New Antiepileptic Drugs for the Treatment of Epilepsy

Mark S. Yerby M.D., M.P.H.
North Pacific Epilepsy Research
Mother Joseph Plaza
9427 SW Barnes Road - Suite 595
Phone: 503-291-5300
Fax: 503-291-5303
Yerby@seizures.net

Clinical Associate Professor of Neurology, Public Health and Ob-Gyn
Oregon Health Sciences University

INTRODUCTION

Medical therapy remains the standard of treatment for most persons with epilepsy. Despite continued improvements in surgical techniques the fact the surgery is only effective for localization related epilepsy, requires extensive and expensive evaluation, and is irreversible leaves anticonvulsant treatment the preferred modality. With the seeming plethora of antiepileptic drugs (AED), one might wonder why new ones are desirable. New AED are necessary because only 80 % of persons with epilepsy are controlled with medication. A major limiting factor of AED are their side effects profiles. Epileptologists like to joke they can stop any patient's seizures if they use enough medication, but most persons find it difficult to function in a stuporous condition. We therefore welcome new medicines to our armamentarium. The next calendar year we can expect two to four new AED to be available for our patients. This article will review these compounds and their appropriate use.

HISTORICAL PERSPECTIVES

The first effective use of pharmacology to treat epilepsy was based on empirical models. The observation the potassium bromide could not only inhibit masturbation and sexual behavior but seizures as well led Sir Charles Locock (1857) to use it as an anticonvulsant. Though it possessed serious side effects: psychosis and dermatitis, it remained the only effective medical therapy for the next 55 years.

The development of Phenobarbital in 1912 permitted the use of a less toxic and more effective AED. Its efficacy led to the development of over 50 barbituric acid analogs over the next 25 years. One of which, mephobarbital was marketed in the United States in 1935.

The development of these drugs was based on empirical observation. One tried a compound on a patient and watched to see if it worked. If it did so then drugs from the same family were tried as well. The development of seizure models led to an entirely new method of evaluating potential AED. The discovery that faradic stimulation of experimental animals produced replicatable seizures (Albertoni 1882), began to be harnessed in screening potential compounds. The use of convulsant chemicals such as picrotoxin, bicuculline, strychnine, and pentylenetetrazol either intravenously or applied directly to the cerebral cortex provided researchers with additional models. These models made it possible to screen large numbers of different compounds for efficacy prior to applying them in humans.

Merritt and Putnam (1938), were the first to successfully utilize this technology. In the course of screening a large number of drugs using electrically induced seizures in cats, they discovered the anticonvulsant properties of diphenylhydantoin. After demonstrating efficacy and tolerability in experimental animals they conducted clinical trials in humans and the drug was marketed all in the same year!

Phenytoin and phenobarbital have a heterocyclic ring structure. The search for new AED focused on compounds with a similar structure. The oxazolidinediones, succinimides, and acetylureas are all variations on this theme. Continued AED development was based on the development of more sophisticated models. Goodman and Swinyard (1982) developed the concept of "threshold vs. spread". It appeared that the effectiveness of some AED was due to their ability to raise the seizure threshold. The model for this was the use of pentylenetetrazol to induce seizures in experimental animals (Porter and Nadi 1987). Drugs which do this such as ethosuximide are effective against absence seizures. In contrast drugs which limit seizure spread as demonstrated by the use of maximal electroschock (MES), models (phenytoin), are effective in partial and generalized tonic clonic seizures. All modern AED are initially tested using these experimental models.

Recent research has focused on the cellular biology of seizures. We now know that epileptiform neurons undergo paroxysmal depolarization shifts (PDS), which result in the excessive sustained neuronal firing seen in epilepsy. These shifts are due to either an impairment of GABA mediated inhibition, or an enhancement of aspartate or glutamate mediated excitatory transmission.

Gamma amino butyric acid (GABA) is the primary inhibitory neurotransmitter. Neurons have 2 types of GABA receptors "A" which open chloride channels and hyper polarize cells, and "B" which open K+ and Ca++ channels. If one modifies GABA one can modify seizure expression. Decreasing GABA synthesis which occurs with isoniazid, can lower seizure threshold. Impairment of GABA synthesis with penicillin, bicuculline, or picrotoxcin can also induce seizures. Increasing GABA therefore raises seizure threshold. A variety of mechanism are being explored to do just that. GABA does not cross the blood brain barrier, but a GABA prodrug progabide, does and holds some pothe seizure threshold. The model for this was the use of pentylenetetrazol to induce seizures in experimental animals (Porter and Nadi 1987). Drugs which do this such as ethosuximide are effective against absence seizures. In contrast drugs which limit seizure spread as demonstrated by the use of maximal electroschock (MES), models (phenytoin), are effective in partial and generalized tonic clonic seizures. All modern AED are initially tested using these experimental models.

