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EPILEPSY Epilepsy is a chronic brain disorder of various etiologies characterized by recurrent, unprovoked seizures. Traditionally, patients with single or only provoked seizures are not considered to have epilepsy. Epilepsy is not a single disease but is divided into various epileptic syndromes. Epileptic syndromes are groups of epileptic patterns, consisting of one or more seizure types. Convulsions are seizures with prominent motor activity (eg, generalized tonic-clonic seizures). Seizures may also be nonconvulsive, manifested only by altered consciousness (eg, absence or complex partial seizures). A seizure may be defined as a periodic attack of disturbed cerebral function due to disturbance in the electrical activity in one or more areas of the brain. Seizures may be classified as partial (focal) or generalized. Each different type of seizure disorder is characterized by a specific pattern of events, as well as a different pattern of motor or sensory SEIZURE TYPE FEATURES Partial seizures: Simple partial The region of cortex activated by the seizure (e.g., if motor cortex representing left thumb, clonic jerking of left thumb results; if somatosensory cortex representing left thumb, paresthesia of left thumb results), lasting approximating 20 to 60 seconds. Key feature is preservation of consciousness. Complex partial Impaired consciousness lasting 30 seconds to 2 minutes, often associated with purposeless movements such as lip smacking or hand wringing. Partial with secondarily generalized tonic- Simple or complex partial seizure evolves clonic seizure into a tonic-clonic seizure with loss of consciousness and sustained contractions (tonic) of muscles throughout the body followed by periods of muscle contraction alternating with periods of relaxation (clonic), Generalized seizures: Absence seizure Myoclonic seizure Tonic-clonic seizure Abrupt onset of impaired consciousness associated with staring and cessation of ongoing activities typically lasting less than 30 seconds. A brief (perhaps a second), shock-like contraction of muscles which may be restricted to part of one extremity or may be generalized. As described above for partial with secondarily generalized tonic-clonic seizures except that it is not preceded by a partial seizure. In contrast to partial seizures, which arise from localized regions of the cerebral cortex, generalized- seizures arise from the reciprocal firing of the thalamus and cerebral cortex ETIOLOGY Seizure disorders are generally categorized as idiopathic or acquired. Idiopathic seizures have no known cause. Acquired seizure disorders have a known cause, including high fever, electrolyte imbalances, uremia, hypoglycemia, hypoxia, brain tumors. Once the cause is removed (if it can be removed), the seizures theoretically cease. The known causes of epilepsy include brain injury at birth, head injuries, and inborn errors of metabolism. In some patients, the cause of epilepsy may be genetic basis. Familial epilepsy usually presents as childhood onset epilepsy without evidence of underlying brain disease. A genetic basis is more likely in patients with generalized rather than partial epilepsies. The genetic defects cause abnormalities of ion channels and/or key structural membrane proteins. Meningitis, encephalitis including herpes simplex, abscess, cysticercosis, toxoplasmosis, rubella, neurosyphilis, tuberculosis. MECHANISM The pivotal role of synapses in mediating communication among neurons in the mammalian brain suggested that defective synaptic function might lead to a seizure. That is, a reduction of inhibitory synaptic activity or enhancement of excitatory synaptic activity might be expected to trigger a seizure; The neurotransmitters mediating the bulk of synaptic transmission in the mammalian brain are amino acids, with Gama -aminobutyric acid (GABA) and glutamate being the neurotransmitters, respectively principal inhibitory and excitatory Generally, anticonvulsants reduce the excitability of the neurons (nerve cells) of the brain. When neuron excitability is decreased, seizures are theoretically reduced in intensity and frequency of occurrence or, in some instances, are virtually eliminated. For some patients, only partial control of the seizure disorder may be obtained with anticonvulsant drug therapy. THERAPEUTIC ASPECTS The ideal antiseizure drug would suppress all seizures without causing any unwanted effects. The drugs used currently not only fail to control seizure activity in some patients, but frequently cause unwanted effects that range in severity from minimal impairment of the CNS to death from aplastic anemia or hepatic failure. The clinician who treats patients with epilepsy is thus faced with the task of selecting the appropriate drug or combination of drugs that best controls seizures in an individual patient at an acceptable level of untoward effects. The degree of success varies as a function of seizure type, cause, and other factors. To minimize toxicity, treatment with a single drug is preferred. If seizures are not controlled with the initial agent at adequate plasma concentrations, substitution of a second drug is preferred