John Doe, M.D. / OUHSC Neurology THE TITLE OF MY TALK
Anti-Epileptic Drugs: Seizures, Spells, & Side Effects
Juliane Chainakul, APRN-CNS, CDE Clinical Instructor, Epilepsy, General Neurology Department of Neurology The University of Oklahoma Health Sciences Center
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LEARNING OBJECTIVES
Describe seizure classification Discuss pharmacological treatment of seizures Describe common side effects of AEDs Describe common drug-drug interactions of AEDs
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What is epilepsy?? Epilepsy is the 4th most common neurological problem. 2.9 million American adults and children live with epilepsy 1 in 26 people in the US will have epilepsy at some point in their life. 1 in 10 Americans will have a seizure. Epilepsy costs the US about $15.5 billion in healthcare and other expenses. The Epilepsy Foundation. www.epilepsy.com
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What is epilepsy?
Epilepsy is a chronic brain disorder of various causes characterized by recurrent, unprovoked seizures due to abnormal electrical activity in the brain. Seizure is a symptom of epilepsy. The seizure features depend on the area of brain involved.
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Common Causes of New Onset Seizures
Benign febrile convulsions of childhood Idiopathic/cryptogenic seizures Cerebral dysgenesis Symptomatic epilepsy ◦ Head trauma ◦ Stroke / vascular malformations ◦ Mass lesions ◦ CNS infections: encephalitis, meningitis, cysticercosis, HIV encelphalopathy Sydor & Edmondson, 2012
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Seizure types
1. Red: Seizure focus. Simple partial seizure = aura. 2. Yellow: Complex partial seizure. 3. Green: Secondary generalized seizure.
Blue: Primary generalized seizure. OU Neurology
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ILAE epilepsy classifications
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Not all seizures are epilepsy
About 1/3 of EMU patients have the diagnosis of non-epileptic spell (psychogenic or pseudoseizure). OU Neurology
Evaluation
Diagnosis: Clinical history General physical exam, neurological exam Lab: CBC, CMP, Ca+, renal, hepatic Supporting/confirmatory studies: EEG CT head MRI brain
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Electroencephalogram (EEG)
EEG is the most important neurophysiological study for the diagnosis, prognosis, and treatment of epilepsy. Graphical depiction of cortical electrical activity, usually recorded from the scalp Activation Procedures ◦ Sleep deprivation, photic stimulation, hyperventilation
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Epilepsy Treatment
AEDs Neuromodulation: ◦ Vagal Nerve Stimulation ◦ Deep Brain Stimulation ◦ Responsive neurostimulation device Diet Surgery
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History of antiepileptic drug therapy in the U.S. 1857 - bromides 1993 – felbamate, gabapentin 1912 – phenobarbital 1995 – lamotrigine 1937 – phenytoin 1997 – topiramate, tiagabine 1999 – levetiracetam 1944 - trimethodione 2000 – oxcarbazepine, 1954 - primidone zonisamide 1960 - ethosuximide 2005 - pregabalin 1974 – carbamazepine 2009 – lacosamide, vigabatrin, rufinamide 1975 – clonazepam 2011- ezogabine, clobazam 1978 – valproate 2013- perampanel, eslicarbazepine
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Epilepsy treatment - AEDs
Anti-epileptic drugs (AED) are the first- line of treatment. ◦ There are 20+ AEDs now. ◦ Only treats seizure (symptom), but not the underlying epilepsy 60-70% of people with epilepsy have well controlled seizures with 1-2 AEDs. 30-40% fail medical therapy and become “medically intractable”.
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Goal Best seizure control, with the least amount of medication,with the least side effects.
