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Transcript
Definition of epilepsy The term epilepsy comes from the Greek word for seizure and therefore the drugs used to control epilepsy or seizure are called antiepileptics or anticonvulsant drugs. Epilepsy is a chronic medical condition produced by sudden changes in the electrical function of the brain. All human activity is made possible by the constant discharge of electrical energy between brain cells, but in persons with epilepsy the discharge is sometimes too great and the visible result is an epileptic seizure. Epilepsy is not a disease, it is a symptom of a disorder of the brain, it can affect any one, at any age at any time. Between seizures, most people with epilepsy are perfectly normal and healthy. Causes of epilepsy The etiology of idiopathic epilepsy is not well known. It has no single cause but can be caused by any number of conditions that injure or affect the function of the brain such as: Genetic Predisposition. About 30% of epileptic patients have a history of seizures in first degree relatives. Usually the mode of inheritance is uncertain; low seizure threshold appears to run in some families. Generalized typical absence seizure (petit mal) is sometimes inherited as autosomal dominant trait with variable penetrance. 1 Developmental Anomalies. Primary generalized epilepsies are due to developmental abnormalities of neuronal control. It is uncertain whether they are anatomical, because of abnormal synaptic connection or due to anomalies in neurotransmitter distribution, release and control. Ectopic dysfunctional areas of cerebral cortex and hypothalamus are other examples of abnormalities present at birth which can cause seizures at some time, even in adult life. Trauma and Surgery. Parental trauma (causing cerebral contusion and hemorrhage) and fetal anoxia are common causes of seizures in childhood. Damage by hypnotics to the hippocampi (mesial temporal sclerosis) is another cause. Brain injury must be sufficient to cause coma (almost always). The presence of early epilepsy, depressed skull fracture, penetrating brain injury, cerebral contusion, dural or intracranial haematoma increases the incidence of late post-traumatic epilepsy. Surgery is followed by seizures in about 10% of patients. Metabolic Abnormalities. Seizures may be seen when there is some metabolic abnormalities, such as hypercalcaemia, hypoglycaemia, hyponatraemia and other metabolic disorders. Some infants lack certain enzymes essential for digesting food. This results in a condition called phenylketonuria (PKU), and if 2 it is not treated early, they develop severe mental retardation and may have seizures. Hyperthermia in children. Convulsions sometimes occur when children under five years of age have high fevers (febrile convulsins). In the majority there is no tendency for the seizures to recur in adult life. Brain tumor. Seventy-five percent of patients will have epilepsy before the age of twenty. Brain tumor, including tuberculoma should be suspected when any patient over the age of twenty develops seizure for the first time. This is the so called late onset epilepsy. Intracranial Mass Lesions. Mass lesions affecting the cerebral cortex can cause epilepsy - either partial or secondarygeneralized seizures. If the onset of seizures is in adult life, the chance of an unsuspected mass lesion such as a tumor being present is around 3%. Hydrocephlous, of any cause, lowers the threshold for seizures. Vascular. Seizures can occasionally follow cerebral infarction, especially in the elderly. Encephalitis and other Inflammatory conditions of the brain. Seizures are frequently the presenting feature of encephalitis, chronic meningitis (e.g. tuberculosis), cerebral abscess, cortical venous thrombosis and neurosyphilis. 3 Degenerative brain disorders. Seizures can occur in Alzheimer’s disease and in many rarer degenerative diseases. Epilepsy is three times more common in patients with multiple sclerosis than in the general population. Drugs, Alcohol and drug withdrawal. Phenothazines, monoamine oxidase inhibitors (MOAIs), tricyclic antidepresants, amphetamines and lignocaine can sometimes provoke fits either in overdose or in therapeutic doses in individuals with a low seizure threshold. Abrupt withdrawal of drugs that depress the central nervous system (CNS), such as alcohol, barbiturates and benzodiazepines may precipitate convulsive episodes, particularly if the drug has been used in high doses for a prolonged period. Photosensitivity and other types of reflex epilepsy. Seizures are occasionally precipitated by flashing lights or a flickering television screen. This photosensitivity can be seen on the occipital recording of the EEG. Very rarely other stimuli (e.g. music) provoke attacks. Triggers Fatigue, stress, poor nutrition, alcohol, lack of sleep may trigger seizures. Epileptic disorders can be considered either Primary or Secondary. 4 1. Primary epilepsy: When no specific anatomic cause for the seizure, such as trauma or neoplasm is evident, the syndrome is called idiopathic or primary epilepsy. These seizures may be produced by an inherited abnormality in the central nervous system (CNS). Patients are treated chronically with antiepileptic drugs, often for life. 2. Secondary epilepsy: A number of reversible disturbances, such as tumors, head injury, hypoglycemia, meningeal infection, or rapid withdrawal of alcohol from an alcoholic, can precipitate seizures. Antiepileptic drugs are given until the primary cause of the seizures can be corrected. Seizures secondary to stroke or trauma may cause irreversible CNS damage. Classification of epileptic seizures The classification of epilepsy is best achieved by: i) The clinical events. ii) The abnormal electrophysiology. iii) The anatomical site of seizures genesis. iv) The pathological cause of the problem. The classification of epileptic disorders plays an essential role in the diagnosis and management for four major reasons. 5 1. The diagnosis of epilepsy is often difficult because of the similarity between certain epileptic attacks and intermittent symptoms of non-epileptic disorders. The classification by specific symptoms is useful for this purpose. 2. Differentiation between partial and generalized seizures is of great clinical value. 3. The seizure type determines the choice of antiepileptic drugs. 4. A number of epileptic syndromes have been defined on the basis of seizure manifestations and other clinical features. Seizures have been classified into two broad groups, partial (or focal), and generalized. 6 1. Partial: Partial seizures EPILEPSY are those in which the electrical discharges are limited to one part of PARTIAL (Focal) the cortex and may remain localized. Their incidence Simple increases Complex with age. This could be simple without loss of GENERALIZED consciousness or complex (altered conscious- Tonic-clonic (grand mal) ness). Partial seizures Absence (petit mal) Myoclonic may progress, beco- Atonic Febrile seizures in children ming generalized tonic- Status epilepticus clonic seizures. 7 1.1. Simple partial (Jacksonian epilepsy): These seizures are caused by a group of hyperactive neurons exhibiting abnormal electrical activity and are confined to a single focus in the brain; the electrical disorder does not spread. A simple seizure generally starts in the toes of one foot or the fingers of one hand or in one corner of the mouth. Suddenly the affected part trembles violently or just feels numb. The patient does not lose consciousness. These simple seizures either remain focal or they may spread and become secondary generalyzed with tonic-clonic activity and loss of consciousness. 1.2. Complex partial (Psychomotor epilepsy): These seizures exhibit complex sensory hallucinations, mental distortion, and change in the level of consciousness. Motor dysfunction may involve chewing movement, diarrhea, and/or urination. Patients may have short period of amnesia, sudden anxiety and moments of incoherent speech or speech arrest. Several times a week they would feel sudden sharp pain in the stomach and after they wake up they remember nothing except the pain and the fear. Most (80%) of individuals with complex 8 partial epilepsy experience their initial seizures before the age of 20. The seizure usually lasts for few minutes, after which the patient recovers with no recollection of the event. 2. Generalized: generalized seizures involve the whole brain, producing abnormal electrical discharge throughout both hemispheres of the brain. Generalized seizures may be convulsive or nonconvulsive; the patient usually has an immediate loss of consciousness. 2.1. Tonic-clonic (grand mal): This is the most commonly encountered and the most dramatic form of epilepsy. A tonic-clonic seizure consists of an initial epileptic cry followed by strong contraction of the whole musculature, causing a rigid extensor spasm. Respiration stops and the patient may bite his tongue and may also lose control of his bladder or bowl function. The tonic phase lasts for about one minute and is followed by a series of violent, synchronous jerks which gradually dies out in 2-4 minutes. The patient stays unconscious for a few more minutes and then gradually recovers, feeling ill and confused. The patient is in no serious danger 9 unless he/she falls on his head on something hard. Such patients should be put on side position with the neck a little extended so as to secure the airways and breathing. 2.2. Absence (petit mal): Absence seizures are much less dramatic but may occur more frequently (many seizures each day) than tonic-clonic seizures. It involves a brief, abrupt and self-limiting loss of consciousness which generally lasts no more than a few seconds. The patient abruptly stopps whatever he was doing, sometimes stopping speaking in midsentence, stares vacantly, neither speaking nor apparently hearing what is said. There is little or no motor disturbance and patients recover abruptly with no after-effects. This type of epilepsy is especially prevalent in childhood and occur at ages 3 to 5 years and lasts until puberty. 2.3. Myoclonic: These seizures involve sudden, brief shock-like contractions which may involve the entire body or be confined to the face, trunk or extremities. Myoclonic seizures are rare and occur at any age. A special type is the so called Juvenile 10 Myoclonic Epilepsy, an inherited type of Epilepsy (autosomal-recessive) relatively common in Saudi Arabia and Middle East. 2.4. Atonic seizures (astatic): It involves sudden diminution of muscle tone, affecting some muscle groups, or loss of all muscle tone; patients may have a brief loss of consciousness. It starts between the ages 2-5 years. The patient’s legs simply give under him and he drops down. It lasts for about 10 seconds to 1 minute. 