Anti-Seizure and Rescue Anti-Seizure and Rescue MedicationsMedications

Anti-Seizure and Rescue Anti-Seizure and Rescue MedicationsMedications

Elia M Pestana Knight, MDElia M Pestana Knight, MD

Cleveland ClinicCleveland Clinic

Epilepsy CenterEpilepsy Center

Topics for this webinarTopics for this webinarTopics 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 treat How doctors select the drugs to treat

the seizures?the seizures?• Common side effectCommon side effect• Considerations in special populationsConsiderations in special populations• Drug interactions Drug interactions • Seizure rescue medicationsSeizure rescue medications

WHAT ARE ANTIEPILEPTIC WHAT ARE ANTIEPILEPTIC DRUGS?DRUGS?WHAT ARE ANTIEPILEPTIC WHAT ARE ANTIEPILEPTIC DRUGS?DRUGS?

• Antiepileptic drugs (AEDs)Antiepileptic drugs (AEDs)

• Anticonvulsant medicationsAnticonvulsant medications

• Anti-seizure medicationsAnti-seizure medications

Anti-seizure medicationsAnti-seizure medicationsAnti-seizure medicationsAnti-seizure medications

• Drugs that decrease the frequency and/or Drugs that decrease the frequency and/or severity of seizures in people with severity of seizures in people with epilepsyepilepsy

• Treat the symptom of seizures, not the Treat the symptom of seizures, not the underlying epileptic condition underlying epileptic condition

• They don’t change the course of the They don’t change the course of the diseasedisease

Antiepileptic drugsAntiepileptic drugsAntiepileptic drugsAntiepileptic drugs

• Drugs that prevent the development of recurrent Drugs that prevent the development of recurrent seizures in people at riskseizures in people at risk

• Drugs that reduce seizure frequency and severity Drugs that reduce seizure frequency and severity outlasting the treatment periodoutlasting the treatment period- Example: after head trauma, stroke, brain Example: after head trauma, stroke, brain

tumors, etctumors, etc

• Animal studies suggest that Levetiracetam and Animal studies suggest that Levetiracetam and Ethosuximide are potential antiepileptic drugs BUT Ethosuximide are potential antiepileptic drugs BUT there are no studies in humans to support thisthere are no studies in humans to support this

Use of anti-seizure Use of anti-seizure medicationsmedications

Use of anti-seizure Use of anti-seizure medicationsmedications

• EpilepsyEpilepsy

• Pain treatmentPain treatment

- Neuralgias, neuropathic pain, etcNeuralgias, neuropathic pain, etc

• Migraine prophylaxisMigraine prophylaxis

• Treatment of bipolar disorder, mood Treatment of bipolar disorder, mood disorder and anxietydisorder and anxiety

How are seizures How are seizures generated?generated?

How are seizures How are seizures generated?generated?

Excitation (too much)Excitation (too much) - Ionic-inward NaIonic-inward Na++, Ca, Ca++++ currents currents- Neurotransmitter: glutamate, aspartateNeurotransmitter: glutamate, aspartate

Inhibition (too little)Inhibition (too little)- Ionic-inward CIIonic-inward CI--, outward K, outward K++ currents currents- Neurotransmitter: GABANeurotransmitter: GABA

How anti-seizure medications How anti-seizure medications work?work?

How anti-seizure medications How anti-seizure medications work?work?