Recent research has focused on the cellular biology of seizures. We now know that epileptiform neurons undergo paroxysmal depolarization shifts (PDS), which result in the excessive sustained neuronal firing seen in epilepsy. These shifts are due to either an impairment of GABA mediated inhibition, or an enhancement of aspartate or glutamate mediated excitatory transmission.

Gamma amino butyric acid (GABA) is the primary inhibitory neurotransmitter. Neurons have 2 types of GABA receptors "A" which open chloride channels and hyper polarize cells, and "B" which open K+ and Ca++ channels. If one modifies GABA one can modify seizure expression. Decreasing GABA synthesis which occurs with isoniazid, can lower seizure threshold. Impairment of GABA synthesis with penicillin, bicuculline, or picrotoxcin can also induce seizures. Increasing GABA therefore raises seizure threshold. A variety of mechanism are being explored to do just that. GABA does not cross the blood brain barrier, but a GABA prodrug progabide, does and holds some pot day, will by the fourth to fifth day have reached a point where the absorption and elimination are balanced and the mean plasma concentration remains stable. One needs to know a drug's half life to prescribe it effectively.

Therapeutic Range

The therapeutic range represents the plasma concentrations at which most drugs are effective for most people. At concentrations below the therapeutic range most persons will not receive a therapeutic response. At concentrations above this range most persons will develop clinical side effects or toxicity. The emphasis here is on most persons. The therapeutic range is derived statistically. It represents 2 standard deviations from the mean effective plasma concentration, As such there are some persons at both tails of the bell shaped curve who function quite well despite levels below or above the therapeutic range. A plasma concentration above the therapeutic range is not toxic. Only a patient can become toxic. Toxicity is a clinical condition not a lab test. The therapeutic range is an important guide to therapy, but we should treat our patients not lab tests.

Plasma Protein Binding

Most AED are highly bound to plasma proteins. It is the free or unbound portion that is available to cross the plasma membrane and the blood brain barrier. When one receives a plasma concentration from the laboratory it represents the total concentration. One can calculate the free concentration if you know the proportion of plasma protein binding. Usually this is not important because the proportions of free to bound drug are fixed. In some conditions however, significant changes in plasma protein binding can occur resulting in higher or lower than expected free concentrations and either inadequate protection from seizures or enough circulating drug to produce toxic symptoms. Renal and hepatic failure can result in higher than expected free levels, pregnancy in lower than expected ones. Co-medication particularly with other AED can lead to competition for plasma proteins and significant changes in free levels. Valproic acid for example has a very high affinity for plasma proteins and frequently raises the free level of concomitantly administered AED. One should be cognizant of the degree of plasma protein binding of the AEDs one uses.

Enzyme Induction

Most AED are metabolized via the hepatic microsomal enzyme system. Drugs or processes which inhibit this system result in higher than expected plasma concentrations. A classic example is the effect of co-medication of erythromycin with carbamazepine. Erythromycin inhibits hepatic microsomal enzymes resulting in elevated carbamazepine concentrations. AED such as phenytoin, phenobarbital, and carbamazepine tend to stimulate hepatic microsomal enzymes and increase the metabolism and clearance of concomitantly administered drugs. An example is the effect of such drugs on oral contraceptives. Enzyme inducing AEDs when given to women taking low or mini dose oral contraceptives can reduce estrogen concentrations to the point where ovulation is no longer inhibited. One needs to know whether or not the drug one is prescribing induces or inhibits microsomal enzymes.

Fundamentals of AED Use

In general one chooses the AED most appropriate for the patient's seizure type. One then introduces the drug gradually, dosing at half life intervals, until there is seizure control or the development of unacceptable side effects. If the first drug is not effective then a second one may be started in a similar fashion. If seizures are then controlled attempt to gradually reduce the first drug and ideally eliminate it entirely. Some patients may however require two drugs for effective seizure control. If the second drug is not effective, withdraw it before starting another medication.