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Choosing Anti-Epileptic Drugs (AEDs) Drug effectiveness for the seizure type/ classification Potential adverse effects Interactions with other AEDs and non-AED medications Medical co-morbidities Age, gender, and child-bearing plans Lifestyle and patient preference Cost Rational polypharmacy
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AEDs by efficacy Broad-Spectrum Narrow-Spectrum valproate carbamazepine clonazepam oxcarbazepine lamotrigine gabapentin levetiracetam pregabalin topiramate phenobarbital zonisamide primidone* felbamate* tiagabine clobazam* eslicarbazepine Unclear spectrum: viagabatrin* - Phenytoin ethosuximide - lacosamide, rufinamide* - Ezogabine* - perampanel* OU Neurology
AED Mechanisms of Action
Continuum, 2013 OU Neurology
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Continuum,OU Neurology2013
Continuum, 2013 OU Neurology
Common side effects of AEDs
Sedation Dizziness Fatigue Nausea Vomiting Cognitive impairment Visual changes Behavior changes: depression/mood
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Phenobarbital
Has been in clinical use since 1912 as sedative and sleep aid First line therapy for infants only. Used infrequently as first line in adults Effective against focal and generalized tonic-clonic seizures but not effective against generalized absence seizures. Can be used in the treatment of status epilepticus
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Phenobarbital
MOA: y-aminobutyric acid (GABA)-A receptor, prolonging the opening of the associated chloride channel Long half-life of 80-100 hours Potent hepatic P450 enzyme inducer, accelerating the metabolism of medications processed by this enzyme system and reducing their plasma concentration. (so it may render concomitant AEDs less effective if they are metabolized by the liver.)
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Phenobarbital
Starting maintenance dose: Start low 30-60mg at bedtime. 1mg/kg/d to 2.5mg/kg/day. Increase dose by 30mg q 2 weeks as needed Adverse side effects: Sedation, decreased concentration, and mood changes. ◦ Long term use: decreased bone density and connective tissue effects; Dupuytren contractures, plantar fibromatosis, and frozen shoulder Pregnancy Category D: Teratogenicity with increased risk of cardiac malformations, decreased cognitive abilities OU Neurology
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Unclear Efficacy Phenytoin (Dilantin) Been in clinical use since 1938 Efficacy against focal and GTC. Not effective against generalized myoclonic or generalized absence seizures and may even exacerbate AVOID in idiopathic generalized epilepsy Binds to the active state of the sodium channel to prolong its fast inactivated state, thus reducing the high- frequency firing as might occur during a seizure, while allowing normal action potentials to occur Highly protein bound Metabolized by liver, cytochrome P450, 2C9, and CYP 2C19 OU Neurology
Phenytoin
Bioavailability is reduced with calcium, antacids, and NG tube feedings Potent enzyme inducer that reduces the efficacy of drugs metabolized by the P450 enzyme system Agents that reduce its metabolism and cause it to accumulate: Amiodarone, fluoxetine, fluvoxamine, isoniazid, and azole anti-fungal agents The PHY protein-free fraction may increase with hepatic and renal failure, in low-protein states, during pregnancy, elderly, and in presence of highly protein- bound drugs such as valproate
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Phenytoin
Dosing: 200mg-400mg/day at bedtime, ER preferred Therapeutic serum concertation range: 10-20mg/L Protein-free levels 1mg – 2mg/L Fosphenytoin – prodrug available for IV/IM. Water soluble, better tolerated and absorbed; ◦ 20mgPE/kg IV-- hypotension and arrhythmias Adverse effects: less sedating than PHB, cognitive effects, ataxia, incoordination, dysarthria, nystagmus, and diplopia. Rash, Stevens-Johnson syndrome with fever, rash, lymphadenopathy, eosinophilia, liver/renal Chronic use: Gingival hyperplasia, acne, hirsutism, cerebellar atrophy, decreased bone density, anemia, and peripheral neuropathy
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Valproate, divalproex, valproic acid (Depakote, Depacon) Broad spectrum – focal and generalized FDA indication also for migraine prophylaxis and bipolar disorder Most effective AED for idiopathic generalized epilepsy with GTC ◦ First choice for men with generalized epilepsy MOA: GABA potentiation, blocking of T-Type calcium changes, blocking of sodium channels Highly protein bound at 90% ◦ The free faction increases with increasing total concentration and with coadministration of phenytoin, with which it competes for protein binding OU Neurology
Valproate (Depakote, Depacon)
Potent inhibitor – reducing the clearance of phenobarbital lamotrigine, rufinamide, and carbamazepine epoxide Dosing: 500mg at bedtime for divalproate ER or 250mg bid for the delayed and immediate release. Increased up to 1000 (for woman of child-bearing age)- 2000mg/day Therapeutic range: 50-100mg/L
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Valproate (Depakote, Depacon)
Adverse effects: tremor, weight gain, hair loss, peripheral edema, thrombocytopenia, liver toxicity, hyperammonemia Rare: idiosyncratic hepatotoxicity & pancreatitis Highest rate of teratogenicity among antiepileptic drugs and should be avoided in women of child bearing age.
