5. History of Antiepileptic
Medications
1912
• Phenobarbital was the primary medication used
for seizures.
• Used for generalized tonic-clonic and to a lesser
extent partial seizures. No effect on absence
seizures.
• Sedative effect occurred in many people.
Hyperactivity noted in children.
6. History of Antiepileptic
Medications
1938
• Diphenylhydantoin (Dilantin) was
discovered to have antiepileptic properties.
• Similar effectiveness to phenobarbital.
• Less sedative side effects.
7. History of Antiepileptic
Medications
1960-1974
• U.S. Food and Drug Administration (FDA)
imposed new regulations on pharmaceutical
companies.
• Medications were now required not only to be safe
but they had to be proven effective against the
illness it was designed to treat.
• Only one medication for seizures was developed
during this time. Valium was found to be an
effective treatment for status epilepticus.
8. History of Antiepileptic
Medications
• 1974: Carbamazepine (Tegretol)
• 1978: Valproic acid (Depakote)
• 1993-Present: Rapid emergence of very
effective seizure medications.
11. When to Treat?
• Are the episodes really seizures?
• EEG: Normal or abnormal?
• Frequency and type of episodes?
• Are there other neurologic problems?
• What is the cause of the seizures? Can the
underlying problem be treated rather then
treating the symptom (i.e. the seizure)?
12. When Not to Treat
• Single seizure
• No history
• Neurologically normal
• Young age
• Side effect concerns
13. First Seizure
• Studies have shown that a otherwise normal
child who had a single seizure has a 15%
chance of having a second seizure if left
untreated.
• Physicians will typically wait until a second
or third seizure before initiating treatment
with antiepileptic medication.
14. First Seizure
• For a child who is neurologically abnormal
or has an abnormal EEG- the risk of
subsequent seizures is substantially
increased to between 50-60%.
15. When to Treat?
Risk-Benefit Ratio
• In determining whether to treat physicians
consider many factors.
• The benefits of further seizure activity is
weighed against the potential side effects of
the antiepileptic medications.
• The decision to treat is a highly individualized
one.
16. Key Concepts in Antiepileptic
Treatment
-Metabolism-
• The process by which medications are
broken down and eliminated by the body.
• Most antiepileptic medications are
metabolized by the liver.
• Some antiepileptic medications are
metabolized by the kidneys.
17. Key Concepts in Antiepileptic
Treatment
-Metabolism-
• Children generally have a faster metabolism
and thus require higher then expected
dosages of medications to maintain
adequate blood levels.
• Older people typically have slower
metabolisms and thus require less
medication. Often they can become toxic on
normal dosages of medication.
18. Key Concepts in Antiepileptic
Treatment
Half-life
• The time it takes your body to eliminate half the
medication in your body.
• After one half-life the amount of medication in
your body will decrease by 50 %.
• After 5 half-lives 95% of the medication will be
removed from your body.
• Half-lives vary greatly among seizure medications.
19. Key Concepts in Antiepileptic
Treatment
Steady State
• A balance obtained when the amount of
medication you take into your body equals
the amount being eliminated.
• May take days to reach a steady state when
starting or changing doses of medications.
• Full therapeutic effect of a medication is not
reached until steady state is achieved.
20. Key Concepts in Antiepileptic
Treatment
Therapeutic Range
• The blood levels of medication that for
most people will provide an adequate
seizure reducing effect without excessive
side effects.
• Treat the person not the range! Everyone
responds differently. Some people can be
effectively treated with blood levels above
or below the therapeutic range.
21. Key Concepts in Antiepileptic
Treatment
Mechanism of Action
• How do medications work? For many
medications this is still not well understood
• Proposed mechanisms involve increasing
the amount of inhibitory neurotransmitters
or changes in the flow of ions (sodium or
chloride) across the neuron cell membrane.
22. Factor Influencing Drug
Selection
• Many antiepileptic medications are
effective against specific seizure types.
• It is very important to know the specific
type or types of seizures a patient is having
so that the appropriate medication can be
chosen.
• On occasion the wrong medication can
actually make seizures worse.
23. Factor Influencing Drug
Selection
• Seizure type
• Syndrome
• Side effects
• Patient age
• Lifestyle
• Childbearing potential
• Other medications
24. Factor Influencing Drug
Selection
Monotherapy or Polytherapy
• Monotherapy is usually the preferred
treatment.
• A single drug is prescribed in increasing
increments until seizures are controlled or
toxicity occurs.
• If the drug is ineffective or side effects
occur, the drug is slowly withdrawn while
another medication is slowly introduced.
