Epilepsy Handout Khartabil

PHAR 835 IPC Epilepsy Khartabil Fall 2023 Epilepsy How to prepare for this topic? 1- Please read this handout entirely. 2- Write any notes or questions to discuss in class. 3- We will build on the knowledge from the tables of anti-epileptic medications (AEMs) and apply them in clinical cases. 4- There are more than 27 approved anti-epileptic medications, out of the approved AEMs, we pay particular attention to the following list: (attention to brand name, mode of action, indication, special pharmacokinetic properties, main side effect profile, drug-drug interactions, and any required monitoring). 5- Most abbreviations are listed at the end of this document, if there is one that you need elaboration on , please note it for our discussion. Important Anti-epileptic Medication: ( listed in alphabetical order ) 1 Carbamazepine (Tegretol, Carbatrol) XR®) 8 Lamotrigine (Lamictal®) 2 Cannabidiol ( Epidiolex®) 9 Levetiracetam (Keppra®) 3 Diazepam (Valium, Diastat, Valtoco) 10 Oxcarbazepine (Trileptal®, Oxtellar XR®) 4 Ethosuximide (Zarontin) 11 Phenobarbital (Luminal®) 5 Fosphenytoin (Cerebyx) 12 Phenytoin (Dilantin®) 6 Gabapentin (Neurontin, Horizant, Gralise) 13 Topiramate (Topamax®) 7 Lacosamide (Vimpat®) 14 Valproic Acid/ Valproate (Depakote, Depakene, Stavzor®) 15 Zonisamide (Zonegran®) Diagnosis of Seizure disorder: “Epilepsy” is a diagnosis – sometimes, the symptoms of seizure (symptom) can culminate in the development of epilepsy (formal diagnosis) . ILAE defines epilepsy as a “disease characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition” – ILAE stands for: International League Against Epilepsy According to ILAE, a person is considered to have epilepsy if they meet any of the following conditions: (1) at least two unprovoked (or reflex) seizures occurring greater than 24 hours apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures like the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; or (3) diagnosis of an epilepsy syndrome 1 2 ** Can you define epilepsy according to ILAE? Can you name the 3 criteria for epilepsy based on ILAE? Diagnosis and labs: Very little use of labs ( no diagnostic lab tests). In some cases, particularly following generalized convulsive seizures, serum prolactin levels obtained within 10-20 minutes can be transiently elevated. Laboratory tests can be done to rule out treatable other medical causes of seizures (examples are hypoglycemia, altered electrolyte concentrations, and infections) – these are not related to having a diagnosis of epilepsy or seizure disorder . An abnormal epileptiform EEG is found in only approximately 50% of the patients with epilepsy Video EEG is the gold standard for diagnosing epilepsy and involves admission to the hospital and recording video and EEG until the patient has a typical event. Brain MRI is indicated in patients with epilepsy and is the preferred imaging technique to identify structural abnormalities (example: sclerosis in the mesial temporal lobes and traumatic brain injury) A computed tomography (CT) scan typically is not helpful except in the initial evaluation for a brain tumor, cerebral bleeding, or gross anatomical injury. **What labs and diagnostic tests would you consider in the evaluation of a patient with epilepsy, presenting with seizure disorders? General treatment approach: Desired Outcomes Antiseizure drug (ASD) therapy is the mainstay of epilepsy treatment. ASDs are symptomatic treatment only, and none have been proven to have any disease modifying properties, and no ASDs are curative. Surgery is the only possibly curative therapy, and only a select number of patients qualify for surgery. The majority of patients will be on lifelong ASD therapy. The goal of ASD therapy is to eliminate symptoms (seizures) with minimal side effects. In most patients the goal is complete seizure freedom In 20-35% of patients this may not be possible, and seizure control must be balanced with QOL goals. Treatment goals can change over time. For those who cannot obtain seizure freedom despite these therapies, more obtainable goals should be established (such as a decrease in the number of seizures and minimized drug adverse effects) The choice of medication is based on age, gender, medical