Project CARE

1. Anti-Seizure and RescueAnti-Seizure and Rescue
MedicationsMedications
Elia M Pestana Knight, MDElia M Pestana Knight, MD
Cleveland ClinicCleveland Clinic
Epilepsy CenterEpilepsy Center

2. Topics for this webinarTopics for this webinar
• What are antiepileptic drugs?What are antiepileptic drugs?
• Historical development of the drugsHistorical development of the drugs
• How doctors select the drugs to treatHow doctors select the drugs to treat
the seizures?the seizures?
• Common side effectCommon side effect
• Considerations in special populationsConsiderations in special populations
• Drug interactionsDrug interactions
• Seizure rescue medicationsSeizure rescue medications

3. WHAT ARE ANTIEPILEPTICWHAT ARE ANTIEPILEPTIC
DRUGS?DRUGS?

4. • Antiepileptic drugs (AEDs)Antiepileptic drugs (AEDs)
• Anticonvulsant medicationsAnticonvulsant medications
• Anti-seizure medicationsAnti-seizure medications

5. Anti-seizure medicationsAnti-seizure medications
• Drugs that decrease the frequencyDrugs that decrease the frequency
and/or severity of seizures in peopleand/or severity of seizures in people
with epilepsywith epilepsy
• Treat the symptom of seizures, not theTreat the symptom of seizures, not the
underlying epileptic conditionunderlying epileptic condition
• They don’t change the course of theThey don’t change the course of the
diseasedisease

6. Antiepileptic drugsAntiepileptic drugs
• Drugs that prevent the development of recurrentDrugs that prevent the development of recurrent
seizures in people at riskseizures in people at risk
• Drugs that reduce seizure frequency and severityDrugs that reduce seizure frequency and severity
outlasting the treatment periodoutlasting the treatment period
- Example: after head trauma, stroke, brainExample: after head trauma, stroke, brain
tumors, etctumors, etc
• Animal studies suggest that Levetiracetam andAnimal studies suggest that Levetiracetam and
Ethosuximide are potential antiepileptic drugs BUTEthosuximide are potential antiepileptic drugs BUT
there are no studies in humans to support thisthere are no studies in humans to support this

7. Use of anti-seizureUse of anti-seizure
medicationsmedications
• EpilepsyEpilepsy
• Pain treatmentPain treatment
- Neuralgias, neuropathic pain, etcNeuralgias, neuropathic pain, etc
• Migraine prophylaxisMigraine prophylaxis
• Treatment of bipolar disorder, moodTreatment of bipolar disorder, mood
disorder and anxietydisorder and anxiety

8. How are seizuresHow are seizures
generated?generated?
 Excitation (too much)Excitation (too much)
- Ionic-inward NaIonic-inward Na++
, Ca, Ca++++
currentscurrents
- Neurotransmitter: glutamate, aspartateNeurotransmitter: glutamate, aspartate
 Inhibition (too little)Inhibition (too little)
- Ionic-inward CIIonic-inward CI--
, outward K, outward K++
currentscurrents
- Neurotransmitter: GABANeurotransmitter: GABA

9. How anti-seizure medicationsHow anti-seizure medications
work?work?
• Suppressing the rapid and excessiveSuppressing the rapid and excessive
firing of neurons during seizuresfiring of neurons during seizures
• Preventing the spread of seizuresPreventing the spread of seizures
within the brainwithin the brain

10. HISTORICAL DEVELOPMENT OFHISTORICAL DEVELOPMENT OF
THE DRUGSTHE DRUGS

11. History of AEDs in the U.S.History of AEDs in the U.S.
 1857 – Bromides1857 – Bromides
 1882 – Paraldehyde (not longer in use in USA)1882 – Paraldehyde (not longer in use in USA)
 1912 – Phenobarbital (PB)1912 – Phenobarbital (PB)
 1937 – Phenytoin (PHT)1937 – Phenytoin (PHT)
 1944 – Trimethodione1944 – Trimethodione
 1953 - Acetazolamide1953 - Acetazolamide
 1954 - Primidone1954 - Primidone
 1960 – Ethosuximide1960 – Ethosuximide
 1963 - Diazepam1963 - Diazepam
 1974 – Carbamazepine (CBZ)1974 – Carbamazepine (CBZ)
 1972 – Clorazepate and Lorazepam1972 – Clorazepate and Lorazepam
 1975 – Clonazepam (CZP)1975 – Clonazepam (CZP)
 1978 – Valproate (VPA)1978 – Valproate (VPA)