These principles apply to both old or established as well as new AED. Most of the new AED have been tested in trials where they have been added on to existing therapy. We are therefore uncertain whether they are effective in monotherapy.

FELBAMATE (2-phenyl-1,3-propanediol dicarbamate) (Felbatol)

This drug is effective both against seizures produced by MES and pentylenetetrazol. It therefore appears to both increase seizure threshold and prevent spread. It appears to have low neurotoxicity (its LD50 is > 5000 mg/kg in rats), and minimal potential for the development of tolerance. It is non oncogenic in rodents, and appears to be non teratogenic in rat and rabbit models.

It has been approved for use in the treatment of partial seizures with or without secondary gerneralization in adults and for the treatment of Lennox Gastaut Syndrome in patients who have failed alternative therapies and have severe epilepsy. It is supplied in 400 and 600 mg tablets. There is little experience with doses over 3600 mg / dy. Most patients appear to have difficulty tolerating doses higher than that. The maximum recommended dose in children is 40 mg / kg.

Kinetics
The time to peak is 1 to 3 hours.
The half life is 14 to 22 hours, mean of 20 hours.
The therapeutic range has not been established.
The plasma protein binding is 24 - 35 %.
The kinetics are linear at doses up to 1600 mg/dy.
Fourteen to 24 % is excreted in the urine unchanged, metabolism is therefore extensive hence the opportunity for many drug interactions.

Drug Interactions
Felbamate increases phenytoin concentrations by approximately 20 %. It reduces carbamazepine concentrations, but elevates the levels of the carbamazepine 10 - 11 epoxide and thus can induce carbamazepine toxicity. It also increases the concentration of valproate in a dose response manner.

Adverse Experiences
The most commonly reported side effects are anorexia, insomnia and a sort of queasy gassy gastrointestinal disturbance. Weight loss has been seen usually in association with gastrointestinal upset but there also appears to be a central anorexia like phenomenon. These symptoms are more common when felbamate is used in polytherapy, and they are dose related responding well to dose reduction. Diplopia, dizziness, blurred vision, headache and ataxia have also been reported to occur more often in felbamate than placebo treated patients. A tolerance to many of these side effects occurs with time often dissipating over several weeks after the initial treatment.

The most serious adverse experiences have been aplastic anemia and hepatic failure. As of September of 1995 there have been approximately 170,000 exposures of individual patients to felbamate. Of these there have been 34 cases of aplastic anemia. Thirteen of the 34 have died. The estimated incidence is 1/4,000 to 1/5,000 giving a relative risk of 10 to 100. Most affect patients were women 22 of 34. Six of 34 have been treated with felbamate monotherapy. The time from initiation of treatment to onset of aplastic anemia averages 173 days ranging from 29 to 339 days. The mean dose was 3 grams/day. The youngest affected person was 14, but the mean age is 42 years. Some potential risk factors have been observed: a history of AED toxicity in 52%, a history of cytopenia in 42%, and a history of autoimmune disease in 33%.

Hepatic failure is less common, with 18 reported cases and 5 deaths. Eleven of the 18 were probably not related to felbamate exposure. Seven of 18 probably are related to felbamate. The incidence of fatal cases is approximately 1/18,500 to 1/25,000. Which is similar to that of valproate 1/10,000 to 1/49,000. Unfortunately no pattern of variables has been described which would enable us to predict which persons are at greatest risk for these serious events. The mean time from initial exposure to presentation with hepatic failure was 217 days (25 - 939 days).

GABAPENTINE (1-(aminomethyl) cyclohexaneacetic acid) (Neurontin)

Though developed as a GABA-mimetic that could easily cross the blood brain barrier, Gabapentine does not appear to act on GABA mediated systems. It appears to protect against seizures induced by pentylenetetrazol, but not MES. Gabapentine displays little toxicity with LD50 > 200 mg / kg when given intravenously, and > 8000 mg / kg p.o. No teratogenicity has been found in rats or rabbits exposed to this drug. Mutagenic activity is absentin the Ames-Salmonella-Test, and in chromosome-metaphase analysis of hamster bone marrow. Acinar carcinoma of the pancreas has been seen in certain strains of male rats.