2.5. Febrile seizures: Young children (6 months to 5 years of age) frequently develop seizures with illness accompanied by high fever. The febrile seizures consist of generalized tonic-clonic convulsions of short duration. They are benign and do not cause death, neurological damage, injury, or learning disorders. Two to 4% of children experience a convulsion associated with a febrile illness. Approximately 25% to 33% of these children will have another febrile convulsion. Only 2% to 3% will develop epilepsy in later years. Several factors 11 are associated with an increased risk of developing epilepsy. These include pre-existing neurological disorder, a family history of epilepsy or a complicated febrile seizure (i.e., the febrile seizure lasted more than 15 minutes). Brief febrile convulsions need only simple treatment such as tepid sponging or bathing, or antipyretic medication, e.g. paracetamol. Prolonged febrile convulsions (those lasting 15 minutes or longer), recurrent convulsions, or those occurring in a child at known risk must be treated more actively, as there is the possibility of resulting brain damage. Diazepam is the drug of choice given either by slow intravenous injection in a dose of 250 micrograms/kg or preferably rectally in solution in a dose of 500 micrograms/kg (max. 10 mg), repeated if necessary. The rectal solution is preferred as satisfactory absorption is achieved within minutes and administration is much easier. Suppositories are not suitable because absorption is too slow. Intermittent prophylaxis (i.e. the anticonvulsant administered at the onset of fever) is possible in only a small proportion of children. 12 Again diazepam is the treatment of choice, orally or rectally. However, the exact role of continuous prophylaxis in children at risk from prolonged or complex febrile convulsions is controversial. Thus, long-term anticonvulsant prophylaxis is rarely indicated. 2.6. Status epilepticus (re-occurring seizures): Characterized by continuous seizures (episodes of grand mal) without regaining the level of consciousness again. It is serious and may be fatal unless rapidly treated. Unclassified - Lennox-Gastaut Syndrome Lennox-Gastaut Syndrome is a disorder of childhood characterized by multiple seizure types, mental retardation and refractoriness to antiepileptic drugs. Common seizure types include a typical absence and generalized tonic and atonic spells; the two latter seizure types can produce injuries from fall. Other seizure types include generalized tonic-clonic, partial and myoclonic seizures. Diagnosis of the disorder is usually quite clear from the patient’s history, physical examination and EEG. 13 Treatment of the child with Lennox-Gastaut syndrome represents one of the great challenges in epilepsy. Because of the mixture of aetiologies, response to treatment can be variable. Valproic acid is the most frequently used medication because it is active against multiple seizure types. Treatment with benzodiazepines, including clobazam, clonazepam, diazepam, clorazepate or nitrazepam, has been successful, although tolerance to treatment develops in many cases. A ketogenic diet or treatment with corticotrophin and glucocorticoids have also been used, as have phenytoin, carbamazepine and barbiturates, although this latter group may exacerbate certain seizure types including myoclonic, atonic and atypical absence. In an add-on study, felbamate appeared to be effective, especially with atonic spells. Some of the newer drugs, including felbamate, lamotrigine and vigabatrin, may have a role in the future management of LennoxGastaut syndrome, although there have been reports of idiopathic, potentially lethal, hepatic toxicity as well as aplastic anaemia during felbamate therapy, and this drug is now only recommended if the patient’s epilepsy is so severe that the risk of these adverse effects is deemed acceptable. 14 The diagnosis of epilepsy The first step in the treatment of epilepsy must inevitably be a proper diagnosis. Practically the diagnosis demands the documentation of two or more seizures occurring over a period of time in the absence of any metabolic disturbance or drug treatment associated with seizures. For most patients the diagnosis is made on the basis of an adequate description of symptoms both from the patient and from eye witnesses. In some patients neurophysiological evidence from the EEG may provide valuable confirmatory evidence for epilepsy. There seems little doubt that the diagnosis is often made in error, frequently because too much weight is attached to minor nonspecific abnormalities reported from standard EEG recordings. Thus, it was found that 20% of patients admitted to a psychiatric hospital with a diagnosis of epilepsy did not have the disorder. A similar high proportion of patients admitted to epileptic institutions are incorrectly diagnosed. Where diagnostic difficulty persists, the best thing is to let time clarify things. One thing that must be avoided is a “therapeutic trial” of antiepileptic drugs. Treatment of Epilepsy Today epilepsy is treated with medications targeting for optimal drug therapy. Epilepsy is completely controlled in about 75% of 15 patients. However, approximately 10% continue to have seizures at intervals of one month or less, which severely disrupts their life and work. Hence, there is a need to improve the efficacy of therapy. It is to be noted that none of the currently used drugs can cure epilepsy, but they have become increasingly successful in preventing seizures as long as they are regularly taken. The choice of a drug depends upon the form of epilepsy and upon the response of the individual. Epilepsy is a chronic long-term problem, and even in patients whose seizures have been well controlled for two or more years, the relapse rate on withdrawal of therapy has been 20 to 40%. Therefore, it is usually necessary to take medications for many years, decades or even life long. PHENYTOIN Phenytoin (Epanutin) is the oldest nonsedative antiepileptic drug which was introduced in 1938. It was known for decades as diphenylhydantoin (DPH) and is still one of the most widely used anticonvulsant drugs. Mechanism of action Phenytoin stabilizes neuronal membranes to depolarization by reducing the influx of sodium ions (Na+) across the cell membrane in the resting state or during depolarization. It also reduces the 16 influx of calcium ions (Ca2+) during depolarization and suppresses repetitive firing of neurons. Pharmacokinetics Following oral administration, the absorption of phenytoin is slow and usually complete, and takes place primarily in the duodenum. Concurrent administration with antacid significantly reduces the absorption of phenytoin. The intravenous route is sometimes used to terminate seizures in status epilepticus. Intramuscular injection should be avoided since absorption is erratic and unpredictable and muscle damage can occur. Phenytoin is highly bound (about 90%) to plasma proteins, mainly plasma albumin. Since several other drugs can also bind to the same protein, phenytoin can be displaced by other drugs, such as salicylates, valproic acid and thyroxine. This increases the free phenytoin concentration, but also increases hepatic clearance of phenytoin, and thus enhances or reduces the effect of phenytoin in a paradoxical manner. Phenytoin is metabolized by the hepatic mixed function oxidase system and is excreted mainly as glucuronide. The metabolites are clinically inactive and are excreted in the urine. Less than 5% of a given dose is excreted unchanged in the urine. The metabolism of phenytoin shows the characteristics of saturation (zero-order kinetics). At low blood levels the rate of 17 metabolism of phenytoin is proportional to the drug’s blood levels (i.e., first-order kinetics). However, at the blood levels usually required to control seizures, the maximum capacity of the drugmetabolizing enzymes is often exceeded (i.e., the enzyme is saturated), and further increases in the dose of phenytoin may lead to a disproportionate increase in the drug’s blood concentration. Since plasma levels continue to increase in such a situation, steadystate levels are not attained and toxicity may occur. The half-life of phenytoin varies from 12 to 36 hours, with an average of 24 hours for most patients with therapeutic blood levels of 10 to 20 g/ml. However, when the dosage increases, the enzyme system becomes saturated resulting in a higher concentrations and longer half-lives. At low blood levels, it takes 5-7 days to reach steady-state blood levels after every dosage change; at higher levels it may be 4-6 weeks before blood levels are stable. Phenytoin induces liver microsomal enzymes, and thus accelerates the rate of metabolism of other drugs (e.g. oral anticoagulants, oral contraceptives). Unwanted effects 18 Side effects of phenytoin begin to appear at plasma concentrations exceeding 100 µmol/L and may be severe above 150 µmol/L. Chronic Gingival hyperplasia, or overgrowth of the gums, is the most common side effect in children (20% of patients). This condition may be minimized by good oral hygiene. This hyperplasia slowly regresses after termination of drug therapy. Coarsening of facial features occurs in children. Depression of the CNS occurs particularly in the cerebellum and vestibular system, causing nystagmus, ataxia, vertigo and diplopia. Gastrointestinal problems (nausea, vomiting) are common. Hirsutism, which probably results from increased androgen secretion, occurs to some degree in most patients. For this reason it is usual to avoid prescribing phenytoin to young women. Megaloblastic anemia, associated with a disorder of folate metabolism, sometimes occurs, and can be corrected by giving folic acid. Hypersensitivity reactions, mainly skin rashes, are quite common. Behavioral abnormalities, such as confusion, hallucinations, and drowsiness may also occur. Inhibition of antidiuretic hormone release occurs as well as hyperglycemia and glycosuria caused by inhibition of insulin secretion. Chronic use may also result in abnormalities of vitamin D metabolism leading to osteomalacia. Phenytoin has also been implicated as a cause of the increased incidence of foetal malformations in children born to mothers with epilepsy, particularly the occurrence of cleft lip, cleft palate, congenital heart 19 disease; this appears to be due to the formation of an epoxide metabolite. Cardiovascular collapse and a systemic lupus pattern are the most serious side administration of phenytoin. effect following intravenous Lymphadenopathy, had also been reported as well as the Hydantoin fetal syndrome in newborn of women taking phenytoin. Intravenous administration of phenytoin (i.e. for treatment of status epilepticus) should be slow and preferably it should be given with sodium chloride (Na Cl). Giving Phenytoin with Dextran must be avoided because of precipitation of the drugs after reacting with sugar and that leads to plugging and damage to the veins. 20 Agent that stimulates metabolism of phenytoin Carbamazepine Phenytoin Inactive metabolite Phenytoin Agents that inhibit metabolism of phenytoin Chloramphenicol Dicumarol Cimetidine Sulfonamides Isoniazid Drugs affecting the metabolism of phenytoin. 