• Suppressing the rapid and excessive Suppressing the rapid and excessive firing of neurons during seizuresfiring of neurons during seizures

• Preventing the spread of seizures Preventing the spread of seizures within the brainwithin the brain

HISTORICAL DEVELOPMENT OF HISTORICAL DEVELOPMENT OF THE DRUGSTHE DRUGSHISTORICAL DEVELOPMENT OF HISTORICAL DEVELOPMENT OF THE DRUGSTHE DRUGS

History of AEDs in the U.S.History of AEDs in the U.S.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)

New AEDs in the U.S.New AEDs in the U.S.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)

Newer DrugsNewer DrugsNewer DrugsNewer Drugs

• 2008 – Lacosamide (Vimpat)2008 – Lacosamide (Vimpat)

• 2008 – Rufinamide (Banzel)2008 – Rufinamide (Banzel)

• 2009 – Vigabatrin (Sabril)2009 – Vigabatrin (Sabril)

• 2011 – Ezogabine (Potiga) and 2011 – Ezogabine (Potiga) and Clobazam (Onfi)Clobazam (Onfi)

• 2012 – Perampanel (Fycompa)2012 – Perampanel (Fycompa)

Other treatments, diet and Other treatments, diet and devicesdevices

Other treatments, diet and Other treatments, diet and devicesdevices

• Sex hormones: ProgesteroneSex hormones: Progesterone

• Diets: Ketogenic diet, Low glycemic Diets: 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

HOW DOCTORS SELECT THE HOW DOCTORS SELECT THE DRUGS TO TREAT THE DRUGS TO TREAT THE SEIZURES?SEIZURES?

HOW DOCTORS SELECT THE HOW DOCTORS SELECT THE DRUGS TO TREAT THE DRUGS TO TREAT THE SEIZURES?SEIZURES?

Goals of treatmentGoals of treatmentGoals 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

Selecting the AEDsSelecting the AEDsSelecting 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 medical Comorbidities and other medical

conditionsconditions• Potential side effects and toxicityPotential side effects and toxicity• Interaction with other drugsInteraction with other drugs

COMMON SIDE EFFECTSCOMMON SIDE EFFECTSCOMMON SIDE EFFECTSCOMMON SIDE EFFECTS

Adverse EffectsAdverse EffectsAdverse 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 seriousness reversibility and seriousness varyvary

Acute, Dose-Related Adverse Acute, Dose-Related Adverse Effects of AEDsEffects of AEDs

Acute, Dose-Related Adverse Acute, Dose-Related Adverse Effects of AEDsEffects of AEDs

Neurologic/psychiatric:Neurologic/psychiatric: most common most common Sedation, fatigue Sedation, fatigue

All AEDs, except unusual with LTG and FBMAll AEDs, except unusual with LTG and FBM

Unsteadiness, uncoordination, dizziness Unsteadiness, uncoordination, dizziness Mainly traditional AEDs Mainly traditional AEDs

May be sign of toxicity with many AEDsMay be sign of toxicity with many AEDs

Tremor - valproic acidTremor - valproic acid

Acute, Dose-Related Adverse Acute, Dose-Related Adverse Effects of AEDsEffects of AEDs (cont.) (cont.)

Acute, Dose-Related Adverse Acute, Dose-Related Adverse Effects of AEDsEffects of AEDs (cont.) (cont.)

Paresthesia (topiramate, zonisamide)Paresthesia (topiramate, zonisamide)

Double vision , blurred vision, visual distortion Double vision , blurred vision, visual distortion

(carbamazepine, lamotrigine)(carbamazepine, lamotrigine)

Mental/motor slowing or impairment (topiramate at higher Mental/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)

Acute, Dose-Related Adverse Acute, Dose-Related Adverse Effects of AEDs (cont.)Effects of AEDs (cont.)

Acute, Dose-Related Adverse Acute, Dose-Related Adverse Effects of AEDs (cont.)Effects of AEDs (cont.)

GastrointestinalGastrointestinal (nausea, heartburn) (nausea, heartburn)

Mild to moderate laboratory Mild to moderate laboratory

changeschanges Hyponatremia: carbamazepine, oxcarbazepineHyponatremia: carbamazepine, oxcarbazepine

Increases in ALT or ASTIncreases in ALT or AST

LeukopeniaLeukopenia

ThrombocytopeniaThrombocytopenia

P-Slide 22

Acute, Dose-Related Adverse Acute, Dose-Related Adverse Effects of AEDsEffects of AEDs (cont.) (cont.)