It has been approved for use as adjunctive therapy for partial seizures in adults and children over the age of 3 years. It is also approved for the treatment of postherpetic neuralgia. Doses of up to 5400 mg / dy have been prescribed with no adverse reactions. It is available in 100, 300 and 400 mg capsules and 600 and 800 mg. tablets. This drug is extremely well tolerated by most patients, but the dose often has to be pushed fairly high to achieve optimum results. Most patients with epilepsy require at least 3600 mg a day. It has also been demonstrated to be effective in treating neuropathic pain, in migraine prophylaxis, bipolar depression, spasticity, post herpetic neuralgia, and diabetic neuropathy

Kinetics
The time to peak is 2 - 3 hr.
The half life is 5 - 8 hr.
There is no plasma protein binding.
Therapeutic range = 5 - 20 ug/ml.
There is no enzyme induction.
Seventy-five to 81 % is excreted unchanged in the urine.

Adverse Experiences
Somnolence or fatigue 18 - 20 %, dizziness 6 - 12 %, weight gain 5 %, asthenia, ataxia, peripheral edema. Most patients rated these symptoms as mild to moderate and the drug is generally well tolerated.

Drug Interactions
None have been reported.

Pregnancy
A Gabapentine Pregnancy Registry has reported 51 pregnancies in 39 women with epilepsy. The rate of malformations was 4.5%. The rate in the general population is 2 — 3%. It is FDA category C.

OXCARBAZEPINE (10,11-dihydro-10-oxo-carbamazepine) (Trileptal)

Oxcarbazepine differs from carbamazepine in that it contains a keto-group in the 10-11 position. This results in a significantly different metabolism into the 10-monohydroxy derivative (MHD). Since there is no 10-11 epoxide metabolite there appear to be fewer side effects, less allergic cross reactivity (27 %), but similar efficacy to carbamazepine. It is effective against MES and pentylenetetrazol, but weakly effective against picrotoxcin and strychnine induced seizures. No teratogenicity has been demonstrated in rodent models, nor mutagenicity with the Ames test.

It is effective against both partial and generalized tonic clonic seizures in man. It is approved for use as adjunctive and monotherapy in partial epilepsy in adults and children over the age of 3 years. Doses of up to 3000 mg / day appear to be well tolerated. The drug has been available in Western Europe for several years and has recently been approved for use in the United States. It comes in 300 and 600 mg tablets.

Kinetics
The time to peak is 1 hr.
The half life is 8 - 10 hrs.
Protein binding MHD = 40 % of OXC = 67%.
Therapeutic range of the MHD = 12 - 30 ug/ml.
The kinetics are linear up to 2700 mg / day.
Volume of distribution = 0.7 - 0.8 L/kg.
There is no enzymatic induction of other AED but induction of P450 IIIA subfamily of hepatic oxidative enzymes appears to result in reduced concentrations and effectiveness of oral contraceptives.

Adverse Experiences
Similar but less frequent than those of carbamazepine. Cross reactivity to rashes induced by carbamazepine is only about 23%. Therefore many persons who develop allergic reactions to carbamazepine may not with oxcarbazepine. Hyponatremia, somnolence (25-30%), headache (15%), dizziness (10-12%) and rash have been reported.

Pregnancy
In the first 12 reported cases of pregnancy with oxcarbazepine there have been 9 live births and 3 spontaneous abortions (Friis et al. 1993). In a prospective study of eleven pregnancies one child with spina bifida exposed to oxcarbazepine in polytherapy was reported. The manufacturer has been notified of 5 cases of fetal malformations in the post marketing period. One was a cardiac defect. There were 3 cleft palates and one facial dysmorphism. Three of the 5 were exposed to AED polytherapy. A report from Argentina of 42 pregnancies found no malformations in 25 montherapy exposed pregnancies and 1 malformation in 17 polytherapy exposed pregnancies. That child had a ventricular septal defect and was exposed to oxcarbazepine and phenobarbital. It is FDA category C.

Little oxcarbazepine is absorbed from the breast milk. The milk/plasma ratio is 0.5. In a single case report of a nursing infant the plasma concentrations fell from equivalent to maternal levels at delivery to only 12% of maternal levels at 5 days of life.

Drug Interactions
Reduction of effectiveness of oral contraceptives.

LAMOTRIGINE (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) (Lamictal)

Many of the conventional AED are folate antagonists. Lamotrigine also has mild antifolate activity. It appears to inhibit the release of excitatory amino acids such as glutamate, and is a potent anticonvulsant. It is effective against seizures induced by MES and pentylenetetrazol.

