Anti-Epileptic Drugs (AED’s) A Quick Review

Mark M. Stecker, M.D. Ph.D

Professor of Neuroscience Joan C. Edwards Marshall University School of Medicine

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Lecture Outline

Classification of Seizure Medication – Old AED’s – New AED’s – Choice of AED Based Upon Seizure Type Side Effects Pharmacokinetics Some Specific Medications – Diastat – Vimpat – Banzel VNS

Classification of AED’s-I

• • “Old vs New vs Recent” Old – Phenobarbital – Dilantin (Phenytoin) – Mysoline (Primidone) – Tegretol (Carbamazepine, Epitol) – Depakote (Depakene, Valproic Acid, Divalproex Sodium) – Zarontin (ethosuccimide) – Benzodiazepines (Ativan, Valium, Clonazepin)

Classification of AED’s-II

• • New – Lamictal (Lamotrigine) – Keppra (Levetiracetam) – Topamax (Topiramate) – Zonegran (Zonisamide) – Trileptal (Oxcarbazepine) Recent – Banzel (Rufinamide) – Sabril (Vigabatrin) – Lacosamide (Vimpat)

Classification of AED’s-III

• General Rule – Old AED’s • More Side Effects • More complex Drug-drug Interactions – New AED’s • Less Side Effects • Simpler Drug-Drug Interactions – Difference in anti-seizure effect is hard to measure. Drugs are individually chosen based upon seizure type and side effect profile.

Typical AED Uses

• Primary Generalized Epilepsy (Childhood Absence Epilepsy, Juvenile Myoclonic Epilepsy genetic) – Depakote – Lamictal – Zarontin (staring only) – Benzodiazepines (Ativan, Clonopin)—slight help especially with staring and myoclonus

Typical AED Uses-II

• • Partial Epilepsy (Structural Injury) – Tegretol – Dilantin – Depakote – Trileptal General Purpose – Keppra – Zonegran

Side Effects of AED’s

Non-Specific Side Effects

• All AED’s can cause – Sleepiness – Difficulty Concentrating – Nausea, Vomiting – Coordination Problems – Double Vision (Trouble Reading) – School Specific Issues • Trouble Concentrating/Day Dreaming • • Slowed Responses Difficulty Multitasking

Specific AED Side Effects-I

• Severe Rash (Stevens-Johnson Syndrome) – Dilantin – Tegretol – Trileptal – Lamictal – Less Likely (Phenobaribital, Topamax, Zarontin, Zonisamide) – Very Unlikely/Never • Keppra • Depakote • Benzodiazepine

Specific Side Effects-II

• • • • Depression (maybe all to some extent) – Phenobarbital – Primidone Anger/Behavior Problems – Keppra Hyperactivity (children) – Phenobarbital Lack of Sleep – Lamictal

Specific Side Effects-III

• • • Serious Liver Problems – Depakote (Age<2 and Polytherapy) – Rare • Tegretol, Dilantin Hematologic Problems – Depakote (platelets) – Tegretol>>Trileptal (Low White Count) Low Sodium – Trileptal>>Tegretol

Pharmacology

8am 8am Time Time 4pm 4pm 8am Time 4pm Therapeutic Level (A) Regular Release Pills Twice a Day (B) Regular Release Pills 4x a Day (C) Extended Release Pills Twice a Day

How Does This Affect a Child In School?

• 2 Pills Twice a Day (A) – Toxic at 8am and 4pm (side effects) – Low Levels at Noon (Seizures) • 4 Pills a Day (B) – Lower Peak Levels so Less Toxicity – Higher Trough Levels so Less Chance of Seizures in School – Has to Take Pill During School • Extended Release Twice a Day – Has the maximum advantage and minimum side effects

Although a Treatment May Work It Has to Be Practical

Newer Medications

Geier-The Symbolism of Epilepsy

Diastat

• Rectal Valium Gel – Well absorbed – Useful with longer than usual seizures before EMS arrives or there is no IV access—to reduce the duration of the seizures. – Very few side effects – Very simple to use

