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ANTIEPILEPTIC DRUGS(ANTICONVULSANT).pptx

This presentation explores epilepsy as a neurological disorder of recurrent seizures. It explains seizure classification, etiology, pathophysiology, and clinical presentation. The therapeutic section details non-pharmacological interventions and a wide range of antiepileptic drugs including their mechanisms, dosing, and adverse effects. It also includes treatment algorithms and clinical considerations for optimized patient care.

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ANTICONVULSANT DRUGS Prepared by:- SATENDRA PRADHAN Research Scholor Department of Pharmacology Rungta Institute of Pharmaceutical Science Bhilai
INTRODUCTION  The word “epilepsy” comes from the Greek word meaning “to seize” and is used to describe a disorder of recurrent seizures due to a chronic, underlying cause.
3 Definition  A “seizure” is defined as the clinical manifestation of excessive or hyper synchronous activity of neurons within the cerebral cortex.  Epilepsy is a disorder that is viewed as a symptom of disturbed electrical activity in the brain caused by a wide variety of etiologies.  It is a collection of many different types of seizures that vary widely in severity, appearance, cause, consequence, and management.
4 The superficial (peripheral) part of the cerebrum is composed of nerve cell bodies or grey matter, forming the cerebral cortex.
5 EPIDEMIOLOGY  The lifetime prevalence of epilepsy is approximately 3%.  The incidence is highest in the first 10 years of life and declines thereafter to the age of 50 when the incidence increases again.  Epilepsy begins before the age of 18 in more than 75% of individuals.  The rate of recurrence of a first unprovoked seizure within 5 years ranges between 23% and 80%.
6 Contd……  Epilepsy is a chronic disorder characterized by recurrent seizures.  The age-adjusted incidence of epilepsy is 44 per 100,000 person-years.  Each year, about 125,000 new epilepsy cases occur;  Of these, 30% are in people younger than age 18 at the time of diagnosis.  At least 10% of patients in long-term care facilities are taking at least one antiepileptic drug (AED).
7 CLASSIFICATION  The International League Against Epilepsy (ILAE) has proposed two major schemes for the classification of seizures and epilepsies:  International Classification of Epileptic Seizures  International Classification of the Epilepsies and Epilepsy Syndromes.
8 International Classification of Epileptic Seizures  I. Partial seizures (seizures begin locally) A. Simple (without impairment of consciousness)  1. With motor symptoms  2. With special sensory or somato sensory symptoms  3. With psychic symptoms B. Complex (with impairment of consciousness)  1. Simple partial onset followed by impairment of consciousness—with or without automatisms  2. Impaired consciousness at onset—with or without automatisms C. Secondarily generalized (partial onset evolving to  generalized tonic-clonic seizures)
9  II. Generalized seizures (bilaterally symmetrical and without local onset)  A. Absence  B. Myoclonic  C. Clonic  D. Tonic  E. Tonic-clonic  F. Atonic  G. Infantile spasms
10  III. Unclassified seizures  IV. Status epilepticus
11  Generalized absence seizures are manifested:  by a sudden onset,  interruption of ongoing activities,  a blank stare,  and possibly a brief upward rotation of the eyes.  They generally occur in young children through adolescence.
12  Partial seizures with an alteration of consciousness are de-scribed as complex partial.  With complex partial seizures, the patient may have automatisms, periods of memory loss, or aberrations of behavior.  Complex partial seizures also may progress to GTC seizures.  Patients with complex partial seizures typically are amnestic to these events.
13 Generalized seizures  Generalized seizures have clinical manifestations that indicate involvement of both hemispheres.  Motor manifestations are bilateral, and there is a loss of consciousness.  Generalized seizures may be further subdivided by EEG and clinical manifestations.  A partial seizure that becomes generalized is referred to as a secondarily generalized seizure.
14 Generalized tonic clonic seizures  The seizure results in a sudden sharp tonic contraction of muscles followed by a period of rigidity and clonic movements.  During the seizure,  the patient may cry or moan, lose sphincter control, bite the tongue, or develop cyanosis.  After the seizure, the patient may have altered consciousness, drowsiness, or confusion for a variable period of time (postictal period) and frequently goes into a deep sleep.  Tonic and clonic seizures may occur separately
15 Myoclonic  Brief shock like muscular contractions of the face, trunk, and extremities are known as myoclonic jerks.  They may be isolated events or rapidly repetitive.  A sudden loss of muscle tone is known as an atonic seizure.  This may be described as a head drop, the dropping of a limb, or a slumping to the ground.  These patients often wear protective head ware to prevent trauma.