to the concurrent administration of another agent. However, multiple-drug therapy may be required, especially when two or more types of seizure occur in the same patient. Measurement of drug concentrations in plasma optimizing antiseizure medication, especially when facilitates The event of therapeutic failure, Toxic effects appear, or Multiple-drug therapy is instituted. Clinical effects of some drugs do not correlate well with their concentrations in plasma, and recommended concentrations are only guidelines for therapy. The ultimate therapeutic regimen must be determined by clinical assessment of effect and toxicity. The general principles of the drug therapy of the epilepsies are summarized below. CHEMICALSUMMARY CLASSIFICATION AND CLINICAL USES DRUG TABLE CLINICAL ASPECTS OF ANTI EPILEPTIC DRUGS AVAILABLE IN INDIA Mechanism of action of anticonvulsant drugs that act on sodium channels. The sodium channel can normally exist in a closed (A), open (B), or inactivated (C) state. A. An activation gate is closed and sodium ions cannot pass through the channel. B. The channel activation gate opens rapidly following depolarization and sodium enters freely. Soon after opening, an inactivation gate (C) closes, preventing further entry of sodium ions into the cell. Drugs sharing carbamazepine this mechanism include (Tegretol), oxcarbazepine phenytoin (Dilantin), (Trileptal), topiramate (Topamax), valproic acid (Depakene), zonisamide (Zonegran), and lamotrigine (Lamictal). All of these agents have the capacity to block sustained highfrequency repetitive firing (SRF) of action potentials. This is accomplished by reducing the amplitude of sodium- dependent action potentials through an enhancement of steady-state inactivation. CARBAMAZEPINE PHARMACOLOGY AND MECHANISM OF ACTION The exact mechanism by which carbamazepine suppresses seizure spread is obscure, although it is believed to act primarily through inhibition of voltage gated sodium channels. In addition, interaction with voltage-gated calcium and potassium channels can also contribute to its activity. Pharmacokinetics The absorption of carbamazepine from immediate- release tablets is slow and erratic because of its low watersolubility. No first-pass metabolism. Fat, may enhance the bioavailability of carbamazepine. The suspension dosage form is absorbed faster than the tablets. Compared with immediate-release carbamazepine, both these formulations have decrease side effects and improve seizure control. The enzyme-induction effect begins within 3 to 5 days of the initiation of therapy and takes 21 to 28 days to complete. Carbamazepine also displays diurnal variation in its serum level with the evening level lower than the morning level. Adverse Effects Side effects of carbamazepine can fluctuate daily, paralleling the rise and decline of serum concentrations. Neurosensory side effects (e.g., diplopia, blurred vision, nystagmus, ataxia, unsteadiness, dizziness, and headache) are the most common, occurring in 35% to 50% of patients. These side effects are more common during initiation of therapy and can dissipate with continued treatment. Carbamazepine can also cause nausea, which can either be caused by a local effect of the drug on the GI tract, in which case food may help, or caused by an effect on the brainstem, which may ultimately require discontinuation of the drug. Drug Interactions Because of concentration-dependent efficacy and side effects, drug interactions with carbamazepine often are very significant. Drugs that inhibit CYP 3A4 potentially may increase carbamazepine Serum Conc Dosage manipulation, including the use of the controlled- or sustained-release preparations, should be tried before the patient is considered to be intolerant of carbamazepine. Leukopenia is the most common hematologic side effect. Leukopenia usually is transient, even when the drug is continued, and can be caused by a redistribution of white blood cells (WBCs) rather than a decrease in their production. In about 2% of patients, the leukopenia is persistent, but even patients with WBC counts of 3,000/mm3 or less do not seem to have an increased incidence of infection. A clinical guide is to continue carbamazepine therapy unless the WBC count drops to less than 2,500/mm3 and the absolute neutrophil Carbamazepine can cause hyponatremia, the incidence of which count drops to less than 1,000/mm3. increases with age, however, its occurrence is lower than that seen with oxcarbazepine. Periodic determinations of serum sodium concentration are Dosing and Administration The variable contributions of the 10,11-epoxide metabolite and freecarbamazepine concentrations have restricted a precise definition of the therapeutic range. Loading doses of carbamazepine are indicated only for critically ill patients. During dosage titration, it should be remembered that carbamazepine clearance increases with time. Doses may be started at onefourth to one-third the anticipated maintenance dose and increased every 2 to 3 weeks. Because of the auto- and heteroinduction of carbamazepine metabolism, it is necessary to administer the drug two to four times per day. The controlled- and sustained release formulations provide fewer