DRUG TREATMENT

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CHAPTER 53 DRUG TREATMENT

Edward B. Bromfield

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:

1. Differences among drugs in efficacy are lesser than differences in pharmacokinetics, interactions, likely adverse effects, and cost.

2. There are several options for nearly every clinical situation.

3. Unless a rapid therapeutic effect is essential, a low starting dosage and slow titration rate should be chosen. This is especially true in the treatment of elderly or ill patients.

4. In general, the dosage should be increased until, after an adequate observation period, it is established that seizures are controlled or until dose-related side effects develop; in the latter case, the dosage should be decreased to the previous level, and the response should be monitored. If seizures are not controlled, another appropriate AED should be initiated and titrated up, usually while the first drug is tapered.

5. In rare cases, increases in dosage may result in worsening of seizures. The dosage should be reduced, and the drug will probably need to be replaced by an alternative AED.

6. For both ethical and logistical reasons, new AEDs are invariably tested as adjunctive therapy in adults with medically intractable partial seizures. Evidence of effectiveness in other settings is generally based on smaller studies that may or may not be well controlled, and it leads to regulatory approval for other uses in only a minority of cases. Therefore, off-label use is justifiable either if approved AEDs are not successful or if the risk of using the off-label alternative appears lower than that of the approved AED.

7. The most common drug interactions involving AEDs are based on induction or, less commonly, inhibition of the hepatic mixed-function oxidase or cytochrome P450 enzyme system. As a group, the older AEDs have much stronger effects on this system than do the newer drugs, although several of the latter are substrates whose metabolism is affected by addition or withdrawal of the older drugs.

8. Serum drug concentrations can be useful in verifying compliance or in providing an initial target for patients with infrequent seizures, but if used mechanically as a guide to dosing, they can hinder rather than help in achieving the goal of treatment: no seizures and no side effects (and ultimately, optimizing quality of life). Even with the older AEDs, published therapeutic ranges have limited scientific support, and individuals may have therapeutic responses or adverse effects either below or above these ranges. For the newer AEDs, therapeutic ranges are even more provisional but are included in the following discussions for completeness.

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:

1. The first group of AEDs includes those that are effective against partial seizures, including simple and complex partial seizures, as well as secondarily generalized seizures. Most if not all of these also prevent primarily generalized tonic-clonic seizures; however, they are not effective against, and may worsen, other generalized seizure types, including absence and myoclonic seizures. Drugs in this class include carbamazepine, phenytoin, phenobarbital, primidone, gabapentin, oxcarbazepine, pregabalin, and tiagabine.

2. The second group includes those that can be viewed as “broad spectrum” AEDS, with activity against a variety of generalized as well as partial seizures. The traditional drug with this characteristic is valproate. There is evidence supporting a similar broad spectrum for the newer drugs lamotrigine, topiramate, levetiracetam, zonisamide, felbamate, and the older drug, methsuximide.

3. The third group includes drugs that do not easily fit in the above categories, including ethosuximide, a narrow spectrum AED with established efficacy against only typical generalized absence seizures. (Interestingly, the closely related drug methsuximide, as noted, has a broader spectrum and is effective against partial seizures as well.) There are also other, less commonly used adjunctive drugs that have different medical uses, such as acetazolamide and perhaps allopurinol. Finally, there are medications used in specific situations, including seizure clusters and status epilepticus, alcohol withdrawal and other drug-related seizures, and specific pediatric syndromes, such as infantile spasms. These include intravenous, sublingual, and rectal benzodiazepines, anesthetic agents, adrenocorticotropic hormone (ACTH), and pyridoxine.

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.

Gabapentin

Advantages of gabapentin include its ability to be rapidly titrated, the facts that it is relatively well tolerated and has no pharmacokinetic interactions, and its additional uses (for neuropathic pain).

Disadvantages include the recommendation of three- to four-times-daily dosing (although it can be given twice daily); it is also perceived as less efficacious than other AEDs, although data are conflicting.

Major dose-related adverse effects include sedation, dizziness, and ataxia. Idiosyncratic adverse effects include weight gain, rash (rare), behavioral changes in children, and myoclonus. There are no known chronic adverse effects.

Teratogenic risk with gabapentin is unknown.

Initiation should be at 300 mg at bedtime, increasing by 300 mg every 1 to 7 days to a target of 1800 to 3600 mg/day; in elderly patients, at 100 at bedtime or twice daily, increasing in 100 to 200-mg increments; in pediatric patients (aged >3 year), at 10 to 20 mg/kg/day, increasing to a target of 30 to 60 mg/day.

With regard to pharmacokinetics, the half-life is 5 to 7 hours (but brain kinetics are probably slower). There is no protein binding.

The provisional therapeutic range is 4 to 16 mg/L.

Preparations include Neurontin capsules, 100, 300, and 400 mg; Neurontin tablets, 600 and 800 mg; and Neurontin solution, 250 mg/5 mL. Generic gabapentin tablets are also available.

Pregabalin

Advantages of pregabalin include the lack of pharmacokinetic interactions, additional uses (for neuropathic pain), and the ability for twice-daily dosing (although three times daily may be better tolerated).

The disadvantage is that relatively slow titration is needed, to avoid sedation.

Major dose-related adverse effects include sedation, dizziness, ataxia, and blurred vision. Idiosyncratic adverse effects include weight gain, edema, and rash (rare). There are no known chronic adverse effects.

Teratogenic risk with pregabalin is unknown.

Initiation should be at 50 or 75 mg at bedtime or twice daily, increasing by a similar amount every 4 to 7 days to a target of 300 twice daily if tolerated.