21 Drug Interactions Drug interactions involving phenytoin are primarily related either to protein binding or to metabolism. Since phenytoin is highly bound, other highly bound drugs, such as phenylbutazone, sulfonamides, benzodiazepines, or anticoagulants, can displace phenytoin from its binding site, leading to an elevation in free drug concentrations and hence intoxication. The protein binding of phenytoin is decreased in the presence of renal disease. A binding inhibitor, which is produced in the presence of uremia, may cause this displacement of phenytoin. Drugs that inhibit the hepatic microsomal enzymes, such as cimetidine, chloramphenicol, sulfonamides, isoniazid, dicumarol and valproate, lead to an increase in the concentration of phenytoin in the plasma by preventing its metabolism and hence result in phenytoin toxicity. Phenytoin has been shown to induce microsomal enzymes responsible for the metabolism of other drugs, such as oral contraceptives, doxycycline, cyclosporine, quinidine, levodopa and other antiepileptics resulting in a reduced blood levels of these drugs. Autostimulation of its own metabolism, however, appears to be insignificant. On the other hand, agents that induce liver microsomal enzymes such as carbamazepine and chronic alcohol administration, decrease phenytoin blood levels. 22 Clinical uses Phenytoin is highly effective for the treatment of generalized tonicclonic seizures and for the treatment of partial seizures with complex symptomatology. It is also used for the treatment of status epilepticus caused by recurrent tonic-clonic seizures. Phenytoin is not effective for absence seizures, which often may worsen if such a patient is treated with this drug. Other uses of phenytoin include, treatment of disturbed psychotic patients without epilepsy, treatment of trigeminal neuralgia, and as an antiarrhythmic agent, particularly in the treatment of digitalis-induced arryhtmias. The therapeutic plasma level of phenytoin for most patients is between 10 and 20 µg/ml. A loading dose can be given either orally or intravenously; the latter is the method of choice for convulsive status epilepticus. When oral therapy is started, it is common to begin adults at a dosage of 300 mg/d regardless of body weight. If seizures continue, higher doses are usually necessary to achieve plasma levels in the upper therapeutic range. The phenytoin dosage should be increased each time by only 25-30 mg in adults, and ample time should be allowed for the new steady state to be achieved before further increasing the dose. A common clinical error is to increase the dose directly from 300 mg/d to 400 mg/d; toxicity frequently occurs at variable times thereafter. In 23 children, a dose of 5 mg/kg/d should be followed by readjustment after steady-state plasma levels are obtained. CARBAMAZEPINE Carbamazepine (Tegretol) is closely related to imipramine and other antidepresssants, it is a tricyclic compound originally developed for the treatment of bipolar depression. It was initially marketed for the treatment of trigeminal neuralgia but has proved useful for epilepsy as well, and is now one of the most widely used antiepileptic drugs. Mechanism of action The mechanism of action of carbamazepine appears to be similar to that of phenytoin. At therapeutic concentrations, carbamazepine reduces the propagation of abnormal impulses in the brain by blocking sodium channels, thereby reducing the generation of repetitive action potentials in the epileptic focus. Although trigeminal neuralgia is not obviously associated with epilepsy, this condition probably involves similar neuronal mechanisms. Pharmacokinetics Carbamazepine is absorbed slowly following oral administration. Peak levels are usually achieved 6-8 hours after administration. It 24 enters the brain rapidly because of its high lipid solubility. The drug is only 70% bound to plasma proteins, no displacement of other drugs from protein binding has been observed. Carbamazepine is metabolized in the liver to Carbamazepine - 10, 11-epoxide which has been shown to have anticonvulsant activity and 10, 11-dihydroxide which is subsequently conjugated and execreted in the urine. Only 2% of carbamazepine is execreted unchanged in the urine. The drug has a notable ability to induce liver microsomal enzymes, and its own half-life therefore decreases with chronic administration. Typically, the half-life of 36 hours observed in subjects following an initial single dose decreases to much less than 20 hours over the first 2-3 weeks of treatment due to “autoinduction” of its own metabolizing enzymes in the liver. Seizure control may then require an increase in dose. During chronic therapy the half-life is extremely variable among individuals. Carbamazepine also alters the clearance of other drugs. For example, carbamazepine has been shown to increase the clearance and decrease the half-life and steady-state blood levels of several other antiepileptic drugs such as phenytoin, primidone, valproic acid or clonazepam. Unwanted effects Nausea and vomiting, especially early in treatment. 25 CNS toxicity: diplopia, dizziness, drowsiness. Ataxia occurs at high doses. Leukopenia is common, especially early in treatment, but severe bone marrow depression is rare. Hyponatraemia, due to potentiation of the action of antidiuretic hormone which can lead to water intoxication. Skin rashes (including Stevens-Johnson syndrome). Risk of teratogenesis including neural tube defects if used during the first trimester of pregnancy. Neonatal bleeding (prophylactic Vitamin K for mother before delivery is advised). 26 Carbamazepine Metabolite Agents that inhibit metabolism of carbamazepine Cimetidine Diltiazem Erythromycin Isoniazid Propoxyphene Drugs affecting the metabolism of carbamazepine. 27 Drug interactions Drug interactions involving carbamazepine are almost exclusively related to its effects on microsomal drug metabolism. Carbamazepine can induce its own metabolism (autoinduction) after prolonged use; its half-life, and serum steady-state concentrations may all be decreased. Carbamazepine also can induce the enzymes that metabolize other antiepileptic drugs including phenytoin, primidone, phenobarbital, valproic acid, clonazepam, and ethosuximide, as well as the metabolism of other drugs such as oral contraceptives and warfarin. Other drugs such as propoxyphene, cimetidine, isoniazid and the macrolide antibiotics (erythromycin and troleandomycin) may inhibit carbamazepine clearance and increase steady-state carbamazepine blood levels. Other antiepileptics, for instance, phenytoin and phenobarbital, may decrease steady-state concentrations of carbamazepine through enzyme induction. No clinically significant proteinbinding interactions have been reported. Clinical uses Carbamazepine is considered the drug of choice for the treatment of all partial seizures (simple and complex). In addition the drug may be effective for generalized tonic-clonic seizures. Carbamazepine is nonsedative in its usual therapeutic range. Both carbamazepine and phenytoin are effective in relieving pain 28 associated with trigeminal neuralgia, an exceedingly painful condition believed to result from a paroxysmal discharge of neurons associated with the trigeminal sensory pathway. Similar to phenytoin, carbamazepine is not effective in absence seizures and might even make these seizures worse. It has occasionally been used in manic-depressive patients to ameliorate the symptoms. It is used successfully in reducing pain in peripheral neuropathy. Carbamazepine is available only in oral form. The drug is effective in children, in whom a dose of 15-25 mg/kg is appropriate. In adults, doses of 1 g or even 2 g are tolerated. Higher doses are achieved by giving multiple doses daily. In patients receiving three or four daily doses, in whom the blood is drawn just before the morning dose (trough level), the therapeutic level is usually 4-8 ug/ml; although many patients complain of diplopia above 7 ug/ml. When blood samples are drawn randomly, levels are frequently above 8 ug/ml, but fluctuations related to absorption make longterm comparisons difficult. The plasma concentration of carbamazepine correlates well with its clinical efficacy and measurement can be useful in monitoring treatment. Salivary concentrations are an alternative guide. Studies have shown that Carbamazepine has the least teratogenic effects when used as monotherapy in pregnant women. 29 PHENOBARBITAL Phenobarbital (Gardinal) is a long-acting barbiturate and one of the first barbiturates to be developed. It is the oldest of the currently available antiepileptic drugs and its anticonvulsant properties were in fact recognized in 1912. Its action against experimentallyinduced convulsions and clinical forms of epilepsy closely resembles phenytoin. Like phenytoin, it is ineffective in treating absence seizures. Although it has long been considered one of the safest of the antiepileptic drugs, the use of other medications with lesser sedative effects has been urged. Mechanism of action Phenobarbital limits the spread of seizure discharges in the brain by elevating the seizure threshold. Its mechanism of action in alleviating seizures is poorly understood. Like phenytoin, phenobarbital suppresses high frequency repetitive firing in neurons in-vitro through its action on Na+ conductance, but only at high concentrations. Also, at high concentrations, barbiturates block some Ca2+ currents. There is also evidence that it may act through potentiation of the inhibitory effects of -aminobutyric acid (GABA)-mediated neurons. Phenobarbital also blocks excitatory responses induced by glutamate. Both the enhancement of GABA-mediated inhibition and the reduction of glutamate- 30 mediated excitation are seen with therapeutically relevant concentrations of phenobarbital. Pharmacokinetics Phenobarbital is well absorbed orally. Approximately 50% of the drug in the blood is bound to plasma albumin. The drug freely penetrates the blood brain barrier. It is eliminated slowly from the plasma (half-life is very long, ranging from 2 and 6 days). about 75% of the drug is metabolized, mainly by oxidation and conjugation, by the hepatic microsomal enzymes, the remaining drug is excreted unchanged by the kidney. Phenobarbital is a potent inducer of the P-450 system, and when given chronically, it enhances the metabolism of other drugs and lowers their plasma concentrations (e.g. steroids, oral contraceptives, warfarin, tricyclic antidepressants). Since phenobarbital is a weak acid, its ionisation and hence renal elimination are increased if the urine is made alkaline. The plasma concentrations of phenobarbital are not closely related to control of seizures. They are only useful as a guide to compliance with treatment. Unwanted effects The major unwanted effect of phenobarbital is sedation, which often occurs at plasma concentrations within the therapeutic range 31 for seizure control. Some degree of tolerance develops to this effect on continued administration, but objective tests of cognition and motor performance show impairment even after long-term treatment. Impaired school performance has been shown to result from treatment of children with phenobarbital. Other unwanted effects that may occur with clinical dosage include megaloblastic anaemia (similar to that caused by