Current Medications for Current Medications for Seizure ControlSeizure Control

Nabil J. Azar, M.D.Nabil J. Azar, M.D.Assistant Professor of NeurologyAssistant Professor of Neurology

Vanderbilt University Medical CenterVanderbilt University Medical CenterNashville, TNNashville, TN

OutlineOutline•• General principles of antiepileptic (AED) drugs useGeneral principles of antiepileptic (AED) drugs use•• AED selection:AED selection:

a. Depends on type of seizures and epilepsy a. Depends on type of seizures and epilepsy syndromesyndromeb. Old vs. new b. Old vs. new AEDsAEDsc. Safety and ease of usec. Safety and ease of used. Presence of other medical conditionsd. Presence of other medical conditionse. Titration rate and dosinge. Titration rate and dosingf. Special populations: f. Special populations:

-- ChildrenChildren-- Women of child bearing ageWomen of child bearing age-- elderly elderly

•• Limitations of AED drug therapyLimitations of AED drug therapy

Is it necessary to treat seizures?Is it necessary to treat seizures?•• Usually, but not alwaysUsually, but not always•• ExceptionsExceptions

–– provoked seizures, if the provocation is goneprovoked seizures, if the provocation is goneex: febrile seizures, seizures provoked by medications, by changex: febrile seizures, seizures provoked by medications, by changes in es in

blood composition blood composition

–– single unprovoked seizures with a normal EEG and MRI single unprovoked seizures with a normal EEG and MRI (the risk of recurrence is about 40%)(the risk of recurrence is about 40%)

–– certain very mild forms of epilepsy where life style changes certain very mild forms of epilepsy where life style changes alone can prevent seizure recurrencealone can prevent seizure recurrence

adequate sleep, with consistent hoursadequate sleep, with consistent hoursavoidance of alcohol and drugsavoidance of alcohol and drugs

–– certain benign focal epilepsies in childrencertain benign focal epilepsies in children

Why should we treat epilepsy?Why should we treat epilepsy?•• Seizures may result in physical injury Seizures may result in physical injury •• Seizures usually restrict life style (driving, working Seizures usually restrict life style (driving, working

with hazardous equipment or in a hazardous with hazardous equipment or in a hazardous environment)environment)

•• Severe very prolonged seizures Severe very prolonged seizures maymay cause brain cause brain damagedamage

•• Frequent seizures over a long period of time may cause Frequent seizures over a long period of time may cause cell loss in some parts of the brain and may impair cell loss in some parts of the brain and may impair some brain functions (particularly memory)some brain functions (particularly memory)

•• Untreated epilepsy may become more entrenched and Untreated epilepsy may become more entrenched and resistantresistant

Goal of epilepsy treatmentGoal of epilepsy treatment

Seizure freedom and no side effectsSeizure freedom and no side effects

Efficacy and tolerabilityEfficacy and tolerability

Initiation of AED therapyInitiation of AED therapy• Diagnosis: seizure type (s), epilepsy syndrome and : seizure type (s), epilepsy syndrome and

etiology (if possible).etiology (if possible).•• Selection of best (or ideal) AED: Selection of best (or ideal) AED:

-- Efficacy: one AED (Efficacy: one AED (monotherapymonotherapy) is the goal) is the goal-- SafetySafety-- TolerabilityTolerability-- Pharmacokinetic advantagesPharmacokinetic advantages-- Titration rateTitration rate-- DosingDosing-- ComorbiditiesComorbidities

Newly treated epilepsyNewly treated epilepsy-- outcome outcome of AED treatmentof AED treatment

470 patients with epilepsy who had never received AED treatment:470 patients with epilepsy who had never received AED treatment: 64% were 64% were seizureseizure--free at followfree at follow--upup

Kwan & Kwan & BrodieBrodie, , EpilepsiaEpilepsia 20012001

Antiepileptic drugs (Antiepileptic drugs (AEDsAEDs))oldold newnew

• Phenobarbital (Luminal) 1912• Primidone (Mysoline)• Phenytoin (Dilantin)• Methsuximide (Celontin)• Ethosuximide (Zarontin)• Clonazepam (Klonopin)• Carbamazepine (Tegretol,

Carbatrol)• Valproate (Depakote) 1978

• Felbamate (Felbatol) 1993• Gabapentin (Neurontin)• Lamotrigine (Lamictal) • Topiramate (Topamax) • Tiagabine (Gabitril)• Levetiracetam (Keppra) • Oxcarbazepine (Trileptal)• Zonisamide (Zonegran)• Pregabalin (Lyrica)• Vigabatrin (Sabril)• Rufinamide (Banzel)• Lacosamide (Vimpat) 2009

Coming soon: Retigabine, Brivaracetam…

Azar & Abou-Khalil; Sem in Neurol 2008

Azar & Abou-Khalil; Sem in Neurol 2008

Failed therapy due to lack of efficacyFailed therapy due to lack of efficacy

•• Option 1Option 1: substitution therapy: substitution therapy-- best best if first AED has failed completely if first AED has failed completely

•• Option 2Option 2: add: add--on therapyon therapy-- best if best if there has been some benefitthere has been some benefit•• all new AEDsall new AEDs

Questions to be answered when Questions to be answered when AEDsAEDs failfail

Some questions have to be asked:Some questions have to be asked:Is the diagnosis correct?Is the diagnosis correct?