Acute, Dose-Related Adverse Acute, 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

Idiosyncratic Adverse Idiosyncratic Adverse Effects of AEDsEffects of AEDs

Idiosyncratic Adverse Idiosyncratic Adverse Effects of AEDsEffects of AEDs

Toxic Epidermal necrolysisToxic Epidermal necrolysis

Stevens-Johnson syndromeStevens-Johnson syndrome- More common in lamotrigine patients receiving valproate More 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

Idiosyncratic Adverse Idiosyncratic Adverse Effects of AEDsEffects of AEDs

Idiosyncratic Adverse Idiosyncratic Adverse Effects of AEDsEffects of AEDs

Hematologic damage Hematologic damage - Marrow aplasia, agranulocytosis, aplastic anemiaMarrow aplasia, agranulocytosis, aplastic anemia

- Early symptoms: abnormal bleeding, acute onset of Early symptoms: abnormal bleeding, acute onset of

fever, symptoms of anemiafever, symptoms of anemia

- Laboratory monitoring probably not helpful in early Laboratory monitoring probably not helpful in early

detectiondetection

- Felbamate aplastic anemia approx. 1:5,000 treated Felbamate aplastic anemia approx. 1:5,000 treated

patientspatients

- Patient educationPatient education

Long-Term Adverse Long-Term Adverse Effects of AEDsEffects of AEDs

Long-Term Adverse Long-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) Phenobarbital Phenobarbital PhenytoinPhenytoin CarbamazepineCarbamazepine ValproateValproate

Altered connective tissue metabolism or Altered 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

AED Hypersensitivity AED Hypersensitivity SyndromeSyndrome

AED Hypersensitivity AED Hypersensitivity SyndromeSyndrome

Characterized by rash, systemic Characterized by rash, systemic involvementinvolvement

Arene oxide intermediates - Arene oxide intermediates - aromatic aromatic ringring

Lack of epoxide hydrolaseLack of epoxide hydrolase Cross-reactivityCross-reactivity

- PhenytoinPhenytoin- CarbamazepineCarbamazepine- PhenobarbitalPhenobarbital- OxcarbazepineOxcarbazepine

Relative cross reactivityRelative cross reactivity - lamotrigine - lamotrigine

CONSIDERATION IN SPECIAL CONSIDERATION IN SPECIAL POPULATIONSPOPULATIONSCONSIDERATION IN SPECIAL CONSIDERATION IN SPECIAL POPULATIONSPOPULATIONS

The ChildrenThe ChildrenThe ChildrenThe Children

NeonateNeonate - often lower per kg doses - often lower per kg doses - Low protein binding Low protein binding - Low metabolic rateLow metabolic rate

ChildrenChildren - higher, more frequent doses - higher, more frequent doses- Faster metabolismFaster metabolism- Better renal clearanceBetter renal clearance

The TeenagersThe TeenagersThe TeenagersThe Teenagers

• FemaleFemale- Avoid some medications with potential Avoid some medications with potential

teratogenesis (damage to the fetus)teratogenesis (damage to the fetus)- Some AEDs reduce the efficacy of oral Some AEDs reduce the efficacy of oral

contraceptive so other contraceptive methods contraceptive so other contraceptive methods should be consideredshould be considered

- Some drugs could have undesirable physical Some drugs could have undesirable physical effectseffects

• Both gendersBoth genders- AEDs have a black label for depression and AEDs have a black label for depression and

suicidal ideation, so screening is importantsuicidal ideation, so screening is important

PregnancyPregnancyPregnancyPregnancy

Increased volume of distributionIncreased volume of distribution

Lower serum albuminLower serum albumin

Faster metabolismFaster metabolism

Higher dose, but probably less than predicted by total Higher 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 2 Return to pre-pregnancy conditions rapidly (within 2 weeks) after deliveryweeks) after delivery

