Epilepsy and Anticonvulsants Patty Ghazvini, PharmD., CGP
Associate Professor of Pharmacy Practice FAMU College of
Pharmacy
Slide 3
Seizures Epilepsy Video
Slide 4
Case Presentation J.H. is a 42-year-old man with complex
partial seizures for which he was prescribed topiramate. He has
been increasing the dose of topiramate every other day according to
instructions from his primary care provider. He comes to your
clinic for a follow-up a few weeks later but seems a little
confused and has difficulty finding the words to have a
conversation with you. Which one of the following is the best
assessment of J.H.s condition?
Slide 5
Case Presentation A. Discontinue topiramate; he is having an
allergic reaction. B. Increase his topiramate dose; he is having
partial seizures. C. Slow the rate of topiramate titration; he is
having psychomotor slowing. D. Get a topiramate serum
concentration; he is likely supratherapeutic. A. Discontinue
topiramate; he is having an allergic reaction. B. Increase his
topiramate dose; he is having partial seizures. C. Slow the rate of
topiramate titration; he is having psychomotor slowing. D. Get a
topiramate serum concentration; he is likely supratherapeutic.
Slide 6
Case Presentation B.V. is a 28-year-old woman brought to your
emergency department for treatment of status epilepticus. She
receives lorazepam 4 mg intravenously with subsequent seizure
cessation. Which one of the following medications is the best next
treatment step for B.V.?
Slide 7
Case Presentation A. Topiramate. B. Phenytoin. C. Zonisamide.
D. Diazepam. A. Topiramate. B. Phenytoin. C. Zonisamide. D.
Diazepam.
Slide 8
Classification of Seizures Generalized seizures (absence,
myoclonic, generalized tonic-clonic) - widespread regions of the
brain Partial (focal) seizures - originate in a localized area of
the cerebral cortex Further, seizures can be divided into simple or
complex seizure depending on whether consciousness is altered
Slide 9
Epidemiology 1. Ten percent of the population will have a
seizure. 2. About 50 million people worldwide have epilepsy. 3.
About 50% of patients with a new diagnosis become seizure free on
their first treatment, with up to 70% becoming seizure free after
treatment adjustment.
Slide 10
Pathophysiology Initially a small number of neurons will fire
abnormally, however, there is a break down of normal membrane
conductance and inhibitory mechanisms which leads to the spread of
the excitability either to a local area or widespread generalized
area. Dramatic increase in metabolic needs. The brain will consume
more oxygen than the vasculature can supply which can lead to brain
damage.
Slide 11
Factors Leading to Membrane Instability Ion channel
abnormalities Increase in Neurotransmitters that enhance
excitability Deficiency in Inhibitory Neurotransmitters
Abnormalities in serum pH can lead to seizures due to the fact that
normal neuronal activity depends on adequate supplies of glucose,
electrolytes, oxygen and amino acids.
Slide 12
Classification of Seizures Focal seizures begin in one
hemisphere of the brain. - A. Without impairment of
consciousness/responsiveness (replaces the term simple partial
seizure) - With observable motor or autonomic components -
Involving subjective sensory (e.g., visual, auditory, olfactory,
gustatory sensations) - B. With impairment of
consciousness/responsiveness (replaces the term complex partial
seizure)
Slide 13
Classification of Seizures Generalized seizures begin in both
hemispheres of the brain: A. Absence: B. Myoclonic: C. Tonic-clonic
5 Phases: - Flexion - Extension - Tremor - Clonic - Postictal D.
Clonic E. Tonic F. Atonic
Slide 14
Lennox-Gestaut Syndrome Presents in preschool age children
Mixture of seizure types Myoclonic, generalized, tonic-clonic,
absence, partial, atonic High seizure frequency Difficult to
control High incidence of status epilepticus 40-80 % will be
severely mentally retarded.
Overview Older AEDs such as carbamazepine, valproic acid, and
phenytoin remain the first line therapy in most seizure types.
Exception is absence seizures is the drug of choice ???? New AED
are generally used as add on therapy for children who have
refractory seizures. Dosages are adjusted according to patient
response and/or serum concentrations Older AEDs such as
carbamazepine, valproic acid, and phenytoin remain the first line
therapy in most seizure types. Exception is absence seizures is the
drug of choice ???? New AED are generally used as add on therapy
for children who have refractory seizures. Dosages are adjusted
according to patient response and/or serum concentrations
Slide 18
Overview Anticonvulsants are thought to carry an increased risk
of suicidal ideation and behavior Patients and caregivers should be
informed of the increased risk of suicidal thoughts and behaviors
and should be advised to immediately report the emergence or
worsening of depression, the emergence of suicidal thoughts or
behavior, thoughts of self-harm, or other unusual changes in mood
or behavior.
