DRUG TREATMENT

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CHAPTER 53 DRUG TREATMENT

Treatment of epilepsy begins as soon as the diagnosis is made. Typically, this occurs after the second unprovoked seizure, but ancillary data, such as neuroimaging and electroencephalographic (EEG) recording, may support the diagnosis after a single seizure (see Chapters 50 and 52). On the other hand, the diagnosis could be inappropriate after even several seizures, if each can be plausibly regarded as provoked or acutely symptomatic of another condition, as in the case of repeated episodes of alcohol withdrawal or hypoglycemia (described as “occasional seizures” in Chapter 52). Of note is that the seizure risk in some clinical situations is sufficiently high that theoretically epilepsy could be suspected even before a single seizure has occurred; however, one practical argument against this approach is the observation that none of the tested antiepileptic drugs reliably prevents the first seizure in this circumstance.

The mainstay of treatment is the use of antiepileptic drugs (AEDs), although, as mentioned, these probably do not prevent the development of epilepsy and could perhaps better be termed “antiseizure drugs,” because they do suppress seizures in established epilepsy; the older term anticonvulsant is no longer widely used because of the observation that many seizures do not involve convulsive movements. The first successful treatment, bromides, was introduced in the mid-19th century but proved to be too toxic for continued use. Phenobarbital has been used since the early 20th century, and phenytoin, the first AED identified by means of systematic testing, since 1938. Most drugs introduced before 1993 were variations of barbiturate, hydantoin, or benzodiazepine structures, but several novel medications have been identified and marketed since then. A relatively small number of comparative studies have failed to demonstrate major differences in efficacy, when used in appropriate situations, among the many approved AEDs. There are, however, major distinctions in common side effects, risk of serious idiosyncratic reactions, pharmacokinetics, drug interactions, and cost, and these differences help inform drug choices.

Approximately half of all patients with newly diagnosed epilepsy (58% if idiopathic, 44% if symptomatic or cryptogenic) respond to the first well-tolerated drug administered, and about two thirds eventually achieve complete seizure control. Any of the remaining third, or those in whom seizure control is achieved at the cost of unacceptable side effects, are potential candidates for alternative therapies. These include vagus nerve stimulation (brain stimulation is under active study); resective brain surgery; disconnection procedures; dietary therapies, including variations of the ketogenic diet; and certain supplements or herbal therapies.

TREATMENT WITH ANTIEPILEPTIC DRUGS

Principles of use are outlined as follows:

Use of Specific Antiepileptic Drugs

AEDs may be categorized in several ways. Mechanistic classifications are logical but of limited clinical relevance, in that several drugs work by more than one mechanism and many work by mechanisms that are unknown or poorly understood. Perhaps the most useful classification concerns spectrum of action:

Drugs for Partial and Tonic-Clonic Seizures

Carbamazepine

Advantages of carbamazepine are that it is considered a first-choice drug for partial and tonic-clonic seizures; it has a long history of use; and slow-release preparations allow twice-daily dosing.

Disadvantages are (1) the need to titrate slowly to avoid dose-related adverse effects and (2) pharmacokinetic interactions (cytochrome P450 enzyme inducer and substrate).

Major dose-related adverse effects include dizziness, diplopia, nausea, sedation, mild leukopenia, hyponatremia, and bradyarrhythmias (elderly). Idiosyncratic adverse effects are rash (including Stevens-Johnson syndrome), agranulocytosis, hepatic failure, pancreatitis, and lupus-like syndrome. Chronic adverse effects include osteopenia (possibly preventable with vitamin D and calcium supplementation).

Carbamazepine has teratogenic effects, including a 0.5% to 1% incidence of neural tube defects (it is unclear whether extra folate prevents these), although data have shown that the risk is not elevated very much.

The initial dosage should be 100 to 200 mg at bedtime or 100 mg twice a day, and the dosage is increased after 3 to 7 days to 200 mg twice a day. Blood values should be checked after 1 week on this dosage: carbamazepine level, complete blood cell count and differential, electrolytes (Na), and perhaps albumin and aspartate transaminase. The dosage should be increased at 3- to 7-day intervals to a level of 4 to 12 mg/L; this level should be rechecked in 4 to 6 weeks, because autoinduction may necessitate further increases. The usual maintenance dosages in adults are 600 to 1600 mg/day, up to 2400 mg/day; in children, the starting dosage is 5 to 10 mg/kg/day, and the maintenance dosage is 15 to 20 mg/kg/day, up to 30 mg/kg/day.

With regard to pharmacokinetics, the half-life is 12 to 20 hours (shorter with enzymeinducing drugs; autoinduction also occurs, with the level falling after 2 to 6 weeks on a stable dosage), and protein binding is 70% to 80%.