12. New AEDs in the U.S.New AEDs in the U.S.
 1993 – Felbamate (FBM), gabapentin (GBP)1993 – Felbamate (FBM), gabapentin (GBP)
 1995 – Lamotrigine (LTG)1995 – Lamotrigine (LTG)
 1996 - Fosphenytoin1996 - Fosphenytoin
 1997 – Topiramate (TPM), tiagabine (TGB)1997 – Topiramate (TPM), tiagabine (TGB)
 1999 – Levetiracetam (LEV)1999 – Levetiracetam (LEV)
 2000 – Oxcarbazepine (OXCBZ), zonisamide (ZNS)2000 – Oxcarbazepine (OXCBZ), zonisamide (ZNS)
 2005 - Pregabalin (PGB)2005 - Pregabalin (PGB)

13. Newer DrugsNewer Drugs
• 2008 – Lacosamide (Vimpat)2008 – Lacosamide (Vimpat)
• 2008 – Rufinamide (Banzel)2008 – Rufinamide (Banzel)
• 2009 – Vigabatrin (Sabril)2009 – Vigabatrin (Sabril)
• 2011 – Ezogabine (Potiga) and2011 – Ezogabine (Potiga) and
Clobazam (Onfi)Clobazam (Onfi)
• 2012 – Perampanel (Fycompa)2012 – Perampanel (Fycompa)

14. Other treatments, diet andOther treatments, diet and
devicesdevices
• Sex hormones: ProgesteroneSex hormones: Progesterone
• Diets: Ketogenic diet, Low glycemicDiets: Ketogenic diet, Low glycemic
diet, modified Atkins dietdiet, modified Atkins diet
• Devices: Vagus Nerve Stimulator (VNS)Devices: Vagus Nerve Stimulator (VNS)
and Neuropaceand Neuropace
• Epilepsy SurgeryEpilepsy Surgery

15. HOW DOCTORS SELECT THEHOW DOCTORS SELECT THE
DRUGS TO TREAT THEDRUGS TO TREAT THE
SEIZURES?SEIZURES?

16. Goals of treatmentGoals of treatment
• Minimal number of seizuresMinimal number of seizures
• Minimal adverse events or side effectsMinimal adverse events or side effects
• Best quality of life possibleBest quality of life possible

17. Selecting the AEDsSelecting the AEDs
• Seizure types or syndromeSeizure types or syndrome
• Age of the patient (oral suspension,Age of the patient (oral suspension,
chewable, sprinkles for children)chewable, sprinkles for children)
• Dosing scheduleDosing schedule
• Comorbidities and other medicalComorbidities and other medical
conditionsconditions
• Potential side effects and toxicityPotential side effects and toxicity
• Interaction with other drugsInteraction with other drugs

18. COMMON SIDE EFFECTSCOMMON SIDE EFFECTS

19. Adverse EffectsAdverse Effects
 Acute dose-related:Acute dose-related: reversiblereversible
 IdiosyncraticIdiosyncratic
- Uncommon - rareUncommon - rare
- Potentially serious or life threateningPotentially serious or life threatening
 Chronic:Chronic: reversibility and seriousnessreversibility and seriousness
varyvary

20. Acute, Dose-Related AdverseAcute, Dose-Related Adverse
Effects of AEDsEffects of AEDs
 Neurologic/psychiatric:Neurologic/psychiatric: most commonmost common
• Sedation, fatigueSedation, fatigue
− All AEDs, except unusual with LTG and FBMAll AEDs, except unusual with LTG and FBM
• Unsteadiness, uncoordination, dizzinessUnsteadiness, uncoordination, dizziness
− Mainly traditional AEDsMainly traditional AEDs
− May be sign of toxicity with many AEDsMay be sign of toxicity with many AEDs
• Tremor - valproic acidTremor - valproic acid

