Antiepileptic Drugs - Antiseizure Drugs Jim McAuley, PhD, RPh Professor of Pharmacy Practice & Neurology McAuley.5@osu.edu

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) Therapy Long-Term Management Strategies for Epilepsy OCBZ Antiepileptic Drug (AED) Therapy TGB TPM RUF LTG VGB PER PGB GBP EZG VPA ZNS PB PHT CBZ FBM CLB LEV LCM Vagus Nerve Stimulator Surgery Ketogenic Diet

Symptomatic Localization-Related Epilepsy - Overall Strategy Monotherapy Monotherapy (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 ? Epilepsy and Behavior 2001;2:A1-A50.

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 Categorization Apply template to “Major Players” Chronology Seizure Type Mechanism of Action Enhance sodium channel inactivation Enhance inhibitory GABA transmission Block calcium channel Other mechanisms Other AEDs Note – most drugs affect more than one target Apply template to “Major Players” Mechanism of Action Clinical Use Pharmacokinetics Drug Interactions Toxicity Clinical Pearl Use outside of epilepsy

AEDs that enhance sodium channel inactivation Phenytoin Carbamazepine Oxcarbazepine Lacosamide Lamotrigine Topiramate Zonisamide

Phenytoin (PHT, Dilantin®) Mechanism: Clinical Use: Pharmacokinetics 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

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

Oxcarbazepine (OCBZ, Trileptal®) Mechanism: Clinical Use: 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+

Lacosamide (LCM, Vimpat®) Mechanism: Clinical Use: Pharmacokinetics Na+ channels Clinical Use: Partial Pharmacokinetics Drug Interactions can be induced Toxicity diplopia, headache, dizziness, nausea Clinical Pearl IV formulation marketed Spring 2009

Lamotrigine (LTG, Lamictal®) Mechanism: Na+ Channels, Glutamate Clinical Use: Partial & Generalized Pharmacokinetics Drug Interactions influenced by others including Estrogen Toxicity sedation, diplopia, ataxia, nausea - Rash Clinical Pearl slow taper - especially Valproate use outside of epilepsy maintenance of bipolar disorder

Topiramate (TPM, Topamax®) Mechanism: Na+ Channels, Glutamate, GABA, Carbonic anhydrase inhibition Clinical Use: Partial & Generalized Pharmacokinetics Drug Interactions 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 Clinical Use: Partial Pharmacokinetics Drug Interactions 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 Clinical Use: Partial & Generalized Pharmacokinetics Drug Interactions 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 Pharmacokinetics Drug Interactions 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 Clinical Use: Partial & Generalized Pharmacokinetics Drug Interactions Enzyme Inhibitor Toxicity sedation, N/V, weight gain, hair loss, tremor, thrombocytopenia Clinical Pearl ≠ woman childbearing age use outside of epilepsy maintenance of bipolar disorder 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 Clinical Use: Partial 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 Clinical Use: Partial Pharmacokinetics Drug Interactions 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 Clinical Use: Partial & Generalized Pharmacokinetics Drug Interactions none Toxicity somnolence, dizziness, behavioral changes Clinical Pearl adjust dose for renal function IV formulation

Ezogabine (EZG, Potiga®) Mechanism: Neuronal K+ channel stabilizer Clinical Use: Partial Pharmacokinetics Drug Interactions 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 Pharmacokinetics Drug Interactions 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 (not major players, not yet on market, approved for specific indications, etc.) Tiagabine Vigabatrin Felbamate Primidone Acetazolamide Rufinamide Eslicarbazepine Stiripentol Clobazam

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) Therapy Long-Term Management Strategies for Epilepsy OCBZ Antiepileptic Drug (AED) Therapy TGB TPM RUF LTG VGB PER PGB GBP EZG VPA ZNS PB PHT CBZ FBM CLB LEV LCM 1st Generation 2nd Generation

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

Thank you for your attention McAuley.5@osu.edu

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