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 OU Neurology LEARNING OBJECTIVES Describe seizure classification Discuss pharmacological treatment of seizures Describe common side effects of AEDs Describe common drug-drug interactions of AEDs OU Neurology 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 OU Neurology 1 John Doe, M.D. / OUHSC Neurology THE TITLE OF MY TALK 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. OU Neurology 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 OU Neurology 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 2 John Doe, M.D. / OUHSC Neurology THE TITLE OF MY TALK ILAE epilepsy classifications OU Neurology 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 OU Neurology 3 John Doe, M.D. / OUHSC Neurology THE TITLE OF MY TALK 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 OU Neurology OU Neurology Epilepsy Treatment AEDs Neuromodulation: ◦ Vagal Nerve Stimulation ◦ Deep Brain Stimulation ◦ Responsive neurostimulation device Diet Surgery OU Neurology 4 John Doe, M.D. / OUHSC Neurology THE TITLE OF MY TALK 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 OU Neurology 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”. OU Neurology Goal Best seizure control, with the least amount of medication,with the least side effects. OU Neurology 5 John Doe, M.D. / OUHSC Neurology THE TITLE OF MY TALK 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 OU Neurology 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 6 John Doe, M.D. / OUHSC Neurology THE TITLE OF MY TALK 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 OU Neurology 7 John Doe, M.D. / OUHSC Neurology THE TITLE OF MY TALK 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 OU Neurology 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.) OU Neurology 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 8 John Doe, M.D. / OUHSC Neurology THE TITLE OF MY TALK 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 OU Neurology 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 OU Neurology 9 John Doe, M.D. / OUHSC Neurology THE TITLE OF MY TALK 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 OU Neurology 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. OU Neurology 10 John Doe, M.D. / OUHSC Neurology THE TITLE OF MY TALK 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 OU Neurology Lamotrigine Estrogen and pregnancy