Antiepileptic Drugs - Antiseizure Drugs Jim McAuley, PhD, RPh Professor of Pharmacy Practice & Neurology [email protected]

Antiepileptic Drugs - Antiseizure Drugs

Jim McAuley, PhD, RPh

Professor of Pharmacy Practice & Neurology

[email protected]

Learning Objectives

Understand treatment goals for patients with epilepsy Identify general treatment approaches with antiepileptic

drugs For the most commonly used antiepileptic drugs (AEDs):

Define the proposed mechanism of action Describe the clinical use List the pharmacokinetic properties (including drug interactions) Explain the potential toxicities Discuss special issues relating to each Recognize their potential use outside of epilepsy

My Practice Site - since 1994

Outpatient Epilepsy Clinic Adult Population

Tertiary Care Referral Center Toolbox Patients with AED_resistant > AED_sensitive

Interdisciplinary Approach Epileptologists Nurse Practitioner Pharmacist

Patient care, teaching & research

Epilepsy

Affects 1 to 2% of US Population

Chronic condition with multiple drug therapies Drugs are mainstay of treatment

Treatment Goals No Seizures & No Side Effects

Antiepileptic Drug (AED) TherapyAntiepileptic Drug (AED) Therapy

PB PHT CBZVPA

FBM

GBP

LTG

TPM

TGB

OCBZ

LEV

ZNS

PGB

LCM

RUF

Vagus Nerve StimulatorSurgeryKetogenic Diet

Vagus Nerve StimulatorSurgeryKetogenic Diet

Long-Term Management Strategies for Epilepsy

VGB

EZG

CLB

PER

Symptomatic Localization-Related Epilepsy - Overall Strategy

Epilepsy and Behavior 2001;2:A1-A50.

MonotherapyMonotherapy

(2nd agent)Monotherapy (addtnl trials)

Combination of 2 AEDs

Evaluate for Surgery

2nd Combination of 2 AEDs

Adtl Combintns of 2 AEDs

Vagus Nerve Stimulator

Combination of 3 AEDs

?

General Treatment Approaches

How do you choose an AED? Few drugs of choice Mechanism of action

Criteria Efficacy

all FDA-approved Toxicity Drug Interactions Dosing schedule Clinical impression Co-morbid condition(s)

Art > Science

Mechanisms: Balance is Important

Excitatory Control Glutamate receptors (NMDA, non-NMDA) Excess is a problem

Inhibitory Control GABAA - major inhibitory neurotransmitter Lacking is a problem

Manipulate both in therapy

A lot to learn about the mechanisms of epilepsy & AEDs

Grouping & Template

Apply template to “Major Players”

Mechanism of Action Clinical Use Pharmacokinetics

Drug Interactions Toxicity Clinical Pearl

Use outside of epilepsy

Categorization Chronology Seizure Type Mechanism of Action

1. Enhance sodium channel inactivation

2. Enhance inhibitory GABA transmission

3. Block calcium channel

4. Other mechanisms

5. Other AEDs

Note – most drugs affect more than one target

AEDs that enhance sodium channel inactivation

Phenytoin Carbamazepine Oxcarbazepine Lacosamide

Lamotrigine Topiramate Zonisamide

Phenytoin

Mechanism: Na+ channel

Clinical Use: Partial & Generalized

Pharmacokinetics Saturable metabolism Drug Interactions

Enzyme Inducer

Toxicity nystagmus, ataxia, gingival hyperplasia, osteomalacia

Clinical Pearl need small dosage adjustments

(PHT, Dilantin®)

Gingival hyperplasia from Phenytoin

A 17-year-old boy had generalized tonic-clonic seizures for four years. When the seizures began, a computed tomographic scan of his brain and an electroencephalogram were normal. Treatment with 300 mg of phenytoin per day was subsequently begun and continued unsupervised for a period of two years. Examination revealed coarsening of facial features and severe gingival hyperplasia (Panel A), brisk deep-tendon reflexes, and cerebellar ataxia. Withdrawal of phenytoin was followed by marked regression of the gingival hyperplasia within three months (Panel B); however, ataxia persisted.