peak-to-trough fluctuations, which can improve adherence, reduce side effects, and improve seizure control. Carbamazepine tablets should not be stored in places where they would be exposed to high heat and high humidity. Advantages Carbamazepine has been well studied. Oral immediate- and extended-release solid and liquid dosage forms are available. The oral solid dosage form is available as an immediate-release tablet and as a sustained-release capsule and a controlled-release tablet as twice-daily dosing Compared with other first-generation AEDs, carbamazepine causes minimal cognitive impairment. DISADVANTAGES Carbamazepine has an active metabolite that can contribute to efficacy and toxicity. Other drugs can alter the concentration of this metabolite without changing the concentration of the parent carbamazepine. It induces its own metabolism, which requires careful dosage titration. It also induces the metabolism of other medications, and other drugs may interact with it and/ or the active metabolite. There is no parenteral formulation. There are clinically meaningful CNS side effects including sedation and nausea. When ingested during the first trimester by pregnant women, carbamazepine has been associated with a 1% risk of spina bifida. Chronic carbamazepine use also has been associated with alterations in bone mineral density in some studies and decreases in 25-hydoxy (OH) vitamin D. PLACE IN THERAPY Carbamazepine should be considered a firstline therapy for patients with newly diagnosed partial seizures and for patients with primary GABAPENTIN PHARMACOLOGY AND MECHANISM OF ACTION Gabapentin was designed to be a GABA agonist but does not react at the GABA receptor, alter GABA uptake, or interfere with GABA transaminase. Gabapentin appears to bind to an amino acid carrier protein and appears to act at a unique receptor. Gabapentin inhibits high-voltage activated calcium channels. It elevates human brain GABA levels, possibly via alterations in GABA synthesis or reversal of the neuronal GABA transporter, resulting in nonvesicular release of GABA. PHARMACOKINETICS Gabapentin is a substrate of the L-amino acid carrier protein in the gut (system L), as well as in the CNS. This amino acid carrier protein transports the drug across the gut membrane by an active process. The binding of gabapentin to this system is saturable, and gabapentin therefore displays dose-dependent bioavailability that appears to vary considerably between individuals. Food, including protein-rich meals, does not appear to interfere with gabapentin oral absorption. Concentrations in human CSF are 5% to 35% of plasma levels, and tissue concentrations are approximately 80% of plasma levels. Because gabapentin is eliminated exclusively by the kidneys, dosage adjustments are necessary in patients with significantly impaired renal function. In anuric patients, 35% of gabapentin is removed by Adverse Effects Fatigue, somnolence, dizziness, and ataxia are the most frequently reported side effects. Aggressive behavior has been reported in children. The CNS effects of gabapentin are generally less than those of traditional AEDs. A withdrawal reaction characterized by anxiety, insomnia, nausea, sweating, and increased pain has also been reported with abrupt discontinuation in patients taking it for pain. Drug Interactions Gabapentin does not induce or inhibit liver enzymes; therefore, drug interactions are not likely to occur with gabapentin. There is a 10% reduction in the clearance of gabapentin in patients taking cimetidine and a 20% reduction in the bioavailability if Dosing and Administration Typical starting doses of gabapentin are 300 mg at bedtime on the first day, increasing to 900 mg/day over 3 days. Pharmacokinetic study suggest gabapentin should be given at least four times a day when the total daily dose is 3,600 mg or greater. Gabapentin does not appear to be absorbed rectally. Patients with endstage renal disease maintained on hemodialysis should receive an initial 300- to 400-mg dose with 200 to 300 mg gabapentin given after every 4 hours of hemodialysis. Advantages Gabapentin has multiple mechanisms of action and is mechanistically different from first-generation AEDs. It is not metabolized and is excreted unchanged by the kidney. Gabapentin has the additional advantages of a broad therapeutic index Disadvantages Gabapentin is absorbed by an active process that saturates at higher doses. This may require more frequent daily dosing for patients who need doses greater than 3,600 mg/day. Doses exceeding the 3,600 mg/day maximum listed in the package insert may be required in some patients to achieve seizure remission. There is no parenteral formulation. Place in Therapy Gabapentin is a second-line agent for patients with partial seizures who have failed initial treatment. In addition, although monotherapy trials have no proven efficacy in previously treated patients. CONTRAINDICATIONS, PRECAUTIONS, INTERACTIONS Barbiturates The barbiturates are used cautiously in patients with liver or kidney disease and those with neurological disorders. The barbiturates (eg, phenobarbital) are used with caution in patients with pulmonary disease and in hyperactive children. When