16 Status Epilepticus  status epilepticus (SE) is a life-threatening condition in which the brain is in a state of persistent seizure.  Traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures for greater than 5 minutes.  It is always considered a medical emergency.
17 The International Classification of Epilepsies and Epilepsy Syndromes  Adds components such as age of onset, intellectual development, findings on neurologic examination, and results of neuro imaging studies to define epilepsy syndromes more fully.  Syndromes can include one or many different seizure types (e.g., Lennox Gastaut syndrome).  The syndromic approach includes seizure type(s) and possible etiologic classifications (e.g., idiopathic, symptomatic, or unknown).
18 ETIOLOGY  Seizures small numbers of neurons discharge abnormally.  Normal homeostasis of neuron  disruption disturbs its stability trigger abnormal activity and seizures. Patients with mental retardation and cerebral palsy are at increased risk for seizures.
19 Contd….  In the elderly, seizures are primarily partial in onset.  The causes of seizures in the elderly may be multifactorial and include cerebrovascular disease (both ischemic and hemorrhagic stroke),  Neurodegenerative disorders, tumor, head trauma, metabolic disorders, and CNS infections.  In some cases, if an etiology can be found and corrected, the patient will not require chronic AED treatment.
20  Hyperventilation may precipitate absence seizures.  Sleep, sleep deprivation, sensory stimuli, and emotional stress may initiate seizures.  Hormonal changes occurring around the time of menses, puberty, or pregnancy have been associated with the onset of or an increased frequency of seizures.  Children who are small for gestational age or with neonatal seizures are also at increased risk for developing epilepsy.
21  In many cases, patients will present with seizures that do not have an identifiable cause and thus have idiopathic epilepsy.  The incidence of idiopathic epilepsy is higher in children. The most clearly established risk factors for epilepsy in all age groups are head trauma (especially in patients in whom the dura mater has been breached  and in whom there is evidence of loss of conciousness), CNS infections, and stroke.
22  A careful history should be obtained from patients presenting with seizures because ;  theophylline,  alcohol,  high-dose phenothiazines,  antidepressants (especially  maprotiline or buproprion), and street drug use have been associated with provoking seizures.  Also, AEDs in toxic concentrations may cause seizures in certain patients.
23 Common Causes of New-Onset Seizures  Primary or Acquired Neurological Disorders Alzheimer's disease or other neurodegenerative diseases Brain tumor Central nervous system infection Cerebro vascular disease Febrile seizures of childhood Genetic or developmental disorders Head trauma
24  Hepatic failure Hypocalcemia Hypoglycemia Hypomagnesemia Hyponatremia Porphyria Renal failure  Alcohol abuse and withdrawal Anoxia or ischemia Drug overdose or toxicity
25 Drugs That Have Been Associated With Provoking or Drugs That May Exacerbate Seizures  Anti arrhythmic agents (class 1B) Antimicrobials β-Lactams and related compounds Isoniazid  Quinolones  Antivirals Acyclovir Ganciclovir  Drugs of abuse Amphetamine Cocaine Ephedra Methylphenidate
26  Psychotropic agents Antidepressants Antipsychotics Lithium Sedative-hypnotic drug withdrawal Alcohol Barbiturates (short-acting) Benzodiazepines (short-acting)
27  Miscellaneous Cyclosporine Lindane Flumazenil Metoclopramide Normeperdine (accumulation in renal failure) Radiographic contrast agents Theophylline Tramadol.
28 PATHOPHYSIOLOGY  Seizure activity is characterized by paroxysmal discharges occurring synchronously in a large population of cortical neurons.  The seizure originates from the gray matter of any cortical or perhaps subcortical area.  Initially, a small number of neurons fire abnormally. Normal membrane conductances and inhibitory synaptic currents break down, and excess excitability spreads, either locally -to produce a focal seizure  or more widely to produce a generalized seizure.
29 CONTD… The clinical manifestations depend on the  site of the focus,  the degree of irritability of the surrounding area of the brain,  and the intensity of the impulse.  An abnormality of potassium conductance,  a defect in the voltage-sensitive ion channels,  or a deficiency in the membrane ATPases linked to ion transport may result in neuronal membrane instability and a seizure.