Teratogenic effect of some medicationsTeratogenic effect of some medications

Metabolic Changes of AEDsMetabolic Changes of AEDsMetabolic 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 of serum 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 AEDs Impairs metabolism and ↑ serum levels of AEDs - ↓ ↓ serum proteins and ↑ free levels of AED serum serum proteins and ↑ free levels of AED serum

concentrations concentrations - Often serum levels can be harder to predict in this situationOften serum levels can be harder to predict in this situation

Metabolic Changes of AEDsMetabolic Changes of AEDsMetabolic 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 bound protein 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

DRUG INTERACTIONSDRUG INTERACTIONSDRUG INTERACTIONSDRUG INTERACTIONS

Pharmacokinetic InteractionsPharmacokinetic InteractionsPharmacokinetic InteractionsPharmacokinetic Interactions

Be aware that drug interactions may Be aware that drug interactions may occur when there is the:occur when there is the:

- Addition of a new medication when you are taking a Addition of a new medication when you are taking a medication that can change the liver metabolism of other medication that can change the liver metabolism of other medicationsmedications

- Addition Addition of another medication that can change the of another medication that can change the liver metabolism of other medicationsliver metabolism of other medications to an existing to an existing medication regimen.medication regimen.

- Removal of Removal of a medication that can change the liver a medication that can change the liver metabolism of other medications metabolism of other medications from chronic from chronic medication regimen.medication regimen.

Hepatic Drug Metabolizing Enzymes Hepatic Drug Metabolizing Enzymes and Specific AED Interactionsand Specific AED Interactions

Hepatic Drug Metabolizing Enzymes Hepatic 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: valproate Inhibitor: 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; and phenytoin, phenobarbital, primidone, carbamazepine; and higher doses of topiramate and oxcarbazepinehigher doses of topiramate and oxcarbazepine

- OCPs and pregnancy significantly decrease serum levels OCPs and pregnancy significantly decrease serum levels of lamotrigine.of lamotrigine.

AEDs and Drug InteractionsAEDs and Drug InteractionsAEDs and Drug InteractionsAEDs and Drug Interactions

AEDs that do not appear to be either AEDs that do not appear to be either inducers or inhibitors of the CYP inducers or inhibitors of the CYP system include:system include:

GabapentinGabapentinLamotrigineLamotriginePregabalinPregabalinTiagabineTiagabineLevetiracetamLevetiracetamZonisamideZonisamide

P-Slide 37

AEDs and FoodsAEDs and FoodsAEDs and FoodsAEDs and Foods

• Grapefruit juiceGrapefruit juice

RESCUE MEDICATIONSRESCUE MEDICATIONSRESCUE MEDICATIONSRESCUE MEDICATIONS

Medicines for the treatment of Medicines for the treatment of acute seizuresacute seizures

Medicines for the treatment of Medicines for the treatment of acute seizuresacute seizures

• Intravenous (in hospital or paramedice Intravenous (in hospital or paramedice use)use)

• Transmucosal (at home use)Transmucosal (at home use)

Transmucosal medicationsTransmucosal medicationsTransmucosal medicationsTransmucosal medications

• Rectal therapyRectal therapy

- DiazepamDiazepam

• Buccal therapyBuccal therapy

- MidazolamMidazolam

• Intranasal therapyIntranasal therapy

- MidazolamMidazolam

- LorazepamLorazepam

Take home pointsTake home pointsTake home pointsTake home points

• Anti-seizure medications are prescribed Anti-seizure medications are prescribed taking into account a number of factorstaking into account a number of factors

• Always disclose to your physician what Always disclose to your physician what other medications or supplements are other medications or supplements are you taking as these can cause drug you taking as these can cause drug interactionsinteractions

• Seizure rescue plan is very important Seizure rescue plan is very important for all people with epilepsyfor all people with epilepsy

Questions?Questions?Questions?Questions?

• Let’s begin with our Question and Let’s begin with our Question and Answer session!Answer session!