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Lamotrigine (Lamictal, Lamictal XR)
Broad spectrum with FDA indications for focal seizures, generalized tonic-clonic seizures, and Lennox-Gastaux syndrome. ◦ Not as effective against generalized absence seizures It can be effective for myoclonic seizures but can also worsen them in others FDA indication for maintenance treatment in bipolar I disorder MOA: blocks sodium channels like phenytoin and carbamazepine
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Lamotrigine Estrogen and pregnancy increase lamotrigine clearance Combined with Valproate, can be synergistic with greater efficacy than predicted Requires very slow titration ◦ Dosing 25mg/day for 2 weeks, followed by 50mg/d x 2 weeks, then 100mg/d x2 weeks up then can be increased by 100mg every 2 weeks. Up to 600mg /day Therapeutic range: 2mg/L to 20mg/L OU Neurology
Lamotrigine
Less sedating, fewer cognitive effects Dose related adverse effects: dizziness, blurred vision, diplopia, unsteadiness, nausea/vomiting, headache and tremor. Stevens-Johnson syndrome / life threatening rash – rare It has the lowest rates of teratogenicity, favoring its use in women of childbearing age
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Levetiracetam (Keppra, Keppra XR)
Broad-spectrum: Focal, GTC, myoclonic MOA: Binds to the synaptic vesicle protein SV2A resulting in non-specific decrease in neurotransmitter release in a state of neuronal hyperactivation. Very safe - no known significant pharmacokinetic interactions Dosing: 500mg bid, increase by 500mg weekly up to 2000mg bid
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Levetiracetam
http://www.keppraxr.com/includes/pdf/Keppra_Injection_PI.pdf OU Neurology
Levetiracetam
Adverse effects: Somnolence, dizziness, and asthenia. Irritability and hostility may occur, especially in children. Depression, mood swings common Not FDA approved for monotherapy in the US, but it is widely used as first-line Excellent adjunctive treatment in view of its safety and absence of interactions
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Topiramate (Topamax, Trokendi XR)
Broad-spectrum, focal and generalized tonic-clonic seizures FDA approved for migraine prophylaxis and weight loss (in combo with phentermine). Off label use for bipolar MOA: Antagonism of a-amino-3-hydroxy-5- methylisoxazole-4-proprionic acid (AMPA)/kainite receptors, augmentation of GABA, & blocking of voltage-gated Na+ channel Mild inducer of the CYP 3A4, a mild inhibitor of CYP 2C19 Dose: 25mg/day, increase by 25mg weekly up to 200mg bid (to decrease cognitive effects)
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Topiramate
Adverse effects: cognitive slowing, decreased attention, memory, impaired executive function, word-finding difficulty, and reduced verbal fluency. Ataxia, depression. Parathesias in the hands and feet. Weight loss. RARE: Acute myopia and secondary angle-closure glaucoma Kidney stones occur in 1.5% of individuals. Hyperammonemia in conjunction with valproate Associated with increased birth defects, particularly cleft lip
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Zonisimide (Zonegran)
Broad spectrum AED, only studied in focal seizures MOA; blocking T-type calcium channels (predictive of efficacy against absence seizures), blocking sodium channels, and weak inhibition of carbonic anhydrase activity Structurally related to sulfonamides Dosing:100mg hs x 2weeks, increase by 100mg every 2 weeks up to max of 600mg/day at bedtime or in two divided doses
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Zonisamide
Adverse effects: sedation, ataxia, dizziness, nausea, fatigue, agitation/irritability, and anorexia, weight loss. Dose-related Cognitive slowing and difficulty with concentration (but less than TOP). Rarely, depression and pscyhosis, serious rash. Kidney stones occur in up to 4%. Children: Oligohydrosis, hypernatremia, and metabolic acidosis (rare) Hydration!!
