NCLEX: Drugs for Epilepsy

Approximately 10% of the population will have at least one seizure in their lifetime. Globally, epilepsy is the third most common neurologic disorder after cerebrovascular and Alzheimer’s disease. Epilepsy is not a single entity but an assortment of different seizure types and syndromes originating from several mechanisms that have in common the sudden, excessive, and synchronous discharge of cerebral neurons.

This abnormal electrical activity may result in a variety of events, including loss of consciousness, abnormal movements, atypical or odd behavior, and distorted perceptions that are of limited duration but recur if untreated. The site of origin of the abnormal neuronal firing determines the symptoms that are produced. For example, if the motor cortex is involved, the patient may experience abnormal movements or a generalized convulsion.

Seizures originating in the parietal or occipital lobe may include visual, auditory, and olfactory hallucinations. Medications are the most widely used mode of treatment for patients with epilepsy. In general, seizures can be controlled with one medication in approximately 75% of patients. Patients may require more than one medication in order to optimize seizure control, and some patients may never obtain total seizure control.


Drugs for Epilepsy


Drugs for Epilepsy: ETIOLOGY OF SEIZURES

Focus topic: Drugs for Epilepsy

In most cases, epilepsy has no identifiable cause. Focal areas that are functionally abnormal may be triggered into activity by changes in physiologic factors, such as an alteration in blood gases, pH, electrolytes, and blood glucose and changes in environmental factors, such as sleep deprivation, alcohol intake, and stress. The neuronal discharge in epilepsy results from the firing of a small population of neurons in a specific area of the brain referred to as the “primary focus.”.

Neuroimaging techniques, such as magnetic resonance imaging, positron emission tomography scans, and single photon emission coherence tomography, may identify areas of concern. Epilepsy can be due to an underlying genetic, structural, or metabolic cause or an unknown cause. Though multiple specific epilepsy syndromes that include symptoms other than seizures have been classified, a discussion of these syndromes is beyond the scope of this chapter.

A. Genetic epilepsy

Focus topic: Drugs for Epilepsy

These seizures result from an inherited abnormality in the central nervous system (CNS). Some genetic mutations have been identified in epilepsy syndromes. Obtaining a detailed family history may provide important information for assessing the possibility of a genetic link to seizures.

B. Structural/metabolic epilepsy

Focus topic: Drugs for Epilepsy

A number of causes, such as illicit drug use, tumor, head injury, hypoglycemia, meningeal infection, and the rapid withdrawal of alcohol from an alcoholic, can precipitate seizures. In cases when the cause of a seizure can be determined and corrected, medication may not be necessary. For example, a seizure that is caused by a drug reaction is not epilepsy and does not require chronic therapy. In other situations, antiepilepsy medications may be needed when the primary cause of the seizures cannot be corrected.

C. Unknown cause

Focus topic: Drugs for Epilepsy

When no specific anatomic cause for the seizure, such as trauma or neoplasm, is evident, a patient may be diagnosed with seizures where the underlying cause is unknown. Most cases of epilepsy are due to an unknown cause. Patients can be treated chronically with antiepilepsy medications or vagal nerve stimulation.


Drugs for Epilepsy



Focus topic: Drugs for Epilepsy

It is important to correctly classify seizures to determine appropriate treatment. Seizures have been categorized by site of origin, etiology, electrophysiologic correlation, and clinical presentation. The nomenclature developed by the International League Against Epilepsy is considered the standard way to classify seizures and epilepsy syndromes. Seizures have been classified into two broad groups: focal and generalized.

A. Focal

Focus topic: Drugs for Epilepsy

Focal seizures involve only a portion of the brain, typically part of one lobe of one hemisphere. The symptoms of each seizure type depend on the site of neuronal discharge and on the extent to which the electrical activity spreads to other neurons in the brain. Focal seizures may progress to become generalized tonic–clonic seizures.

