Drug Management of Epilepsy: Current Problems and the Possible Role of Calcium Antagonists

Pharmaceutical sciences

Larkin, John Gerarde

University:University of Glasgow

关键词: Pharmaceutical sciences;   

Others  :  http://theses.gla.ac.uk/78224/1/11007616.pdf

来源: University of Glasgow

【 摘 要 】

Prologue and Introduction Epilepsy is a disease which has struck fear into the hearts of both sufferers and onlookers for many centuries. Only in the past hundred years or so has effective medication become available, and medical management still relies on a small group of antiepileptic drugs (AEDs). These can often abolish seizures, and very frequently diminish their frequency such that patients can enjoy a normal life-style. A significant minority of patients, however, do not respond satisfactorily. Combining different drugs is complicated by their sharing the same side-effect - sedation - which seems more additive than does any therapeutic effect. It is for the benefit of these patients with refractory epilepsy that research continues, to improve our use of the present AEDs, and to find new drugs which might, when used alone or in combination, improve their lot. Therapeutic Drug Monitoring (TDM) In Chapter 1, current use of TDM in the epilepsy clinic is analysed. By recording physicians' decisions both before and after serum anticonvulsant concentrations were made available at 488 clinic visits, we found that management decisions were affected at 23% of these consultations. However, physicians did not appear to follow a "target concentration strategy" as a high proportion of results (26%) in the "target range" were followed by a change in dosage. A drawback with the "target concentration strategy" was highlighted by the correlation between carbamazepine concentration and time since dosing (P< 0.005). The possible benefits of an approach combining clinical and biochemical information are discussed. Cognitive function In Chapter 2, the effects of many AEDs on mental function are assessed. Deterioration in "cognitive" or "psychomotor" abilities is a generally recognised side-effect of all current AEDs. However, most evidence compares patients taking AEDs with healthy volunteers, the effect on mental function of the disease itself thus being uncontrolled. Other studies show short term deterioration in volunteers given AEDs for a limited period, or in patients abruptly taking an increased dose. These respectively fail to allow for any beneficial effect which controlling seizures might have on mental function, and the effect of tolerance to the drugs' side-effects. In EXPT. 2, 66 patients on AED therapy performed a battery of psychomotor function tests, and their results were compared with those of 14 untreated epileptic patients and 11 healthy controls. A clear "step-wise" deterioration in function was seen with reaction times, short-term memory, card-sorting, and finger-tapping speeds. Untreated epileptics fared worse than controls (P <0.05 - P <0.001) but better than treated patients (P< 0.05 -P <0.01). This demonstrated the deliterious effect of epilepsy itself. The drugs may aggravate this, though clearly the treated patients had more severe epilepsy. No differences were found between the individual drugs. In EXPT. 3, the effect of tolerance was demonstrated in a small group (n=13) of new patients commenced on carbamazepine. After an initial deterioration in reaction time (P<0.05) and finger-tapping (P< 0.001) at one week, these abilities returned to normal by twelve weeks, while mean serum concentrations of carbamazepine only fell from 8.5 mg/L to 7.1 mg/L. The relevance of short-term cognitive deterioration demonstrated in many studies is thus brought into question. Since diurnal variation in serum concentrations has been shown to correlate with carbamazepine neurotoxicity, EXPT. 4 tested the pharmacokinetics of a controlled-release preparation (Tegretol Retard, CBZ-CR). Eight healthy volunteers took this and conventional carbamazepine 200mg bd for two weeks in a double-blind, crossover fashion. Serum concentrations "plateaued" for 56h after single dose CBZ-CR, while chronic dosing resulted in diurnal fluctuation of only 12% compared with 24% on conventional carbamazepine (P <0.025), and produced less rapid changes in concentration (P< 0.02). Enzyme induction appeared similar with both preparations, but the bioavailability of CBZ-CR was possibly slightly lower. The "smoother" pharmacokinetic profile of CBZ-CR did not produce a detectable improvement in psychomotor function. Enzyme induction Many AEDs (carbamazepine, phenytoin, phenobarbitone) induce an increase in hepatic metabolising enzyme activity. This results in accelerated metabolism of the drugs themselves, of some other drugs which undergo oxidative metabolism, and of endogenous hormones. The clinical implications of this last aspect remain unclear.(Abstract shortened by ProQuest.).