21. Acute, Dose-Related AdverseAcute, Dose-Related Adverse
Effects of AEDsEffects of AEDs (cont.)(cont.)
• Paresthesia (topiramate, zonisamide)Paresthesia (topiramate, zonisamide)
• Double vision , blurred vision, visual distortionDouble vision , blurred vision, visual distortion
(carbamazepine, lamotrigine)(carbamazepine, lamotrigine)
• Mental/motor slowing or impairment (topiramate at higherMental/motor slowing or impairment (topiramate at higher
doses)doses)
• Mood or behavioral changes (levetiracetam)Mood or behavioral changes (levetiracetam)
• Changes in libido or sexual function (carbamazepine,Changes in libido or sexual function (carbamazepine,
phenytoin, phenobarbital)phenytoin, phenobarbital)

22. Acute, Dose-Related AdverseAcute, Dose-Related Adverse
Effects of AEDs (cont.)Effects of AEDs (cont.)
 GastrointestinalGastrointestinal (nausea, heartburn)(nausea, heartburn)
 Mild to moderate laboratoryMild to moderate laboratory
changeschanges
• Hyponatremia: carbamazepine, oxcarbazepineHyponatremia: carbamazepine, oxcarbazepine
• Increases in ALT or ASTIncreases in ALT or AST
• LeukopeniaLeukopenia
• ThrombocytopeniaThrombocytopenia
P-Slide 22

23. Acute, Dose-Related AdverseAcute, Dose-Related Adverse
Effects of AEDsEffects of AEDs (cont.)(cont.)
 Weight gain/appetite changesWeight gain/appetite changes
- Valproic acidValproic acid
- GabapentinGabapentin
- PregabalinPregabalin
 Weight lossWeight loss
- TopiramateTopiramate
- ZonisamideZonisamide
- FelbamateFelbamate
P-Slide 23

24. Idiosyncratic AdverseIdiosyncratic Adverse
Effects of AEDsEffects of AEDs
 Toxic Epidermal necrolysisToxic Epidermal necrolysis
 Stevens-Johnson syndromeStevens-Johnson syndrome
- More common in lamotrigine patients receiving valproateMore common in lamotrigine patients receiving valproate
and/or aggressively titrated.and/or aggressively titrated.
Signs of potential Stevens-Johnson syndromeSigns of potential Stevens-Johnson syndrome
- Hepatic damageHepatic damage
- Early symptoms: abdominal pain, vomiting, jaundiceEarly symptoms: abdominal pain, vomiting, jaundice
- Laboratory monitoring probably not helpful in early detectionLaboratory monitoring probably not helpful in early detection
- Patient educationPatient education
- Fever and mucus membrane involvementFever and mucus membrane involvement

25. Idiosyncratic AdverseIdiosyncratic Adverse
Effects of AEDsEffects of AEDs
 Hematologic damageHematologic damage
- Marrow aplasia, agranulocytosis, aplastic anemiaMarrow aplasia, agranulocytosis, aplastic anemia
- Early symptoms: abnormal bleeding, acute onset ofEarly symptoms: abnormal bleeding, acute onset of
fever, symptoms of anemiafever, symptoms of anemia
- Laboratory monitoring probably not helpful in earlyLaboratory monitoring probably not helpful in early
detectiondetection
- Felbamate aplastic anemia approx. 1:5,000 treatedFelbamate aplastic anemia approx. 1:5,000 treated
patientspatients
- Patient educationPatient education

26. Long-Term AdverseLong-Term Adverse
Effects of AEDsEffects of AEDs
 Endocrine/Metabolic EffectsEndocrine/Metabolic Effects
• Osteomalacia, osteoporosisOsteomalacia, osteoporosis
• CarbamazepineCarbamazepine
• PhenobarbitalPhenobarbital
• PhenytoinPhenytoin
• OxcarbazepineOxcarbazepine
• ValproateValproate
• Folate (anemia, teratogenesis)Folate (anemia, teratogenesis)
• PhenobarbitalPhenobarbital
• PhenytoinPhenytoin
• CarbamazepineCarbamazepine
• ValproateValproate
• Altered connective tissue metabolism orAltered connective tissue metabolism or
growth (facial coarsening, hirsutism,growth (facial coarsening, hirsutism,
gingival hyperplasia or contractures)gingival hyperplasia or contractures)
• PhenytoinPhenytoin
• PhenobarbitalPhenobarbital
 NeurologicNeurologic
• NeuropathyNeuropathy
• Cerebellar syndrome -Cerebellar syndrome -
phenytoinphenytoin
 Sexual Dysfunction -Sexual Dysfunction -
30-60%30-60%
• PhenytoinPhenytoin
• CarbamazepineCarbamazepine
• PhenobarbitalPhenobarbital
• PrimidonePrimidone