New England Journal of Medicine -- February 3, 2000 -- Vol. 342, No. 5

Carbamazepine

Mechanism: Na+ channel

Clinical Use: Partial > Generalized

Pharmacokinetics Auto-induction Drug Interactions

Enzyme Inducer

Toxicity dizziness, diplopia,

leukopenia

Clinical Pearl may worsen Primary

Generalized Seizures use outside of epilepsy

maintenance of bipolar disorder

pain (Trigeminal Neuralgia)

(CBZ, Tegretol®, Carbatrol®, Equetro®)

Oxcarbazepine

Mechanism: Na+ Channels

Clinical Use: Partial > Generalized

Pharmacokinetics Drug Interactions

influenced by others inhibit PHT, induce OCs

Toxicity dizziness, diplopia, ataxia, hyponatremia

Clinical Pearl monitor Na+

(OCBZ, Trileptal®)

Lacosamide

Mechanism: Na+ channels

Clinical Use: Partial


can be induced

Toxicity diplopia, headache, dizziness, nausea

Clinical Pearl IV formulation marketed Spring 2009

(LCM, Vimpat®)

Lamotrigine(LTG, Lamictal®)

Mechanism: Na+ Channels, Glutamate



influenced by others including Estrogen

Toxicity sedation, diplopia, ataxia,

nausea - Rash

Clinical Pearl slow taper - especially

Valproate use outside of epilepsy


Topiramate(TPM, Topamax®) Mechanism:

Na+ Channels, Glutamate, GABA, Carbonic anhydrase inhibition



influenced by others alter OC metabolism

Toxicity difficulty concentrating, kidney stones, weight loss

Clinical Pearls fluids use outside of epilepsy

migraine prophylaxis weight loss

Zonisamide(ZNS, Zonegran®) Mechanism:

Na+ and T-calcium channels, Carbonic anhydrase inhibition



not clinically significant

Toxicity somnolence, dizziness, kidney stones, weight loss

Clinical Pearl approved in Japan & Korea 1989 fluids

AEDs that enhance inhibitory GABA transmission Phenobarbital

[Benzodiazepines] Diazepam Lorazepam Clonazepam Midazolam

Phenobarbital(PB, Various Manufs) Mechanism:

GABAA



Enzyme Inducer

Toxicity sedation, paradoxical hyperactivity, osteomalacia

Clinical Pearl better options available

AEDs that block calcium channels

Ethosuximide Valproic acid

Ethosuximide(Zarontin®) Mechanism:

Reduces T-type Ca++ current

Clinical Use: Generalized - Absence


Can be induced and inhibited

Toxicity sedation, GI (nausea, vomiting, pain)

Clinical Pearl drug of choice for absence seizures

[This practitioner has little experience with this drug]

Valproic Acid(VPA, Depakote®, Depakene®, Depakote-ER®) Mechanism:

Ca++, Na+ channel, GABA



Enzyme Inhibitor

Toxicity sedation, N/V, weight gain,

hair loss, tremor, thrombocytopenia

Clinical Pearl ≠ woman childbearing age use outside of epilepsy


migraine prophylaxis

AEDs that act via OTHER mechanisms

Gabapentin Pregabalin Levetiracetam Ezogabine Perampanel

Gabapentin(GBP, Neurontin®)

Mechanism: Presynaptic alpha2-delta

site of voltage-gated calcium channels Note: ≠ GABA


Pharmacokinetics Absorption: saturable Drug Interactions

none with AEDs

Toxicity fatigue, dizziness, ataxia

Clinical Pearl adjust for renal function use outside of epilepsy

Pain Post-herpetic Neuralgia Diabetic Peripheral

Neuropathy Restless Leg Syndrome

Pregabalin(PGB, Lyrica®)

Mechanism: Presynaptic alpha2-delta

site of voltage-gated calcium channels Note: ≠ GABA



none

Toxicity dizziness, ataxia, weight

gain

Clinical Pearl adjust for renal function use outside of epilepsy

Pain Post-herpetic Neuralgia Diabetic Peripheral

Neuropathy Fibromyalgia [Anxiety]