Lamotrigine is effective against both partial and generalized tonic clonic seizures and in Lennox-Gastaut syndrome. It has been also shown to be of benefit in absence, myoclonic and atonic seizures but the experience with these seizure types has been more limited. It is approved for use as adjunctive therapy in partial and genralized seizures of Lennox-Gastaut, and conversion to monotherapy for adults with partial epilepsy. A number of patients have reported a pleasant sense of well being while taking lamotrigine even though their seizures were unchanged. It binds to melanin. Lamotrigine is non teratogenic in rats, and non mutagenic in bacterial and lymphocyte systems. It has been used in humans at doses of up to 800 mg / day. and is available in 25, 50, 100, and 150 mg scored tablets.

Kinetics
The time to peak is 2 - 4 hr.
The half life is 24 hr.
Plasma protein binding is 55 %.
The kinetics are linear.
There is no enzymatic induction.
Therapeutic range = 3 — 14ug/ml.
It is metabolized largely to a glucuronide, 8 % being excreted unchanged in the urine.

Adverse Experiences
Asthenia 17 %, diplopia 15 %, headache 13 %, insomnia 13 %, ataxia 12 %, dizziness 9 %, nausea 4 %, nervousness 4 %. The incidence of rash is higher with lamotrigine than with most other AED ranging from 4 to 10 % in different series. A Stevens Johnson Syndrome has been reported. The incidence of rash increases with increased rate of loading. A gradual advancement of this drug is much less likely to result in rash and is therefore recommended.

Pregnancy
There have been 334 pregnancies reported in women taking lamotrigine in the first trimester. The malformation rate in montherapy is 1.8%, in polytherapy 4.3% and in polytherapy with valproic acid 10%. It is FDA category C.

Drug Interactions
Lamotrigine is very sensitive to enzyme induction and inhibition. When used in polytherapy care must be taken to initiate it carefully.

Lamotrigine increases the half-life of carbamazepine, phenytoin and valproate.

Valproic acid increases the half-life of lamotrigine to 30 - 90 hrs. When adding lamotrigine to valproate start with 25 mg. qod for 2 weeks, then 25 mg. qd for 2 weeks. Then increase it by 25 mg/day each week until seizures are improved or side effects occur.

Phenytoin, phenobarbital, primidone and carbamazepine reduce the half-life of lamotrigine to 15 hr. When adding lamotrigine to one of these compounds one can start with 50 mg/day. for the first 2 weeks, and increase by 50 mg. / day each week thereafter.

TIAGABINE (R-)-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid hydrochloride (Gabatril)

Tigabine is a potent inhibitor of GABA reuptake into neurons and glia. It is a "designer" drug consisting of the potent anticonvulsant nipecotic acid joined to a lipophilic anchor which permits its passage across the blood brain barrier. It is effective against partial seizures both as adjunctive and monotherapy in adults and children. It has been used in oral doses up to 80 mg / day. It is available in 4, 12, 16 and 20 mg tablets. Minimum effective dose appears to be around 32 mg/day. Despite its short half-life it is effective in bid dosing, probably because it causes sustained elevations of extracellular GABA which lasts for several hours. The elevated GABA is not strictly correlated with tiagabine plasma concentrations. No teratogenic effects in experimental animals have been noted. In 23 reported pregnancies: 9 live births; 6 miscarriages; 5 therapeutic abortions; 1 empty gestational sac, 1 C-section for breech presentation; one woman drowned while pregnant 3 months after stopping tiagabine therapy.

 Kinetics
The time to peak is 0.5 - 1.0 hr.
The half life is 4.5 - 13 hrs. with a mean of 7 hrs.
Kinetics are linear.
Protein binding is 95%.
Metabolism via hepatic microsomal enzyme system.
No active metabolites.
Urinary excretion 25%, fecal excretion 63%.
No enzyme induction or inhibition.
No effect on oral contraceptives.

Adverse Experiences
The drug is fairly well tolerated with few adverse experiences reported. Dizziness 27%, asthenia 20%, nervousness 10%, tremor 9% and difficulty concentrating 6%, have been most frequently observed. Rarely transient weakness of the knees causing brief buckling without falling has been seen with high doses in children. Adverse experiences appear to be related both to dose and rate of titration. This drug can induce agitation and irritability which is often not as noticeable to the patient as it is to friends and family members.

Drug Interactions
Enzyme inducing AEDs can reduce the concentration of tiagabine.