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Carbamazepine (Tegretol, Carbatrol, Tegretol XR) Narrow-spectrum Focal. Not for generalized Indications: trigeminal neuralgia, acute mania, and bipolar disorder MOA: Similar to PHY, blocks sodium channel in a voltage-and use-dependent fashion, reducing high frequency neuronal firing Potent enzyme inducer Autoinducer ◦ induces its own metabolism which results in an increased clearance over 2-4 weeks, with shortened half-life and lower serum concentrations
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Carbamazepine
Can accumulate with inhibitors of the CYP3A4, such as erythromycin, other macrolide antibiotics (except azithromycin), fluoxetine, propoxyphene, and grapefruit juice, valproate, felbamate Dosing: 100mg bid or 200mg at bedtime with ER, increase by 200mg every 3 days, up to 200- 400mg bid Therapeutic range: 4-12mg/L HLA-B1502 allele is predictive of CBZ induced rash in individuals of Asian descent
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Carbamazepine
Adverse effects: nausea, headache, dizziness, sedation, cognitive impairment, blurred vision, diplopia, nystagmus, unsteadiness, incoordination, tremor, hyponatremia, weight gain and decreased bone density Check periodic labs every 3 months, Bone density scan, Vit D levels Calcium supplementation
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Oxcarbazepine (Trileptal, Oxtellar XR)
Focal, avoid in generalized epilepsy MOA: Binds to Na channels inhibiting high- frequency neuronal firing Weak inducer of the CYP3A4, responsible for estrogen metabolism, reduces efficacy of OCP at high doses (900mg/d) Not an autoinducer and NOT affected by the CYP 3A4 inhibitors (erythromycin, fluoxetine, propoxyphene, and grapefruit juice)
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Oxcarbazepine
Dosing: 150mg bid, increase by 300mg weekly up to 1200mg bid Therapeutic range: 15mg/L to 35mg/L Adverse effects: drowsiness, headache, fatigue, dizziness, blurred vision, diplopia, nausea, vomiting, ataxia. Rash, HYPONATREMIA more likely
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Eslicarbazepine acetate (Aptiom)*
Approved 2014, 3rd generation, focal MOA: Blocks Na channels and stabilizing the inactive states of the voltage-gated sodium channel Weak inducer of CYP 3A4, potentially decreasing plasma concentrations of estrogen Weak inhibitor of CYP 2C19, potentially increasing plasma concentration of phenytoin
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Eslicarbazepine acetate
Dosing: 400mg daily, increase by 400mg/d every week, up to 1600mg/day Adverse effects: less frequent than CBZ and OXC ◦ dizziness, somnolence, headache, diplopia, nausea, vomiting, fatigue, ataxia. Hyponatremia and rash less common
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Ethosuximide (Zarontin)
AED of choice and is selective for generalized absence seizures. MOA: Blocks T-type calcium currents which predicts efficacy against absences. Dosing: 250mg/d for patients between 3-6 yoa, 250mg bid >6yoa. Increase dose by 250mg weekly not to exceed 500mg tid Therapeutic range: 40-100mg/L
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Ethosuximide Dose-related adverse effects: nausea, abdominal discomfort, anorexia, vomiting, diarrhea, drowsiness, insomnia, nervousness, dizziness, fatigue, ataxia, and behavior changes. Headaches, psychosis, depression, and hallucinations RARE: Idiosyncratic adverse reactions: rash, Stevens-Johnson syndrome, systemic lupus erythematosus, rare aplastic anemia, thrombocytopenia, agranulocytosis, and rare autoimmune thyroiditis
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Lacrosamide (Vimpat) Unclear efficacy: Narrow spectrum AED against focal seizures. It does not exacerbate absence or myoclonic seizures Indicated as monotherapy and as adjunctive therapy for focal seizures. Anecdotal reports of effectiveness in status epilepticus Blocks sodium channels enhancing slow inactivation, unlike most classic sodium channel blockers which enhance fast sodium channel inactivation Excellent bioavailability, IV formulation
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Lacrosamide
Dosing: 100mg hs or 50mg bid. Increase by 100mg/week up to 300mg bid Side effects: dizziness, headache, nausea, vomiting, diplopia, fatigue, sedation Greater efficacy and better tolerability if it is combined with a non-sodium channel drug
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Gabapentin (Neurontin) Narrow-spectrum for adjunctive treatment for focal seizures. Often chosen for its anecdotal benefit in treatment of headache, neuropathic pain, or sleep ◦ but can worsen myoclonus.. Approved for post-herpetic neuralgia, restless legs syndrome MOA: Binds to alpha-2-delta subunit of voltage- gated calcium channels, reducing the influx of calcium and associated neurotransmitter release under hyperexcitable conditions.
