Antiepileptic Medications PDF

Antiepliptics  Overview 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...

Antiepliptics  Overview 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.  Etiology 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.” Epilepsy can be due to an underlying genetic, structural, or metabolic cause or an unknown cause.  Genetic 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.  Structural/metabolic 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.  Unknown cause 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.  Classification of Seizures 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 (Figure 1). Seizures have been classified into two broad groups: focal and generalized.  A.Focal 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.  A.1.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.  A. 2.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.  B. Generalized 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.  B.1. 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.  B.2. 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.  B.3. 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.  B.4. 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.  B.5. Tonic These seizures involve increased tone in the extension muscles and are generally less than 60 seconds long.  B.6. Atonic These seizures are also known as drop attacks and are characterized by a sudden loss of muscle tone.  Mechanism of action of antiepilepsy medications 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. Antiepilepsy medications suppress seizures but do not “cure” or “prevent” epilepsy.  Drug Selection 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).  Antieplipsy medications A. Benzodiazepines 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 and clobazam may be prescribed as adjunctive therapy for particular types of seizures. Diazepam is also available for rectal administration to avoid or interrupt prolonged generalized tonic–clonic seizures or clusters when oral administration is not possible.  Antieplipsy medications B. Carbamazepine Carbamazepine 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. 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  Antieplipsy medications B. Carbamazepine 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.  Antieplipsy medications C. Eslicarbazepine Eslicarbazepine acetate is a prodrug that is converted to the active metabolite eslicarbazepine (S-licarbazepine) by hydrolysis. S-licarbazepine is the active metabolite of oxcarbazepine. 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.  Antieplipsy medications D. Ethosuximide Ethosuximide 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.  Antieplipsy medications E. Ezogabine Ezogabine 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.  Antieplipsy medications F. Felbamate Felbamate 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.  Antieplipsy medications G. Gabapentin Gabapentin 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.  Antieplipsy medications I. Lamotrigine Lamotrigine 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.  Antieplipsy medications L. Perampanel Perampanel 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.  Antieplipsy medications M. Phenobarbital and primidone The primary mechanism of action of phenobarbital 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.  Antieplipsy medications N. Phenytoin and fosphenytoin Phenytoin 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).  Antieplipsy medications N. Phenytoin and fosphenytoin 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.  Antieplipsy medications N. Phenytoin and fosphenytoin Fosphenytoin 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.  Antieplipsy medications T. Vigabatrin Vigabatrin 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.  Status epilepticus 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.  Women’s health and epilepsy 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 counselled 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.