27. AED HypersensitivityAED Hypersensitivity
SyndromeSyndrome
 Characterized by rash, systemicCharacterized by rash, systemic
involvementinvolvement
 Arene oxide intermediates -Arene oxide intermediates - aromaticaromatic
ringring
 Lack of epoxide hydrolaseLack of epoxide hydrolase
 Cross-reactivityCross-reactivity
- PhenytoinPhenytoin
- CarbamazepineCarbamazepine
- PhenobarbitalPhenobarbital
- OxcarbazepineOxcarbazepine
 Relative cross reactivityRelative cross reactivity - lamotrigine- lamotrigine

28. CONSIDERATION IN SPECIALCONSIDERATION IN SPECIAL
POPULATIONSPOPULATIONS

29. The ChildrenThe Children
 NeonateNeonate - often lower per kg doses- often lower per kg doses
- Low protein bindingLow protein binding
- Low metabolic rateLow metabolic rate
 ChildrenChildren - higher, more frequent doses- higher, more frequent doses
- Faster metabolismFaster metabolism
- Better renal clearanceBetter renal clearance

30. The TeenagersThe Teenagers
• FemaleFemale
- Avoid some medications with potentialAvoid some medications with potential
teratogenesis (damage to the fetus)teratogenesis (damage to the fetus)
- Some AEDs reduce the efficacy of oralSome AEDs reduce the efficacy of oral
contraceptive so other contraceptive methodscontraceptive so other contraceptive methods
should be consideredshould be considered
- Some drugs could have undesirable physicalSome drugs could have undesirable physical
effectseffects
• Both gendersBoth genders
- AEDs have a black label for depression andAEDs have a black label for depression and
suicidal ideation, so screening is importantsuicidal ideation, so screening is important

31. PregnancyPregnancy
 Increased volume of distributionIncreased volume of distribution
 Lower serum albuminLower serum albumin
 Faster metabolismFaster metabolism
 Higher dose, but probably less than predicted by totalHigher dose, but probably less than predicted by total
level (measure free level)level (measure free level)
 Consider more frequent dosingConsider more frequent dosing
 Return to pre-pregnancy conditions rapidly (within 2Return to pre-pregnancy conditions rapidly (within 2
weeks) after deliveryweeks) after delivery
 Teratogenic effect of some medicationsTeratogenic effect of some medications

32. Metabolic Changes of AEDsMetabolic Changes of AEDs
 Febrile IllnessesFebrile Illnesses
- ↑↑ metabolic rate and ↓ serum concentrationsmetabolic rate and ↓ serum concentrations
- ↑↑ serum proteins that can bind AEDs and ↓ free levels ofserum proteins that can bind AEDs and ↓ free levels of
AED serum concentrationsAED serum concentrations
 Severe Hepatic DiseaseSevere Hepatic Disease
- Impairs metabolism and ↑ serum levels of AEDsImpairs metabolism and ↑ serum levels of AEDs
- ↓↓ serum proteins and ↑ free levels of AED serumserum proteins and ↑ free levels of AED serum
concentrationsconcentrations
- Often serum levels can be harder to predict in this situationOften serum levels can be harder to predict in this situation

33. Metabolic Changes of AEDsMetabolic Changes of AEDs
 Renal DiseaseRenal Disease
- ↓↓ the elimination of some AEDsthe elimination of some AEDs
- Gabapentin, pregabalin, levetiracetamGabapentin, pregabalin, levetiracetam
 Chronic Renal DiseaseChronic Renal Disease
- ↑↑ protein loss and ↑ free fraction of highly protein boundprotein loss and ↑ free fraction of highly protein bound
AEDsAEDs
- It may be helpful to give smaller doses more frequently to ↓It may be helpful to give smaller doses more frequently to ↓
adverse effectsadverse effects
- Phenytoin, valproic acid, tiagabinePhenytoin, valproic acid, tiagabine
P-Slide 33