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Gabapentin
Bioavailability is low and variable. ◦ Decreases with increasing doses. Dosing: 300mg/day, increased by 300mg daily up to 4800mg total in 3 divided doses Adverse effects: drowsiness, dizziness, ataxia, tiredness, weight gain, peripheral edema. Cognitive slowing in elderly. Emotional liability in children
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Pregablin (Lyrica)
Narrow spectrum: focal-seizures ◦ may exacerbate myoclonus and absence seizures Official FDA epilepsy indication is adjunctive therapy for adult patients with partial-onset seizures, neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralagia, and fibromyalgia.
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Pregablin
Dosing: 75mg hs, increase by 75mg weekly to max of 300mg bid Schedule V Adverse effects: dizziness, somnolence, increased appetite, weight gain, and peripheral edema. Myoclonus may occur with higher doses
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Benzodiazepines Clobazam (Onfi), Clonazepam (Klonopin), Lorazepam (Ativan), Diazepam (Valium), Midazolam (Versed), Clorazapte (Tranxene) Broad spectrum agent, FDA indication is for generalized seizure types Benzodiazepine acting mainly on GABA-A receptor, increasing the frequency of GABA- mediated chloride channel openings. Schedule IV Clobazam Dosing: 5mg po bid, increase by 10mg/day weekly up to 40mg/day.
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Benzodiazepines Adverse effects: Drowsiness which improves over time. Dose-related: nystagmus, incoordination, unsteadiness, and dysarthria. Tolerance may develop Withdrawl seizures may occur with rapid discontinuation Long-term routine use discouraged Other benzos as rescue medication for seizure clusters or prolonged seizures
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Seizure rescue dosing
Ativan 1mg po daily prn seizure clusters or prolonged seizures more than 5 min Klonopin ODT: 1mg SL daily prn ◦ <10 yo or < 30kg 0.1-0.2mg/kg/day Diastat (diazepam rectal) ◦ 12 and up: 0.2mg/kg PR x1 ◦ 6-11: 0.3mg/kg PR x1 ◦ 2-5: 0.5mg/kg PR x1
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Marjor Drug interactions
Drug Combination Challenges Phenobarbital + Valproate Sedation / weight gain Phenytoin + Carbamazepine Dizziness, diplopia. Decreases each other’s blood level Valproate + Lamotrigine Valproate increase level of Lamotrigine
Valproate + additive drugs Valproate may increase level of other drugs Topiramate, Lamotrigine, Zonisimide + Any of these drugs may decrease enzyme inducers (Carbamazepine, blood levels of additive drugs, including Phenytoin, Phenobarbital) other seizure medications and other drugs like heart medications, lipid- lowering drugs, warfarin, anti-HIV drugs, anti-fungal drugs, chemotherapy drugs, immunosuppressant drugs, and some antidepressants and antipsychotics OU Neurology
Major categories of drugs reported to cause seizures Categories Drug Antibiotics Quinolones, penicillins, isoniazid Anticholinesterases Organophosphates, physostigimine Antihistamines Antipsychotics Phenothiazines, butyrophenones, atypicals Chemotherapeutics Etoposide, ifosfamide, cisplatin Cyclosporine Tacromlimus Hypoglycemics Insulin Lithium Local anesthetics Bupivacaine, lidocaine, procaine, etidocaine Methylxanthines Theophylline, aminophylline Narcotic analgesics Fentanyl, meperidine, pentazocine, propoxyphene Sympathomimetics Amphetamines, cocaine, ecstasy, ephedrine, phenylpropanolamine,OU terbutaline Neurology
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Seizure precautions
You may not drive, operate heavy machinery, climb tall ladders or heights, take tub drain baths or swim in a lake or pool unsupervised, or participate in any activity where sudden loss of consciousness can harm you or those around you for 6 months or until cleared by your neurologist. Oklahoma is a self-reporting state
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THE END
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Bassel, W. A.K. Antiepilpetic Drugs. Continuum 2016; 132-156. The Epilepsy Foundation. www.epilepsy.com Sydor, A. M. & Edmonson, K. G. Seizures & Syncope. 2012; 354-371. The McGraw Hill Companies UCB, Inc. 2016. Medication Guide and Full Prescribing Information. http://www.keppraxr.com/includes/pdf/Keppra_Inje ction_PI.pdf
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Tiagabine (Gabitril)*
Narrow spectrum of efficacy against focal seizures only, adjunctive only ◦ May exacerbate generalized absence and myoclonic seizures Off-label in management of spasticity in MS, in the treatment of addiction, and to increase deep sleep proportion Inhibits GABA reuptake at the synapse