conditions, seizure type, susceptibility to certain adverse events. The decision to initiate or change a medication is not only related to efficacy (control of seizures) but rather a combination of other factors including achieving a tolerable adverse effect profile, ability to comply with a regimen (preference to once daily vs 3 to 4 times /day), interaction with 2 3 certain medications and how fast we need to reach therapeutic levels (for example avoid ASMs which requires slow titration as lamotrigine or topiramate). Discovery of anti-epileptic medications (ASMs) originated in 1857. These medications can be categorized by time of discovery (hence 1st,2nd and 3rd generation), or by mode of action. Table 1, 2, and 3 include a summary of 1st, 2nd, and some third generation ASMs. When reviewing the tables below, please note that there are acute and chronic side effects, dose dependent and idiosyncratic (idiosyncratic is generally not dose dependent). The highlighted text in red font represents important points, or black box warnings that are specific to that medication. These special characteristics may require special monitoring or make the drug not a good choice for certain patient groups (for example for childbearing female patient, all anti-epileptic medications it is best to avoid valproate and phenytoin, due to their high teratogenic effect). There is a general recommendation to supplement folic acid to all women on anti-epileptic drugs prior conception and during pregnancy. We will discuss in class when to start treatment, how, when to stop and how to plan and manage treatment regimen. Most common side effects association with specific ASMs: Side Effect Highly prevalent with ASM (not inclusive) Weight gain Valproic Acid Gabapentin Weight loss Topiramate Zonisamide Kidney stones Topiramate Zonisamide Rash-SJS-DRESS* Carbamazepine Lamotrigine Pancreatitis Valproic Acid Peripheral field irreversible vision loss Vigabatrin DRESS: Drug Rash with Eosinophilia and Systemic Symptoms (severe hypersensitivity reaction). 3 Phenobarbital (schedule IV) Phenytoin (Dilantin ®,Phenytek®) ASM Table1: First Generation ASMs Indication (s) MOA GTC Voltage dependent complex partial seizure blockade of Na+ prevention/treatment of channel activation seizures following neurosurgery Focal and generalized (not FDA approved) Binds to GABAA modulates Cl conductance Common Side effects Serious but Rare *Gingival hyperplasia SJS, DRESS, purple glove (reversible upon d/c) syndrome in IV Blood dyscrasias ( lower with fosphenytoin) Facial hair growth, lymphadenopathy , enlarged facial features Warnings Hypotension, Arrhythmia when given IV [BBW] Severe dermatologic reaction DDI Things to know Inducer of CYP450 and 1-Aggrevate Absence seizure UGT CNS: Nystagmus fatigue, sedation (dose dependent) Blood dyscrasias (idiosyncratic) Many DDIs Highly protein bound (displaced phenytoin causes level) Highly protein bond 4-Fosphenytoin (Cerebyx®) is water soluble prodrug used IV, IM for SE. Teratogenicity (fetal hydantoin syndrome) Free phenytoin (unbound) = Active 5- Phenytoin may be orally or IV loaded in pt. who require steady state Metabolic bone disease: osteoporosis. (chronic) Caution with low protein status pts. (ESRD, critically ill) (adjusted equation to calculate level) 1-Intellectual blunting Potent Inducer of 2- Slow tapering when CYP450 and UGT d/c 6- Vitamin K supplementation for pregnant women (to decrease risk of bleeding) CNS: Nystagmus, SJS, DRESS fatigue, sedation, Respiratory depression, dizziness, ataxia. megaloblastic anemia. paroxysmal effects (excitement, irritability in older adults , children) (dose dependent) Primidone Carbamazepine (Tegretol®) (Carbatrol®) (Equetro®) Prodrug to phenobarbital CNS effects (ataxia, nystagmus, diplopia, hyperirritability) PB SJS, DRESS, blood dyscrasias Enhance fast inactivation of voltage gated Na+ channel CBZ special *Rash* Hyponatremia (SIADH) CNS effects: (ataxia, nystagmus, diplopia). Teratogenecity 1-Additive CNS depression may cause fatal respiratory depression 2- Monitor LFTs, CBC with differential Intellectual blunting, behavioral changes OCP level Inducer of CYP450 1- Tolerance, dependence 2-Useful in pts with essential tremor 3- Contraindicated in