antiepileptic drugs - antiseizure drugs jim mcauley, phd, rph professor of pharmacy practice &...
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Antiepileptic Drugs - Antiseizure Drugs
Jim McAuley, PhD, RPh
Professor of Pharmacy Practice & Neurology
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
Pharmacokinetics Drug Interactions
can be induced
Toxicity diplopia, headache, dizziness, nausea
Clinical Pearl IV formulation marketed Spring 2009
(LCM, Vimpat®)
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
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
Thank you for your attention
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