Are we dealing with a different seizure type than we thought?Are we dealing with a different seizure type than we thought?are seizures nonare seizures non--epileptic?epileptic?

Are seizure medications used optimally?Are seizure medications used optimally?Is the patient taking the medication consistently?Is the patient taking the medication consistently?Are there other factors such as stress, sleep deprivation, Are there other factors such as stress, sleep deprivation, alcohol, drug abuse, another medication that worsens alcohol, drug abuse, another medication that worsens seizures?seizures?

Epilepsy may be truly resistant to medication Epilepsy may be truly resistant to medication treatmenttreatmentEpilepsy surgery, VNS, Epilepsy surgery, VNS, ketogenicketogenic diet, new drug diet, new drug trialstrials

Advantageous combinationsAdvantageous combinations

•• Advantages can be based on lack of Advantages can be based on lack of interactioninteraction•• no significant interaction in either direction:no significant interaction in either direction:

gabapentingabapentin, , levetiracetamlevetiracetam, , pregabalinpregabalin•• do not significantly affect others, but have do not significantly affect others, but have

shorter halfshorter half--life when added to an enzymelife when added to an enzyme--inducing AED: inducing AED:

lamotriginelamotrigine, topiramate, , topiramate, tiagabinetiagabine, oxcarbazepine, , oxcarbazepine, zonisamidezonisamide

•• Combinations with synergistic effects:Combinations with synergistic effects:•• LamotrigineLamotrigine + + valproatevalproate•• LevetiracetamLevetiracetam + + lamotriginelamotrigine

Pharmacokinetic overview of old AEDsPharmacokinetic overview of old AEDs

PHTPHT

bioavailabilitybioavailability

Protein bindingProtein binding

T1/2T1/2

AutoinductionAutoinduction

>90%>90% 7575--85%85% >90%>90% >90%>90%

90%90% 75%75% 90%90% 45%45%

77--4242 66--2020 55--1515 6565--110110

nono yesyes nono nono

CBZCBZ VPAVPA PHBPHB PMDPMD

>90%>90%

<20%<20%

88--1515

nono

ESXESX

>90%>90%

<10%<10%

3030--6060

nono

CZPCZP

>80%>80%

86%86%

3030--4040

nono

% Metabolism% Metabolism 95%95% >95%>95% >96%>96% <80%<80%

Metabolism siteMetabolism site LiverLiver LiverLiver LiverLiver LiverLiver LiverLiver LiverLiver LiverLiver

6565--90%90% ~80%~80%

EnzEnz. induction. induction yesyes yesyes yesyes yesyesnono nono nono

EnzEnz. Inhibition. Inhibition yesyes

Pharmacokinetic overview Pharmacokinetic overview of new AEDsof new AEDs

FBMFBM

AbsorptionAbsorption

dose dependentdose dependent

bioavailabilitybioavailability

TmaxTmax (hrs)(hrs)

Protein bindingProtein binding

T1/2T1/2

AutoinductionAutoinduction

nono yesyes nono nono

>90%>90% ~60%~60%>98%>98% >>80%80%

11--44 22--33 1.41.4--4.84.8 11--44

25%25% 0%0% 55%55% 15%15%

1818--2424 55--88 1212--7070 2020--3030

nono nono slightslight nono

GPNGPN LTGLTG TOPTOP TGBTGB

nono

>>89%89%

0.90.9--2.62.6

96%96%

22--99

nono

LEVLEV

nono

~100%~100%

~1~1

0%0%

66--88

nono

OXCOXC

nono

99%99%

44--6*6*

40%*40%*

9*9*

slightslight

ZNSZNS

nono

~100%~100%

22--66

40%40%

6363

nono

* applies to * applies to monohydroxyderivativemonohydroxyderivative (MHD), the main active metabolite(MHD), the main active metabolite

PGBPGB

nono

90%90%

11--2.52.5

0%0%

nono

5.55.5--6.76.7

Effect of newer AEDs on blood Effect of newer AEDs on blood concentration of established AEDsconcentration of established AEDs

AED serum concentration with add-on

PGBFBM GPN LTG TPM TGB LEV OXC ZNS

CBZ

PHT

VPA

*

* an increase in PHT level may occur at high OXC doses

Pharmacological propertiesPharmacological propertiesOld Old AEDsAEDs::