porphyria Metabolic bone diseases (Osteoporosis) Monotherapy/ adjunctive therapy for focal onset and TC seizures 3-Exhibit Michaelis-Menten Kinetics 3-Tolerance, dependence Osteoporosis (chronic) Monotherapy/ adjunctive therapy for focal onset and TC seizures Recommended to use 2-Monitor serum phenytoin, LFTs,CBC non-hormonal OCP with with differential chronic phenytoin use SJS, DRESS, Aplastic anemia Avoid in pt if prior rash with other ASM, or in pt. with hx of bone marrow depression, not within 14 days of MAO inhibitor Inducer and Autoinducer CBZ levothyroxine, warfarin, OCP 1- Avoid in Absence Seizure 2-BBW: Aplastic Anemia, Agranulocytosis, increased risk of SJS/TEN with HLA-B*1502 allele 3-Useful in Bipolar disorder and trigeminal neuralgia Can't be used with 4- Monitor : CBC, differential, NNRTIs ( nonplatelets,LFT,Na+, renal function nucleoside reverse (baseline , 3-5 days after initiation and 4 transcriptase inhibitors) weeks after) 4 Clonazepam ( Klonopin®) (schedule IV) Ethosuximide (Zarontin®) Valproic acid/ Divalproate ( Depakene®) (Depakote®) Table1: First Generation ASMs (~Continued) Indication (s) MOA Monotherapy/adjunctive Binds to GABAa therapy receptor LGS (petit-mal), akinetic, absence Absence Seizure Inhibition of T-type Ca channels Common Side effects Serious but Rare CNS: cognitive impairment, Blood dyscrasias Hepatomegaly ataxia 1-GI side effects: Nausea/Vomiting (dose 2-CNS : night terror Monotherapy & adjunctive Increases GABA, blocks CNS: Nystagmus, fatigue, therapy for complex partial, sodium channels, inhibits sedation, dizziness, ataxia simple partial seizures, T type Ca channels complex absence seizures; adjunctive for multiple seizure types including absence seizures Hyperammonemia (chronic use) Polycystic ovary syndrome Blood: Neutropenia Alopecia** (Idiosyncratic) Blood dyscrasias Warnings DDI Things to know BBW: Concomitant use May increase 1- Useful when a long acting BDZ is needed with opioids may result in Phenytoin level. respiratory depression May be affected by enzyme inducing drugs 2- Dependence may occur Worsen TC seizures BBW: Not the drug of choice in 1- Hepatotoxicity especially for childbearing age group children <2 years Valproic acid may increase level of ethosuximide 3-Withdrawal may cause SE Drug of choice for Absence seizure Valproate (Depacon®) IV, can be used for SE. Inhibitor Valproic acid is highly protein bound so will affect other protein bound medications, phenytoin level increased. 2-Fetal risk including neural tube defects, other major malformations, and decreased IQ 3- Pancreatitis including fatal hemorrhagic pancreatitis (Idiosyncratic) Weight gain (chronic) 5 Gabapentin (Neurontin®, Gralise®,Horizant®) Lamotrigine (Lamictal®) Topiramate (Topamax®) Table2: Second Generation ASMs Indication (s) MOA Adjunctive therapy for focal onset seizures with and subunit of Ca channels without TC seizures in with unknown antiseizure effect Common Side effects 1-CNS: Ataxia, dizziness, somnolence, fatigue, irritability (acute) 2-Weight gain (chronic) 3-Behavior problems (Idiosyncratic) Serious but Rare None Warnings None DDI Not significant Things to know 1-Nearly 100% renally eliminated (dose adjustment warranted) 2-Use in neuropathic pain (post herpetic neuralgia) 4- Pedal edema (idiosyncratic) Adjunctive therapy in focal Enhances fast onset and TC seizures, inactivation of voltagegeneralized seizures of LGS gated Na+ channels, inhibits glutamate monotherapy in patients with focal-onset seizures Monotherapy/ adjunctive therapy for focal onset seizures or primary generalized TC seizures in adjunctive therapy for of age Antagonizes voltagegated sodium channel; binds to GABAA receptor and augments GABAergic transmission, antagonizes AMPA/kainate glutamate receptor, weak carbonic anhydrase inhibitor 1-Rash (SJS) and benign 1-DRESS rash* (idiosyncratic) (BBW) 2-CNS : Diplopia, dizziness 2-Blood dyscrasias 3-Infection: aseptic meningitis (HA, fever, stiff neck) (acute) 1-CNS: Behavioral changes, 1-Renal stones irritability, cognitive problems (WORD FINDING) , ataxia, fatigue (acute) Rash (HLH) appears in 3-4 Significant with 1-SLOW titration to avoid SJS weeks and can progress to valproate SJS 2-Rash increase if given with valproate Monitor decreased