TOPIRAMATE (Topomax)

A potent compound for the adjunctive treatment of partial seizures with or without secondary generalization, primarily generalized seizures, drop attacks in Lennox-Gastaut syndrome, and West's syndrome. It is approved both for adults and children as young as 2 years of age. It has been found to produce leiomyosarcomas in Swiss Webster derived strains of mice. A form of tumor which appears to be unique to that rodent species and not seen in man. Topiramate has been used in doses of up to 1600 mg / day, but most persons report significant side effects at doses over 1000 mg /day. In adults the minimal effective dose appears to be between 200 and 400 mg / day. It is available in 25, 100, and 200, mg tablets and 15 and 25mg. sprinkle filled capsules.

Kinetics
The time to peak is 1.8 - 4.3, mean 2 hrs.
The half life is 19 - 23 hrs., mean 21 hrs.
Plasma protein binding is 9 - 17 %.
There is no enzyme induction.
51% renal excretion.
Volume of distribution = 0.6 - 0.8 L/kg

Adverse Experiences
Slowed mentation and somnolence are commonly reported during initiation of therapy. Dizziness (13-25%), somnolence 13-29%),ataxia (1-25%), nervousness (4-16%), psychomotor slowing (0-13%), word finding difficulty (1-13%), memory difficulty (1-12%), confusion (3-11%), dipolpia (0-10%), anorexia (10-15%) and ataxia (1-16%) have been reported in clinical trials. Paresthesias have also been reported. A tolerance to these side effects often develops. Venous thrombosis, and renal calculi (1.5%), have occasionally been seen as have hostile and psychotic behavior, anxiety and asthenia. These side effects respond to dose reduction. It has caused digital absence in rats and vertebral malformations in rabbits.

As of November 2001 there have been 23 cases of acute myopia and angle closure glaucoma. This is characterized by acute pain and decreased visual acuity. It tends to occur within the first month of therapy. It requires rapid discontinuation of Topiramate.

Pregnancy
We have no idea of the number of pregnancies with topiramate exposure. During the clinical trials there were 28 pregnancies and one malformation. There is one case report of a child exposed to topiramte monotherapy who developed growth deficiency, hirsutism, a third fontanelle, and upturned nasal tip, and distal digital hypoplasia. It is listed as FDA category C.

 Drug Interactions
Topiramate increases valproate concentrations in humans. It also reduces the concentrations of hormonal contraceptives increasing the risk of unplanned pregnancy. Enzyme inducing AEDs can increase the clearance and reduce the concentration of topiramate.

VIGABATRIN (gamma-vinyl GABA), (Sabril)

Vigabatrin is a selective irreversible inhibitor of GABA-transaminase, and causes dose dependent increases in brain and CSF GABA concentrations. It has been marketed in Great Britain since 1989, but concerns about intramyelinic edema seen in rats and dogs and concentric visual field defects which are appearantly irreversible in human subjects have inhibited its release in North America. It is effective against partial seizures and Lennox Gastaut Syndrome . Doses of up to 6000 mg / day have been well tolerated, and it is available in 500 mg scored tablets.

Kinetics
The time to peak is 2 hrs.
The half-life is 5 - 8 hrs.
The plasma protein binding is 0 %.
100% renal elimination.

Adverse Experiences
Irritation, aggression, memory disturbances (18.5 %), and weight gain(6.7 %) have been reported. Overt psychosis has been seen in 4 - 5 % of patients usually shortly after initiation of therapy. This is reversible with discontinuation of the drug.

A decrease in SGOT of 10 - 12 %, SGPT of 30 - 50 % has been seen and is thought to be an artifact of the biochemical methodology used to make these determinations.

In rats and beagle dogs intramyelinec edema has been seen. Some cases of optic neuritis have been reported in humans, and cases of circumferential restrictions of visual field with nasal sparing which appear to be irreversible have been reported. It is unlikely to ever be approved in the United States.

Drug Interactions
Vigabatrin decreases phenytoin concentrations by 23 %.

ZONISAMIDE (Zonegran)

A sulfonamide antiepilepsy drug which has been demonstrated to block voltage sensitive sodium channels, voltage dependent calcium currents and suppress neuronal hyper synchronization. It is approved as adjunctive therapy for partial seizures in adults. It is taken up by erythrocytes binding to carbonic anhydrase. It appears to be effective in partial and primarily generalized seizures, infantile spasms, myoclonus and Lennox-Gastaut syndrome. Its long half life requires a slow titration with initial doses of 100-200 mg day in adults, 2-4 mg/kg in children and dose increases every two weeks. The adult maintenance dose is usually 200-600 mg/day.