25. Advantages of Monotherapy
• 70-80% of patients are controlled on
monotherapy.
• Fewer side effects.
• No drug interactions.
• Easier dosing = Greater compliance
• Lower cost.
26. Advantages of Polytherapy
• May control an additional 20% of patients
that could not be controlled with
monotherapy.
• May provide synergistic effects. (1+1=3)
27. Side Effects
• All seizure medications can have side
effects.
• Side effects can be grouped as:
– Dose related
– Dose unrelated (occur at any dosage)
– Idiosyncratic
28. Side Effects
Dose related
• Some effects are dose related. That is they
become more likely as the amount of
medication is increased.
• Sleepiness, slurred speech, and unsteadiness
are common effects of seizure medications
at higher doses.
29. Side Effects
Dose unrelated
(Common at any dose)
• Some side effects can occur at any dosage.
• Examples include double vision, weight gain,
hyperactivity, sleep disturbances, irritability, hair
growth, gum growth, and changes in mood.
• On occasion these effects are seen at the start of
treatment and gradually get better with time.
30. Side Effects
Idiosyncratic
• A rare side effect that occurs because of a
patients individual sensitivity or allergic
reaction to a particular medication.
• Examples include: Liver failure, aplastic
anemia, severe rashs (Steven Johnson
Syndrome).
32. Side Effects
Pregnancy
• All seizures medication pose some risk to the
developing fetus.
• None of the commonly used seizure
medication are absolutely contraindicated in
pregnancy.
• Possible side effects include cleft palate/lips,
cardiac abnormalities, and spinal tube
defects.
33. Side Effects
Pregnancy
• Antiepileptic medications can reduce the
effectiveness of certain birth control pills.
• It is important to tell your doctors about all
the medications you are taking so that
potential interactions can be discussed and
avoided.
34. Side Effects
Pregnancy
• Folic acid is frequently prescribed to all
women of child baring age as it is believed
to protect against some birth defects.
• Good news! 90% of women with epilepsy
who become pregnant will give birth to
normal healthy babies.
35. Compliance
• The degree to which the patient follows the
physicians directions on how and when
medications should be taken.
• 73% of people with epilepsy were found to
be compliant with medications.
• Compliance is very important in epilepsy
treatment as blood levels of medications
will fall low if dosages are missed.
36. Reasons for non-compliance
• Do not need so much medication
• Unpleasant side effects
• Making the drug last longer because of cost
• Forgetfulness
• Confusion about dosages and times
• Inconvenience of schedule
• Misunderstand directions
37. Effectiveness of Treatment
• 75-80% of patients with epilepsy will have
reliable long term control of their seizures
with currently available medications.
• For the remainder of patients with intractable
seizures other options exist such as epilepsy
surgery, neuro-stimulators and the ketogenic
diet.
38. Discontinuing Antiepileptic
Medications
• Antiepileptic medications may not have to
be taken for a lifetime.
• When seizures have been controlled over a
period of time (usually one to two years),
there is a good chance that withdrawal of
medication will be successful.
39. Factors Associated with Seizure
Recurrence
• Abnormal EEG
• Hard to control seizures
• Neurologic deficits
• Epilepsy type
40. Factors Associated with
Non-Recurrence in Adults
• Primary generalized seizure type
• Under 30 years of age
• Prompt initial control
• 2-5 years of seizure freedom
43. Sabril (Vigabatrin)
• Approved as monotherapy for patients 1
month to 2 years of age with infantile
spasms.
• Approved as add-on therapy for adults with
complex partial seizures.
• Can cause eye injury (Retinal damage).
44. Banzel (Rufinamide)
• Approved for the treatment of seizures for
children and adults (> 4 years old) with
Lennox-Gastaut Syndrome.
45. Clobazam (Onfi)
• New Drug on market:
• MOA: works on GABA receptors
• Indication: Adjunctive treatment of seizures
associated with Lennox-Gestault syndrome
• Dosage: initiate at 5mg daily, then slowly titrate
to 10mg twice daily.
• Significant reduction in drop seizures was end
point of trials
• Side effects: somnolence, fever, drooling,
lethargy, constipation
46. Vimpat (Lacosamide)
• Approved as add-on treatment in adults
with partial onset seizures.
• Unique mechanism of action.
• Low side effect profile.