With regard to pharmacokinetics, the half-life is 6 hours (but brain kinetics are probably slower). There is no protein binding.

The provisional therapeutic range is unknown.

Preparations include Lyrica capsules, 25, 50, 75, 100, 150, 200, 225, and 300 mg.

Tiagabine

Advantages of tiagabine are that it may have antianxiety or analgesic effects and it can sometimes be given twice daily.

Disadvantages include its sedating effects, the risk of nonconvulsive status epilepticus; and the fact that it is a cytochrome P450 substrate.

Major dose-related adverse effects include dizziness, somnolence, nausea, and cognitive slowing. Idiosyncratic adverse effects include rash, mood changes, and generalized nonconvulsive status epilepticus (with dosages of 48 mg/day or greater). There are no known chronic adverse effects.

Teratogenic risk with tiagabine is unknown.

Initiation should be at 4 mg at bedtime, increasing by 4 to 8 mg/day weekly to a target of 36 to 54 mg/day, taken twice or three times daily. Titration should be at 2 to 8 mg/day, increasing by 2 to 8 mg/day at weekly intervals to a target of 24 to 56 mg/day in two to four doses. In pediatric patients (aged >12 years), the initial dosage is 4 mg/day, increasing by 4 mg/week to a target of 20 to 32 mg/day.

With regard to pharmacokinetics, the half-life is 4 to 9 hours; protein binding is 96%.

The provisional therapeutic range is unknown.

Preparations include Gabitril, 2-, 4-, 12, and 16-mg tablets.

Vigabatrin

Advantages of vigabatrin are that it is very effective against partial seizures and against infantile spasms in patients with tuberous sclerosis.

A disadvantage is that it may exacerbate generalized epilepsies.

Major dose-related adverse effects include sedation, dizziness, and diplopia. Idiosyncratic adverse effects include psychiatric disturbances. Chronic adverse effects include retinal toxicity (which causes visual field defects that are detectable in high proportion with detailed testing, although they are often asymptomatic) and weight gain.

Teratogenic risk with vigabatrin is unknown.

In adults, vigabatrin should be initiated at 1 g/day and increased by 1 g/day weekly to a target of 3 to 4 g/day, taken twice daily; in children, the initial dosage should be 40 mg/kg/day, taken twice daily, and increased to a target of 40 to 150 mg/kg/day.

With regard to pharmacokinetics, the half-life is 5 to 8 hours, but the biological effect (γ-amino butyric acid transaminase inhibition) lasts days; protein binding is 0%.

The provisional therapeutic range is unknown.

Preparations include Sabril, 500-mg tablets, and a powder sachet, 500 mg.

Phenobarbital

Advantages of phenobarbital include a long half-life (daily dosing) and its low cost.

Disadvantages include cognitive and behavioral side effects and drug interactions (it is a cytochrome P450 inducer).

Major dose-related adverse effects include sedation, depression, and cognitive impairment. Idiosyncratic adverse effects include rash, hyperactivity (in children), hepatic failure (rare), and aplastic anemia (rare). Chronic adverse effects include osteoporosis and connective tissue disorders (e.g., frozen shoulder).

Phenobarbital is teratogenic, causing a two- to threefold increase over baseline in major congenital malformations.

Initiation should be at 90 to 250 mg/day; up to 20 mg/kg (<100 mg/hour for status epilepticus) can be loaded intravenously, but sedation is universal. Steady-state levels should be checked in 2 to 3 weeks (4 to 5 weeks if valproate is taken concurrently). The pediatric dosage is 2 to 7 mg/kg/day.

With regard to pharmacokinetics, the half-life is 72 to 168 hours (less in children, more when coadministered with valproate).

The usual therapeutic range is 10 to 40 mg/L (arguably 5 to 30 mg/L).

Preparations include generic tablets 15, 30, 60 (or 62.5), and 100 mg; a generic suspension, 15 or 20 mg/5 mL; and a generic parenteral formulation, 30, 60, and 130 mg/mL.

Primidone

Advantages of primidone are that the parent compound may have efficacy beyond that of phenobarbital metabolite, at least against myoclonic seizures, and that it is effective against tremor at low doses.

Disadvantages include the facts that it is possibly more sedating than phenobarbital alone; it must be taken in divided doses, usually three or four times daily; and that it is a cytochrome P450 inducer.

Primidone is metabolized to phenobarbital.

Major dose-related, idiosyncratic, and chronic adverse effects are the same as those of phenobarbital.

Primidone is teratogenic, with similar risk of major congenital malformation.

Initiation should be at 100 to 125 mg at bedtime, increasing by 125 to 250 mg every 2 to 7 days to a target of 500 to 1500 mg/day. In pediatric patients, the initial dosage is 50 mg/day, increasing to 10 to 25 mg/kg/day.

With regard to pharmacokinetics, the half-life is 6 to 22 hours (72 to 168 hours for phenobarbital metabolite); cytochrome P450 inducers promote conversion to phenobarbital.

The usual therapeutic range is 5 to 12 mg/L (10 to 40 mg/L for phenobarbital metabolite).

Preparations include Mysoline and generic tablets, 50 and 250 mg, and a generic suspension, 250 mg/5 mL.

Drugs for Generalized Seizures, Including Absence and Myoclonic, as Well as Tonic-Clonic

These also are effective against partial seizures.

Valproate

Advantages of valproate include its long history of use and the fact that it is the best established broad-spectrum AED; its concomitant effects on migraine and bipolar illness; and the fact that slow-release preparations allow twice- or possibly once-daily dosing.

Disadvantages include its acute and chronic adverse effects, particularly weight gain, and its interactions (it is a cytochrome P450 inhibitor and also competes for protein binding sites).

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