Antiepileptic Drugs

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Antiepileptic drugs

Definition

Antiepileptic drugs are all drugs used to treat or prevent convulsions, as in epilepsy .

Purpose

Antiepileptic drugs (AEDs) are designed to modify the structures and processes involved in the development of a seizure, including neurons, ion channels, receptors, glia, and inhibitory or excitatory synapses. These processes are modified to favor inhibition over excitation in order to stop or prevent seizure activity.

Description

The ideal AED would suppress all seizures without causing any unwanted side effects. Unfortunately, the drugs currently used not only fail to control seizure activity in some patients, but frequently cause side effects that range in severity from minimal impairment of the central nervous system (CNS) to death from aplastic anemia or liver (hepatic) failure.

Prior to 1993, the choice of an antiepileptic medication was limited to traditional drugs, as phenobarbital , primidone , phenytoin, carbamazepine and valproate. Although these drugs have the advantage of proven efficacy (effectiveness), many patients are left with refractory (break-through) seizures. Since 1993, many new medications have been approved by the United States Food and Drug Administration (FDA), expanding treatment options. The newer AEDs offer the potential advantages of fewer drug interactions, unique mechanisms of action, and a broader spectrum of activity.

The AEDs can be grouped according to their main mechanism of action, although many have several different actions and others work through unknown mechanisms. The main groups include sodium channel blockers, calcium current inhibitors, gamma-aminobutyric acid (GABA) enhancers, glutamate blockers, and drugs with unknown mechanisms of action.

Sodium Channel Blockade

Blocking the sodium channel in the cell membrane is the most common and the most well-characterized mechanism of currently available AEDs. AEDs that target these sodium channels prevent the return of the channels to the active state by stabilizing the inactive form. In doing so, repetitive firing of nerve impulses from the axon of the nerve is prevented. The blockade of sodium channels of nerve axons causes stabilization of the neuronal membranes and limits the development of seizure activity. Sodium channel blocker drugs include: carbamazepine, phenytoin, fosphenytoin, oxcarbazepine, lamotrignine, and zonizamide.

Calcium Current Inhibitors

Calcium channels are small channels in the nerve cell that function as the "pacemakers" of normal rhythmic brain cell activity. Calcium current inhibitors are particularly useful for controlling absence seizures. The drug ethosuximide is a calcium current inhibitor.

GABA Reuptake Inhibitors

GABA reuptake inhibitors boost the levels of GABA, a neurotransmitter, in the brain. Neurotransmitters such as GABA are naturally occurring chemicals that transmit messages from one neuron (nerve cell) to another. When one neuron releases GABA, it normally binds to the next neuron, transmitting information and preventing the transmission of extra electrical activity. When levels of GABA are reduced, there may not be enough GABA to sufficiently bond to the neuron, leading to extra electrical activity in the brain and seizures. Tiagabine works to block GABA from being re-absorbed too quickly into the tissues, thereby increasing the amount available to bind to neurons.

GABA Receptor Agonist

GABA receptor agonists bind with certain cell-surface proteins and produce changes that mimic that action of GABA, thereby reducing excess electrical activity and seizures. Clonazepam, phenobarbital, and primidone are examples of GABA receptor agonist drugs. Some drugs such as valproate enhance the synthesis of GABA, in addition to other potential mechanisms of action, and thus prevent seizures.

Glutamate Blockers

Glutamate and aspartate are the two most important excitatory neurotransmitters in the brain. By blocking glutamate action, the excess electrical activity that causes seizures is controlled. Topiramate and felbamate are examples of glutamate blocker drugs, but their use is limited because they sometimes produce hallucinations and behavior changes.