Rufinamide

• • • • Mechanism: Stabilization of the sodium channel inactive state • Prevents conduction of certain nerve impulses Approved as adjunctive treatment of seizures in patients with Lennox-Gastaut syndrome older than the age of 4. 45% of patients had more than 50% reduction in seizure frequency in trials (Kluger et. al. Acta neurol Scand 2010). This drops to 27% at 18 months after starting the medication (Kluger et. al. Epilepsy Behav 2010) – 32% reduction in seizure frequency – 53% of Banzel patients showed improvement in seizure severity vs 31% with placebo Side Effects: – Dizziness, headache, fatigue, nausea

Vimpat (Lacosamide)

• • • • • • Enhances slow inactivation of sodium channels.

• Impairs conduction of certain nerve impulses Adjunctive treatment of partial seizures.

Responder rate (40.5%-Lacosamide) vs (25.8%-Placebo).

36% seizure reduction rate vs 20.5% for placebo REMEMBER many patients were already taking multiple anticonvulsants in the study thus these numbers are falsely low.

Side effects – Dizziness – Headache, ataxia, tremor, vomiting, diplopia

Vigabatrin (Sabril)

• • • Inhibits GABA transaminase and increases GABA levels.

• GABA is an inhibitory neurotransmitter FDA approval monotherapy children 1month-2years of age with infantile spasms – Other countries: adjunctive treatment for complex partial seizures, secondary generalized seizures.

Side effects – May lower dilantin and tegretol levels.

– Sleepiness, headache, fatigue – Atrophy of the retinal nerve fibre layer—may have visual problems and visual evoked potentials become abnormal in half of patients.

Retigabine

• • • Opens KCNQ/Kv7 potassium channels—but only affects neuronal and not cardiac potassium channels and so should have limited cardiac side effects.

• Hyperpolarizes nerve membranes and prevents transmission of certain nerve impulses.

Completed clinical trials – Seizure Frequency Reduced 35% compared to 13% for placebo – 33% responded to the drug and 16% to placebo – Peak dose 1.5 hours after taking – Half-Life 8 hours Still Awaiting approval by FDA

Brivaracetam

• • • • • • Chemically related to keppra (levetiracetam) Works by binding to synaptic vesicle protein 2A-- thus impairs the release of neurotransmitters: – Prevents transmission of signals from cell to cell Not yet released 36% responder rate in early studies 40-50% seizure reduction rate Phase III clinical trials not in agreement regarding effectiveness. Release pending additional studies/analysis.

New Surgical Treatments for Epilepsy

Vagal Nerve Stimulator-I

• 1997, the US Food and Drug Administration (FDA) approved the use of VNS.

– Adjunctive treatment for refractory partial-onset seizures in adults and adolescents older than 12 years. To date, probably more than 8,000 people have been treated with VNS. • Epilepsia. 2001 Aug;42(8):1017-20. Vagus nerve stimulation:

analysis of device parameters in 154 patients during the long term XE5 study.

DeGiorgio CM , et. al.

• Epilepsia. 1994 May-Jun;35(3):616-26. Vagus nerve stimulation for

treatment of partial seizures: 1. A controlled study of effect on seizures. First International Vagus Nerve Stimulation Study Group.

Ben-Menachem E , et. al.

Bromfield EB-an introduction to Epilepsy www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi...

Vagal Nerve Stimulator-II

– – – – 29-50% responder rate (50% seizure reduction) 21-51% seizure reduction rate 11% had >75% reduction in seizures With longer periods of stimulation the seizure reduction rate may go up to 52% after 12 years.

• Neurology. 2004 Sep 28;63(6):1124-6. Effectiveness of vagus

nerve stimulation in epilepsy patients: a 12-year observation.

Uthman BM, et. al. – This means that frequent evaluation of the settings and appropriate adjustments are critical to the function of the device.

Summary

• Anticonvulsants (AED’s) do help 75% of patients with epilepsy.

• Understanding the effects that these medications may have on school performance is important.