Most epileptics can be controlled with phenytoin (Dilantin), primidone (Mysoline), phenobarbital, or other agents. Frequently drug combinations are required. Therapy is usually a long-term project. When toxicity develops, many of these therapeutic agents produce symptoms that could also be caused by central nervous system (CNS) disease, such as confusion, somnolence, and various changes in mental behavior. Some drugs, such as primidone, must be carefully brought to a therapeutic level by stages rather than in a single dose. Most antiepileptic drugs are administered to control seizures; but if seizures are infrequent, it is difficult to be certain that the medication is sufficient to prevent future episodes. When drug combinations are used, levels for all the agents should be obtained so that if only one drug is involved in toxicity or therapeutic failure, it can be identified.

When specimens are sent to the laboratory for drug assay, the physician should list all drugs being administered. Some are metabolized to substances that themselves have antiepileptic activity (e.g., primidone is partially metabolized to phenobarbital), and the laboratory then must assay both the parent drug and its metabolite. Without a complete list of medications, there is a good chance that one or more drugs will be overlooked. Once drug blood levels have been obtained, the physician should remember that they are often not linear in relation to dose, so that a percentage change in dose may not result in the same percentage change in blood level. Repeated assays may be needed to guide dosage to achieve desired blood levels. Finally, published therapeutic ranges may not predict the individual response of some patients to the drug. Clinical judgments as well as laboratory values must be used.

Phenytoin. Phenytoin is about 90% bound to serum proteins. About 70% is metabolized in the liver, although only 5% or less is excreted unchanged through the kidneys. Peak phenytoin levels are reached 4-8 hours after an oral dose and within 15 minutes after IV administration. Serum half-life is about 18-30 hours (literature range, 10-95 hours), with an average of about 24 hours. This variation occurs in part because higher doses saturate the liver metabolic pathway and thus increase the half-life with nonmetabolized drug. The serum dose-response curve is not linear, so that relatively small increases in dose may generate relatively large changes in serum levels. Time to reach steady state is usually 4-6 days but may take as long as 5 weeks. Administration by intramuscular injection rather than oral intake is said to reduce blood levels about 50%. The therapeutic range is 10-20 µg/ml. Specimens for TDM are usually drawn just before the next scheduled dose to evaluate adequacy of dosage. Specimens drawn during symptoms or peak levels are needed to investigate toxic symptoms.

Certain drugs or diseases may affect phenytoin blood levels. Severe chronic liver disease, hepatic immaturity in premature infants, or disulfiram (Antabuse) therapy often increase phenytoin levels. Certain other drugs, such as coumarin anticoagulants, chloramphenicol (Chloromycetin), methylphenidate (Ritalin), and certain benzodiazepine tranquilizers such as diazepam (Valium) and chlordiazepoxide (Librium) have caused significant elevations in a minority of patients. Acute alcohol intake may also elevate plasma levels. On the other hand, pregnancy, acute hepatitis, low doses of phenobarbital, carbamazepine (Tegretol), and chronic alcoholism may decrease phenytoin plasma levels, and they may also be decreased in full-term infants up to age 12 weeks and in some patients with renal disease. As noted previously, there may be disproportionate changes in either bound or free phenytoin in certain circumstances. About 10% of total phenytoin is theoretically free, but in one study only about 30% of patients who had free phenytoin measured conformed to this level with the remainder showing considerable variation. Certain clinical conditions or acidic highly protein-bound drugs may displace some phenytoin from albumin, causing the unbound (free) fraction of serum phenytoin to rise. Initially, total serum concentration may be decreased somewhat if the liver metabolizes the newly released free drug. However, the hepatic metabolic pathway may become saturated, with resulting persistent increase in the unbound fraction and return of the total phenytoin level into the reference range. At this time the usual phenytoin assay (total drug) could be normal while the free drug level is increased. Drugs that can displace phenytoin from albumin include valproic acid (Depakene), salicylates, oxacillin, cefazolin, cefotetan, and phenylbutasone. Large quantities of urea or bilirubin have a similar effect. Infants aged 0-12 weeks have reduced phenytoin protein binding. On the other hand, hypoalbuminemia means less binding protein is available and may result in increased free phenytoin levels coincident with decreased total phenytoin levels.

Phenytoin has some interesting side effects in a minority of patients, among which are megaloblastic anemia and a type of benign lymphoid hyperplasia that clinically can suggest malignant lymphoma. Occasional patients develop gum hypertrophy or hirsutism. Phenytoin also can decrease blood levels of cortisol-type drugs, thyroxine (T4), digitoxin, and primidone, and can increase the effect of coumadin and the serum levels of the enzymes gamma-glutamyltransferase and alkaline phosphatase. Phenytoin produces its effects on drugs by competing for binding sites on protein or by stimulating liver microsome activity. Phenytoin alters the serum enzymes by its effect on the liver microsome system.