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Tiagabine
Dosing: 4mg hs, incrased by 4mg/week to max of 12-16mg tid Adverse effects: dizziness, asthenia, nervousness, tremor, depression, and emotional lability. May be associated with dose-related episodes of nonconvulsive status epilepticus or encephalopathy, which may occur even in the absence of epilepsy
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Primidone (Mysoline) * Effective against: focal and GTC, myoclonic seizures, essential tremor Converted in the liver to phenobarbital and phenylethylmalonamide (PEMA) Enzyme inducer Adverse effects: Sedation, decreased concentration, mood changes, decreased bone density, connective tissue effects, dizziness, ataxia, nausea, vomiting, acute toxicity Dosing: 50mg at bedtime, increase gradually by 50mg every 3-7 days up to 250mg tid
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Vigabatrin (Sabril) * Reserved for adjunctive therapy in refractory epilepsy ◦ worsen absence or myoclonic seizures Effective in infantile spasms, particularly in the presence of tuberous sclerosis MOA: Irreversible inhibitor of GABA transaminase, resulting in accumulation of GABA. Weak inducer of the CYP 2C9
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Vigabatrin
Starting adult dose is 500mg bid, increase by 500mg/week up to1500mg bid Adverse effects: Sedation, fatigue, dizziness and ataxia. Irritability, behavior changes, psychosis, and depression, weight gain Progressive & permanent bilateral concentric visual field constriction can occur in 30-40% of patients, dependent on dose and duration of therapy Visual assessment required at baseline and every 3 months. Only continue treatment if considerable benefit seen
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Rufinamide (Banzel)* FDA indication as adjunctive treatment for seizures associated with Lennox- Gastaut syndrome Sodium channel blocker Weak inhibitor of CYP 2EI and a weak inducer of CYP3A4 and uridine diphosphate glucuronyltransferase (UDP- GT). The addition of valproate decreases rufinamide clearance and increases rufinamide levels by up to 70%
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Rufinamide
Starting dose: 400mg/day, after which it is increased by 400mg qod until a max daily dose of 1800mg bid Adverse effects: dizziness, fatigue, somnolence, ataxia, and headache. Vomitting may occur in children. May cause shortening of QT interval
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Ezogabine (Potiga) *
Narrow spectrum AEDS effective only against focal seizures, adjunctive Potassium channel opener Extensively metabolized to the active N-acetyl metabolite (NAMR), which is also subsequently glucuronidated. Dosing: 100mg tid, increase by 50mg tid up to max of 1200mg/d Adverse effects: dizziness, somnolence, fatigue, confusion, blurred vision, tremor, and nausea, and weight gain. Urinary retention Long-term use associated with bluish pigmentation in the skin, nails, and retina, may be reversible
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Perapamel (Fycoma)* Indicated as adjunctive tx for focal seizures and primary GTCs MOA: Noncompetitive AMPA glutamate receptor antagonist. At doses of 12mg, it accelerates the metabolism of of levonorgestrel, a progesterone component of the OTC pills Adverse effects: dizziness, somnolence, headache, fatigue, ataxia, blurred vision. Aggression and hostility may occur
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Felbamate (Felbatol) *
Broad spectrum effective against both focal and generalized seizures, Lennox-Gastaut syndrome Multiple MOA: N-methyl-D-aspartate (NMDA) receptor antagonism, GAB enhancement, and sodium channel blocking Inhibitor of CYP 2C19, CYP 1A2, and B-oxidation, inhibiting the metabolism of phenobarbital, phenytoin, valproate, carbamazepine epoxide, and warfarin Weak inducer of CYP 3A4, decreasing carbamazepine levels and reducing oral contraceptive efficacy
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Felbamate Dosing: 600mg bid, titration by 600- 1200/weekly up to 1200mg tid Adverse effects: GI irritation with anorexia, nausea/vomiting. Insomnia, irritability, headache, and weight loss. Serious: (unlikely after 1 year of administration) ◦ lethal aplastic anemia (est 1:5000) ◦ hepatic failure (1:26,000) Check CBC, and liver function every 2 weeks in first 6 months of treatment
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Efficacy of Select AEDs
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Suggested Pediatric AED Dosing
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Pediatric Dosing
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