phenytoin), ataxia, nystagmus, vertigo, mild hypersensitivity reactions and osteomalacia, as well as hemorrhage in babies born to mothers receiving phenobarbital. Like other barbiturates, it must not be given to patients with porphyria. In overdose, phenobarbital produces coma, respiratory and circulatory failure, as all barbiturates do. Dependence with a physical withdrawal reaction is seen after long-term treatment. Rebound seizures can occur upon rapid discontinuation of phenobarbital. Drug interactions Phenobarbital interacts with other central nervous system depressant drugs, leading to additive effects. Following continuous use of phenobarbital, it induces hepatic microsomal enzyme system. For example, in human, phenobarbital has been shown to increase the rate of metabolism of dicumarol, phenytoin, digitalis compounds, and griseofulvin - effects that could lead to decreased response to these agents. Concentrations of phenobarbital in 32 plasma may be elevated by as much as 40% during concurrent administration of valproic acid and other drugs that inhibit hepatic microsomal enzymes. Clinical uses Phenobarbital is useful in the treatment of generalized tonic-clonic seizures and simple partial seizures, but it is not very effective for complex partial seizures. There is little evidence for its effectiveness in generalized seizures such as absence, atonic attacks, or infantile spasms. The drug has been regarded as the first choice in treating recurrent seizures in children, including febrile seizures. However, phenobarbital can depress coginitive performance in children when it is used for febrile seizures, and the drug should be used cautiously in this condition. Phenobarbital is also used to treat status epilepticus, especially in patients who do not respond to diazepam together with phenytoin. The therapeutic levels of phenobarbital in most patients range from 15 to 40 ug/ml. PRIMIDONE Primidone (mysoline) was marketed in the early 1950s. It is structurally related to phenobarbital. In fact, much of primidone’s efficacy comes from its metabolites Phenobarbital and phenylethyl malonamide, which have longer half-lives than the parent drug. 33 Mechanism of action Although primidone is converted to phenobarbital, the mechanism of action of primidone itself may be more like that of phenytoin. Pharmacokinetics Primidone is well absorbed following oral administration and exhibits poor protein binding. It is converted in the liver to two active metabolites: Phenobarbital and phenylethylmalonamide (PEMA). Optimal blood levels of phenobarbital derived from the metabolism of primidone are similar to those found when Phenobarbital itself is given. Concentrations of unchanged primidone should be maintained below 10ug/ml to prevent overt CNS depression. Primidone has a larger clearance than other antiepileptic drugs (2L/kg/d), corresponding to a half-life of 6-8 hours. PEMA clearance is approximately half that of primidone, but phenobarbital has a very low clearance. Unwanted effects Rashes, leukopenia, thrombocytopenia and systemic lupus erythematosus have been reported. Some personality changes and megaloblastic anaemia have also occured. As with phenobarbital, the most common side effects associated with primidone therapy are related to CNS depression. 34 Drug interactions Drug interactions described for phenobarbital can also occur following primidone administration. Clinical uses Primidone is effective against partial seizures and appears to be more effective than phenobarbital. This result is presumably due to the activity of its metabolite, PEMA. Primidone is also effective in generalized tonic-clonic seizures and focal epilepsy. It is frequently combined with phenytoin, but since it is, in part, converted to phenobarbital, combination with phenobarbital makes little sense. Primidone is most efficacious when plasma levels are in the range of 8-12 ug/ml. Concomitant levels of its metabolite, phenobarbital, at steady state will usually vary from 15-30 ug/ml. Doses of 10-20 mg/kg/d are necessary to obtain these levels. It is very important, however, to start primidone at low doses and gradually increase over days to a few weeks to avoid prominent sedation and gastrointestinal complaints. 35 VALPROIC ACID Valproic acid (Depakene), also available as the sodium salt, sodium valproate, was found to have antiepileptic properties when it was used as a solvent in the search for other drugs effective against seizures. It was marketed in France in 1967 but was not licensed in the USA until 1978. It inhibits most kinds of experimentally induced convulsions, and is effective in many clinical types of epilepsy. Mechanism of action It is probable that valproic acid works by more than one mechanism, since it has a very broad spectrum of anticonvulsant activity. Although the precise mode of action of valproate remains uncertain, attention, however, has been paid to the effects of valproic acid on the inhibitory amino acid, -aminobutyric acid (GABA). Several studies have shown that valproate causes a significant increase in the GABA content of the brain, and also decreases the amount of the excitatory neurotransmitter aspartate. It is a weak inhibitor of two enzyme system that inactivate GABA, namely GABA-transaminase and succinic semialdehyde dehydrogenase. At high concentrations, valproic acid has been shown to increase membrane potassium conductance. Furthermore, low concentrations of valproic acid tend to hyperpolarize membrane 36 potentials. These findings have led to speculation that valproic acid may exert an action through a direct effect on the potassium channels of the membrane. Pharmacokinetics Valproic acid is well absorbed from the gut, with bioavailability greater than 80%. Peak blood levels are observed within 2 hours. To reduce the risks of gastric upset, conventional tablets should be taken with food or enteric coated tablets can be given. The drug is about 90% bound to plasma proteins, but the proportion of free (and therefore active) drug rises with increasing blood concentration. Drug concentration in plasma does not correlate well with therapeutic effect and routine monitoring is only useful to assess compliance or to avoid toxic concentrations. Valproic acid is extensively metabolized in the liver by the P-450 system, but it does not induce P-450 enzyme synthesis. The glucuronylated metabolites are excreted in the urine. Clearance of valproic acid is very slow, corresponding to the small volume of distribution and accounting for a half-life of 9-18 hours. Unwanted effects The most common dose-related adverse effects of valproic acid are nausea, vomiting, and other gastrointestinal complaints such as abdominal pain and “heart burn”. The drug should be started 37 gradually to avoid these symptoms. Potentially the most serious side effect is hepatotoxicity. An increase in serum glutamic oxaloacetic transaminase (SGOT), which signals liver damage of some degree, commonly occurs, but proven cases of valproateinduced hepatitis are rare. In some patients, a rash and hair loss (alopecia) may occur, but this effect is reversible. Bleeding times may increase because of both thrombocytopenia and an inhibition of platelet aggregation. Valproic acid inhibits phenobarbital metabolism, thereby increasing circulating levels of phenobarbital. Metabolic effects, including hyperglycemia and hyperammonemia, have been reported. An increase in body weight has been noted. There is evidence that valproic acid may be teratogenic, with increased incidence of spina bifida and neural tube defects in first trimester. Neonatal bleeding and neonatal hepatotoxicity have also reported. Therefore, is not recommended for use during pregnancy. Drug interactions The clearance of valproic acid is dose-dependent, caused by changes in both the intrinsic clearance and protein binding. Valproic acid inhibits its own metabolism at low doses, thus decreasing intrinsic clearance. At higher doses, there is an increased free fraction of valproic acid, resulting in lower total drug levels than expected. It may be clinically useful, therefore, to measure both total and free levels. Valproic acid also displaces 38 phenytoin from plasma proteins leading to an increase in unbound phenytoin and hence its toxicity. The dosage of phenytoin should be adjusted as required. In addition, valproic acid inhibits the metabolism of several drugs, including phenobarbital, phenytoin and carbamazepine, leading to higher steady-state concentrations. The inhibition of phenobarbital metabolism may cause levels of the barbiturate to rise causing stupor or coma. The concomitant use of valproic acid and clonazepam may produce absence status. Clinical uses Valproic acid has become a major antiepileptic drug against several seizure types. It was originally approved for use in absence seizures, particularly in myoclonic types that had been difficult to treat with other drugs, and this is still its major indication when it is used alone. In addition, valproic acid can be used either alone or in combination with other drugs for the treatment of generalized tonic-clonic epilepsy and for partial seizures with complex symptomatology and in febrile convulsions. Doses of 25-30 mg/kg/d may be adequate in some patients, but others may require 60 mg/kg or even more. Therapeutic levels of valproic acid range from 50-100 ug/ml. 39 ETHOSUXIMIDE Ethosuximide (zarontin) was introduced in 1960 and belongs to the succinamide class. It was developed by modifying the barbituric acid ring structure. It is used in cases of petit mal epilepsy. Mechanism of action The mechanism of action of ethosuximide may be due to antagonist activity in cell membrane on T-type calcium channels. It also inhibits Na+, K+ - ATPase, depresses the cerebral metabolic rate and inhibits GABA transaminase. Pharmacokinetics Ethosuximide is well absorbed when given orally. Peak levels are observed 3-7 hours after oral administration of the capsules. Plasma steady-state levels are reached after about 9 days of single daily dosing. Ethosuximide is uniformly distributed throughout perfused tissues and does not penetrate fat. It is not bound to plasma proteins. About 25% of the drug is excreted unchanged in the urine, and 75% is converted to inactive metabolites in the liver by the microsomal P-450 enzyme system. Ethosuximide does not induce P-450 enzyme synthesis. The plasma half-life of ethosuximide is about 30-40 hours. 40 Unwanted effects The most common dose-related side effect of Ethosuximide is gastric distress, including pain, nausea and vomiting. This can often be avoided by starting therapy at a low dose, with gradual increase in the therapeutic range. Other dose-related adverse effects include transient lethargy or fatigue and, much less commonly, headache, dizziness, hiccup and euphoria. A variety of blood dyscrasias, including pancytopenia and aplastic anaemia, have occurred. Eosinophilia develops in about 10% of patients. Systemic lupus erythematosus and Stevens-Johnson syndrome also have been reported. The drug may precipitate tonic-clonic seizures in susceptible patients. Drug interactions Administration of ethosuximide with valproic acid results in a decrease in ethosuximide clearance and higher steady-state concentrations due to inhibition of metabolism. Clinical uses The only indication for ethosuximide is in the treatment of uncomplicated absence epilepsy (first choice drug). However, it can be combined safely with other anticonvulsants in patients with absence as well as other types of epilepsy (multiple seizure types). 