  • Simple partial: These seizures are caused by a group of hyperactive neurons exhibiting abnormal electrical activity and are confined to a single locus in the brain. The electrical discharge does not spread, and the patient does not lose consciousness or awareness. The patient often exhibits abnormal activity of a single limb or muscle group that is controlled by the region of the brain experiencing the disturbance. The patient may also show sensory distortions. This activity may spread. Simple partial seizures may occur at any age.
  • Complex partial: These seizures exhibit complex sensory hallucinations and mental distortion. Motor dysfunction may involve chewing movements, diarrhea, and/or urination. Consciousness is altered. Simple partial seizure activity may spread to become complex and then spread to a secondarily generalized convulsion. Complex partial seizures may occur at any age.


Drugs for Epilepsy


B. Generalized

Focus topic: Drugs for Epilepsy

Generalized seizures may begin locally and then progress to include abnormal electrical discharges throughout both hemispheres of the brain. Primary generalized seizures may be convulsive or nonconvulsive, and the patient usually has an immediate loss of consciousness.

  • Tonic–clonic: These seizures result in loss of consciousness, followed by tonic (continuous contraction) and clonic (rapid contraction and relaxation) phases. The seizure may be followed by a period of confusion and exhaustion due to the depletion of glucose and energy stores.
  • Absence: These seizures involve a brief, abrupt, and self limiting loss of consciousness. The onset generally occurs in patients at 3 to 5 years of age and lasts until puberty or beyond. The patient stares and exhibits rapid eye-blinking, which lasts for 3 to 5 seconds. An absence seizure has a very distinct three-per-second spike and wave discharge seen on electroencephalogram.
  • Myoclonic: These seizures consist of short episodes of muscle contractions that may recur for several minutes. They generally occur after wakening and exhibit as brief jerks of the limbs. Myoclonic seizures occur at any age but usually begin around puberty or early adulthood.
  • Clonic: These seizures consist of short episodes of muscle contractions that may closely resemble myoclonic seizures. Consciousness is more impaired with clonic seizures as compared to myoclonic.
  • Tonic: These seizures involve increased tone in the extension muscles and are generally less than 60 seconds long.
  • Atonic: These seizures are also known as drop attacks and are characterized by a sudden loss of muscle tone.

C. Mechanism of action of antiepilepsy medications

Focus topic: Drugs for Epilepsy

Drugs reduce seizures through such mechanisms as blocking voltage-gated channels (Na+ or Ca2+), enhancing inhibitory γ-aminobutyric acid (GABA)-ergic impulses and interfering with excitatory glutamate transmission. Some antiepilepsy medications appear to have multiple targets within the CNS, whereas the mechanism of action for some agents is poorly defined. Antiepilepsy medications suppress seizures but do not “cure” or “prevent” epilepsy.

Drugs for Epilepsy: DRUG SELECTION

Focus topic: Drugs for Epilepsy

Choice of drug treatment is based on the classification of the seizures, patient-specific variables (for example, age, comorbid medical conditions, lifestyle, and personal preference), and characteristics of the drug (such as cost and drug interactions). For example, focal-onset seizures are treated with a different set of medications than primary generalized seizures, although the list of effective agents overlaps.

The toxicity of the agent and characteristics of the patient are major considerations in drug selection. In newly diagnosed patients, monotherapy is instituted with a single agent until seizures are controlled or toxicity occurs. Compared to those receiving combination therapy, patients receiving monotherapy exhibit better medication adherence and fewer side effects.

If seizures are not controlled with the first medication, monotherapy with an alternate medication or the addition of medications should be considered. Failing that, other medical management (vagal nerve stimulation, surgery, etc.) should be considered. Awareness of the antiepilepsy medications available and their mechanisms of action, pharmacokinetics, potential for drug–drug interactions, and adverse effects is essential for successful treatment of the patient.