Recommended dosage

Antiepileptic drugs are usually prescribed in an initial dose, then gradually increased over time until maximum seizure control is achieved with a minimum of side effects. Recommended dosages for specific antiepileptic drugs include:

  • Carbamazepine: In generalized tonic-clonic seizures or partial seizures, by mouth, ADULT: initially 100 mg twice daily, increased gradually according to response to usual maintenance dose of 0.81.2 g; ELDERLY: reduce initial dose; CHILD: 1020 mg/kg daily in divided doses. Trigeminal neuralgia , by mouth, ADULT: initially 100 mg 12 times daily increased gradually according to response; usual dose 200 mg 34 times daily with up to 1.6 g daily.
  • Clonazepam: Epilepsy, by mouth, ADULT: initially 1 mg at night for 4 nights, increased gradually over 24 weeks to a usual maintenance dose of 48 mg daily in divided doses; ELDERLY: initial dose 500 micrograms increased as above; CHILD: up to 1 year initially 250 micrograms increased as above to 0.51 mg daily in divided doses; 15 years: initially 250 micrograms increased to 13 mg daily in divided doses; 512 years: initially 500 micro-grams increased to 36 mg daily in divided doses.
  • Diazepam : Emergency management of recurrent epileptic seizures, by slow intravenous injection (at rate of 5 mg/minute), ADULT: 1020 mg, repeated if necessary after 3060 minutes; may be followed by intravenous infusion to maximum 3 mg/kg over 24 hours; CHILD: 200 to 300 micrograms/kg (or 1 mg per year of age); by rectum as solution, ADULT and CHILD over 10 kg: 500 micrograms/kg; ELDERLY: 250 micrograms/kg; repeated if necessary every 12 hours. Febrile convulsions, by rectum as solution; CHILD over 10 kg: 500 micrograms/kg (maximum 10 mg), with dose repeated if necessary. Seizures associated with poisoning, by slow intravenous injection (at rate of 5 mg/minute), ADULT: 1020 mg.
  • Ethosuximide: Absence seizures, by mouth, ADULT and CHILD over 6 years: initially 500 mg daily, increased by 250 mg at intervals of 47 days to a usual dose of 11.5 g daily (occasionally, up to maximum of 2 g daily); CHILD under 6 years: initially 250 mg daily, increased gradually to usual dose of 20 mg/kg daily.
  • Felbamate: By mouth, ADULT: 24004600 mg per day; CHILD: 4060 mg/kg per day. Optimal individual maintenance doses will be determined by clinical response.
  • Fosphenytoin: For emergency management of repeated seizures, by intravenous injection, 22.5 to 30 mg per kg. For nonemergent therapy, by intravenous injection, 15 to 30 mg per kg, followed by 6 to 12 mg per kg for maintenance therapy.
  • Lamotrigine : ADULT: by mouth, if added to valproate monotherapy, 25 mg daily for two weeks, then 50 mg daily for two weeks, then titrate up to 150 mg twice daily. If added to carbamazepine, phenytoin, phenobarbital, or primidone, initial dose 50 mg twice daily, subsequent increases up to 100200 mg twice daily. CHILD, by mouth, if added to valproate monotherapy, initial dose 0.5 mg/kg/day, final maintenance dose of 15 mg/kg/day. If added to carbamazepine, phenytoin, phenobarbital, or primidone: initial doses 2 mg/kg/day, with subsequent increases to 515 mg/kg/day.
  • Levetiracetam: ADULT: by mouth, 10003000 mg/day. CHILD: dosage range not established.
  • Oxcarbazepine: ADULT: by mouth, 6002400 mg per day; CHILD: by mouth, 1030 mg/kg per day.
  • Phenobarbital: Generalized tonic-clonic seizures, partial seizures, by mouth, ADULT: 60-180 mg at night; CHILD: up to 8 mg/kg daily. Febrile convulsions, by mouth, CHILD: up to 8 mg/kg daily. Neonatal seizures, by intravenous injection (dilute injection 1 in 10 with water for injections), NEWBORN: 510 mg/kg every 2030 minutes up to plasma concentration of 40 mg/liter. By intravenous injection (dilute injection 1 in 10 with water for injections), ADULT: 10 mg/kg at a rate of not more than 100 mg/minute (up to maximum total dose of 1 g); CHILD: 510 mg/kg at a rate of not more than 30 mg/minute.
  • Phenytoin sodium: Generalized tonic-clonic seizures, partial seizures, by mouth, ADULT: initially 34 mg/kg daily (as a single dose or in 2 divided doses), increased gradually by 25 mg at intervals of 2 weeks as necessary (with plasma-phenytoin concentration monitoring); usual dose 200500 mg daily; CHILD: initially 5 mg/kg daily in 2 divided doses; usual dose range 48 mg/kg daily (maximum 300 mg).
  • Primidone: ADULT: by mouth, 5001250 mg per day. CHILD: by mouth, 520 mg/kg per day. Optimal individual maintenance doses will be determined by clinical response.
  • Sodium valproate: Generalized tonic-clonic seizures, partial seizures, absence seizures, atonic seizures; myoclonic seizures, by mouth, ADULT: initially 600 mg daily in 2 divided doses, preferably after food, increased by 200 mg daily at 3-day intervals to maximum of 2.5 g daily in divided doses; usual maintenance dose 12 g daily (2030 mg/kg daily); CHILD: up to 20 kg, initially 20 mg/kg daily in divided doses, may be increased provided plasma concentrations monitored; CHILD over 20 kg: initially 400 mg daily in divided doses, increased until control (usually in range of 2030 mg/kg daily); maximum 35 mg/kg daily.
  • Tiagabine: By mouth, suggested ADULT maintenance dose 32 to 56 mg/day. Dosage titrations of 48 mg/day weekly are suggested by the manufacturer.
  • Topiramate: ADULT: by mouth, 400 mg per day. An initiation schedule, where the medication dose is increased by 50 mg/day each week, is recommended to reduce adverse effects; slower rates of initiation are used by some physicians.
  • Zonisamide: ADULT: by mouth, 100400 mg/day; CHILD dosage range not established.