41 The optimal plasma ethosuximide levels are between 40-100 ug/ml; these levels provide control in 80% of patients with absence epilepsy. The starting dose for children up to 6 years of age is 250 mg/d, and this increased gradually to the usual dose of 20 mg/kg/d. Adults and children over 6 years are started with 500 mg/d, and increased by 250 mg at 4-7 days interval to the usual dose of 1-1.5 g/d. BENZODIAZEPINES Several benzodiazepines play prominent roles in the treatment of epilepsy, but their roles cannot be classified under a single seizure disorder. Although many benzodiazepines are quite similar chemically, subtle structural alterations result in differences in activity. With most benzodiazepines, the sedative effect is too pronounced to be used as maintenance anticonvulsant therapy. Of all the antiepileptics, the benzodiazepines are the safest and most free from severe side effects. Mechanism of action Benzodiazepines through binding to GABA-associated receptors, promote influx of chloride ions and neuronal hyperpolarization. 42 Pharmacokinetics Benzodiazepines are well absorbed, widely distributed, and extensively metabolized, with many active metabolites. The rate of distribution of benzodiazepines within the body is different from that of other antiepileptic drugs. Diazepam and lorazepam in particular are rapidly and extensively distributed to the tissues, with volume of distribution between 1 and 3 L/kg. The onset of action, therefore, is also very rapid. Total body clearance of parent drug and metabolites, however, is very slow, corresponding to halflives of 40-50 hours. Unwanted effects Two prominent aspects of benzodiazepines limit their usefulness. The first is their pronounced sedative effects, which is unfortunate both in the treatment of status epilepticus and in chronic therapy. The second problem is tolerance, in which seizures may initially respond, but within a few months the initial improvement may diminish. Respiratory depression and cardiac depression may occur when given intravenously in acute situations. In addition, children may manifest a paradoxic hyperactivity, as with barbiturates. 43 Drug interactions Benzodiazepines have additive or synergistic effects with other centrally acting drugs such as antihistamines, alcohol and barbiturates. This may increase the impairment of motor or intelectual function or worsen respiratory depression. Clinical uses Diazepam (valium), given intravenously is the drug of choice to treat status epilepticus, a life-threatening condition in which epileptic seizures occur almost without a break. Its advantage in this situation is that it acts very rapidly compared with other antiepileptic drugs. In adults, the drug is administered by intravenous injection in a dose of 10-20 mg at a rate of 0.5 ml (2.5 mg) per 30 seconds, repeated if necessary after 30-60 minutes, and may be followed by intravenous infusion to a maximum dose of 3 mg/kg over 24 hours. The dose in children is 200-300 µg/kg or 1 mg per year of age, given intravenously. Diazepam can also be administered by the rectal route as rectal solution in a dose of 500 µg/kg for adults and children over 10 kg and 250 µg/kg in the elderly. Clonazepam (Rivotril) is claimed to be a relatively selective anticonvulsant. It is effective in absence, myoclonic, atonic, and akinetic seizures. It is generally less effective than valproate or 44 ethosuximide in absence seizures. Sedation is prominent, especially on initiation of therapy and starting doses should be small. Maximally tolerated doses are usually in the range of 0.1-0.2 mg/kg. Therapeutic blood levels are usually less than 0.1 ug/ml and are not routinely measured in most laboratories. It is given by either intravenous injection (over 30 seconds) or by intravenous infusion in a dose of 1 mg, repeated if necessary, whereas, for children of all ages, the dose is 500 µg. Chlorazepate dipotassium (Tranxene) is a benzodiazepine approved in the U.S.A. as an adjunct to treatment of complex partial seizures in adults. Drowsiness and lethargy are its common adverse effects. Nitrazepam (Mogadon) is not marketed in the U.S.A., but is used in many other countries, especially for infantile spasms, myoclonic seizures; and Lennox-Gastaut syndrome. It is less potent than clonazepam, and whether it has any clinical advantages over clonazepam remains unclear. For adults, it is given in a dose of 5-10 mg at bed time; whereas in elderly it is given in a dose of 2.5-5 mg. It is not recommended in children. 45 Clobazam is not available in the U.S.A. but is marketed in most countries. It is a 1,5-benzodiazepine (unlike the marketed compounds, all of which are 1,4-benzodiazepines) and reportedly has less sedative potential than other benzodiazepines. Whether the drug has significant clinical advantages over other benzodiazepines is not clear. It is given in a dose of 20-30 mg/d, with maximum daily dose of 60 mg. The dose for children over 3 years of age is not more than half of the adult dose. 46 NEW ANTI-EPILEPTIC DRUGS In the last few years a number of new anticonvulsants have been introduced into clinical practice mainly as add-on therapy in patients whose epilepsy is resistant to standard antiepileptic drugs. However, the precise role of these new agents in the overall management of epilepsy remains to be clearly defined. Lamotrigine, vigabatrin, gabapentin, felbamate, tiagabine and topiramate, are among the most promising antiepileptic drugs. Lamotrigine Lamotrigine (lamictal) is a promising new antiepileptic drug which is structurally unrelated to the major antiepileptics in current use. Mechanism of action Although its precise mechanism of action is unknown, current evidence suggests that lamotrigine exerts its antiepileptic effects by blocking the voltage-dependent sodium channels, stabilizing neuronal membranes and thus inhibiting the release of excitatory neurotransmitters, predominantly glutamate. Pharmacokinetics Lamotrigine is rapidly and completely absorbed after oral administration and has a volume of distribution in the range of 47 1-1.4L/kg. Protein binding is only about 55%. It undergoes biotransformation in the liver primarily by hepatic glucuronidation to the inactive 2N-glucuronide metabolite. Hence, any drug which is able to induce or inhibit this glucuronidation reaction may potentially interact with lamotrigine. Its elimination reveals linear Kinetics with a mean half-life of approximately 25.5 10.2 hours in healthy young adults. Unwanted effects The most common adverse effects of lamotrigine include rash, somnolence, blurred vision, dizziness, headache, diplopia, ataxia, nausea and vomiting. The rash occurs in about 10% of treated patients, usually within 2-8 weeks of starting lamotrigine, however isolated cases have been reported after prolonged use. Although the majority recover on drug withdrawal, however, in rare cases these reactions may be fatal. Hence, all patients (adults and children) who develop a rash should be evaluated and lamotrigine should be withdrawn immediately unless the rash is clearly not drug related. It is important to note that early manifestations of hypersensitivity (e.g. fever, lymphadenopathy) may occur without evidence of a rash. It is therefore, recommended that patients should be instructed to report any signs of hypersensitivity to his/her physician immediately. The drug’s safety in pregnancy is 48 unknown, so it is better to avoid its prescription to pregnant women. Contraindications Hepatic impairment. Drug interactions The concurrent administration of lamotrigine together with phenytoin, carbamazepine, phenobarbital or primidone has been shown to reduce the half-life of lamotrigine to approximately 15 hours. Lamotrigine has also been reported to reduce the plasma concentrations of valproic acid by approximately 25% over a few weeks. Drugs which are known to accelerate gastric emptying, such as metoclopramide may increase the rate of oral absorption of lamotrigine from the gastrointestinal tract; whereas, those which are known to delay gastric emptying, for example, imipramine, may decrease the absorption of orally administered lamotrigine from the gastrointestinal tract. Clinical uses Lamotrigine is effective as an add-on therapy for partial and secondary generalized tonic-clonic seizures with dosages typically between 100 and 300 mg/d and with a therapeutic blood level near 49 3 µg/ml. It may also be effective for other types of epilepsy, such as absence, myoclonic, tonic and clonic seizures and those associated with the Lennox-Gastaut syndrome. In addition, it is also of experimental interest in the therapy of other neurological disorders, such as Parkinson’s disease. Pharmacological studies have indicated that the anticonvulsant profile of lamotrigine is similar to that of phenytoin and carbamazepine and it is better tolerated. VIGABATRIN Mechanism of action Vigabatrin (Sabril) is a structural analogue of gamma-aminobutyric acid (GABA). It is an irreversible inhibitor of GABA aminotransferase, the enzyme responsible for the degradation of GABA at synaptic sites, thus enhancing inhibitory effect of GABA against the generation of epileptic discharges. Pharmacokinetics Vigabatrin is rapidly absorbed from the gut and peak plasma levels are attained in 1-3 hours. The half-life of the drug is short (6-8 hours) but because of its irreversible binding to the enzyme it results in a long duration of action which is not related to the plasma drug concentration. Hence, monitoring of plasma 50 concentration is not required. Unlike most of the older antiepileptics, vigabatrin binds minimally to plasma proteins and is devoid of significant enzyme inducing or inhibiting properties. It is not metabolised through the cytochrome P450 enzyme system and is excreted mostly unchanged in the urine. Unwanted effects Sedation and fatigue. Psychotic reactions, especially in patients with a history of psychiatric disorder. Hence, preexisting mental illness is a relative contraindication. Weight gain. Vigabatrin reduces plasma phenytoin concentrations by an unknown mechanism. Visual disturbances including visual field defect, photophobia and retinal disorders have been reported. Hence, regular testing of visual field is recommended and the patient should be advised to report any visual changes. Clinical uses It is effective for use in chronic epilepsy not satisfactorily controlled by other antiepileptics. It is useful primarily as adjunctive treatment for patients with partial seizures refractory to 51 the conventional antiepileptic drugs. In adults, vigabatrin should be started at a dosage of 500 mg twice daily; a total of 1.5 g (or more) daily may be required to produce its full effect. GABAPENTIN Mechanism