Drugs for Epilepsy



Focus topic: Drugs for Epilepsy

During the past 20 years, the Food and Drug Administration has approved many new antiepilepsy medications. Some of these agents are thought to have potential advantages over drugs approved prior to 1990 in terms of pharmacokinetics, tolerability, and reduced risk for drug–drug interactions. However, studies have failed to demonstrate that the newer drugs are significantly more efficacious than the older agents. For that reason, the antiepilepsy medications are described below in alphabetical order, rather than attempting to rank them by efficacy. Suicidal behavior and suicidal ideation have been identified as a risk with antiepilepsy medications. In addition, virtually, all antiepilepsy medications have been associated with multiorgan hypersensitivity reactions, a rare idiosyncratic reaction characterized by rash, fever, and systemic organ involvement.

A. Benzodiazepines

Focus topic: Drugs for Epilepsy

Benzodiazepines bind to GABA inhibitory receptors to reduce firing rate. Most benzodiazepines are reserved for emergency or acute seizure treatment due to tolerance. However, clonazepam [kloe-NAY-zepam] and clobazam [KLOE-ba-zam] may be prescribed as adjunctive therapy for particular types of seizures. Diazepam [dye-AZ-e-pam] is also available for rectal administration to avoid or interrupt prolonged generalized tonic–clonic seizures or clusters when oral administration is not possible.


Drugs for Epilepsy

Drugs for Epilepsy


B. Carbamazepine

Focus topic: Drugs for Epilepsy

Carbamazepine [kar-ba-MAZ-a-peen] blocks sodium channels, thereby inhibiting the generation of repetitive action potentials in the epileptic focus and preventing their spread. Carbamazepine is effective for treatment of focal seizures and, additionally generalized tonic–clonic seizures, trigeminal neuralgia, and bipolar disorder. Carbamazepine is absorbed slowly and erratically following oral administration and may vary from generic to generic, resulting in large variations in serum concentrations of the drug.

It induces its own metabolism, resulting in lower total carbamazepine blood concentrations at higher doses. Carbamazepine is an inducer of the CYP1A2, CYP2C, and CYP3A and UDP glucuronosyltransferase (UGT) enzymes, which increases the clearance of other drugs. Hyponatremia may be noted in some patients, especially the elderly, and may necessitate a change in medication. Carbamazepine should not be prescribed for patients with absence seizures because it may cause an increase in seizures.

C. Eslicarbazepine

Focus topic: Drugs for Epilepsy

Eslicarbazepine [es-li-kar-BAZ-a-peen] acetate is a prodrug that is converted to the active metabolite eslicarbazepine (S-licarbazepine) by hydrolysis. S-licarbazepine is the active metabolite of oxcarbazepine (see below). It is a voltage-gated sodium channel blocker and is approved for partial-onset seizures in adults. Eslicarbazepine exhibits linear pharmacokinetics and is eliminated via glucuronidation. The side effect profile includes dizziness, somnolence, diplopia, and headache. Serious adverse reactions such as rash, psychiatric side effects, and hyponatremia occur rarely.

D. Ethosuximide

Focus topic: Drugs for Epilepsy

Ethosuximide [eth-oh-SUX-i-mide] reduces propagation of abnormal electrical activity in the brain, most likely by inhibiting T-type calcium channels. It is only effective in treating absence seizures.

E. Ezogabine

Focus topic: Drugs for Epilepsy

Ezogabine [e-ZOG-a-been] is thought to open voltage-gated M-type potassium channels leading to stabilization of the resting membrane potential. Ezogabine exhibits linear pharmacokinetics and no drug interactions at lower doses. Possible unique side effects are urinary retention, QT interval prolongation, blue skin discoloration, and retinal abnormalities.

F. Felbamate

Focus topic: Drugs for Epilepsy

Felbamate [FEL-ba-mate] has a broad spectrum of anticonvulsant action with multiple proposed mechanisms including the blocking of voltage-dependent sodium channels, competing with the glycine coagonist binding site on the N-methyl-d-aspartate (NMDA) glutamate receptor, blocking of calcium channels, and potentiating GABA action. It is an inhibitor of drugs metabolized by CYP2C19 and induces drugs metabolized by CYP3A4. It is reserved for use in refractory epilepsies (particularly Lennox-Gastaut syndrome) because of the risk of aplastic anemia (about 1:4000) and hepatic failure.

