Anti-epileptic Drugs:

Anti-epileptic Drugs:

Anti-epileptic Drugs: Facts and Case Studies By: Stephanie S. Beckstrom, DNP, APRN, AGPCNP-BC, Katelyn M. Johnson, DNP, APRN, FNP-C, Cristin M. Rassi, APRN, ACNS-BC, CNRN Conflict of interest disclosure Presenters declare no conflicts of interest. General Neurology Fellowship 12 month program Transition from graduate to APRN clinician Rotations in neurology subspecialties including dementia, epilepsy, stroke, movement disorders,

multiple sclerosis, vertigo, and headache clinic General Neurology Access Clinic Weekly attendance of lectures with neurology residents Objectives

Differentiate between seizure types Identify common mimics of seizures Understand the importance of seizure control Differentiate between broad and narrow spectrum anti-epileptic drugs (AEDs) Identify common adverse reactions of AEDs Understand how to start and stop AEDs Understand how to monitor medication therapy Identify AED medication interactions Identify considerations for specific populations Seizures are Paroxysmal Episodic

Electrical What is Epilepsy? Epilepsy: a disorder involving nerve cells in the brain causing recurrent, unprovoked seizures A person is diagnosed with epilepsy if they have two unprovoked seizures (or one unprovoked seizure with the likelihood of more) that were not caused by some known and reversible medical condition like alcohol withdrawal or extremely low blood sugar. Epilepsy Foundation (2019) Statistics More people live with epilepsy than with autism spectrum disorders, Parkinsons disease, multiple sclerosis and cerebral palsy combined. - Epilepsy

Foundation (2019) 3.4 million people with Epilepsy in the United States Medication provides effective control for of individuals with epilepsy >1 million people have uncontrolled epilepsy Diagnosis History EEG (electroencephalogram) Routine (awake/drowsy) Video EEG Ambulatory EEG MRI Brain Identifying risk factors

Age Seizures in childhood Head injuries/trauma Family history Stroke

Dementia Brain tumor Brain infections Drug abuse Understanding triggers

Poor sleep Dehydration Hypoglycemia Stress Infection/illness Alcohol Drug abuse Photosensitivity Menstruation Missed doses of AED Goals of Epilepsy Management 1. Control seizures

2. Avoid side effects 3. Restore or maintain quality of life Why is it important to control epilepsy? Falls/injuries Increased emergency department visits Driving restrictions Ability to work Missed social opportunities Increased anxiety/depression Death When to start AED therapy?

Provoked vs. unprovoked* Abnormal EEG Abnormal findings on neurological exam or neuroimaging A first time seizure that occured during sleep (nocturnal seizure) Case #1 (part 1) 20 year old male. New onset seizure. Unprovoked generalized tonic clonic seizure in sleep. Witnessed by college roommate. Brought in by EMS and back to baseline. EEG at ER normal. MRI Brain normal. Denied family hx of seizures. Denied alcohol and drug use. Start an AED or wait???

Case #1 (part 2) 20 year old male. New onset seizure. Unprovoked generalized tonic clonic seizure in sleep. Witnessed by college roommate. Brought in by EMS and back to baseline. EEG at ER normal. MRI Brain normal. Denied family hx of seizures. Denied alcohol and drug use. Start an AED. Choosing an AED Age and gender (childbearing plans) Spectrum of efficacy Pharmacokinetic properties Safety and tolerability Comorbidities

Considerations AED affordability Prior authorization Good Rx Compliance Dose frequency and schedule Understanding medication instructions Coping Resources Social Work Anti-epileptics drugs (AEDs) Anti-epiletpic drugs

Broad spectrum Generalized onset Focal onset Narrow spectrum Focal onset Focal evolving to bilateral convulsive

AEDs Broad Spectrum valproate levetiracetam lamotrigine topiramate zonisamide

Narrow Spectrum phenobarbital clobazam rufinamide perampanel lacosamide phenytoin

pregabalin gabapentin oxcarbazepine carbamazepine ethosuximide eslicarbazepine vigabatrin