of action Gabapentin (neurontin) is an amino acid, chemically related to GABA. However, it does not mimic GABA in the brain. It does not interact with the excitatory neurotransmitter receptor sites or with voltage-dependent sodium channels, nor does it influence benzodiazepine, catecholamine, acetylcholine or opioid receptors. Gabapentin binds with high affinity to a specific site in the brain, which appear to be the amino acid transporter system that is present occurs in many neurons and other cells. Pharmacokinetics Gabapentin is incompletely absorbed from the intestine. Food has no effect on the rate and extent of absorption. It is not appreciably metabolized in humans nor does it interfere with the metabolism of the commonly used antiepileptic drugs. The drug does not bind to plasma proteins and is excreted unchanged by the kidneys, minimizing the likelihood of drug interactions. Dosage adjustment in patients with compromised renal function or undergoing 52 hemodialysis is recommended. Gabapentin elimination half-life is 5-7 hours which might require thrice daily dosing, although there is some evidence that twice daily dosing is sufficient. Unwanted effects CNS effects including somnolence, dizziness, ataxia, fatigue, nausea and/or vomiting and nystagmus have been reported. The absorption of Gabapentin from the intestine depends on the amino acid carrier system, and shows the property of saturability, which means that increasing the dose does not proportionately increase the amount absorbed. This makes Gabapentin relatively safe and free of side effects associated with overdosing. Up to date no serious drug interactions were reported. There are no teratogenicity data in man when it was used during pregnancy. Clinical uses Gabapentin is indicated as adjunctive (add-on) therapy in patients over 12 years of age with partial seizures with and without secondary generalization in adults with epilepsy. It is given orally with or without food. The effective dose is 900 - 1800 mg/day and given in divided doses (three times a day) using 300 or 400 mg capsules. It is not necessary to monitor gabapentin plasma concentrations to optimize gabapentin therapy. Further, because there are no significant pharmacokinetic interactions between 53 gabapentin and other commonly used antiepileptic drugs, its concurrent use with other antiepileptics does not significantly alter the plasma levels of the latter. FELBAMATE Felbamate (Felbatol) is structurally similar to meprobamate, an obsolete anxiolytic drug. Mechanism of action Felbamate’s mechanism of action is unknown, but in neuronal cultures it blocks sustained repetitive neuronal firing, possibly through an effect on sodium channels. Experiments on animals suggest that felbamate has a broad spectrum anticonvulsant activity and causes less behavioral toxicity than carbamazepine, valproate or phenytoin. Pharmacokinetics Felbamate is available for oral use only. More than 90% is absorbed, even in the presence of food or antacids. Serum concentrations reach a peak in 1 to 3 hours. It circulates primarily as free drug; only 20% to 25% is bound to plasma proteins. It is partly metabolized in the liver (metabolites are inactive) and 54 excreted in the urine. The half-life of felbamate is about 20-23 hours. Unwanted effects Headache, insomnia, anorexia, fatigue, nausea, vomiting, dyspepsia, weight loss, constipation and diarrhea were the most frequent adverse effects reported with felbamate. They occurred in less than 10% of patients, and were mainly mild to moderate in severity, and seldom required discontinuation of the drug. Rash developed in about 3% of patients taking felbamate and sometimes required withdrawal of the drug. Leukopenia, thrombocytopenia, agranulocytosis, and Stevens-Johnson syndrome have occurred rarely, but only when felbamate was taken with other drugs. Felbamate safety in pregnancy is unknown, so it is advised not to be used during pregnancy. Drug interactions The metabolism of felbamate is complex; it apparently induces and inhibits hepatic cytochrome P450 enzymes, leading to clinically important interactions with several other antiepileptic drugs. Felbamate decreases plasma concentrations of carbamazepine by about 30%, but increases concentrations of the pharmacologically active metabolite of carbamazepine, carbamazepine-10,11-epoxide by about 60%. Felbamate increases serum concentrations of 55 phenytoin and valproate. Both phenytoin and carbamazepine increase clearance of felbamate, but not that of valproate, according to felbamate’s manufacturer. Clinical uses Felbamate appears to be effective against both partial and generalized seizures. However, its main use today is in the treatment of intractable seizures in children, associated with mental retardation (Lennox-Gastaut syndrome). The recommended starting dose for an adult is 1200mg of felbamate per day in three or four divided doses. The dosage can be increased biweekly in 600mg increments to 2400mg / day, if necessary. It can be increased to a maximum of 3600mg / day. In children with the Lennox-gastaut syndrome, the initial dosage of felbamate is 15mg / kg / day in three or four divided doses, increased weekly in 15mg / kg / day increments to a target dosage of 45mg / kg / day. In both children and adults, a 20% to 30% reduction in the daily dosage of phenytoin, valproate, or carbamazepine when given concurrently with felbamate is usually necessary to minimize adverse effects related to drug interactions. TIAGABINE Tiagabine is a derivative of nipecotic acid and was rationally designed as an inhibitor of GABA uptake. 56 Mechanism of action Tiagabine inhibits GABA uptake into glial cells and neurones. Pharmacokinetics Tiagabine is very well absorbed when given orally. Food decreases the peak plasma concentration but not the area under the curve (AUC). It is highly protein bound with half-life of 5-8 hours. It does not induce or inhibit liver microsomal enzymes and hepatic impairment slightly decreases its clearance. Unwanted effects Dizziness, asthenia, nervousness, tremor, depression and emotional lability. Clinical uses It appears to be effective against both partial and generalized tonicclonic seizures. The adult dose is 16-48 mg/day. The drug is given three or four times per day. TOPIRAMATE Topiramate is a substituted monosaccharide structurally different from all other antiepileptic drugs. 57 Mechanism of action Topiramate is a weak carbonic anhydrase inhibitor it probably acts by blockade of sodium channels or within the GABA system. Pharmacokinetics Topiramate is well absorbed (about 4 hours), with an oral bioavailability of 80 percent. Food does not affect its absorption, minimal (15%) plasma protein binding, only moderate (20-50%) metabolism and the metabolites are inactive, the remainder is excreted unchanged in the urine. The lack of extensive metabolism reduces its interactions with other antiepileptics. The half-life of topiramate is about 20 to 30 hours. This renders it suitable for once daily dosing. Increased plasma levels are seen with renal failure and hepatic impairment. Unwanted effects These are primarily related to central nervous system and gastrointestinal disturbances. They include impaired concentration and memory, confusion, emotional lability with mood disorders and depression, impaired speech, dizziness, drowsiness, fatigue, visual disturbances, diplopia, nystagmus, taste disorder, abdominal pain, nausea, anorexia and weight loss. 58 Drug interactions Topiramate decreases ethinylestradiol concentrations of oral contraceptive preparations, and higher estrogen doses may be required. Inducers of hepatic enzymes such as phenytoin and carbamazepine decrease topiramate plasma concentrations by approximately 50 percent. Clinical uses The drug is indicated as adjunctive treatment of partial seizures with or without secondary generalization. Experience is still limited with this drug. It is given initially as a single dose of 50100mg per day for a week and then very slowly increased to 200mg daily in two divided doses for a further week, further dose increments of 200mg daily should be made at weekly intervals; usual dose 200-400mg daily in two divided doses. 59 TREATMENT OF EPILEPSY Usual Daily Oral Dosage Seizure Type Drugs Adults Children Usual Therapeutic serum concentrations Tonic-clonic (grand mal) Phenytoin 300-400 mg 4-8 mg/kg 10-20 g/ml OR Valproate 1000-3000 mg 15-60 mg/kg 50-120 g/ml OR Phenobarbital 90-150 mg 2-5 mg/kg 15-35 g/ml Drug of choice: Alternatives: Lamotrigine 100-500 mg Not approved Not established Primidone 750-1250 mg 10-20 mg/kg 6-12 g/ml Carbamazepine 800-1600 mg 10-30 mg/kg 6-12 g/ml Carbamazepine Partial (focal) (simple or complex) 800-1600 mg 10-30 mg/kg 6-12 g/ml OR Phenytoin 300-400 mg 4-8 mg/kg 10-20 g/ml OR Valproate 1000-3000 mg 15-60 mg/kg 50-120 g/ml Primidone 750-1250 mg 10-20 mg/kg 6-12 g/ml 90-150 mg 2-5 mg/kg 15-35 g/ml Lamotrigine (as adjunct) 100-500 mg Not approved Not established Gabapentin (as adjunct) 900-2400 mg Not approved Not established 1000-3000 mg 15-60 mg/kg 50-120 g/ml 750-1250 mg 20-40 mg/kg 40-100 g/ml Clonazepam 1.5-20 mg 0.05-0.2 20-80 ng/ml Lamotrigine 100-500 mg mg/kg Not established Drug of choice: Alternatives: Phenobarbital Absence (Petit mal) Drug of choice: Valproate OR Alternatives: Ethosuximide Not approved Myoclonic, Atonic Drug of choice: Valproate Alternatives: Clonazepam Felbamate (as adjunct) 1000-3000 mg 15-60 mg/kg 50-120 g/ml 1.5-20 mg 0.05-0.2 20-80 ng/ml mg/kg Not established 1200-3600 mg 15-60 mg/kg Status Epilepticus Drug of choice: OR Alternative: Febrile Seizures Diazepam, i.v. 10-20 mg Phenytoin, i.v. 10-15 mg/kg Phenobarbital, i.v. 200-300 g/kg 10-20 g/ml 15-35 g/ml 50-200 mg Diazepam,rectal*solutio n Diazepam, i.v. Valproate * Preferred 60 - 500 g/kg - 250 g/kg 1000-3000 mg 15-60 mg/kg 50-120 g/ml Guidelines for Anticonvulsant Therapy The decision whether or not to initiate drug therapy after a single major seizure remains controversial. Therapy should start with a single well-tried and relatively nontoxic drug. The majority of patients can be controlled on one drug (monotherapy). In patients receiving, and complying with optimal doses of a single antiepileptic drug, the addition of further agents is likely to result in a significant (>75%) improvement in seizure control in only approximately 10% of patients. Such a policy, however, inevitably increases the risks of dose-related, idiosyncratic reactions and chronic drug toxicity. Therefore, even when it is anticipated that multiple drug therapy will be required, medication is initiated with a single drug with gradual increases in the dose (over 2 to 3 months) until seizures are controlled. If a single drug fails to control seizures it should not be replaced by another drug unless obvious toxicity or monitoring of drug concentration in plasma indicate that the patient is actually taking the medication as prescribed. If seizures continue despite high optimum blood levels after a single drug, either a second drug is added with a similar increase of the dose or to rapidly achieve optimum blood levels of the second drug and then gradually (to minimize the risk of precipitation of status epilepticus) withdraw the first drug. If 61 seizures continue despite optimum use of the two drugs, it is advisable not to add further drugs, but to explore nonpharmacological measures. It should be expected that some patients will continue to have seizures despite an optimum level of one or two drugs. Because of the many physical changes that take place as the child grows, it is not unusual for a seizure-free child to start having seizures again. This does not mean that medication is not effective or that the condition is getting worse, usually a change in the dose will control the seizure episodes. Abrupt withdrawal. Effective therapy must never be stopped suddenly either by the doctor or by the patient, or status epilepticus may occur. But if sudden withdrawal is imposed by occurrence of toxicity, a substantial dose of another antiepileptic should be given at once. This trial of drug after drug should be continued until the epilepsy is controlled, or until there are no more drugs to try. Up to 3 months may be needed to try a drug thoroughly in an individual. In cases where fits are liable to occur at a particular time of day, dosage should be adjusted to achieve maximal drug effect at that time. The patient should keep a diary of seizures. 