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
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 Epilepsygenetic)
– 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
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
Blood Level
Therapeutic Level
(A)
8am
4pm
Regular Release
Pills Twice a Day
Blood Level
Time
(B)
Regular Release
Pills 4x a Day
Time
4pm
Blood Level
8am
(C)
8am
Time
4pm
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 longterm 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.