G. Gabapentin

Focus topic: Drugs for Epilepsy

Gabapentin [GA-ba-pen-tin] is an analog of GABA. However, it does not act at GABA receptors, enhance GABA actions or convert to GABA. Its precise mechanism of action is not known. It is approved as adjunct therapy for focal seizures and treatment of postherpetic neuralgia. Gabapentin exhibits nonlinear pharmacokinetics due to its uptake by a saturable transport system from the gut. Gabapentin does not bind to plasma proteins and is excreted unchanged through the kidneys. Reduced dosing is required in renal disease. Gabapentin is well tolerated by the elderly population with partial seizures due to its relatively mild adverse effects. It may also be a good choice for the older patient because there are few drug interactions.


Drugs for Epilepsy

Drugs for Epilepsy


H. Lacosamide

Lacosamide [la-KOE-sa-mide] in vitro affects voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. Lacosamide binds to collapsin response mediator protein-2 (CRMP-2), a phosphoprotein involved in neuronal differentiation and control of axonal outgrowth. The role of CRMP-2 binding in seizure control is unknown. Lacosamide is approved for adjunctive treatment of focal seizures. It is available in an injectable formulation. The most common adverse events that limit treatment include dizziness, headache, and fatigue.

I. Lamotrigine

Lamotrigine [la-MOE-tri-jeen] blocks sodium channels, as well as high voltage-dependent calcium channels. Lamotrigine is effective in a wide variety of seizure types, including focal, generalized, absence seizures, and Lennox-Gastaut syndrome. It is also used to treat bipolar disorder. Lamotrigine is metabolized primarily to the 2-N-glucuronide metabolite through the UGT1A4 pathway.

As with other antiepilepsy medications, general inducers increase lamotrigine clearance leading to lower lamotrigine concentrations, whereas divalproex results in a significant decrease in lamotrigine clearance (higher lamotrigine concentrations). Lamotrigine dosages should be reduced when adding valproate to therapy. Slow titration is necessary with lamotrigine (particularly when adding lamotrigine to a regimen that includes valproate) due to risk of rash, which may progress to a serious, life-threatening reaction.

J. Levetiracetam

Levetiracetam [lee-ve-tye-RA-se-tam] is approved for adjunct therapy of focal onset, myoclonic, and primary generalized tonic–clonic seizures in adults and children. The exact mechanism of anticonvulsant action is unknown. It demonstrates high affinity for a synaptic vesicle protein (SV2A). The drug is well absorbed orally and excreted in urine mostly unchanged, resulting in few to no drug interactions. Levetiracetam can cause mood alterations that may require a dose reduction or a change of medication.

K. Oxcarbazepine

Oxcarbazepine [ox-kar-BAY-zeh-peen] is a prodrug that is rapidly reduced to the 10-monohydroxy (MHD) metabolite responsible for its anticonvulsant activity. MHD blocks sodium channels, preventing the spread of the abnormal discharge. It is also thought to modulate calcium channels. It is approved for use in adults and children with partial-onset seizures. Oxcarbazepine is a less potent inducer of CYP3A4 and UGT than carbamazepine. The adverse effect of hyponatremia limits its use in the elderly.

L. Perampanel

Perampanel [per-AM-pa-nel] is a selective α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid antagonist resulting in reduced excitatory activity. Perampanel has a long half-life enabling once-daily dosing. It is approved for adjunctive treatment of partial-onset seizures in patients 12 years or older. Perampanel is a newer antiepileptic agent, and limited data are available in patients.