The usual therapeutic range is 4 to 12 mg/L.

Preparations of carbamazepine include Tegretol tablets, 100 and 200 mg; generic 200-mg tablets; a generic suspension of 100 mg/5 mL (which can solidify in tube feedings); and slow-release preparations, including Tegretol-XR in 100, 200, and 400-mg caplets and Carbatrol in 200 and 300-mg capsules.

Oxcarbazepine

Advantages of oxcarbazepine include its rapid titration, twice-daily dosing, minor interactions, and no known hepatic or hematological adverse effects; it was approved as initial monotherapy for partial seizures.

Disadvantages include dose-related effects similar to those of carbamazepine; although it is only a weak cytochrome P450 inducer, it can lower hormone (e.g., contraceptive) levels.

Oxcarbazepine is very similar chemically to carbamazepine but is not converted to epoxide metabolite, which is believed to account for many adverse effects of carbamazepine.

Major adverse effects include dose-related dizziness, diplopia, hyponatremia, somnolence, ataxia, and gastrointestinal upset. An idiosyncratic adverse effect is rash (25% cross-reactivity with carbamazepine). No chronic adverse effects are known.

Teratogenic risk with oxcarbazepine is unknown (lack of epoxide metabolite may suggest that oxcarbazepine is preferable over carbamazepine).

Initiation should be at 150 to 300 mg twice daily, increasing by 300 to 600 mg every 1 to 2 weeks to a target of 1200 to 2400 mg/day. Pediatric (age >4 years) dosages are 8 to 10 mg/kg/day, titrated to 20 to 40 mg/kg/day. Of importance is that conversion from carbamazepine can be rapid, over 1 day to 2 weeks, at a ratio of 300 mg of oxcarbazepine to 200 mg of carbamazepine.

With regard to pharmacokinetics, the half-life is 2 hours, but the drug is converted to an active monohydroxy-derivative, whose half-life is 8 to 10 hours. Protein binding is 40%.

The therapeutic range is 10 to 35 mg/L (monohydroxy-derivative).

Preparations include Trileptal tablets, 150, 300, and 600 mg, and Trileptal syrup, 300 mg/5 mL.

Phenytoin

Advantages of phenytoin are that it is arguably still a first-choice drug for partial and tonic-clonic seizures, although it is used much less in Europe than in the United States. It also has a long history of use; a long duration of action, especially with slow-release preparations (dosing is usually twice daily but can be daily); and there is a parenteral loading option. It is effective against generalized tonic as well as tonic-clonic seizures, although it is not effective against absence or myoclonic seizures.

Disadvantages include its zero-order kinetics; pharmacokinetic interactions (strong cytochrome P450 inducer); chronic cosmetic effects; and other adverse effects.

Major dose-related adverse effects are dizziness, ataxia, diplopia, and nausea. Idiosyncratic adverse effects are rash, including Stevens-Johnson syndrome; blood dyscrasias; hepatic failure; and lupus-like syndrome. Chronic adverse effects include gingival hyperplasia, hirsutism, osteopenia, pseudolymphoma, possibly lymphoma, and possibly cerebellar degeneration.

Phenytoin is teratogenic, causing a nonspecific doubling of the risk of major congenital malformations and a higher incidence of cosmetic anomalies.

In adults in nonemergency situations, the drug can be loaded orally; two doses of 500 mg or three doses of 300 mg can be taken 4 to 6 hours apart. Parenteral loading can be achieved intravenously (15 mg/kg, or 20 mg/kg for status epilepticus, not more than 50 mg/minute; the precursor drug fosphenytoin may be preferable for status epilepticus). When loading is not needed, an estimated maintenance dosage of 300 to 400 mg/day can be initiated, usually in two doses; blood levels should be checked in 1 to 2 weeks. Because of zero-order kinetics, increases must be proportionately lower as the level rises; for example, if the steady-state level on 300 mg/day is 12 mg/L, then 330 mg/day, a 10% dose increase, may be sufficient to raise the level to 15 mg/L, a 25% increase. The pediatric dosage is 4 to 5 mg/kg/day, up to 8 mg/kg or more, depending on level.

With regard to pharmacokinetics, the half-life (level-dependent) is 20 to 30 hours when the usual therapeutic range is used; protein binding is 90% (higher with renal failure or hypoalbuminemia).

The usual therapeutic range is 10 to 20 mg/L (arguably 5 to 25 mg/L).

Preparations include Dilantin tablets, 50 mg; Dilantin and generic extended-release capsules, 30 and 100 mg; a suspension, 125 mg/5 mL (must be adequately mixed in the bottle); and Phenytek capsules, 200 and 300 mg.