Precautions

Withdrawal

Treatment is normally continued for a minimum of two years after the last seizure. Withdrawal should be extended over a period of several months, as abrupt withdrawal can lead to complications such as status epilepticus , a serious event where seizures occur rapidly and continuously. Many adult patients relapse once treatment is withdrawn and it may be justified to continue treatment indefinitely, particularly when the patient's livelihood or lifestyle can be endangered by recurrence of a seizure.

Pregnancy and Breast-feeding

Untreated epilepsy during pregnancy may cause harm to the fetus; there is, therefore, no justification for abrupt withdrawal of treatment. Withdrawal of therapy with antiepileptic medications may be an option if the patient has been seizure-free for at least two years. Resumption of treatment may be considered after the first trimester. If antiepileptics are continued in pregnancy, a single medication with the lowest effective dose is preferred, and blood levels of the medication should be monitored. There is an increased risk of birth defects with the use of AEDs, particularly carbamazepine, valproate, and phenytoin. However, if there is good seizure control, many physicians see no advantage in changing pregnant patients' AEDs. In view of the risks of neural tube and other defects, patients who may become pregnant should be informed of the risks and referred for advice, and pregnant patients should be offered counseling and screening. To counteract the risk of neural tube defects, adequate folic acid supplements are advised for women before and during pregnancy. In view of the risk of bleeding associated with carbamazepine, phenobarbital, and phenytoin, prophylactic phytomenadione (vitamin K1) is recommended for the mother before delivery and the newborn. Use of AEDs can often be continued during breastfeeding.

Driving

Regulations are in place in many countries that may restrict driving by patients with epilepsy. Further, AEDs may cause central nervous system depression , particularly in the early stages of treatment. Patients affected by adverse effects such as drowsiness or dizziness should not operate machinery or drive.

Side effects

The most common side effects of therapy with antiepileptic drugs are drowsiness and dizziness. Other drug-specific side effects include:

  • Carbamazepine: Dizziness, double vision, nausea, loss of coordination, and blurred vision.
  • Clonazepam: Sedation, ataxia (loss of coordination), hyperactivity, restlessness, irritability, depression, cardiovascular or respiratory depression. Children and infants may have excess saliva production. Occasionally, tonic seizures may be exacerbated.
  • Diazepam: Drowsiness, dizziness, tiredness, weakness, dry mouth, diarrhea, upset stomach, changes in appetite, restlessness or excitement, constipation, difficulty urinating, frequent urination, blurred vision, changes in sex drive or ability.
  • Ethosuximide: Drowsiness, upset stomach, vomiting, constipation, diarrhea, stomach pain , loss of taste and appetite, weight loss, irritability, mental confusion, depression, insomnia, nervousness, and headache .
  • Felbamate: Insomnia, weight loss, nausea, decreased appetite, dizziness, fatigue , ataxia (loss of coordination), and lethargy.
  • Fosphenytoin: Burning/tingling sensations, groin pain, itching, nausea, dizziness or drowsiness may occur. Serious side effects may occur: mental/mood changes, loss of coordination, rash, eye/vision problems.
  • Lamotrigine: Rash is the main concern associated with this drug. Other commonly reported adverse reactions are headache, blood dyscrasias, ataxia (loss of coordination), double vision, psychosis, tremor, hypersensitivity reactions, and prolonged sleepiness or insomnia.
  • Levetiracetam: Sleepiness, asthenia (loss of strength), dizziness, accidental injury, convulsion, infection, pain, pharyngitis, and a flu-like syndrome.
  • Oxcarbazepine: Sleepiness, headache, dizziness, rash, low blood sodium level, weight gain, and hair loss.
  • Phenobarbital: Thought and behavior alterations, sedation, psychomotor slowing, poor concentration, depression, irritability, ataxia (loss of coordination), and decreased libido.
  • Phenytoin sodium: Ataxia (loss of coordination), abnormal rapid eye movements, drowsiness and lethargy, nausea and vomiting, rash, blood disorders, headaches, vitamin K and folate deficiencies, loss of libido, hormonal dysfunction, and bone marrow suppression.
  • Primidone: Intense sedation, dizziness, and nausea at the onset of treatment.
  • Sodium valproate: Nausea, vomiting, tremor, sedation, confusion or irritability, and weight gain, elevated blood sugar levels, and hair loss or curling of hair.
  • Tiagabine: Dizziness, fatigue, depression, confusion, impaired concentration, speech or language problems, lack of energy, weakness, upset stomach, nervousness, tremor, and stomach pain.
  • Topiramate: Dizziness, sleepiness, ataxia (loss of coordination), confusion, fatigue, decreased sensation in lower extremities, speech difficulties, double vision, impaired concentration, and nausea.
  • Zonizamide: Dizziness, anorexia, headache, ataxia (loss of coordination), confusion, speech abnormalities, mental slowing, irritability, tremor, weight gain, excessive sleepiness, and fatigue.

Interactions

Antiepilectic drugs may be prescribed alone or in combination with other antiepileptic drugs. In general, drugs that cause central nervous system depression, including alcohol, should be used with caution by those taking antiepileptic medications. Many antiepileptic medications also reduce the effectiveness of oral contraceptives (birth control pills). Specific drug interventions include:

  • Carbamazepine: Several drugs, such as macrolide antibiotics (erythromycin and clarithromycin), isoniazid, chloramphenicol, calcium channel blockers, cimetidine, and propoxyphene, inhibit liver enzyme function responsible for the metabolic breakdown of carbamazepine, thereby raising its levels in the blood. Phenobarbital, phenytoin, felbamate, and primidone decrease efficiency of carbamazepine. Toxic symptoms or breakthrough seizures may occur if the dose of carbamazepine is not adjusted. Grapefruit juice and St. John's wort can increase carbamazepine levels. Carbamazepine reduces the effectiveness of tricyclic antidepressants, oral contraceptives, cyclosporin A, and warfarin.
  • Clonazepam: Clonazepam blood levels are decreased by coadministration of enzyme-inducing drugs. No significant clinical interactions have been reported.
  • Diazepam: Diazepam may increase the effects of other drugs that cause drowsiness, including antidepressants, alcohol, antihistamines, sedatives, pain relievers, anxiety medicines, seizure medicines, and muscle relaxants. Antacids may decrease the effects of diazepam.
  • Ethosuximide: Ethosuximide may increase the amount of other antiseizure medications in the blood. Such medications include phenytoin, mephenytoin, and ethotoin. These drugs must be monitored if they are used with ethosuximide to prevent the occurrence of dangerous side effects. Ethosuximide may decrease the level of primidone in the blood, which could lead to a loss of seizure control. Valproic acid may increase or decrease ethosuximide levels and must be used with caution.
  • Felbamate: Felbamate increases blood levels of phenytoin. Adjustments in dosage may be necessary. Its levels are increased by carbamazepine. Felbamate also increases levels of valproic acid in blood.
  • Fosphenytoin: Fosphenytoin has no specific known interactions.
  • Lamotrigine: Levels increase with concomitant use of valproate.
  • Levetiracetam: No significant drug interactions have been identified.
  • Oxcarbazepine: Interacts with oral contraceptives, thereby reducing their efficacy.
  • Phenobarbital: Metabolism of phenobarbital is inhibited by phenytoin sodium, valproate, felbamate, and dextropropoxyphene. Enzyme inducers, such as rifampicin, decrease phenobarbital levels. Because of the potent induction of liver enzymes, phenobarbital increases the metabolism of estrogen, steroids, warfarin, carbamazepine, diazepam, clonazepam, and valproate.
  • Phenytoin sodium: Among all AEDs, phenytoin sodium has one of the most problematic drug interaction profiles. Carbamazepine and phenobarbital have variable and unpredictable effects (i.e., increase or decrease) on phenytoin sodium levels. Valproate raises levels of phenytoin sodium by displacing phenytoin sodium from its protein-binding site and inhibiting its metabolism. Other drugs that significantly increase phenytoin sodium levels are isoniazid, cimetidine, chloramphenicol, dicumarol, and sulfonamides. Drugs that lower phenytoin sodium levels are vigabatrin and amiodarone. Phenytoin sodium itself is a strong inducer of liver enzymes and alters levels of other drugs. It decreases levels of carbamazepine, ethosuximide, felbamate, primidone, tiagabine, and phenobarbital. It inhibits dicumarol, warfarin, and corticosteroids; clotting factors and immunosuppression must be monitored and doses adjusted accordingly. Other drugs whose levels are reduced by phenytoin sodium and require monitoring and adjustment include furosemide, cyclosporin, folate, and praziquantel. Levels of chloramphenicol and quinidine are elevated by phenytoin sodium.
  • Primidone: Primidone interacts with most other AEDs. Acetazolamide , carbamazepine, ethosuximide, and methsuximide may all decrease the effects of primidone, and larger primidone doses may be necessary. Phenytoin, ethotoin, mephenytoin, and isoniazid may increase blood levels of primidone, and an adjustment of primidone dosage may be necessary. Carbamazepine blood levels may be higher during therapy with primidone, and an adjustment of the carbamazepine dosage may also be necessary.
  • Sodium valproate: Increases plasma levels of free fractions of phenytoin sodium, phenobarbital, carbamazepine epoxide, and lamotrigine. It decreases total phenytoin sodium level. The levels of sodium valproate are decreased by enzyme-inducing drugs and are increased by felbamate and clobazam.
  • Tiagabine: Causes a small decrease in valproate levels. Hepatic-inducing drugs increase the clearance of tiagabine by two thirds. Drug plasma concentrations are not affected by valproate, cimetidine, or erythromycin.
  • Topiramate: Enzyme-inducing drugs, such as phenytoin sodium or carbamazepine, decrease topiramate concentrations in the blood by approximately 50%. Topiramate generally does not affect the steady-state concentrations of the other drugs given in polytherapy, although phenytoin sodium levels may rise occasionally. Topiramate reduces ethyl estradiol levels by 30% and may inactivate the low-dose contraceptive pill. It may cause a mild reduction in digoxin levels.
  • Zonisamide: Phenytoin sodium, carbamazepine, pheno-barbital, and valproic acid reduce levels of zonizamide in the blood; however, zonizamide does not affect the levels of these drugs.

Resources

BOOKS

Hardman, Joel Greiffith, Lee E. Limbird, and Alfred G. Gilman. Goodman & Gilman's The Pharmacological Basis of Therapeutics. New York: McGraw-Hill Professional, 2001.

PERIODICALS

LaRoche, S., and S. Helmers. "The New Antiepileptic Drugs." JAMA 291 (2004): 605614.

OTHER

"Antiepileptic Drugs: An Overview." eMedicine. <http://www.emedicine.com/neuro/topic692.htm> (April 26, 2004).

"Seizure Medicines." Epilepsy.com. <http://www.epilepsy.com/epilepsy/seizure_medicines.html> (April 26, 2004).

ORGANIZATIONS

The Epilepsy Foundation. 4351 Garden City Drive, Landover, MD 20785-7223. (800) 332-1000. <http://www.epilepsyfoundation.org/

U.S. Food and Drug Administration. 5600 Fishers Lane, Rockville, MD 20857. (888) 463-6332. <http://www.fda.gov>.

Greiciane Gaburro Paneto

Iuri Drumond Louro, M.D., Ph.D.

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