). The relationship between primidone dose and serum concentration is non-linear, apparently due to induction by primidone of its own metabolism. Serum concentrations and therapeutic effect of a new benzodiazepine anticonvulsant, clonazepam, are described in Chapter 6. Improvement in seizure control was greater and side-effects were less in patients who were receiving clonazepam alone or low doses of other drugs. There was no effect of clonazepam on serum concentrations of other anticonvulsants, but administration of other anticonvulsants appeared to induce the metabolism of clonazepam, possibly to a toxic derivative. A comparative trial of clonazepam against another recently introduced anticonvulsant, sodium valproate, is reported in Chapter 7. Neither drug significantly reduced the frequency of major seizures but sodium valproate therapy significantly improved control of minor seizures. Sodium valproate administration produced an increase in phenobarbitone serum concentrations in some patients and in this trial phenobarbitone doses were reduced where necessary to ensure that the therapeutic action of sodium valproate was not mediated via this effect. Serum concentrations of sodium valproate were similar in different patients and there was no apparent effect of administration of other drugs. In Chapter 7 it is also shown that sodium valproate administration reduces serum concentrations of phenytoin and it is suggested that this may be due to displacement of phenytoin from its plasma protein binding sites. Tissue concentrations of drugs depend on the free concentrations in serum and studies of protein binding of phenytoin and other anticonvulsants was described in Section 2 of this Thesis. (Abstract shortened by ProQuest.).