30  Selected neurotransmitters (e.g., glutamate, aspartate, acetylcholine, norepinephrine, histamine, corticotropin-releasing factor, purines, peptides, cytokines, and steroid hormones) enhance the excitability and propagation of neuronal activity,  whereas γ -aminobutyric acid (GABA) and dopamine inhibit neuronal activity and propagation.
31  A relative deficiency of inhibitory neurotransmitters such as GABA  an increase in excitatory neurotransmitters such as glutamate ABNORMAL NERONAL ACTIVITY
32 Control of abnormal neuronal activity with AEDs is accomplished by :  elevating the threshold of neurons to electrical or chemical stimuli or  by limiting the propagation of the seizure discharge from its origin.  Raising the threshold stabilization of neuronal membranes,  limiting the propagation depression of synaptic transmission and reduction of nerve conduction.
33  During a seizure, there is a large increase in the demand for blood flow to the brain to carry off CO2 and to bring substrates for neuronal metabolic activity.  The more prolonged the seizure, the more likely the brain is to suffer ischemia that may result in neuronal destruction and brain damage.  Also, the continued exposure to glutamate, an excitatory neurotransmitter, may contribute to neuronal damage.
34 CLINICAL PRESENTATION  SYMPTOMS  Symptoms of a specific seizure will depend on seizure type.  While seizures can vary between patients.  Complex partial seizures may include somatosensory or focal motor features. • Complex partial seizures are associated with altered conciousness.  Absence seizures may appear relatively bland, with only very brief (seconds) periods of altered conciousness.  Generalized tonic-clonic seizures are major convulsive episodes and are always associated with a loss of conciousness.
35  Idiopathic describes syndromes that are presumably genetic but also those in which no underlying etiology is documented or suspected.  A family history of seizures is commonly present, and neurologic function is essentially normal except for the occurrence of seizures.
36  Symptomatic cases involve evidence of brain damage or a known underlying cause.  A cryptogenic syndrome is assumed to be symptomatic of an underlying condition that cannot be documented.
37  Unknown or undetermined is used when no cause can be identified.  This syndromic classification is more important for prognostic determinations than for a classification based simply on seizure type.
38 DIAGNOSTIC TESTS  EEG is very useful in the diagnosis of various seizure disorders.  The EEG may be normal in some patients who still have the clinical diagnosis of epilepsy.  While MRI is very useful (especially imaging of the temporal lobes), CT scan typically is not helpful except in the initial evaluation for a brain tumor or cerebral bleeding.
39  TREATMENT
40 NONPHARMACOLOGIC THERAPY  includes :  diet,  surgery,  vagal nerve stimulation  (VNS), which is implantation of a vagal nerve stimulator.  A vagal nerve stimulator is an implanted medical device approved for use in epilepsy.
41  most common side effect associated with stimulation; voice alteration,  increased cough,  pharyngitis,  dyspnea,  dyspepsia,  and nausea.
42  Serious adverse effects reported include ;  infection,  nerve paralysis,  hyesthesia,  facial paresis,  left vocal chord paralysis,  left facial paralysis,  left recurrent laryngeal nerve injury,  urinary retention,  low-grade fever.
43  Surgery is the most widespread and most useful non pharmacologic therapy.  A focus in the temporal lobe has the best chance for a positive outcome; however,  extra temporal foci may be excised successfully in more than 75% of patients.  The procedure is not without risk.  Learning and memory are most susceptible to impairment postoperatively
44 Contd..  general intellectual abilities are also affected in a  small number of patients.  Surgery may be particularly useful in children with intractable epilepsy.  Patients may still need to receive AED therapy for a period of time following successful epilepsy surgery in order to prevent seizure recurrence.
45 Diet  Protein and calorie intake are set at levels that will meet requirements for growth.  Most of the calories are provided in the form of heavy cream and butter.  No sugar is allowed.  Vitamins and minerals are supplemented.  Medium-chain triglycerides may be substituted for the dietary fats.  Fluids are also controlled.