Case #2 (part 1) 60 year old female, recent history of ischemic stroke, s/p tPA presents to ED 2 weeks later for what she thought was another stroke including what she described as light headedness, trouble speaking (per spouse), numbness and tingling in RUE, and brief episode of confusion (per spouse). Further work up - imaging negative for new ischemic event. Symptoms resolved. What is on your differential? Start AED? Case # 2 (part 2) EEG abnormal - no events captured but abnormal slowing in frontotemporal region indicating a possible seizure focus. Lamotrigine started

Broad Spectrum Name Side Effects levetiracetam (Keppra) Hostility, irritability, mood changes, depression, lamotrigine (Lamictal) Oral lesions, xerostomia, nausea, headache, blurred vision, double vision, Stevens-Johnson syndrome (uncommon-severe)

valproate (Depakote) Dose related tremor, hair loss, weight gain, nausea, hepatotoxicity, thrombocytopenia. Excessive bleeding may result when combined with asa or NSAIDs topiramate (Topamax) Dizziness, tiredness, speech problems, difficulty with memory, sensory distortion. Alcohol and drugs that cause sedation may increase the sedative effects

zonisamide (Zonegran) Dizziness, drowsiness, tiredness, lack of coordination. Alcohol and drugs may increase sedative effects Narrow Spectrum Name Side Effects carbamazepine (Tegretol) Xerostomia, nausea, headache, dizziness, sedation, weight gain, rash, hepatotoxicity, and

tiredness lacosamide (Vimpat) Dizziness, headache, nausea, diplopia oxcarbazepine (Trileptal) Xerostomia, headache, fatigue, nausea, vomiting, hyponatremia phenytoin (Dilantin) Xerostomia, ataxia, incoordination, dysarthria, nystagmus, and double vision

pregabalin (Lyrica) Xerostomia, dizziness, drowsiness, edema, blurred vision, reduced platelet counts. Alcohol and drugs may increase sedative effects gabapentin (Neurontin) Xerostomia, edema, fatigue, dizziness Mechanism of action MOA Drug

Calcium Channel valproate, ethosuxamide, gabapentin, pregabalin, zonisamide Sodium Channel phenytoin, carbamazepine, oxcarbazepine, topiramate, felbamate, lamotrigine, lacosamide, rufinamide, eslicarbazepine, valproate, zonisamide Glutamate Receptors

topiramate, zonisamade, perampanel, felbamate GABA phenobarbital, topiramate, clobazam, valproate, tiagabine, valproate, felbamate Protein SV2A levetiracetam AEDs and adverse reactions Hyponatremia risk)

(the elderly and patients on diuretics are at increased carbamazepine, oxcarbazepine Renal calculi topiramate, zonisamide Weight gain

valproate, gabapentin, carbamazepine, pregabalin Weight loss topiramate, zonisamide Aplastic anemia carbamazepine, oxcarbazepine Steven Johnson Syndrome Most AEDs Cognitive difficulties topiramate Worsening mood levetiracetam, zonisamide, topiramate, phenobarbital AEDs and other conditions

Bipolar disorder/depression lamotrigine, valproate, carbamazepine, oxcarbazepine Migraine topiramate, valproate Pain syndromes/neuropathy/neuralgia pregabalin, gabapentin, carbamazepine, oxcarbazepine Obesity topiramate, zonisamde Women of childbearing age lamotrigine, levetiracetam, oxcarbazepine, zonisamide

Avoid valproate, topiramate, phenobarbital Renal insufficiency avoid gabapentin, levetiracetam, pregabalin Dosing Frequency Once daily zonisamide, phenobarbital, perampanel, phenytoin, valproate ER, lamotrigine XR, levetiracetam XR, oxcarbazepine XR, topiramate XR Twice daily carbamazepine ER, levetiracetam, lamotrigine, lacosamide, topiramate, pregabalin Three times daily gabapentin

Case #3 70 year old female started on AED following new onset seizures. Presents to clinic with rash. Medication changed and rash resolves. You see patient 1.5 months later and patient has recently been treated for a new rash by PCP. Contact dermatitis or AED related? Case # 3 continued The answer is not clear. Was rash responsive to treatment?

