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 0.8–1.2 g; ELDERLY: reduce initial dose; CHILD: 10–20 mg/kg daily in divided doses. Trigeminal neuralgia, by mouth, ADULT: initially 100 mg 1–2 times daily increased gradually according to response; usual dose 200 mg 3–4 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 2–4 weeks to a usual maintenance dose of 4–8 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 0.5–1 mg daily in divided doses; 1–5 years: initially 250 micrograms increased to 1–3 mg daily in divided doses; 5–12 years: initially 500 micro-grams increased to 3–6 mg daily in divided doses.
Diazepam: Emergency management of recurrent epileptic seizures, by slow intravenous injection (at rate of 5 mg/minute), ADULT: 10–20 mg, repeated if necessary after 30–60 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: 10–20 mg.
Ethosuximide: Absence seizures, by mouth, ADULT and CHILD over 6 years: initially 500 mg daily, increased by 250 mg at intervals of 4–7 days to a usual dose of 1–1.5 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: 2400–4600 mg per day; CHILD: 40–60 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 100–200 mg twice daily. CHILD, by mouth, if added to valproate monotherapy, initial dose 0.5 mg/kg/day, final maintenance dose of 1–5 mg/kg/day. If added to carbamazepine, phenytoin, phenobarbital, or primidone: initial doses 2 mg/kg/day, with subsequent increases to 5–15 mg/kg/day.
Levetiracetam: ADULT: by mouth, 1000–3000 mg/day. CHILD: dosage range not established.
Oxcarbazepine: ADULT: by mouth, 600–2400 mg per day; CHILD: by mouth, 10–30 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: 5–10 mg/kg every 20–30 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: 5–10 mg/kg at a rate of not more than 30 mg/minute.
Phenytoin sodium: Generalized tonic-clonic seizures, partial seizures, by mouth, ADULT: initially 3–4 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 200–500 mg daily; CHILD: initially 5 mg/kg daily in 2 divided doses; usual dose range 4–8 mg/kg daily (maximum 300 mg).
Primidone: ADULT: by mouth, 500–1250 mg per day. CHILD: by mouth, 5–20 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 1–2 g daily (20–30 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 20–30 mg/kg daily); maximum 35 mg/kg daily.
Tiagabine: By mouth, suggested ADULT maintenance dose 32 to 56 mg/day. Dosage titrations of 4–8 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, 100–400 mg/day; CHILD dosage range not established.
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