Levetiracetam(LEV, Keppra®) Mechanism:

Synaptic vessel protein (SV2A) Modifies release of glutamate and GABA



none

Toxicity somnolence, dizziness, behavioral changes

Clinical Pearl adjust dose for renal function IV formulation

Ezogabine(EZG, Potiga®) Mechanism:

Neuronal K+ channel stabilizer



can be induced

Toxicity Dizziness, fatigue, diplopia, ataxia,

Urinary retention

Clinical Pearl Provides another option

Especially AED resistant patients Available Spring 2012

Perampanel(PER, Fycompa®) Mechanism

Dampens excitatory amino acid

Clinical Use Partial


can be induced shown to interact with OCs

Toxicity Dizziness / somnolence / fatigue / irritability / ataxia / weight gain

Clinical Pearl Provides another option

Especially AED resistant patients Available Spring 2013

Other AEDs

Tiagabine Vigabatrin Felbamate Primidone Acetazolamide

Rufinamide Eslicarbazepine Stiripentol Clobazam

(not major players, not yet on market, approved for specific indications, etc.)

AED uses beyond Epilepsy

Use in multiple psychiatric and neurologic conditions Extent of data varies FDA-approved > non-FDA-approved

Usage of drugs – no matter the indication drug interactions adverse effects women of childbearing age

Antiepileptic Drug (AED) TherapyAntiepileptic Drug (AED) Therapy

PB PHT CBZVPA

FBM

GBP

LTG

TPM

TGB

1st Generation 2nd Generation

OCBZ

LEV

ZNS

PGB

LCM

RUF

Long-Term Management Strategies for Epilepsy

VGB

EZG

CLB

PER

Summary of 1st Generation AEDs

Vast Clinical Experience Use in Both Partial and Primary Generalized Epilepsies

exception: Carbamazepine - Absence

Incomplete Efficacy Unfavorable Kinetics:

Saturable metabolism

Narrow Therapeutic Range Small window between efficacy & toxicity

Adverse CNS Effects Drug-Interactions

Summary of 2nd Generation AEDs

Safer Can be more expensive

most have generics now available

May help with intractable partial seizures Not profoundly more potent Less drug interactions Use outside of Epilepsy

Psychiatry, Headache, Pain, etc.

Future

Breviracetam Carisbamate Eslicarbazepine acetate Huperizine A

Case: Medication Change

50 YOF (KL) with h/o complex partial seizures & mechanical aortic valve

Medication profile for last 12 months Carbamazepine and Warfarin

During recent hospitalization Switched from Carbamazepine to Levetiracetam due to recent

seizure activity Discharged on only on Warfarin and Levetiracetam

No other changes

How would you respond to this situation?

Case: Medication Change

KL at risk for supra-therapeutic INR because carbamazepine no longer inducing warfarin Warfarin dose previously stabilized in the presence of enzyme-inducer

Recommend very close INR monitoring Consider decrease in warfarin dose

Note - Modeled after a real case KL was seen shortly after d/c in emergency room with significant GI bleed due to

“supraphysiologic INR” Reminder to think about drug

interactions when add OR remove drug

Add an Inhibitor

Remove an Inducer

Add an Inducer

Remove an Inhibitor

Serum Concentration

Antiepilepsy Drugs Quiz

Revisit our Learning Objectives

Understand treatment goals for patients with epilepsy Identify general treatment approaches with antiepileptic

drugs For the most commonly used antiepileptic drugs (AEDs):

Define the proposed mechanism of action Describe the clinical use List the pharmacokinetic properties (including drug interactions) Explain the potential toxicities Discuss special issues relating to each Recognize their potential use outside of epilepsy

[email protected]

Thank you for your attention

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Documents

Antiepileptic Drugs - Antiseizure Drugs Jim McAuley, PhD, RPh Professor of Pharmacy Practice & Neurology [email protected]