Primidone. Primidone is not significantly bound to serum proteins and is about 50% metabolized in the liver. About 50% is excreted unchanged by the kidneys. Its major metabolites are phenobarbital (about 20%) and phenylethylmalonamide (about 20%), both of which have anticonvulsant activity of their own and both of which accumulate with long-term primidone administration. Phenobarbital is usually not detectable for 5-7 days after beginning primidone therapy. The ratio of phenobarbital to primidone has been variously reported as 1.0-3.0 after steady state of both drugs has been reached (unless phenobarbital is administered in addition to primidone). If phenytoin is given in addition to primidone, primidone conversion to phenobarbital is increased and the phenobarbital/primidone ratio is therefore increased. Peak serum concentration of primidone occurs in 1-3 hours, although this is somewhat variable. Serum half-life in adults is about 6-12 hours (literature range, 3.3-18 hours). Steady state is reached in about 50 hours (range, 16-60 hours). The therapeutic range is 5-12 µg/ml. It is usually recommended that both primidone and phenobarbital levels be assayed when primidone is used, rather than primidone levels only. If this is done, one must wait until steady state for phenobarbital is reached, which takes a much longer time (8-15 days for children, 10-25 days for adults) than steady state for primidone. Specimens for TDM are usually drawn just before the next scheduled dose to evaluate adequacy of dosage. Specimens drawn during symptoms or peak levels are needed to investigate toxic symptoms.

Phenobarbital. Phenobarbital is about 50% bound to serum protein. It has a very long half-life of 2-5 days (50-120 hours) and takes 2-3 weeks (8-15 days in children, 10-25 days in adults) to reach steady state. About 70%-80% is metabolized by the liver and about 10%-30% is excreted unchanged by the kidneys. Phenobarbital, as well as phenytoin, carbamazepine, and phenylbutasone, has the interesting ability to activate hepatic microsome activity. Thus, phenobarbital increases the activation of the phenytoin liver metabolic pathway and also competes with phenytoin for that pathway. Phenobarbital incidentally increases degradation of other drugs that are metabolized by hepatic microsome activity, such as coumarin anticoagulants, adrenocorticosteroids, quinidine, tetracycline, and tricyclic antidepressants. Acute alcoholism increases patient response to phenobarbital and chronic alcoholism is said to decrease response. Specimens for TDM are usually drawn just before the next scheduled dose to evaluate adequacy of dosage. Specimens drawn during symptoms or peak levels are needed to investigate toxic symptoms.

Valproic Acid. Valproic acid has been used to treat petit mal “absence” seizures and, in some cases, tonic-clonic generalized seizures and myoclonic disorders. About 90% is bound to plasma proteins. There is a relatively small volume of distribution, because most of the drug remains in the vascular system. More than 90% is metabolized in the liver, with 5% or less excreted unchanged by the kidneys. Time to peak after oral dose is 1-3 hours. Food intake may delay the peak. Serum half-life is relatively short (about 12 hours; range, 8-15 hours), and steady state (oral dose) is reached in 2-3 days (range, 30-85 hours in adults; 20-70 hours in children). Liver disease may prolong the interval before steady state. Interestingly, therapeutic effect usually does not appear until several weeks have elapsed. There is some fluctuation in serum values (said to be 20%-50%) even at steady state. Hepatic enzyme-inducing drugs such as phenytoin, phenobarbital, carbamazepine, and primadone increase the rate of valproic acid degradation and thus its rate of excretion, and therefore tend to decrease the serum levels. Hypoalbuminemia or displacement of valproic acid from albumin by acidic strongly protein-bound drugs such as salicylates decrease total valproic acid blood levels. Valproic acid can affect phenytoin and primidone levels, but the effect is variable. Phenobarbital levels are increased due to interference with liver metabolism. One report indicates that ethosuximide levels may also be increased. Specimens for TDM are usually drawn just before the next scheduled dose to evaluate adequacy of dosage. Specimens drawn during symptoms or peak levels are needed to investigate toxic symptoms.

Rarely, valproic acid may produce liver failure. Two types have been described. The more common type appears after months of therapy, with gradual and potentially reversible progression signaled by rising aspartate aminotransferase (AST) levels. Periodic AST measurement has been advocated to prevent this complication. The other type is sudden, is nonreversible, and appears soon after therapy is started.

Carbamazepine. Carbamazepine is used for treatment of grand mal and psychomotor epilepsy. About 70% (range, 65%-85%) is protein bound, not enough to make binding a frequent problem. Carbamazepine is metabolized by the liver. It speeds its own metabolism by activation of the liver microsome system. Only 1% is excreted unchanged in the urine. The major metabolites are the epoxide form, which is metabolically active, and the dihydroxide form, which is derived from the epoxide form. The metabolites are excreted in urine. Carbamazepine absorption after oral dose in tablet form is slow, incomplete (70%-80%), and variable. Pharmacologic data in the literature are likewise quite variable. Dosage with tablets results in a peak level that is reached in about 6-8 hours (range, 2-24 hours). Dosage as a suspension or solution or ingestion of tablets with food results in peak levels at about 3 hours. Serum half-life is about 10-30 hours (range, 8-35 hours) when therapy is begun. But after several days the liver microsome system becomes fully activated, and when this occurs the half-life for a dose change may be reduced to about 12 hours (range, 5-27 hours). Phenytoin, phenobarbital, or primidone also activate the liver microsome system, thereby increasing carbamazepine metabolism and reducing its half-life. The time to steady state is about 2 weeks (range, 2-4 weeks) during initial therapy. Later on, time to steady state for dose changes is about 3-4 days (range, 2-6 days). Transient leukopenia has been reported in about 10% of patients (range, 2%-60%) and persistent leukopenia in about 2% (range, 0%-8%). Thrombocytopenia has been reported in about 2%. Aplastic anemia may occur, but it has been rare.