Kinetics}
The time to peak is 2.8 to 3.9 hours.
The half life is 50 to 60 hours.
The kinetics are linear.
Plasma protein binding = 40 %.
Therapeutic range = 20 - 30 ug/ml.
Volume of distribution = 1.45L/kg.

Adverse Experiences
The most commonly reported side effects have been: somnolence, ataxia, anorexia, confusion, abnormal thinking, nervousness, fatigue, and dizziness. These experiences have generally been minor and did not lead to discontinuation. Renal calculi have been reported at a rate of 2.6% in American and European studies. The Japan the rates are much lower 0.2%. The stones are predominantly calcium phosphate and oxalate.

In children there is an increased risk (1/10,000) of oligohidrosis (decreased sweating) and hyperthermia (elevated temperature) often in a setting or increased environmental temperatures. Forty children have been reported world wide. Children taking Zonisamide should be monitored closely for decreased sweating and increased body temperature particularly in hot weather.

Pregnancy
There have been 26 reported pregnancies with zonisamide exposure. Two of the 26 (7.7%) had congenital malformations. One child was also exposed to phyenytoin and the other to both phenytoin and valproic acid. Zonisamide is excreted in breast milk. The milk/plasma ratio is approximately 0.93. It is an FDA category C.

Drug interactions
Enzyme inducing AEDs increase the clearance and reduce the concentration of zonisamide. Zonisamide increases the concentration of carbamazepine 10-11 epoxide.

LEVETIRACETAM ((S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide, Keppra)

This is the most recent antiepileptic drug approved by the FDA. It is recommended for use as adjunctive therapy in partial epilepsies in adults. Its mechanism of action is unknown. It does appear to inhibit hypersynchronization of epileptiform discharges. Its is not extensively metabolized and not by the hepatic cytochrome P-450 system. The primary metabolite is inactive. Sixty six percent is excreted unchanged in the urine. It appears to have an extremely low side effect profile compared to other AED. It has been tested in humans with epilepsy at doses of up to 5000 mg/day. One thousand mg./day appears to be the minimal effective dose in adults. It is recommended that it be given twice a day. It is available in tablets of 250, 500, and 750 mg.

Kinetics
The time to peak = 1 hour
Half-life = 6 - 8 hours
Protein binding < 10%
The kinetics are linear
66% renal excretion
No effect on oral contraceptives

Adverse experiences
Somnolence (14.8%), asthenia ( 14.7%) and ataxia (3.4%) are the most frequently reported adverse experiences. Behavioral problems have been reported in younger patients and children. A 0.7% incidence of psychosis characterized by agitation, hallucinations, hostility, anxiety, apathy, emotional lability, depersonalization and depression. Minor decreases in RBC, hemoglobin and hematocrit have been seen. No other laboratory abnormalities have been reported.

It like most other AED is a pregnancy category C. In rodent models minor skeletal abnormalities and decreased fetal weights have been described.

Drug interactions
None have been reported. There does not appear to be any effect on oral contraceptives.

CONCLUSIONS

At the present time the effectiveness and lower side effect profile has made these newer AED quite popular and some such as lamotrigine and oxcarbazepine could be considered first line drugs. Our total clinical experience is still limited however, and we still have much to learn about potential drug interactions and possible teratogenicity. I expect that more of these compounds will become first line drugs for the treatment of certain seizure types. Much of the information contained in this review is incomplete. Therapeutic ranges have yet to be established for most of these drugs. Formulations and dose schedules used in clinical trials will probably be modified as these drugs are used more frequently in the United States.

At present gabapentine, felbamate, and lamotrigine, oxcarbazapine, tiagabine, topiramate, zonisamide and levetiracetam have been approved for use in the treatment of partial seizures in adults by the FDA. Lamotrigine, topiramate and zonisamide probably have a broad spectrum against several seizure types. The Epilepsy Foundation of America's Library can serve as a non biased resource for information on these compounds and their clinical trials. This is a particularly exciting time for the treatment of epilepsy. With the advent of these and other new AED we have the potential to further reduce the population of refractory and uncontrolled seizure patients.

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