47. Seizures: Eslicarbazepine acetate
(Aptiom)
• New drug on market
• Indicated for adjunctive treatment for partial onset
seizures in adults
• Dosage: 400mg/day x 1 week, max 1200mg/day,
taken whole or crushed, with or without food
• Inhibits voltage gated sodium channel
• Metabolized in liver, excreted in urine
• Side effects: dizziness, somnolence, nausea,
vomiting, headache, diplopia, fatigue, blurred
vision, abnormal gait, hyponatremia
48. Seizures: Eslicarbazepine acetate
(Aptiom)
• No clinically significant drug-drug interactions
when administered with valproate, lamotrigine,
topiramate, leviteracetam, or gabapentin.
Dosage adjustments if used with
carbamazepine or phenytoin
• Does not induce its own metabolism
• No therapeutic drug monitoring required
• Not a controlled substance
49. Seizures: Perampanel (Fycompa)
• New drug on market
• Indicated for adjunctive treatment of partial onset seizures
• MOA: reduces glutamate-mediated neuronal excitation
• Metabolized in liver, excreted in urine/feces
• Start at 4mg and increase to 8-12 mg
• Side effects: dizziness, somnolence, headache, fatigue, falls,
irritability, hyponatremia
• Black box warning: serious or life threatening reactions
including aggression, hostility, irritability, anger, homicidal
ideation and threats w/ or w/o previous psychiatric diagnosis
50. Seizures: Ezogabine (Potiga)
• New drug on market
• Indicated for adjunctive therapy for partial seizures
• MOA: activates potassium ion channels, stabilizing
neuronal membranes and reducing brain excitability,
augments GABA
• Dosing: 200-400mg tid, start at 100mg tid
• Metabolized in liver, excreted in urine
• Side effects: dizziness, somnolence, fatigue, nausea,
diplopia, tremor, confusion
• Black box warning: retinal abnormalities and potential
vision loss (similar to vigabatrin (Sabril))
51. Seizures: Topiramate (Qudexy
XR)
• Long acting formulation of drug on market
• Indication: monotherapy and adjunctive therapy in partial
seizures; monotherapy and adjunctive therapy in primary
generalized seizures; adjunctive therapy in Lennox-Gastaut
seizures
• Dosage: 200-400mg/day (start at 50mg x1 wk, then increase
weekly as needed)
• MOA: blocks voltage dependent sodium channels; augments
GABA activity; antagonizes glutamate receptors; inhibits
carbonic anhydrase (inhibits fluid buildup)
• Metabolized in liver, excreted in kidney
• Side effects: metabolic acidosis, somnolence, dizziness, weight
loss, fatigue, anorexia, cognitive issues
52. Briviact (Brivaracetam)9,14
• Approved by the FDA in February 2016
• Approved for the treatment of partial onset seizures related to
epilepsy
• Studied use alongside carbamazepine, lacosamide, lamotrigine,
keppra, oxcarbazepine, phenobarbital, phenytoin, pregabalin,
topiramate, valproic acid, and zonisamide
• Antiepileptic
• Mechanism of Action is currently unknown
• Class-V controlled substance
• Why develop med?
– For patients not adequately controlled by 1-2 concomitant
AED’s and available in multiple formulations.
53. Briviact (Brivaracetam)9,14
• FDA approval of Briviact stems from three major trials that evaluated
the efficacy of Briviact.
• Available in tablet, oral solution, and IV administration formulations
– May give tablet formulation with or without food and are to be
swallowed with liquid.
– Injection should be administered intravenously over 2-15 minutes.
– May further dilute or mix with 0.9% NS, Lactated Ringer’s, or
D5W injections.
• Recommended starting dose is 50mg twice daily (100mg daily).
• May adjust dosage to as low as 25mg twice daily (50mg daily) or
100mg twice daily (200mg daily).
54. Briviact (Brivaracetam)9,14
• Warning
– May increase the risk of suicidal behavior and/or suicidal
ideation
• Side-Effects:
– Somnolence/sedation
– Dizziness
– Fatigue
– Nausea/vomiting
– Euphoria
– Infusion site pain
– Feelings of “drunkenness”
55. Newer Treatments
Neuro-stimulators
Deep Brain Stimulation
• Promising new technology for medically-
refractory seizures.
• Stimulator electrodes are placed deep
within the brain and are connected to a
pacemaker-like device in the chest.
56. Newer Developments
MEG
(Magnetoencephalography)
• Measures the small electrical currents
arising inside the neurons of the brain.
• Similar to EEG but provides greater
accuracy.
• Used to locate where seizures are coming
from within the brain.
• Can be used to map brain functions
Notes de l'éditeur
Studied use while alongside carbamazepine, lacosamide, lamotrigine, keppra, oxcarbazepine, phenobarbital, phenytoin, pregabalin, topiramate, valproic acid, and zonisamide. No benefit was seen while using Briviact alongside lamotrigine.