Notify Neurology provider. May need hospitalization for safe withdrawal or medication and initiation of new medication. PEARLS Phenytoin, carbamazepine, and oxcarbazepine may exacerbate generalized absence and myoclonic seizures and should be avoided in idiopathic generalized epilepsy Gabapentin and pregabalin have similar potential Benzodiazepines like clonazepam are typically used as adjunctive therapy and limited data supports monotherapy use

Starting and stopping AEDs Initiation Titrate Educate Discontinuation Why? o alternate therapy/ineffective o side effects o seizure free 2-4 years Titrate - abrupt withdrawal may causes seizures 1 medication at a time Educate - breakthrough seizures Failed Medication Monotherapy

Why did medication fail? Tolerability vs. lack of efficacy Tolerability try alternate monotherapy Lack of efficacy switch to another monotherapy OR add adjunctive therapy Monitoring AEDs Seizure response to medication Side effects Trough level Additional lab monitoring Additional Lab Monitoring

Baseline - Obtain CBC, electrolytes, BUN, creatinine and LFTs Blood counts carbamazepine, oxcarbazepine (aplastic anemia) phenytoin (thrombocytopenia) Hepatic function phenytoin (hepatotoxity) Electrolytes oxcarbazepine (hyponatremia) Renal function Drug Interactions Depakote can reduce clearance (increase serum

concentration) of phenobarbital, lamotrigine, and carbamazepine Phenytoin can increase metabolism and decrease effect of carbamazepine, clonazepam, lamotrigine, levetiracetam, oxcarbazepine, valproate and zonisamide Antibiotics and AEDs decreased antimicrobial effect increased and decreased anticonvulsant effect Antiepileptics that react with antimicrobials *Phenytoin (dilantin), phenobarbital, carbamazepine, diazepam, clonazepam, valproate, carbamazepine

Antimicrobial Anticonvulsant Antimicrobial Effect Anticonvulsant Effect Fluconazole Phenytoin level

level Ketoconazole Phenytoin level level Clindamycin Diazepam None

effect Doxycycline Phenobarbital absorption, serum terminal half-life level Ciprofloxacin Phenytoin

None or Erythromycin Carbamazepine None level, toxicity Phenytoin

None level Valproate None level Carbamazepine None level, toxicity

Phenytoin None level Valproate None level Phenobarbital

level Phenytoin level Sulfonamides Phenytoin None level Sulfamethoxazoletrimethoprim

Phenytoin None level Clarithromycin Metronidazole Generic Substitutions Evidence is mixed - potential problem Check with clinician before accepting substitution

from pharmacy May need additional drug monitoring Considerations for Specific Populations Women Females of Childbearing Age Pregnancy Breastfeeding Menopause Catamenial epilepsy Men Elderly

Females of Childbearing Age Choosing an AED Plans to get pregnant o Medically refractory - is VNS appropriate? o folic acid supplementation Education *Avoid Depakote - highest incidence of teratogenicity* Contraceptives AEDS may decrease efficacy of contraceptives AEDS have no effect on IUDS AEDs and Contraceptives AED

Effect on Hormonal Contraception Effect on AED Clonazepam, diazepam, ethosuximide, ezogabine, gabapentin, lacosamide, lorazepam, levetiracetam, pregabalin, vigabatrin, and zonisamide None

No Carbamazepine, clobazam, esclicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone and rufinimide Decreased ethinyl estradiol levels Decreased progestin levels Unknown Topiramate

Decreased ethinyl estradiol levels (dose dependent effect) Unknown Decreased progestin levels Unknown lamotrigine Decreased progestin levels valproate

No Decreased lamotrigine levels (with estrogen-containing contraception) Perampanel Decreased valproate levels (with estrogen-containing contraception) Folic Acid Supplementation Folic acid is important to prevent neural tube defects