M. Phenobarbital and primidone

The primary mechanism of action of phenobarbital [fee-noe-BARbih-tal] is enhancement of the inhibitory effects of GABA-mediated neurons. Primidone is metabolized to phenobarbital (major) and phenylethylmalonamide, both with anticonvulsant activity. Phenobarbital is used primarily in the treatment of status epilepticus when other agents fail.


Drugs for Epilepsy


N. Phenytoin and fosphenytoin

Phenytoin [FEN-i-toin] blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and slowing its rate of recovery. It is effective for treatment of focal and generalized tonic– clonic seizures and in the treatment of status epilepticus. Phenytoin induces drugs metabolized by the CYP2C and CYP3A families and the UGT enzyme system. Phenytoin exhibits saturable enzyme metabolism resulting in nonlinear pharmacokinetic properties (small increases in the daily dose can produce large increases in plasma concentration, resulting in drug-induced toxicity.

Depression of the CNS occurs particularly in the cerebellum and vestibular system, causing nystagmus and ataxia. The elderly are highly susceptible to this effect. Gingival hyperplasia may cause the gums to grow over the teeth. Long-term use may lead to development of peripheral neuropathies and osteoporosis. Although phenytoin is advantageous due to its low cost, the actual cost of therapy may be much higher, considering the potential for serious toxicity and adverse effects.

Fosphenytoin [FOS-phen-i-toin] is a prodrug that is rapidly converted to phenytoin in the blood within minutes. Whereas fosphenytoin may be administered intramuscularly (IM), phenytoin sodium should never be given IM, as it causes tissue damage and necrosis. Fosphenytoin is the drug of choice and standard of care for IV and IM administration of phenytoin. Because of sound-alike and look-alike trade names, there is a risk for prescribing errors. The trade name of fosphenytoin is Cerebyx®, which is easily confused with Celebrex®, the cyclooxygenase- 2 inhibitor, and Celexa®, the antidepressant.


Drugs for Epilepsy



O. Pregabalin

Pregabalin [pree-GA-ba-lin] binds to the α2-δ site, an auxiliary subunit of voltage-gated calcium channels in the CNS, inhibiting excitatory neurotransmitter release. The exact role this plays in treatment is not known, but the drug has proven effects on focal-onset seizures, diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia. More than 90% of pregabalin is eliminated renally. Dosage adjustments are needed in renal dysfunction. It has no significant metabolism and few drug interactions. Weight gain and peripheral edema have been reported.

P. Rufinamide

Rufinamide [roo-FIN-a-mide] acts at sodium channels. It is approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children over age 4 years and in adults. Rufinamide is a weak inhibitor of CYP2E1 and a weak inducer of CYP3A4 enzymes. Food increases absorption and peak serum concentrations. Serum concentrations of rufinamide are affected by other antiepilepsy medications. As with other antiepilepsy medications, it is induced by carbamazepine and phenytoin and inhibited when given with valproate. Adverse effects include the potential for shortened QT intervals. Patients with familial short QT syndrome should not be treated with rufinamide.

Q. Tiagabine

Tiagabine [ty-AG-a-been] blocks GABA uptake into presynaptic neurons permitting more GABA to be available for receptor binding, and therefore, it enhances inhibitory activity. Tiagabine is effective as adjunctive treatment in partial-onset seizures. In post-marketing surveillance, seizures have occurred in patients using tiagabine who did not have epilepsy. Tiagabine should not be used for indications other than epilepsy.

R. Topiramate

Topiramate [toe-PEER-a-mate] has multiple mechanisms of action. It blocks voltage-dependent sodium channels, reduces high-voltage calcium currents (L type), is a carbonic anhydrase inhibitor, and may act at glutamate (NMDA) sites. Topiramate is effective for use in partial and primary generalized epilepsy. It is also approved for prevention of migraine. It inhibits CYP2C19 and is induced by phenytoin and carbamazepine. Adverse effects include somnolence, weight loss, and paresthesias. Renal stones, glaucoma, oligohidrosis (decreased sweating), and hyperthermia have also been reported.