sweating and increased body temperature (especially children) Weak inhibitor (CYP2C19) Inducer of CYP3A4 Avoid in patients with preexisting cognitive issues 2-Weight loss (dose 2-Glaucoma dependent, chronic) 3-Myopia, secondary angle 3-Hyperammonemia closure glaucoma (Idiosyncratic) 4-Metabolic acidosis (should be avoided with ketogenic diet) 6 Levetiracetam (Keppra®) Oxcarbazepine (Trileptal®) Diazepam ( Valium®, Valtoco® Nasal , Diastat® rectal gel) Zonisamide (Zonegran®) (ZNS) Table2: Second Generation ASMs (~Continued) Indication (s) MOA Common Side effects Children: Adjunctive Binds to and selectively 1-CNS: Somnolence, therapy for focal onset inhibits synaptic vesicle hostility, aggression seizures in patients >14 SV2A protein thereby (especially in children) months, Adults: myoclonic preventing seizures in patients with neurotransmitter release Serious but Rare Psychosis, hallucination Warnings May worsen depression, anxiety DDI Minimal interaction Things to know Must adjust dose in renal failure/ dialysis generalized TC seizures in with generalized epilepsy Pregnancy category C Monotherapy/ adjunctive therapy for focal onset Enhances fast inactivation of voltagegated Na+ channels of age; adjunctive therapy for focal onset seizures in 1- Higher incidence of hyponatremia ( than CBZ) but milder 2-CNS: dizziness, diplopia, nystagmus 1-SJS, TEN 2-Blood dyscrasias Acute treatment of intermittment, sterotypic frequent seizures ( seizure clusters) Binds GABAA receptor and potentiates GABA by modulating chloride conductance 1-CNS: Sedation, headache Respiratory depression + + Monitor Na level (Na < 125 mmol/L is clinically significant) Pts at higher risk + concomitant use of diuretics. Monohydroxy derivative (MHD) is the active metabolite BBW: Concomitant Opioid use, respiratory depression 2- Nasal spray: nasal discomfort, runny nose Useful in bipolar disorder No autoinduction Dose conversion 1.2 to 1.5 daily dose of CBZ Monitor active metabolite level (MHD) Watch for Not for maintenance therapy breathing Increase risk of suicidal thoughts Rectal gel (for increased seizures episodes 2 years and above age group) Adjunctive therapy for focal Enhances fast 1-CNS : Sedation, dizziness, 1- SJS onset seizures in adults inactivation of voltage- cognitive impariment (acute) gated Na+ channels; inhibits T-type Ca channels; weak carbonic anhydrase inhibitor 2-Weight loss (chronic) 3-Kideny stones (Idiosyncratic) Inhibitor of CYP2C19, inducer of CYP3A4 (may increase lamotrigine level) 2-Blood dyscrasias 3-Metabolic acidosis 1-SULFONAMIDE derivative, rash , DRESS 2-Warning regarding oligohydrosis and heat stroke CYP3A4 Useful in Tremor inhibitors and inducers may later ZON levels Once a day dosing 4-Oligohidrosis (Idio) 5-Rash (sulfa derivative) 7 Brivaracetam (Briviact®) Pregabalin (Lyrica®) (Schedule V) Perampanel (Fycompa®) (Schedule III) Eslicarbazepine (Aptiom®) (ESL) Table3: Third Generation ASMs Indication (s) MOA Monotherapy/Adj. therapy Inhibit synaptic vesicle SV2A protein years of age Use mainly in drug resistant seizures. Adjunctive therapy for focal onset seizures in subunit of calcium channels Common Side effects Serious but Rare CNS: headache, somnolence, Angioedema irritability. Bronchospasm Warnings Dose adjustment in hepatic impairment DDI Briv. Things to know It may be considered in converting wellcontrolled patients on levetiracetam with intolerable psychiatric adverse reactions. Hematologic abnormalities Briv. CNS: dizziness, somnolence, Misuse potential with opiates blurred vision, difficulty with concentration and attention. 100 % renal elimination Nonsignificant Useful for neuropathic pain BBW: Aggression, hostility, homicidal ideation CBZ, PHT, PB, Avoid in active psychosis Avoid in severe hepatic, renal impairment or hemodialysis Dry mouth; edema Weight gain (chronic) Treatment/ adjunctive treatment partial-onset seizures with or without secondary generalized Non-competitive AMPA CNS effects including DRESS glutamate receptor dizziness, somnolence, antagonist fatigue, falls, vertigo, ataxia, headache, confusion; adjunctive) GI effects including nausea, weight gain Monotherapy or adjunctive Selectively enhances fast CNS: dizziness, diplopia, therapy for focal onset inactivation