Slide 19
Differences between the Generations First generation Second
generation
Slide 20
Limitations with 1st Generation Anticonvulsants Enzyme
Induction/Inhibition Cognitive impairment Metabolic Products
CBZ-epoxide, hyperammonemia Hematological Disorders bone marrow
depression, thrombocytopenia
Slide 21
2nd Generation Anticonvulsants No required therapeutic
monitoring Fewer Drug Interactions Adjunct therapy &
monotherapy; Indicated for partial seizures with or without
generalization Orally administered Not used for Status Epilepticus
Used Outside of the Box
Slide 22
Partial Seizures First Line Therapy Second Line Therapy Adjunct
Therapy
Slide 23
Absence Seizures First Line Therapy Second line therapy
Slide 24
Myoclonic Seizures First Line Therapy Second Line Therapy Third
Line Therapy Adjunct Therapy
Slide 25
Tonic-Clonic, Atonic Seizures First Line Agents Carbamazepine,
Valproic Acid, Oxcarbazepine Second Line Agent Phenytoin Third Line
Agents Lamotrigine, Topiramate Atonic Seizures Valproic Acid or
Clonazepam
Carbamazepine ( Tegretol ) MOA: limits the influx of sodium
ions Therapeutic Serum Concentrations 4-12 mg/L Administration The
solution should be given 3-4 times a day Tablets may be given 2-4
times a day Do not mix the solution with other medications it may
decrease the effect. Suspension will produce a higher peak level
than tablets at the same dose Start suspensions at the lower dosage
range and titrate slowly to avoid ADE. Side Effects
Slide 29
Oxcarbazepine ( Trileptal ) MOA: B lock Na+ channels inhibiting
repetitive neuronal firing and stabilizing neuronal membranes Cross
hypersensitivity can occur with carbamazepine ( 20-35%) Monitor
sodium levels in person who receive other medications that also
alter sodium levels. Suspension is stable for 7 weeks after opening
the bottle Side Effects Sedation, ataxia, nausea, hyponatremia
Slide 30
Valproic Acid ( Depakote ) MOA: increases GABA availability and
action Therapeutic Serum Concentrations??? Should not be used in
children < 2 years. Increased risk of developing fatal
hepatotoxicity Do not substitute Depakote ER for Depakote May take
with food. Do not administer with carbonated drinks Do not give the
tablet with milk Depakote Sprinkles may be sprinkled on food and
swallowed immediately. Do not chew or crush. Side Effects????
Slide 31
Phenytoin ( Dilantin ) MOA: Increases efflux or decreases the
influx of sodium across the cell membrane. Therapeutic Serum
Concentrations Neonates 8-15 mg/L Children 10-20 mg/L Use with
caution in neonates Capsules and suspension contain Sodium Benzoate
and may cause gasping syndrome. Food may affect absorption
depending on formulation. High fat meals decrease the rate of
absorption of Dilantin Kapseals and decreases the bioavailability
of generic extended release phenytoin sodium. Administer at the
same time with regard to meals Separate the doses of other
medications or tube feedings by 2 hours. Side Effects Ataxia,
sedation, cognitive impairment, visual disturbances,hirsutism
Slide 32
Gabapentin ( Neurontin ) MOA: GABA agonist activity
Neuropsychiatric ADEs have occurred in pediatric population
Hostility, aggressive behaviors Do not discontinue abruptly; taper
over at least one week Oral Solution must be refrigerated Side
Effects Somnolence, ataxia, dizziness, weight gain
Slide 33
Zonisamide (Zonegran) Approved for adjunctive treatment of
partial seizures in adults with epilepsy Blocks sodium channels,
thereby stabilizing neuronal membranes Used off-label in children
Adverse effects:???????
Slide 34
Topiramate ( Topamax ) MOA: Thought to block sodium channels,
potentiate GABA and inhibit the activation of glutamate. May cause
an ocular syndrome characterized by acute angle closure glaucoma
Typically occurs within 1 month of initiation of therapy. Advise
patients to report any blurred vision to physician immediately May
cause kidney stones Parents should report any pain upon urination
Tablets may be crushed, mixed with water and administered
immediately Sprinkle capsules should not be chewed.
Slide 35
Felbamate ( Felbatol ) MOA: regulates Na, enhances GABA
Associated with ? and ?. Currently FDA recommends that it only be
used in patients who have failed therapy with all other AEDs and
who have such severe epilepsy that the benefits outweigh the risk.