S. Valproic acid and divalproex

Focus topic: Drugs for Epilepsy

Possible mechanisms of action include sodium channel blockade, blockade of GABA transaminase, and action at the T-type calcium channels. These varied mechanisms provide a broad spectrum of activity against seizures. It is effective for the treatment of focal and primary generalized epilepsies. Valproic acid [val-PRO-ik A-sid] is available as a free acid. Divalproex [dye-val-PRO-ex] sodium is a combination of sodium valproate [val-PROE-ate] and valproic acid that is converted to valproate when it reaches the gastrointestinal tract.

It was developed to improve gastrointestinal tolerance of valproic acid. All of the available salt forms are equivalent in efficacy (valproic acid and sodium valproate). Commercial products are available in multiple- salt dosage forms and extended-release formulations. Therefore, the risk for medication errors is high, and it is essential to be familiar with all preparations. Valproate inhibits metabolism of the CYP2C9, UGT, and epoxide hydrolase systems. Rare hepatotoxicity may cause a rise in liver enzymes, which should be monitored frequently. Teratogenicity is also of great concern.

T. Vigabatrin

Focus topic: Drugs for Epilepsy

Vigabatrin [vye-GA-ba-trin] acts as an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T). GABA-T is the enzyme responsible for metabolism of GABA. Vigabatrin is associated with visual field loss ranging from mild to severe in 30% or more of patients. Vigabatrin is only available through physicians and pharmacies that participate in the restricted distribution SHARE program.

U. Zonisamide

Focus topic: Drugs for Epilepsy

Zonisamide [zoe-NIS-a-mide] is a sulfonamide derivative that has a broad spectrum of action. The compound has multiple effects, including blockade of both voltage-gated sodium channels and T-type calcium currents. It has a limited amount of carbonic anhydrase activity. Zonisamide is approved for use in patients with focal epilepsy. It is metabolized by the CYP3A4 isozyme and may, to a lesser extent, be affected by CYP3A5 and CYP2C19. In addition to typical CNS adverse effects, zonisamide may cause kidney stones. Oligohidrosis has been reported, and patients should be monitored for increased body temperature and decreased sweating. Zonisamide is contraindicated in patients with sulfonamide or carbonic anhydrase inhibitor hypersensitivity.


Focus topic: Drugs for Epilepsy

In status epilepticus, two or more seizures occur without recovery of full consciousness in between episodes. These may be focal or primary generalized, convulsive or nonconvulsive. Status epilepticus is life threatening and requires emergency treatment usually consisting of administration of a fast-acting medication such as a benzodiazepine, followed by a slower-acting medication such as phenytoin.


Focus topic: Drugs for Epilepsy

Women of childbearing potential with epilepsy require assessment of their antiepilepsy medications in regard to contraception and pregnancy planning. Several antiepilepsy medications increase the metabolism of hormonal contraceptives, potentially rendering them ineffective. These include phenytoin, phenobarbital, carbamazepine, topiramate, oxcarbazepine, rufinamide, and clobazam. These medications increase the metabolism of contraceptives regardless of the delivery system used (for example, patch, ring, implants, and oral tablets). Pregnancy planning is vital, as many antiepilepsy medications have the potential to affect fetal development and cause birth defects.

All women considering pregnancy should be on high doses (1 to 5 mg) of folic acid prior to conception. Divalproex and barbiturates should be avoided. If possible, women already taking divalproex should be placed on other therapies prior to pregnancy and counseled about the potential for birth defects, including cognitive and behavioral abnormalities and neural tube defects. The pharmacokinetics of antiepilepsy medications and the frequency and severity of seizures may change during pregnancy. Regular monitoring by both an obstetrician and a neurologist is important. All women with epilepsy should be encouraged to register with the Antiepileptic Drug Pregnancy Registry.


Drugs for Epilepsy

Drugs for Epilepsy




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