of voltage- ataxia gated Na+ channels of age levels CNS: dizziness, diplopia, ataxia Avoid concomitant use Hyponatremia (SIADH) with CBZ, OXC Dose adjustment in renal failure Useful in non-adherent cases ( once a day) estrogen level Hyponatremia (SIADH) Clobazam (Onfi®) Schedule IV Cannabidiol (Epidiolex®) (CBD) (not scheduled) ESL level. Indicated for the treatment Unknown of seizures associated with LGS, Dravet syndrome, tuberous sclerosis complex CNS: somnolence, fatigue, sleeping disorder. Hepatotoxicity • Monitor Baseline, 1 month, 3 months, 6 months, &periodically: AST, ALT, and total bilirubin. transaminase elevations GI decreased appetite, diarrhea Binds GABAA receptor and Adjunctive therapy for potentiates GABA by years of age modulating chloride conductance Consider dose adjustment Sleepiness, tiredness, fever, drooling, aggressive behavior, irritability, lack of coordination. active metabolite Rash (SJS, TEN); anemia; liver enzyme elevations; respiratory depression Concomitant use with CBZ, felbamate, Avoid abrupt d/c ( causes withdrawal opioids increases risk of syndrome) death (BBW) 8 Other Anti-epileptic medications: Felbamate (Felbatol®) 2nd generation o Indications: *LGS, *GTCS, *PS. Treatment resistant adjunctive & monotherapy PS +/- generalization • Treatment resistant adjunctive therapy for PS associated with Lennox-Gastaut syndrome in children o MOA: Sodium channel blocker, calcium channel blocker, inhibits glutamate, enhances GABA. o Broad spectrum ASM but with limited use due to serious side effect profile: BBW Aplastic anemia. Tiagabine (Gabitril®) TGB o Indicated as adjunctive therapy for focal onset seizures >12 years of age. o Mode of action: inhibit GABA reuptake transporter. o It is a second generation ASM, shown to increase generalized seizures, causing abnormal EEG, its reserved use after failure of other ASMs. Vigabatrin (Sabril®): o Indicated as to 2 years where benefits outweigh the risk of vision loss. o Mode of action: It is an amino acid that is a structural analog of GABA and is a selective, irreversible inhibitor of GABAtransaminase, the enzyme that degrades GABA. o Ophthalmologic Testing – BL, 3 months then 4-6 months later then upon discharge • Required registry prior to dispensing –REMS o Causes increased effect of CBZ. Stiripentol (Diacomit®) o Indications: Adjunctive treatment of seizures associated with Dravet syndrome in patients years taking clobazam. o MOA: Allosteric modulation of GABA-A-receptors, possible partial agonism of GABAergic inhibitory neurotransmission. o Stiripentol may cause neutropenia and thrombocytopenia which necessitates frequent monitoring of blood counts including prior to the first dose and every 6 months during and 6 months after discontinuing. Fenfluramine (Fintepla®) o Indications: Treatment of seizures associated with o MOA: • Fenfluramine & active metabolite, norfenfluramine, increases extracellular levels of serotonin • Interacts with transporter proteins & exhibits agonist activity at 5HT-2 receptors. o Cardiovascular: Valvular disease & pulmonary arterial hypertension due to 5-HT2B receptor agonist activity [BBW] – REMS Program; aortic insufficiency, increased BP; EKG required baseline, during (every 6 months) & following treatment (once 3-6 months post-treatment) 9 Rufinamide (Banzel®) o Indications: Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome o Mode of action: modulates sodium channels by prolonging inactive states. o Contraindicated in familial short QT syndrome. ** Can you notice any anti-epileptic drug cousins ( sharing same side effects and safety considerations) can you point out 4 cousins? AE adverse events LCM lacosamide AED antiepileptic drug LEV levetiracetam BBW Black box warning LGS Lennox Gastuat Syndrome CBZ carbamazepine LTG Lamotrigine CLB clobazam MOA Mode of Action DDI Drug-drug interaction OXC oxcarbazepine ESL eslicarbazepine PER perampanel ETS ethosuximide PGB pregabalin EZG ezogabine PHT phenytoin FBM felbamate RFN rufinamide GBP gabapentin SE Status Epileptics GE generalized epilepsy TGB tiagabine GTC generalized tonic–clonic TPM topiramate IV Intravenous injection VGB vigabatrin IM Intramuscular injection VPA valproic acid JME juvenile myoclonic epilepsy ZNS zonisamide 10