Factors Influencing Drug Selection

Different seizure types and different types of epilepsy have different natural histories (i.e., how the disorder develops over time). These unique features may dictate when to treat and for how long. They may also affect choice of medication, since some drugs are effective against specific seizures and syndromes.

Achieving seizure control through drug treatment, with minimal side effects, generally depends on selection of a drug specific to the seizure type or epilepsy syndrome, minimizing the number of drugs prescribed, and educating the patient and family to encourage compliance with the dosing schedule.

Other factors affecting choice of drugs include potential side effects, the complexity or simplicity of dosing schedules, age of the patient, child-bearing potential, use of other medication, patient life style and, in some cases, cost.

Seizure type and syndrome. Antiepileptic drugs are relatively specific for certain types of seizures; in some cases, the wrong drug can make seizures worse. The International Classifications of Seizures and Epilepsy provide frameworks on which selection of seizure preventing medications is based. If a syndrome can be diagnosed, the choice of therapy can be narrowed further. One of the cluster of factors that is used to define an epilepsy syndrome is whether it is associated with a specific drug or other form of treatment.

Factors Affecting Choice of Drug:

  • Syndrome
  • Side effects
  • Patient age
  • Lifestyle
  • Childbearing potential
  • Other therapy

Monotherapy or polytherapy. Monotherapy is usually the preferred treatment, with a single drug prescribed in increasing increments until seizures are controlled or toxicity occurs. If the drug is ineffective or side effects are troublesome, the first drug is slowly withdrawn while an alternative is slowly introduced.

Monotherapy has the advantage of reducing the possibility of drug interactions and is usually easier for the patient to comply with. However, some people will require more than one medication to control or reduce their seizures. When this is necessary, no more than one new medication is generally added at a time so that interactions or side effects can be tracked and assigned.

Advantages of Monotherapy:

  • 70-80 percent controlled on monotherapy
  • fewer side effects
  • reduced teratogenicity
  • no drug interactions
  • easier dosing—greater compliance
  • lower cost (possibly

Advantages of Polytherapy

  • may control an additional 20 percent
  • may offer synergistic or add-on effects

Side effects. Like all drugs, epilepsy medicines have side effects. Some are dose-related, and become more likely as the dose increases. Sedation, slurring of speech, and unsteadiness are common effects of antiepileptic drugs at high doses. The condition is usually referred to as toxicity. Similar effects may occur at standard doses at the beginning of treatment and then slowly resolve as the body becomes accustomed to them. Alternatively, if clearance of the drug is compromised by age, illness, or drug interaction, a normal dose may slowly build up to a level which produces these effects.

Side Effect Warning Signs Include:

  • Prolonged fever
  • Rash
  • Severe sore throat
  • Mouth ulcers
  • Easy bruising
  • Pinpoint bleeding
  • Weakness
  • Excessive fatigue
  • Swollen glands
  • Lack of appetite
  • Increased seizures

Other side effects are associated with specific medications, and occur fairly frequently, regardless of dose. Depending on the drug involved, these effects may include double vision, weight gain, hyperactivity (in children), sleep disturbances, irritability, gum dysplasia, hirsutism, and changes in mood. In many cases, side effects occur at the beginning of treatment and may become less troublesome or even disappear as the body adjusts. Starting out at high doses may also increase side effects; these drugs are usually started at gradually increasing doses.

The most common side effects associated with epilepsy medicines are: drowsiness, irritability, nausea, rash, and clumsiness. Some drugs produce changes in emotions, memory or behavior, or affect learning. Occasionally, a drug will increase the number of seizures a person is having.

A third, rarer, type of side effect develops because of individual sensitivity or allergic reaction to a particular drug or drugs. This phenomenon may be termed an idiosyncratic reaction. Potentially fatal liver damage, aplastic anemia, and the severe rash of Stevens Johnson syndrome and related disorders are among the serious reaction group. While studies indicate an elevated risk for some populations and with some drugs (e.g., hepatic failure in young children on sodium valproate polytherapy; aplastic anemia in people taking felbamate; and an increased risk of severe rash in children on lamotrigine), most of the anticonvulsant drugs carry a slim but real risk of such reactions in people who are susceptible to them.

A prudent rule of thumb for parents and individuals on these medications is to be aware of the side effect profiles and to report changes in health, behavior, or mood to their attending physicians. Instances of prolonged fever, rashes, severe sore throat, mouth ulcers, easy bruising or pinpoint bleeding under the skin, weakness, listlessness, swollen glands, or lack of appetite may be signs that serious problems are developing and should be reported to the doctor at once.

None of the currently available antiepileptic drugs is proven safe in pregnancy; trimethadione and paramethadione are the only two known to be contra-indicated in pregnancy; both are older drugs which have now largely disappeared from use. Most of the front line established drugs have the potential to produce birth defects in a limited number of susceptible patients; polytherapy and elevated doses appear to increase the risk.

The most serious of these effects are cleft lip/cleft palate, cardiac abnormalities, and spinal tube defects (spina bifida). Taking folic acid prior to and during pregnancy has been recommended as a protection against spina bifida. A syndrome similar to fetal alcohol syndrome (wide set eyes, low set ears, short upper lip, slight abnormalities in fingers) has also been reported. Despite the elevated risk however, more than 90% of women with epilepsy who become pregnant give birth to normal, healthy babies.

Drug interactions. How well an epilepsy drug works may be affected by other antiepileptic drugs or drugs being taken for a different medical condition, and vice versa. Known as drug interaction, these relationships may involve how the drug is absorbed, metabolized and otherwise distributed in the body. They may, for example, speed up or slow down how quickly an epilepsy drug is eliminated, either making it less effective at preventing seizures (because a lower level is present in the blood) or more likely to build up to toxic levels and cause side effects.

Interactions are sometimes used to manipulate levels in polytherapy; however, the potential for interaction, together with other conditions, can complicate treatment of epilepsy with antiepileptic drugs, and explain the often extended period of trial and error as the physician seeks the right drug at the right dose for each individual patient.

A concern for women is the effect that several of the major antiepileptic drugs have on contraceptive pills, reducing the effectiveness of standard strength products.

Possible Effects of Interaction on Antiepileptic Drugs

  • Changes in absorption in the gastrointestinal tract (for example, antacids retard phenytoin absorption)
  • Alteration in metabolism (the most common and generally most important effect, as coadministered antiepileptic drugs may slow down or increase the speed and efficiency with which the liver processes the drugs)
  • Changes in protein binding resulting in variations in the amount of free drug available to produce a therapeutic effect
  • Potentiation of physiologic or toxic effect at receptor sites
  • Changes in excretion through the kidneys