46 Initiating Antiepileptic Drug Therapy  AEDs are more frequently associated with adverse effects during initiation of therapy;  therefore, treatment should begin with low doses and the dose should be gradually escalated according to the patient's clinical status.  When therapy is initiated too aggressively, patients may experience uncomfortable adverse effects and are often unwilling to continue treatment with that agent despite a reduction in dosage
47 ALGORITHM FOR THE TRAETMENT OF EPILEPSY
48 Diagnosis of epilepsy Begin treatment with 1 AED.choose AED based on seizure classification & types Box 3 Siezure free? Intolerable side effects Intolerable side effects yes No No Yes Optimal QOL? Decrease the AED dose Go to box 3 No Yes Increase AED dose Go to box 3 Decrease dose of Ist AED ADD II nd AED
49 Optimal QOL? Continue current treatment Explore QOL issues: refer appropriately Go to box 3 Siezure free for < than 2 years? Consider withdrawa l of AED Go to box 3 no yes yes no
50 Box 4 seizure free? Consider removing Ist AED go to box 3 Intolerable side effects Remove least effective AED Add another II nd AED Increase dose of II nd AED Check for interactions Check compliance Go to box 4 Seizure free? Continue current Rx or go to box 4 Reconfirm diagnosis Consider surgery or other AED s yes no yes no yes no
51 seizure type Partial Seizures Generalized Tonic-Clonic Absence Myoclonic, Atonic, Atypical Absence Drugs of choice Carbamazepin e Phenytoin Lamotrigine Oxcarbazepine Topiramateb Valproate Carbamazepi ne Phenytoin Topiramate Lamotrigine Ethosuximide Lamotrigine Valproate Valproate Lamotrigine Alternatives Gabapentinb Levetiracetam Phenobarbital Pregabalin Primidone Tiagabineb Valproate Levetiraceta m Phenobarbita l Phenytoin Primidone Clonazepam Clonazepam Topiramate Felbamate
52 ANTI EPILEPTIC DRUGS- SIDE EFFECTS..
53 Acute Side Effects AED Concentration Dependent Idiosyncratic Chronic Side Effects Carbamazepine Diplopia Dizziness Drowsiness Nausea Unsteadiness Lethargy Blood dyscrasias rash Hyponatremia Ethosuximide Ataxia Drowsiness Gl distress Unsteadiness Hiccoughs Anorexia Rash Blood dyscrasias Behavior changes Headache AED side effects…
54 AED Con dependent idosyncratic chronic Felbamate Anorexia Nausea Vomiting Insomnia Headache Aplastic anemia Acute hepatic failure Not established Gabapentin Dizziness Fatigue Somnolence Ataxia Pedal edema Weight gain Lamotrigine Diplopia Dizziness Unsteadiness Headache Rash Not established
55 AED Con dependent idiosyncratic chronic Levetiracetam Sedation Behavioral disturbance Not established Not established Oxcarbazepine Sedation Dizziness Ataxia Nausea Rash Hyponatremia Phenobarbital Ataxia Hyperactivity Headache Unsteadiness Nausea Sedation Blood dyscrasias Rash Behavior changes Connective tissue disorders Intellectual blunting Metabolic bone disease Sedation Mood change
56 AED Conc dep idosyncratic chronic Phenytoin Ataxia Behavior changes Nystagmus Dizziness Headache Incoordination Sedation Lethargy Cognitive impairment Fatigue Visual blurring Blood dyscrasias Rash Immunologic reaction Behavior changes Cerebellar syndrome Connective tissue changes Skin thickening Folate deficiency Gingival - hyperplasia Hirsutism Coarsening of facial features Acne Cognitive impairment Metabolic bone disease
57 AED Con dep idiosyncratic chronic PRIMIDONE Behavior changes Headache Nausea Sedation Unsteadiness Blood dyscrasias Rash Behavior change Connective tissue disorders Cognitive impairment Sedation TIAGABINE Dizziness Fatigue Difficulties concentrating Nervousness Tremor Blurred vision Depression Weakness Spike-wave stupor Not established
58 AED Con dep idiosyncratic chronic TOPIRAMATE Difficulties concentrating Psychomotor slowing Speech or language problems Somnolence, fatigue Dizziness Headache Metabolic acidosis Acute angle glaucoma Oligohidrosis Kidney stones Weight loss VALPROIC ACID Gl upset Sedation Unsteadiness Tremor Thrombocytopen Acute hepatic failure Acute pancreatitis Alopecia Polycystic ovary- like syndrome Weight gain Hyperammonem ia
59 AED Con dep idiosyncratic chronic ZONISAMIDE Sedation Dizziness Cognitive impairment Nausea Rash Oligohydrosis Kidney stones Weight loss
60 CLINICAL CONSIDERATIONS WITH SPECIFIC DRUGS  CARBAMAZEPINE  The absorption of carbamazepine from immediate-release tablets is slow and erratic because of its low water solubility.  There is no first-pass metabolism.  Food may enhance the bioavailability of carbamazepine.  The suspension dosage form is absorbed faster than the tablets.  Controlled-release (Tegretol-XR) and sustained-release (Carbatrol) preparations are also available. These dosage forms are bioequivalent in twice-daily (ev-ery 12 hours) dosing to dosing four times daily (every 6 hours) with immediate-release carbamazepine.  Patients should be told to take Tegretol-XR with food and that the casing will be excreted in the feces.  Tegretol-XR cannot be broken or crushed.