62 Pharmacokinetic Principles Dose planning for individual antiepileptic drugs depends on pharmacokinetics factors that determine the amount of available drug in the blood. The therapeutic range refers to the range of steady state levels of each drug that by trial and error have been most effective in controlling seizures with minimal or no side effects. The proper dose schedule for a newly introduced drug depends on balancing the need for rapid control of seizures against the avoidance of side effects. It is more important that the patient accept the drug of first choice. Patient can be encouraged to remain on medication by beginning a drug regimen slowly, taking the medication with meals when nausea is anticipated, using higher doses at bedtime when sedation is anticipated, and reducing doses transiently when ultrasound side effects occur. A loading dose can be given practically for some drugs (phenytoin and phenobarbital) when the risk of repeated seizures requires therapeutic levels to be achieved rapidly despite side effects. Maintenance of steady-state level of a drug can be achieved with an interdose interval of approximately one-half life. A dose schedule that requires a drug to be taken too frequently may be inconvenient and reduces compliance. An interdose interval of 0.5 half-lives, which amounts to one to four times a day for the commonly used medication is usually recommended. Therapeutic failure using, recommended dose schedules most commonly reflects noncompliance by the 63 patient, but also may result from aberrant absorption and metabolism. Dose schedules must then be determined individually from measurement of serum drug levels. The recommended therapeutic range for a given drug is based on average measures. Once an effective maintenance schedule has been achieved, determination of serum drug level, always drawn at some time after a given dose, provide a reliable long-term record in steady state conditions. Such measurements are useful when recurrent seizures or side effects result from a decrease or an increase in the dose of the drug. Routine drug concentration monitoring is particularly useful with phenytoin (which shows saturation kietics). It is seldom really useful with other drugs unless there is a specific problem to be solved. Unnecessary monitoring wastes expensive resources. Monitoring is useful in the following circumstances: 2-4 weeks after commencing therapy When fits occur with standard dosage: the patient may be noncompliant, or compliant and simply needs a higher dose of the drug When adverse effects occur When sodium valproate is added to another drug (pharmacokinetic interaction) When another antiepileptic drug is withdrawn in the presence of sodium valproate 64 During pregnancy When there is hepatic or renal disease. Note. Many patients are controlled at plasma concentrations below the lower limit of the therapeutic range, and substantial diurnal fluctuations may occur. Starting therapy Antiepileptic treatment has been previously advocated before seizure occurance. Such a prophylactic measure has been undertaken in patients with a high prospective risk of epilepsy after head injury and craniotomy. Today single seizures are not routinely treated. This practice is based on information from hospital-based surveys that indicate a 20-30% risk of a second seizure within 1-2 years of a first unprovoked seizure. However, data from less selected populations suggests that up to 80% of patients with a single seizure experience a recurrence. Where two or more unprovoked seizures have occurred within a short interval, antiepileptic therapy is usually indicated. Problems do, however, arise in defining a short interval. Most physicians would include period of 6 months to 1 year within the definition, but difficulties arise regarding whether seizures which occur in widely separated periods of time demand therapy or not. Even when seizures occur in a close temporal relationship, the identification of specific precipitating factors may make it more 65 important to counsel patients than to commence drug therapy. The most common examples are febrile convulsions in children and alcohol-withdrawal seizures in adults. Less frequently seizures may be precipitated in photosensitive subjects by television and other photic stimuli. Withdrawal Considering that approximately 70% of patients achieve long-term remission there is remarkably little data on the success or failure rates following stoppage of antiepileptic therapy. Overall, approximately 20% of children and 40% of adults are likely to relapse when anticonvulsants are withdrawn after a seizure-free period of 2 years or more. Some factors seem likely to influence outcome. These include the duration of epilepsy and frequency of seizures prior to the onset of remission, and whether the epilepsy is symptomatic of an underlying cerebral disorder. The influence of different seizure types on outcome and the question whether the EEG may be predictive of outcome remain controversial, at least in the adult patients. To date it is hardly possible to identify groups of patients who are particularly at high or low risk for relapse after discontinuation of therapy. There is no indication of whether there is an optimal period for continuing therapy while patients are in remission before 66 drugs are withdrawn. It is also hardly possible to define an optimal rate at which anticonvulsants should be withdrawn. Abrupt withdrawal of antiepileptic drugs should be avoided as this can cause increased seizure frequency and severity. Barbiturates and benzodiazepines are the most difficult to discontinue. Reduction in dosage should be carried out over weeks and in the case of barbiturates, the withdrawal process may take months. The change over from one antiepileptic drug regimen to another should be made cautiously, withdrawing the first drug only when the new regimen has been largely established. In patients receiving several antiepileptic drugs, only one drug should be withdrawn at a time. The decision to withdraw all antiepileptics from a seizure-free patients, and its timing, is often difficult and may depend on individual patient factors. Even in patients who have been seizurefree for several years, there is a significant risk of seizure recurrence on drug withdrawal. However, if a patient is seizurefree for 3 or 4 years, gradual discontinuance is usually warranted. Overdose Antiepileptic drugs are central nervous system depressants, but are rarely lethal. Highly elevated plasma levels are usually necessary before overdoses can be considered life-threatening. Respiratory depression is the most serious side effect seen after large overdoses 67 of antiepileptics. Treatment of antiepileptic drug overdose is supportive; stimulants should not be used. In addition, urine alkalinization is usually ineffective to hasten removal of antiepileptic drugs. Common causes of failure of antiepileptics Improper diagnosis of the type of seizures. Incorrect choice of drug. Inadequate or excessive dosage. Poor compliance by the patients. Pregnancy, hormonal contraception and anticonvulsants The overall risk of birth defects in mothers who take an anticonvulsant is around 5%, higher than in the general population. Counseling before conception is essential. Some women choose to withdraw the anticonvulsants prior to becoming pregnant. If drugs are continued, monotherapy with a first-line drug is advisable together with folic acid (5 mg a day) as supplement. Vitamin K (20 mg) orally should also be prescribed daily to the mother during the week prior to delivery, to prevent neonatal haemorrhage, caused by inhibition of vitamin K transplacental transport. 68 Anticonvulsants which induce hepatic enzymes (carbamazepine, phenytoin and phenobarbitone) reduce efficacy of the contraceptive pills. A combined contraceptive pill containing at least 50 g of oestrogen, or an IUCD or barrier methods of contraception, should be used. Treatment with antiepileptic drugs during pregnancy The effects of pregnancy on the antiepileptic drug disposition were studied in humans and animals, but the results reported showed great variability. At constant drug dosage the serum level of most antiepileptic drugs tends to decrease during pregnancy, but returns to pre-pregnancy levels within the first month after delivery. It is a common practice to increase dosage whenever the plasma levels of antiepileptic drugs are low. However, a decrease in plasma levels of antiepileptic drugs alone does not generally justify an increase in dose. The overall clinical state should be assessed. Recent studies suggest that total carbamazepine serum levels are slightly lower during the third trimester as compared with baseline, whereas the unbound, pharmacologically active concentration remains essentially unchanged. In contrast, while total phenytoin serum levels decrease steadily as pregnancy progresses, unbound 69 levels decrease far less. Total valproate serum levels also decrease as pregnancy proceeds, but the change in unbound concentrations may be significant. Serum levels of ethosuximide usually remain fairly constant during pregnancy. Recent findings indicate that total serum levels may be misleading, and that monitoring of unbound concentrations may be advantageous during pregnancy. Thus, preferably both total and unbound serum levels should be closely monitored (once a month in patients with unstable seizure control and less frequently in well controlled patients) to determine the lowest effective dose and to avoid the harmful effects of seizures and drugs to the mother and fetus. The changes in the pharmacokinetics of antiepileptic drugs occurring during pregnancy may be due to decreased absorption of the drugs, changes in the volume of distribution, protein binding and hepatic elimination capacities. The