Discuss with female patients of childbearing age Some AEDs decrease levels of folic acid valproic acid, carbamazepine, oxcarbazepine, phenobarbital, phenytoin and primidone Research is controversial Pregnancy Pregnancy Monotherapy is goal 1st line treatment: lamotrigine or levetiracetam Weigh risks versus benefit Drug levels will decrease because of altered hepatic absorption, increased volume, increased renal clearance - monitor regularly

Adjust medications antepartum and postpartum Encourage all pregnant women to enter North American Anti-Epileptic Drug Pregnancy Registry Breastfeeding Exposed to AEDs in utero lower levels are transferred in breast milk than through the placenta Weigh pros/cons - more beneficial than potential risks Watch for drowsiness Reported side effects are rare Timing - take medication after breastfeeding

Menopause Perimenopause high estrogen secretion contributes to seizures exacerbation medication levels need monitored and possibly increased Menopause seizures stabilize and generally have a decrease in frequency Postmenopausal women with long term AED use have increased risk of osteopenia, osteoporosis, and fractures review risk factors and follow recommendations Men

Sexual dysfunction may occur from decreased circulating hormones Altered brain function (focal epilepsy) Anti epileptic medications Antiepileptic medications phenobarbital, phenytoin (dilantin), carbamazepine (tegretol), primidone Challenges with Elderly Population Reduced function of liver and kidneys May experience adverse effects at therapeutic levels Usually need lower doses of medication

Dosing throughout day - more even levels to reduce chance for seizures Polypharmacy Medication adherence and memory Concerns in Elderly Population Epilepsy Foundation (2019) Medical Marijuana and Epilepsy Approved for Epilepsy in Illinois Medical marijuana card Medical marijuana dispensary June 25, 2018 - Epidiolex was approved by the FDA

as the first CBD-based product on the US market. Lennox-Gastaut syndrome Dravet syndrome $$$$ Summary Identify your comfort level Consult with/Refer to Neurology Start with broad AEDs Start slow and monitor trough levels Medication interactions Antibiotics, contraceptives and other AEDs Watch for rashes Adherence to regimen is key 90 day supplies

Pill organizers and medication reminders Helpful Resources Epilepsy Foundation Neurology Continuum UpToDate Epocrates Questions

References Abou-Khalil, B.W. (2019). Update on antiepileptic drugs 2019. Continuum. (25)2, 508-536. Epilepsy foundation. (2019). Effects of epilepsy medications. Retrieved from Epilepsy foundation. (2019). Epilepsy and the African American community. Retrieved from Epilepsy foundation. (2019). Medical marijuana and epilepsy. Retrieved from pilepsy Epilepsy foundation. (2019). Men and epilepsy. Retrieved from Epilepsy foundation. (2019). Side effects. Retrieved from Epilepsy foundation. (2019). Triggers of seizures. Retrieved from Epilepsy foundation. (2019). What is epilepsy. Retrieved from

Epilepsy foundation. (2019). What are the risk factors. Retrieved from References Cont. Ergene, E., Rassi, C. (2019). An approach to seizures and spells. [Powerpoint slides] Gerard, E.E., Meador, K.K. (2016). Managing epilepsy in women. Continuum. 22, 204-223. Karseski, S. (2019). Initial treatment of epilepsy in adults. UpToDate. Retrieved from %20epilepsy%20in%20adults&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 Loyd, C. (2019). Epilepsy. [Powerpoint slides] Pack, A.M. (2019) Epilepsy overview and revised classification of seizures and epilepsies. Continuum. (25)2, 306-321 Sazgar, M. (2019). Treatment of Women with Epilepsy. Continuum. (25)2, 408-430. Schachter, S.C., Garcia, P., Dashe, J.F. (2019) Overview of the management of epilepsy in adults. UpToDate. Retrieved from ource=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 U.S. Food and Drug Administration. (2018). FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. Retrieved from -marijuana-treat-rare-severe-forms

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