61  Carbamazepine Tegretol  Usual initial dose: 400 mg/day  Usual max. daily dose: 400–2400 mg  Target serum con range :4–14 mcg/mL  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.  The sustained- and controlled-release dosage forms allow for twice-daily dosing.
62  Carbamazepine has the unique ability to induce its own  metabolism (autoinduction). which requires careful dosage titration.  Carbamazepine should be considered a first-line therapy for patients with newly diagnosed partial seizures,  and for patients with primary generalized convulsive seizures who are not in an emergent situation.
63  ETHOSUXIMIDE  Metabolism occurs in the liver by hydroxy-lation, and the metabolites are believed to be inactive.  Ethosuximide usual initial dose:500 mg/day  Usual max daily dose: 500–2000 mg  Target serum con range:40–80 mcg/mL  A loading dose of ethosuximide is not required.  Titration over 1 to 2 weeks to maintenance doses of 20 mg/kg per day usually results in concentrations of approximately 50 mcg/mL.
64  The total daily dose is usually divided into two  equal doses.  This drug is very effective in the treatment of absence seizures. It is generally well tolerated and has few pharmacokinetic interactions.  Disadv :  Ethosuximide has a very narrow spectrum of activity
65  FELBAMATE  Felbamate is rapidly and well absorbed.  The absorption is unaffected by food or antacids.  About 40% to 50% of a dose of felbamate is metabolized by hydroxylation and conjugation pathways in the liver, with the remainder being excreted unchanged in the urine.  Drug Interactions: Felbamate inhibits the clearance and increases the serum concentration of phenytoin, valproic acid, and phenobarbital.
66  If felbamate is used as monotherapy, the dose is initiated at 1200 mg/day  (15 mg/kg in children) and then is increased by 600 mg every 2 weeks up to a maximum dose of 3600 mg (45 mg/kg in children).  Effective in treating patients with partial seizures.  This agent should be reserved for patients not responding to other AEDs.  Disadvantages. The use of felbamate is limited by the association with aplastic anemia and hepatotoxicity, as well as multiple drug interactions.
67  GABAPENTIN  Gabapentin is eliminated exclusively by the kidneys, dosage adjustments will be necessary in patients with significantly impaired renal function.  Typical starting doses of gabapentin are 300 mg at bedtime on the first day, increasing to 900 mg/day over 3 days.  Faster titration rates (e.g., starting at 300 to 900 mg three times daily) have been well tolerated.  Gabapentin has the additional advantages of a broad therapeutic index with minimal CNS adverse effects and no drug interactions.
68  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 diagnosed refractory patients, there may be a role for this drug in patients with less severe seizure disorders, such as new-onset partial epilepsy, particularly in the elderly patient.  Gabapentin also has been shown to be useful in the treatment of chronic pain and other nonepilepsy conditions.
69  LAMOTRIGINE  Lamotrigine is potentially a broad-spectrum AED, having efficacy in partial seizures as well as several types of generalized seizures.  A pediatric dosage form is available. It does not induce or inhibit the metabolism of other AEDs.  Lamotrigine has linear pharmacokinetics and is not highly protein bound.  Lamotrigine appears to be generally well tolerated in both children and elderly adult patients and does not cause weight gain.
70  Lamotrigine is useful as both adjunctive treat- ment in patients with partial seizures and as monotherapy.  useful alternative therapy in patients with primary generalized seizure types such as absence.
71  LEVETIRACETAM  Levetiracetam, an S-enantiomer pyrolidone derivitive, is chemically unrelated to other available AEDs.  Typical initial dosing of this agent is 500 mg orally twice daily, titrating at 1000-mg/day increments every 2 weeks to a maximum recommended dose of 3000 mg/day (1500 mg twice daily).  Currently, levetiracetam is indicated for pa-tients with partial seizures who have failed initial therapy.
72  OXCARBAZEPINE  Oxcarbazepine, which is structurally related to carbamazepine, is a prodrug that is rapidly converted to a 10-monohydrate derivative (MHD), which is the active component  In adults, the starting dose of oxcar-bazepine as monotherapy is 300 mg once or twice a day.  The dose is titrated upward at a rate of 600 mg/day per week to a maximum dose of 2400 mg/day.