use of antiepiliptic drugs must be continued throughout the entire gestational period. Hence, changes in their pharmacokinetics during pregnancy may have important consequences both on the mother and the fetus. A pregnant woman with epilepsy should be treated, whenever possible, with a single antiepileptic drug, with the lowest effective 70 dosage that protects against tonic-clonic seizures. All major changes in medication, if possible, should be made prior to pregnancy. Treatment during pregnancy demands a balance between the possible teratogenic effects of antiepileptic drugs and the hazards of seizures to mother and the foetus. In recent years there has been an increased concern about the potential teratogenic effects of antiepileptic drugs. A number of epidemiological surveys in various parts of the world have reported an increase in the incidence of cleft palate/lip, skeletal anomalies, congenital heart disease, central nervous system abnormalities, mental retardation and genitourinary anomalies in offsprings born to mothers with epilepsy who are receiving antiepileptic drugs during pregnancy when compared to the normal population. Neonates born to mothers with epilepsy who have been treated with antiepileptic drugs are at an increased risk of haemorrhage. Neonatal hemorrhage can be prevented by giving women vitamin K during pregnancy. Studies have shown that children born to mothers with epilepsy who had been taking drugs had roughly twice as many 71 malformations as children of mothers in the population as a whole. Since about 3% of all newborn babies have a significant congenital abnormality the chance of the child of a mother with epilepsy having a significant abnormality are about 6%. It is probably more encouraging to talk to the mother in terms of a 94% chance of having a normal child. It is difficult in such a situation to determine whether the increased malformation rate is due to the disease or to the drugs used in its treatment. Apart from the possibility of a genetic association between epilepsy and the risk of fetal abnormality, seizures could cause fetal damage through hypoxia or associated trauma. Fetal monitoring during a maternal tonic-clonic seizure lasting three minutes showed that the onset of the seizure was immediately followed by fetal bradycardia lasting about 15 minutes. Prolonged maternal seizures, or status epilepticus, could therefore harm the fetus. However, the incidence of malformations is higher in epileptics receiving drug treatment during the relevant pregnancy. The evidence certainly seems fairly strong that the antiepileptic drugs are teratogenic and this is supported by studies had been carried out on these drugs in animals. 72 All established major antiepileptic drugs (phenobarbital, phenytoin, carbamazepine, ethosuximide and valpoate) have a teratogenic potential. However, the available clinical data on the use of the new drugs in human pregnancy are very limited and mainly confined to new drugs used in combination with established antiepileptic drugs. The documentation is not sufficient to allow definitive conclusions on the teratogenic potential and profile, and on the pharmacokinetics of the new drugs during pregnancy to be drawn. The prevalence of malformations appears to increase with increasing numbers of antiepileptic drugs used concomitantly. Hence, it is advisable to simplify anticonvulsant regimens to avoid adverse effects and possible interactions between drugs. Breast-feeding and antiepileptic drugs Phenytoin The levels of phenytoin in breast milk are much lower than in the mother’s plasma, and the serum levels in nursing infants are generally below the therapeutic levels. The clearance of phenytoin in newborn infants who have been exposed to the drug prenatally 73 has been shown to be comparable to that in adults. Excessive accumulation of the drug in infants would therefore not be expected. Hence, there appears to be no risk to nursing infants if phenytoin is given to the mother as monotherapy in normal doses. Phenobarbital and Primidone Phenobarbital, given directly or formed from primidone is transferred via breast milk and can accumulate in the nursing infant’s plasma. The elimination of phenobarbital and primidone in neonates varies greatly. Enzymes induction may play an important role. Infants who have been exposed to phenobarbital or other drugs that induce liver microsomal enzymes prenatally had generally show much shorter half-lives for phenobarbitone or primidone than in the unexposed neonates. Due to the slow elimination of phenobarbital, especially in the first weeks of life, accumulation of the drug to relatively high levels in the infant’s plasma is possible. Sedation of the nursing infants is seen during maternal use of phenobarbital. Therefore, close monitoring of the infant by determining the serum levels of phenobarbital is recommended. 74 Carbamazepine Serum levels of carbamazepine in nursing infants have been found to be low in general. Hence, breast feeding is considered to be safe when the mother is on carbamazepine monotherapy at normal doses. Ethosuximide Ethosuximide levels in breast milk are similar to those in maternal plasma. It can be transferred via breast milk to the child in relatively high concentrations, and plasma concentrations in nursing infants can be close to the recommended therapeutic levels. However, it is not clear if such high concentrations would be associated with any risk to the nursing child. Close monitoring of the child is recommended, and plasma concentration measurements may be useful. Valproic acid Concentrations of valproic acid in breast milk are low, usually less than 10% of the concentrations in maternal plasma. Serum levels of valproate in the nursing infant are low and not likely to cause any adverse effects. However, the possibility of idiosyncratic reactions, even to low doses should be observed. 75 Clonazepam Levels of clonazepam in breast milk have been reported to be 1:3 or 0.37 of the maternal plasma levels. These ratios are slightly higher than those reported for diazepam (0.10 - 0.20). Respiratory depression was reported in some infants who had been exposed to clonazepam during pregnancy. Lamotrigine, vigabatrin, gabapentin and felbamate. Lamotrigine is to a large extent glucuronidated via the so-called UDP - glucuronyl transferase. In the newborn, the capacity to glucuronidate is not fully developed, but increases gradually during the first months of life. Hence, it is likely that the infant’s ability to eliminate lamotrigine will be affected. Vigabatrin and gabapentin are mainly excreted unchanged in the urine. It is unlikely that infants with fully developed renal function will accumulate these drugs. Felbamate should be avoided during breast feeding, because of the risk of serious haematological adverse effects to the infant, which are probably not directly related to the drug concentrations in plasma. Index absence seizure (petit mal), 1 acetylcholine, 51 76 alopecia, 37 Alzheimer’s disease, 3 -aminobutyric acid (GABA), 29, 49 anorexia, 54, 57 antacids, 16, 53 anticoagulants, 17, 21 antihistamines, 43 aplastic anaemia, 13, 40 arrythmias, 22 ataxia, 18, 24, 31, 47, 52 atonic seizures, 10 benzodiazepines, 4, 13, 21, 41-43, 45, 66 blood brain barrier, 30 blood dyscrasias, 40 brain tumor, 3 breast milk, 72-75 breast-feeding, 72, 74-75 carbamazepine, 13, 20-21, 23-24, 26-28, 38, 48-49, 53-55, 58-59, 68, 72, 74 cardiac depression, 42 cardiovascular collapse, 18 catecholamine, 51 cerebral abscess, 3 chloramphenicol, 20, 21 chlorazepate dipotassium, 44 cimetidine, 20, 21, 26, 27 cimetidine, 21, 27 cleft lip, 18, 70 cleft palate, 18, 70 clobazam, 13, 45 clonazepam, 13, 24, 27, 38, 43-44, 59, 75 complex partial seizures, 7, 32, 44 77 constipation, 54 Developmental anomalies, 2 diarrhea, 7, 54 diazepam, 11, 13, 32, 42-43, 59, 75 dicumarol, 20, 21, 31 digitalis, 22, 31 Diltiazem, 26 diplopia, 18, 24, 28, 47, 57 dizziness, 24, 40, 52, 56, 57 drowsiness, 18, 24, 44, 5 dyspepsia, 54 electroencephalogram (EEG), 4, 12, 14, 65 encephalitis, 3 eosinophilia, 40 erythromycin, 26, 27 ethinylestradiol, 58 ethosuximide, 27, 39, 40-41, 44, 59, 59, 72, 74 euphoria, 40 febrile seizures, 10, 32, 59 felbamate, 13, 46, 53-55, 59, 75 fetal bradycardia, 71 first-order kinetics, 16 gabapentin, 46, 51-52, 59, 75 GABA-transaminase, 35, 39 generalized seizures, 3, 6, 8, 32, 55 generalized tonic-clonic seizures, 6, 10, 12, 22, 27, 32, 34,38, 48, 56 Gingival hyperplasia, 17 glucuronide, 16, 47 glucuronyl transferase, 75 glutamate, 29, 46 78 glutamic oxaloacetic transaminase (GSGOT), griseofulvin, 31 heart burn, 36 hemorrhage, 2, 31, 70 hepatic impairment, 48, 56-57 hepatotoxicity, 37 hirsutism, 18 hydantoin fetal syndrome, 19 hyperammonemia, 37 hyperglycemia, 2, 18, 37 hypersensitivity reactions, 18, 31 hyperthermia, 3 hyponatraemia, 2, 25 imipramine, 23, 48 infantile spasm, 32, 44 insomnia, 54 isoniazid, 20, 21, 26, 27 Jacksonian epilepsy, 7 juvenile myoclonic, 9 Ketogenic diet, 13 lamotrigine, 13, 46-49, 59, 75 Lennox-Gastaut syndrome, 12-13, 44, 49, 55 lethargy, 40, 44 leukopenia, 25, 33, 54 lymphadenopathy, 18, 47 megaloblastic anemia, 18, 33 mental retardation, 2, 12, 55, 70 meprobamate, 53 metabolic abnormalities, 2 79 37 microsomal enzymes, 17, 21, 24, 30, 32, 56, 73 myoclonic, 9, 12-13, 38, 43-44, 49, 59 neonatal bleeding, 25, 37 neurosyphilis, 3 nitrazepam, 13, 44 opioid receptors, 51 oral anticoagulants, 17 oral contraceptives, 17, 27, 30 osteomalacia, 18, 31 overdose, 4, 31, 66-67 pancytopenia, 40 paradoxic hyperactivity, 42 Parkinson’s disease, 49 partial seizures, 6, 22, 27, 32, 34, 44, 38, 44, 50, 52, 58 peripheral neuropathy, 28 phenobarbital, 27, 29-34, 37-38, 48, 59, 62, 72, 73 phenylbutazone, 21 phenylethyl malonamide, 32, 33 phenylketonuria, 2 Phenytoin, 13, 15-20, 21-23, 27-29, 31-34, 37-38, 48-50, 53-55, 58-59, 62-63, 68, 72-73 photosensitivity, 4 pregnancy, 25, 37, 47, 52, 54, 64, 67-72, 75 primary epilepsy, 4, 5 primidone, 24, 27, 32-34, 48, 59, 73 propoxyphene, 26, 27 Psychomotor epilepsy, 7 rash, 33, 37, 47, 54 rebound seizures, 31 respiratory depression, 42-43, 66, 75 secondary epilepsy, 5 80 simple partial seizures, 7, 32 skin rashes, 18, 25 somnolence, 47, 52 starting therapy, 40, 64 status epilepticus, 12, 16, 19, 22, 32, 42-43, 59-61, 71 steroids, 30 Stevens-Johnson syndrome, 25, 40, 54 succinic semialdehyde dehydrogenase, 35 sulfonamides, 20, 21 systemic lupus erythematosus, 33, 40 teratogenesis, 25 teratogenic effects, 28, 70 thrombocytopenia, 33, 37, 54 tiagabine, 46, 55-56 toleandomycin, 27 tolerance, 13, 31, 42 tonic-clonic seizures, 6, 9, 22, 27, 32, 34, 40, 48, 56, 70 topiramate, 46, 56, 57, 58 tricyclic antidepressants, 4, 23, 30 trigeminal neuralgia, 22-23, 27-28 tuberculosis, 3 valproic acid, 13, 16, 24, 27, 32, 35-38, 40, 48, 74 venous thrombosis, 3 vertigo, 18, 31 vigabatrin, 13, 46, 49-50, 75 visual disturbances, 50, 57 vitamin D, 18 vitamin K, 25, 67, 70 warfarin, 27, 30 weight gain, 50 weight loss, 54, 57 withdrawal, 4-5, 15, 31, 47, 54, 61, 65-66 81 zero-order kinetics, 16 REFERENCES: Al-Humayyd, M.S. 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