-- Liver induction / Liver induction / inhibitioninhibition

-- Important autoImportant auto--inductioninduction

-- High protein bindingHigh protein binding-- Common blood level Common blood level

monitoringmonitoring-- Prevalent drugPrevalent drug--drug drug

interaction

New New AEDsAEDs::

-- No / mild liver No / mild liver induction / inhibitioninduction / inhibition

-- No / mild No / mild autoinductionautoinduction

-- Low protein bindingLow protein binding-- Less common Less common bloddblodd

level monitoringlevel monitoring-- Minimal drugMinimal drug--drug drug

interactioninteraction interaction

IdiosynchraticIdiosynchratic toxicity of old toxicity of old AEDsAEDs

PHT

CBZ

VPA

Rash, enlarged lymph nodes, liver failure, blood abn

Rash, other hypersensitivity, liver failure, blood abn

Liver failure, pancreatitis (rare), blood abn

PHB Rash, connective tissue disorders, liver failure, blood

PMD Connective tissue disorders

ESX Blood abnormalitities

CZP Rash

Old Old AEDsAEDs: most problematic adverse : most problematic adverse effectseffects

PHT

CBZ

VPA

Sedation, gum swelling

Sedation, fatigue

Sedation, weight gain, hair loss, hormonal changes

PHB Sedation, slow thinking, lower IQ

PMD Sedation, slow thinking

ESX Gastrointestinal malaise

CZP Sedation, constipation, tolerance

IdiosynchraticIdiosynchratic toxicity of new toxicity of new AEDsAEDs

FBM

GPN

LTG

Aplastic anemia, liver failure

-

Skin rash

TPM acute angle-closure glaucoma, oligohydrosis

TGB -

LEV -

OXC Rash

Rash, oligohydrosisZNS

New AEDs: most problematic New AEDs: most problematic adverse effectsadverse effects

FBM

GPN, PGB

LTG

GI upset, headache, insomnia

Weight gain, myoclonus

Insomnia

TPM

TGB

Speech disorder, behavior changes, kidney stones

Confusion, dizziness

LEV Irritability, nightmares

OXC Low sodium (hyponatremia)

ZNS Behavioral changes, kidney stones

TolerabilityTolerability

•• New AEDs compared by large studies New AEDs compared by large studies (lowest to highest)(lowest to highest)–– gabapentingabapentin, , lamotriginelamotrigine, levetiracetam, levetiracetam–– tiagabinetiagabine, oxcarbazepine, oxcarbazepine–– topiramate, topiramate, zonisamidezonisamide

Tolerability Tolerability -- cognitive profiles of new cognitive profiles of new AEDsAEDs

•• BestBest-- LamotrigineLamotrigine-- FelbamateFelbamate-- GabapentinGabapentin-- LevetiracetamLevetiracetam-- OxcarbazepineOxcarbazepine-- PregabalinPregabalin-- LacosamideLacosamide

•• IntermediateIntermediate-- TiagabineTiagabine-- ZonisamideZonisamide

•• WorstWorst-- TopiramateTopiramate

Prevalence of Prevalence of comorbiditycomorbidity

•• Depression (50%)Depression (50%)•• Bipolar disorder (10%)Bipolar disorder (10%)•• Panic attacks 50 %Panic attacks 50 %•• Migraine: 25 %Migraine: 25 %•• Sleep disturbances: >25% Sleep disturbances: >25% •• Restless leg syndrome: 10 %Restless leg syndrome: 10 %•• Obesity 30 %Obesity 30 %•• Spasticity: cerebral palsy, multiple sclerosisSpasticity: cerebral palsy, multiple sclerosis•• Peripheral neuropathyPeripheral neuropathy•• Chronic pain syndromesChronic pain syndromes

Nonepileptic indications

Azar & Abou-Khalil, Sem in Neurol 2008

How other medical conditions influence our How other medical conditions influence our choicechoice

–– Migraine:Migraine: depakotedepakote, , topamaxtopamax (? for (? for kepprakeppra, , zonegranzonegran))

–– Bipolar disease:Bipolar disease: lamictallamictal, , depakotedepakote( ? ( ? neurontinneurontin, , topamaxtopamax, , oxcarbazepineoxcarbazepine))

–– Obesity:Obesity: topamaxtopamax, , zonisamidezonisamide, , felbamatefelbamate((lamotriginelamotrigine, , levetiracetamlevetiracetam, , tiagabinetiagabine, ,

oxcarbazepineoxcarbazepine are weight neutral)are weight neutral)–– Obesity + migraine:Obesity + migraine: topamaxtopamax–– Peripheral neuropathy, chronic pain Peripheral neuropathy, chronic pain

syndromes:syndromes: pregabalinpregabalin, , gabapentingabapentin

Titration rates: initiation at therapeutic Titration rates: initiation at therapeutic dosesdoses