Weekly or biweekly monitoring of CBC and Liver Function tests are
recommended with use.
Slide 36
Tiagabine (Gabitril) Indicated for the adjunctive treatment of
partial seizures Inhibits the reuptake of GABA, the major
inhibitory neurotransmitter in the CNS. Side Effects: mostly GI
(diarrhea, nausea, abdominal pain)
Slide 37
Levetiracetam (Keppra) FDA-approved as adjunctive therapy for
adults and children 4 years of age and older with partial seizures
FDA-approved for adults and children 6 years of age and older with
primary generalized tonic-clonic seizures FDA-approved for adults
and adolescents greater than 12 years of age with myoclonic
seizures.
Slide 38
Vigabatrin (Sabril) Structural analog of GABA and was designed
to inhibit the metabolism of GABA First drug to be FDA approved for
the treatment of infantile spasms Also FDA-approved for adjunctive
therapy in the treatment of adults with refractory complex partial
seizures. Due to the risk of ?????????, vigabatrin is only
available through a restricted distribution program called
SHARE.
Slide 39
Pregabalin (Lyrica) Binds to voltage-gated calcium channel and
results in a decrease in the release of several excitatory
neurotransmitters More potent than gabapentin Minimal CNS side
effects; no drug interactions May cause weight gain and edema FDA
approved for ????????
Slide 40
Lamotrigine ( Lamictal ) MOA: affects voltage regulated sodium
channels and inhibits the presynaptic release of glutamate and
aspartate Potential to cause ???????????; risk factors are Young
age, concurrent VPA therapy, high initial dose, rapid titration
Occurs as a result of a toxic arene oxide intermediate metabolite
which is produced through the P450 pathway
Slide 41
Newer Agents Lacosamide (Vimpat) - MOA: Slow sodium channel
blocker - FDA approval: Oral or IV use as add-on in adults with
partial-onset seizures - Maximal dose of 300mg/d with CrCl of
30mL/min or less or hepatic impairment -SE:????????? - Controlled
substance schedule V:???? - Parenteral formulation: FDA indication
only for replacement of oral formulation
Slide 42
New Agents Rufinamide (Banzel) - MOA: inhibition of
sodium-dependent action potential - FDA-approved for ?????????????
- Absorption is increased by food - Decreases concentration of
ethinyl estradiol and northindrone - Slightly shortens QT
interval
Slide 43
New Agents Clobazam (Onfi) - Oral benzodiazepine - Approved for
????????????? - Inhibitor of 2D6; drugs metabolized by 2D6
(fluoxetine, paroxetine, etc>) - Metabolized through ???????;
Diflucan and Prilosec can increase serum concentrations of the
metabolite
Slide 44
New Agent Ezogabine (Potiga) - Approved for ????????????? -
MOA: potassium channel facilitator; reduces the degree of
depolarization needed to pen the channel which opens faster and
stays open longer, slowing repetitive firing in the brain -
Dose-related mean weight increases of 1.2- 2.7 kg - Urinary
retention requiring catheterization has been reported; psychotic
symptoms (dose related) has occurred. - Schedule V due ??????? - QT
prolongation has been reported
Slide 45
Status Epilepticus Continuous or intermittent seizures lasting
more than 30 minutes, without full recovery of consciousness
between seizures. Therapeutic principles: time is brain If a
treatment fails, there should be no interval between the end of a
failed protocol and the initiation of next therapy
Slide 46
First-Line Therapies Benzodiazepines IV diazepam (0.2 mg/Kg
given at 5mg/min) and lorazepam (0.1 mg/kg given at 2 mg/min)
Phenytoin limitation is the rate at which it can be delivered
Fosphenytoin prodrug of phenytoin; can be infused at rates faster
than phenytoin; less vascular irritation; can be given IM
Slide 47
Other First-Line Therapies Valproate Phenobarbital Works on the
GABA receptors; causes profound respiratory depression and
hypotension
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Refractory Status Epilepticus Failure of adequate amounts of
two IV drugs to stop seizures. Add enough anticonvulsant to reach a
high therapeutic or low toxic serum anticonvulsant concentration
Should be no hesitation to depress respiration and intubate, but
severe arterial hypotension should be avoided since it will curtail
cerebral blood flow.
Slide 49
Refractory Status Epilepticus Midazolam continuous infusion due
to short duration of action; less hypotension Propofol ??????????
Anesthetic Barbiturates Pentobarbital and thiopental
Role of the Pharmacist Improve compliance - Education - Refer
to patient support groups - Reinforce importance of treatment -
Provide written instructions
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