34. DRUG INTERACTIONSDRUG INTERACTIONS

35. Pharmacokinetic InteractionsPharmacokinetic Interactions
Be aware that drug interactions mayBe aware that drug interactions may
occur when there is the:occur when there is the:
- Addition of a new medication when you are taking aAddition of a new medication when you are taking a
medication that can change the liver metabolism of othermedication that can change the liver metabolism of other
medicationsmedications
- AdditionAddition of another medication that can change theof another medication that can change the
liver metabolism of other medicationsliver metabolism of other medications to an existingto an existing
medication regimen.medication regimen.
- Removal ofRemoval of a medication that can change the livera medication that can change the liver
metabolism of other medicationsmetabolism of other medications from chronicfrom chronic
medication regimen.medication regimen.

36. Hepatic Drug Metabolizing EnzymesHepatic Drug Metabolizing Enzymes
and Specific AED Interactionsand Specific AED Interactions
 Phenytoin:Phenytoin: CYP2C9/CYP2C19CYP2C9/CYP2C19
- Inhibitors: valproate, ticlopidine, fluoxetine, topiramate,Inhibitors: valproate, ticlopidine, fluoxetine, topiramate,
fluconazolefluconazole
 Carbamazepine:Carbamazepine: CYP3A4/CYP2C8/CYP1A2CYP3A4/CYP2C8/CYP1A2
- Inhibitors: ketoconazole, fluconazole, erythromycin,Inhibitors: ketoconazole, fluconazole, erythromycin,
diltiazemdiltiazem
 Lamotrigine:Lamotrigine: UGT 1A4UGT 1A4
- Inhibitor: valproateInhibitor: valproate
• Important note about oral contraceptives (OCPs):Important note about oral contraceptives (OCPs):
- OCP efficacy is decreased by inducers, including:OCP efficacy is decreased by inducers, including:
phenytoin, phenobarbital, primidone, carbamazepine; andphenytoin, phenobarbital, primidone, carbamazepine; and
higher doses of topiramate and oxcarbazepinehigher doses of topiramate and oxcarbazepine
- OCPs and pregnancy significantly decrease serum levels ofOCPs and pregnancy significantly decrease serum levels of
lamotrigine.lamotrigine.

37. AEDs and Drug InteractionsAEDs and Drug Interactions
 AEDs that do not appear to be eitherAEDs that do not appear to be either
inducers or inhibitors of the CYPinducers or inhibitors of the CYP
system include:system include:
GabapentinGabapentin
LamotrigineLamotrigine
PregabalinPregabalin
TiagabineTiagabine
LevetiracetamLevetiracetam
ZonisamideZonisamide
P-Slide 37

38. AEDs and FoodsAEDs and Foods
• Grapefruit juiceGrapefruit juice

39. RESCUE MEDICATIONSRESCUE MEDICATIONS

40. Medicines for the treatment ofMedicines for the treatment of
acute seizuresacute seizures
• Intravenous (in hospital or paramediceIntravenous (in hospital or paramedice
use)use)
• Transmucosal (at home use)Transmucosal (at home use)

41. Transmucosal medicationsTransmucosal medications
• Rectal therapyRectal therapy
- DiazepamDiazepam
• Buccal therapyBuccal therapy
- MidazolamMidazolam
• Intranasal therapyIntranasal therapy
- MidazolamMidazolam
- LorazepamLorazepam

42. Take home pointsTake home points
• Anti-seizure medications are prescribedAnti-seizure medications are prescribed
taking into account a number of factorstaking into account a number of factors
• Always disclose to your physician whatAlways disclose to your physician what
other medications or supplements areother medications or supplements are
you taking as these can cause drugyou taking as these can cause drug
interactionsinteractions
• Seizure rescue plan is very importantSeizure rescue plan is very important
for all people with epilepsyfor all people with epilepsy

43. Questions?Questions?
• Let’s begin with our Question andLet’s begin with our Question and
Answer session!Answer session!