barbiturates are used with other CNS depressants (eg, alcohol, narcotic analgesics, and antidepressants), an additive CNS depressant effect may occur. BENZODIAZEPINES The benzodiazepines are contraindicated in patients with known hypersensitivity to the drugs. The benzodiazepines are used cautiously during pregnancy (Category D) and in patients with psychoses, acute narrow angle glaucoma, liver or kidney disease, and neurologic disorders. The benzodiazepines are used cautiously in elderly patients. When the benzodiazepines are used with other CNS depressants (eg, alcohol, narcotic analgesics, and antidepressants), an additive CNS depressant effect may occur. Increased effects of the benzodiazepines are seen when the drugs are administered with cimetidine, disulfiram, and oral contraceptives. When the benzodiazepines are administered with theophylline, there is a decreased effect of the benzodiazepines. HYDANTOINS The hydantoins are contraindicated in patients with known hypersensitivity to the drugs. Phenytoin is contraindicated in patients with sinus bradycardia, sinoatrial block, second and third degree AV block, and Adams-Stokes syndrome; it also is contraindicated during pregnancy (ethotoin and phenytoin are Pregnancy Category D) and lactation. Ethotoin is contraindicated in patients with hepatic abnormalities. When the hydantoins are used with other CNS depressants (eg, alcohol, narcotic analgesics, and antidepressants), an additive CNS depressant effect may occur. The hydantoins are used cautiously in patients with liver or kidney disease and neurologic disorders. Phenytoin is used cautiously in patients with hypotension, severe myocardial insufficiency, and hepatic impairment. Phenytoin interacts with many different drugs. For example, isoniazid, chloramphenicol, sulfonamides, benzodiazepines, succinimides, and cimetidine all increase phenytoin blood levels. The barbiturates, rifampin, theophylline, and warfarin decrease phenytoin blood levels. When administering the hydantoins with meperidine, the analgesic effect of meperidine is decreased. Phenytoin has been shown to induce microsomal enzymes responsible for the metabolism of a number of drugs. Autostimulation of its own metabolism, however, appears to be insignificant. Other drugs, notably phenobarbital and carbamazepine, cause decreases in phenytoin steady-state concentrations through induction of hepatic microsomal enzymes. On the other hand, isoniazid inhibits the metabolism of phenytoin, resulting in increased steady-state concentrations when the two drugs are given together. OXAZOLIDINEDIONES The Oxazolidinediones are contraindicated in patients with known hypersensitivity to the drugs. Trimethadione is classified as a Pregnancy Category D drug and is contraindicated during pregnancy and lactation. Trimethadione is used with caution in patients with eye disorders (eg, retinal or optic nerve disease), liver or kidney disease, and neurologic disorders. When trimethadione is used with other nervous system (CNS) depressants (eg, alcohol, narcotic analgesics, and antidepressants), an additive CNS depressant effect may occur. SUCCINIMIDES The succinimides are contraindicated in patients with known hypersensitivity to the drugs. The succinimides are contraindicated in patients with bone marrow depression or hepatic or renal impairment and during lactation. Ethosuximide is classified as a Pregnancy Category C drug and is used with caution during pregnancy. As with all anticonvulsants, when the succinimides are used with other CNS depressants (eg, alcohol, narcotic analgesics, and antidepressants), an additive CNS depressant effect may occur. When the hydantoins are administered with the succinimides there may be an increase in the hydantoin blood levels. Concurrent administration of valproic acid and the succinimides may result in either a decrease or an increase in succinimide blood levels. When primidone in administered with the succinimides, lower primidone levels may occur. When the hydantoins are administered with the succinimides there may be an increase in the hydantoin blood levels. Concurrent administration of valproic acid and the succinimides may result in either a decrease or an increase in succinimide blood levels. When primidone in administered with the succinimides, lower primidone levels may occur. UNITED STATES FDA PHARMACEUTICAL PREGNANCY CATEGORIES PREGNANCY CATEGORY A Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters). PREGNANCY CATEGORY B Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women or animal studies which have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester. PREGNANCY CATEGORY C Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. PREGNANCY CATEGORY D There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. PREGNANCY CATEGORY X Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. One characteristic of the FDA definitions of the pregnancy categories is that the FDA requires a relatively large amount of highquality data on a pharmaceutical for it to be defined as Pregnancy Category A. As a result of this, many drugs that would be considered Pregnancy Category A in other countries are allocated to Category C by the FDA.