Pharmacologic principles applicable in the management of epileptic patients include those expressed in pharmacokinetics and pharmacodynamics. Experience from monitoring the blood levels of antiepileptic drugs over the past decades has shown that there is reasonable correlation between the administered dose and the plasma level. An individual patient typically shows higher levels with higher doses, but the same dose in mg/kg may produce quite different concentrations in different individuals. The actual effective and toxic levels for an individual patient may fall in or out of these ranges and are therefore determined empirically. The correlation between blood level and clinical effects, particularly intoxication, may change over time as tolerance develops. Markedly reduced binding is often seen in patients with uremia, chronic liver disease, or systemic lupus erythematosus. In patients with poor renal function, the uremic products compete for the biding sites, and structural change of binding proteins probably occurs from carbamylation.
Diazepam (DZP) (7-chloro-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzo-diazepam-one) has a molecular weight of 284.7 and a pKa of 3.3. DZP appears as a colorless crystalline material which is relatively insoluble in water, but is soluble in propylene glycol, alcohol, and other organic solvents. Rarely is DZP used as an adjunctive antiepileptic drug on a long-term basis. Drugs such as clobazam, clorazepate, CZP, and nitrazepam are more effective. When treating status epilepticus, DZP is given intravenously. A dose of 10 mg often stops the seizures, however, the effect may last no longer than 20 to 30 minutes. In some patients, DZP has caused elevation of phenytoin (PHT) blood levels, but in others the opposite effect has occurred. In some patients who ingested DZP and alcohol simultaneously, high DZP blood levels were found, but chronic alcohol use may induce DZP metabolism and therefore lower blood levels. Modest elevation of DZP levels may be caused by cimetidine.
Measurement of blood levels of antiepileptic drugs has been carried out for over a decade. In earlier years, mostly spectrophotometric and colonmetric methods were used to determine diphenylhydantoin and phenobarbital concentrations. In more recent years, gas-liquid chromatographic methods have been employed which generally offer greater specificity and allow determination of several drugs simultaneously. Ceneral experience from the determination of antiepileptic drug blood levels indicates that there is some correlation between (1) the drug dose and blood level, (2) blood level and therapeutic effects, and (3) blood level and some toxic effects. The relationships are evident and usually reproducible in any individual patient. However, there are marked variations in these relationships among different patients due to variations in their individual-specific pharmacokinetic characteristics and/or external factors. Thus a wide range of blood levels may be seen in patients receiving the same dose and a wide range of clinical effects may be seen in patients having the same blood level. Nevertheless, an expected range of blood levels from a given dose can be defined, as well as an expected range of blood levels in which toxic or therapeutic effects are usually seen in the majority of patients. These expected values are clinically useful in that they caution the physician to look for specific causes in those patients whose blood levels fall far above or below the expected range. WHAT DOSAGE REGIMEN TO USE The majority of antiepileptic drugs are eliminated slowly and cause relatively stable blood levels to be maintained as long as the drug intake is constant.
Baclofen is a centrally acting muscle relaxant used for treatment of spasticity. Some patients, to experience adequate symptomatic relief, require dosages of baclofen that significantly exceed the conventional 80 mg daily maximum advocated by the 1992 Physicians' Desk Reference. In this pilot study of baclofen kinetics and dynamics in eleven patients, the safety and efficacy of high dose baclofen was confirmed. The data suggest that the pharmacokinetics of high dose baclofen may vary from those described previously. Time-to-peak plasma levels and plasma half-lives were noted to be substantially longer than prior reports indicate. Baclofen blood levels were observed to rise gradually over time in some patients on a stable dosing regimen, probably a result of impaired renal clearance. These findings may indicate that a change in pattern of prescription is warranted and that a reliable and practical measurement of systemic baclofen levels has a useful role in clinical practice, particularly for the patient with neurogenic bladder and potential renal insufficiency.
Diphenylhydantoin was administered orally or intravenously to 20 uremic and 20 nonuremic patients. In the former this drug and 5-phenyl-5-parahydroxyl-phenylhydantoin, its major metabolite, were measured in blood and urine. In the nonuremic patients, only diphenylhydantoin levels in plasma were measured. Regardless of the route of administration, diphenylhydantoin concentrations were uniformly lower in uremic than in nonuremic patients. In uremic patients, plasma concentrations of 5-phenyl-5-parahydroxyl-phenylhydantoin were higher than reported values in nonuremic subjects. After a single intravenous injection of 250 mg of diphenylhydantoin, its rate of elimination from plasma (half-life) was 8.1 hours in five uremic patients and 13.0 hours in three nonuremic subjects. These observations suggest an altered metabolic disposition of the drug in uremia.
The kindling of amygldaloid and cortical seizures in cats was used to study the prophylactic effects of phenobarbital, phenytoin, ethosuximide, acetazolamide, and dexamethason. Phenobarbital prevented the evolution of such seizures beyond stage 4 in all amygdaloid-kindling animals during 160 days of study. The prophylactic effect persisted on periodic challenge after the drug had been discontinued. Phenytoin, ethosuximide, acetazolamide, and dexamethasone appeared to have no prophylactic effect against the development of kindled amygdaloid seizures. With cortical kindling, both phenobarbital and phenytoin retarded the evolution of seizures without achieving true prophylaxis. The drugs appeared to act as suppressants. Prophylaxis was not an "all-or-none" phenomenon but rather a limitation of the stage of seizure evolution.