73  For children aged 4 to 16 years, the starting dose is 8 to 10 mg/kg given twice daily, not to exceed 600 mg/day  The dose is titrated to the target dose over 2 weeks.  The recommended daily dose according to weight is 20–29 kg: 900 mg/day;  29.1–39 kg: 1200 mg/day;  greater than 39 kg: 1800 mg/day.
74  Oxcarbazepine is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and as monotherapy and adjunctive therapy in the treatment of partial seizures in patients as young as 4 years of age with epilepsy.  It is also a potential first-line drug for patients with primary generalized convulsive seizures.  Oxcarbazepine may be effective in patients not demonstrating a response to carbamazepine.
75  PHENOBARBITAL  Phenobarbital penetrates the brain at a rate comparable with that of phenytoin, and peak concentrations are achieved 3 to 20 minutes after an intravenous dose.  In nonacute situations, phenobar-bital should be started in low doses and titrated upward.  Because the half-life of pheno-barbital is long, doses can be given once daily.  Bedtime dosing may minimize CNS depression.  Because of its long half-life, phenobarbi-tal takes 3 to 4 weeks to reach steady state.
76  Therefore, rapid dosage adjustments should be avoided in a nonacute situation.  Phenobarbital is the drug of choice for neonatal seizures but in other situtations is reserved for patients who have failed other AEDs.  It may be useful given intravenously in refractory status epilepticus.
77  PHENYTOIN  Four dosage forms are used for oral administration of phenytoin .  The salt content should be considered when changing from one dosage form to another.  Changes between dosage forms may lead to changes in phenytoin concen-tration. Phenytoin capsules are designated as immediate-release or extended-release  Only the extended-release capsules should be used in once-a-day dosing.
78  Phenytoin has long been a first-line AED for primary generalized convulsive and partial seizures.  Its use in therapy may be reevaluated as more experience is gained with newer AEDs.  Phenytoin or fosphenytoin is a first-line drug for the treatment of status epilepticus.
79  VALPROIC ACID  Valproic acid is available as a soft gelatin capsule, an enteric-coated tablet, a syrup, a “sprinkle,” an extended- release formulation designed for once-daily dosing, and a parenteral (intravenous) for-mulation for replacement of oral therapy or in situations where rapid loading of valproic acid is deemed necessary.  Valproic acid is available in multiple dosage formulations. It has a wide therapeutic index and can be considered a broad-spectrum AED.  It also may be useful in other neurologic or psychiatric disorders, including migraine headache and bipolar- affective  disorder.
80  Valproic acid is first-line therapy for primary generalized seizures such as myoclonic, atonic, and absence seizures.  It can be used as both monotherapy and adjunctive therapy for partial seizures, and it can be very useful in patients with mixed seizure disorders
81  ZONISAMIDE  Zonisamide is currently approved for the adjunctive treatment of partial seizures.  Thus far, insufficient data exist to support its use as initial monotherapy.  potentially effective in a variety of partial and primary generalized seizure types,  The dose should be titrated slowly to patient response.  Renal stones and oligohydrosis also have been associated with zonisamide.
82  TOPIRAMATE  Topiramate is a sulfamate-substituted monosaccharide.  The kidney mainly eliminates it, although some liver metabolism occurs.  Topiramate is a second-line AED for patients with partial seizures who have failed initial therapy.  Its role as a primary AED and in other seizure types is being evaluated.  Starting doses are 12.5 to 50 mg/day, increasing by 12.5 to 50 mg/day every week or every other week.  The minimally effective dose of topiramate is approximately 200 mg/day.
83 EVALUATION OF THERAPEUTIC OUTCOMES  Patients should be chronically monitored for seizure control, side effects, social adjustment, drug interactions, compliance, quality of life, and toxicity.  Screening for neuropsychiatric disorders is also important.  Clinical response is more important than serum drug concentrations.  Patients should be asked to record severity and frequency of seizures in a seizure diary.
84  Outcomes can be assessed by prospective clinical monitoring, drug utilization review, and quality-of- life assessments.  Clinical monitoring involves identifying the number and type of seizures.  A therapeutic range should be established for each patient.  This range should define concentrations that result in minimal side effects and optimal seizure control.  This therapeutic plasma concentration range should be used to identify the appropriate patient specific dose.
85