•• Rapid titration:Rapid titration:-- Most of old Most of old AEDsAEDs-- FelbamateFelbamate-- GabapentinGabapentin-- ZonisamideZonisamide-- LevetiracetamLevetiracetam **-- PregabalinPregabalin-- LacosamideLacosamide *

•• Slow titration:Slow titration:-- LamotrigineLamotrigine-- TopiramateTopiramate-- TiagabineTiagabine

*

* Available in intravenous form

Special considerations in ChildrenSpecial considerations in Children

• General rules:- Avoid sedating AEDs because of comorbiddisorders (autism, mental retardation…)- Go slower and lower

• Specifics:- Rash with lamictal is more serious- Psychosis with keppra is more common- Oligohydrosis with topamax and zonegranmore lethal- Fulminant liver failure with depakote is more likely (2 years<) Nadkarni et a; Neurology 2005

Bryant & Dreifuss; Neurology 1996Pellock & Brodie; Epilepsia 1997

Women of childbearing potentialWomen of childbearing potential•• Infertility:Infertility: more common than normal populationmore common than normal population

•• Reproductive and sexual dysfunction:Reproductive and sexual dysfunction:•• DeapkoteDeapkote causing PCOS reversible with causing PCOS reversible with lamotriginelamotrigine

•• Oral contraceptive pills (OCP):Oral contraceptive pills (OCP):-- Lowered efficacy by enzyme inducing Lowered efficacy by enzyme inducing AEDsAEDs; PHB, PHT, CBZ, ; PHB, PHT, CBZ, PMD, TPM (>200 mg) and OXC (>900 mg)PMD, TPM (>200 mg) and OXC (>900 mg)-- estradiolestradiol (OCP, pregnancy) lowers efficacy of (OCP, pregnancy) lowers efficacy of lamotriginelamotrigine

•• Developmental abnormalities in exposed fetus:Developmental abnormalities in exposed fetus:VPA has the highest risk (7VPA has the highest risk (7-- 8 %) especially in 8 %) especially in polytherapypolytherapy and high and high dosages, followed by CBZ and PHT (5dosages, followed by CBZ and PHT (5--6 %).6 %).Some new Some new AEDsAEDs appear safer in event of unexpected pregnancy appear safer in event of unexpected pregnancy (ex: LTG, OXC, ? LEV ?, TPM ?, ZNS ?)(ex: LTG, OXC, ? LEV ?, TPM ?, ZNS ?)Folic acid (1Folic acid (1--4 mg daily)4 mg daily)

Lofren et al; Epilepsy Res 2007Artama et al; Neurology 2005

Special considerations in the elderlySpecial considerations in the elderly• General rules:

- Avoid sedating AEDs because of comorbid disorders (polytherapy, dementia…)- Go slower and lower: respond better to low doses- Avoid enzyme-inducing and highly protein-bound AEDs (i.e AEDs)- Anaylze blood levels with caution (ask for free levels)- Use extended release formulation (especially with CBZ, VPA)- Use new AEDs

• Specifics:- Hyponatremia with trileptal is common (especially when taking diuretics)- Reversible Parkinsonism with chronic VPA is not rare- Renal calculi with TPM and ZNS are more likely- Osteopenia and osteaporosis with PB, PHT and CBZ are very common

Armaon et al; Neurology 1996Perucca et al; Epilepsy Res 2006Saetre et al; Epilepsia 2007

New versus old New versus old AEDsAEDs-- summarysummary•• OldOld

-- Established efficacyEstablished efficacy-- Poor tolerability: more Poor tolerability: more sedationsedation-- Safety issuesSafety issues-- Fast titrationFast titration-- Major interactionsMajor interactions-- Blood level monitoringBlood level monitoring-- Disrupt hormonal milieuDisrupt hormonal milieu-- Reduce bone density

•• NewNew-- Similar efficacySimilar efficacy-- Better tolerabilityBetter tolerability-- Better safetyBetter safety-- Slower titrationSlower titration-- Less interactionsLess interactions-- More expensiveMore expensive-- Less Less teratogenicityteratogenicity-- High in breast milk High in breast milk

Reduce bone density

Limitations of AED therapyLimitations of AED therapy

•• Treats the symptoms or seizures and not the Treats the symptoms or seizures and not the disease or epilepsydisease or epilepsy–– Does not prevent the development or progression Does not prevent the development or progression

of epilepsyof epilepsy–– Does not cure epilepsyDoes not cure epilepsy

•• We need drugs with:We need drugs with:-- Better efficacy and tolerabilityBetter efficacy and tolerability-- Prevent epilepsyPrevent epilepsy-- Reverse the process of Reverse the process of epileptogenesisepileptogenesis