Epilepsy Fall 2024

Epilepsy Nadia Khartabil, Pharm D, BCGP, Aph, MAS West Coast University School of pharmacy Fall 2024 Epidemiology and Etiology Forth most common neurologic disorder in the US (following stroke, migraine, Alzheimer’s disease) Mortality rate is 2-3 times that of the general population , this include sudden unexplained death in epilepsy (SUDEP). Economic considerations : cost of treatment was $12.5 billion in 1995. Inability to drive is the most important barrier. Major causes of epilepsy and seizure disorders (risk factors and triggers) Etiology Drug induced causes : Theophylline ( at toxic levels), alcohol intoxication, street drugs, phenothiazines (high doses), antidepressants ( bupropion at high doses). Medications that lower seizure threshold Bupropion Carbapenems (imipenem) Clozapine Lithium Meperidine Penicillin Quinolones Tramadol Antipsych Antibiotic Pathogenesis Seizure: a sudden alteration in behavior or in motor function caused by an electrical discharge in the brain. Mutations to channels (K+, Na+, Ca++, Cl-) can all account for seizure disorders at the genetic level. The severity of a seizure and clinical manifestations depends on the site of the focus, the degree of irritability of the surrounding area of the brain, and the intensity of the impulse. Seizures can also cause structural changes over time, and this increases sensitivity to future seizures and increase risk of chronic seizure disorders worsening if untreated or unmanaged. Can be related to stroke, birth injury, CNS neoplasms, head trauma. Definitions Term Aura Thesense thatseizureishappeningbeforeithappens a Dossiers Seizure a Definition Perceptual disturbance (autonomic or sensory symptoms) that may precede a seizure, and may represent a focal seizure that may generalize Abnormal electrical activity in the brain resulting in physical or behavioral changes Convulsion Physical manifestation of a tonic-clonic seizure Epilepsy Requires occurrence of at least one seizure that is not acutely provoked and that can give rise to other seizures Altered state of consciousness after a seizure a Postictal confusion Prodrome Unprovoked Seizures Refractory Seizures Status Epilepticus Awareness that a seizure is about to occur Seizure of unknown etiology or remote cause Failure of two or more seizure medications and occurrence of seizures/month over 18 months Historically, continuous seizures lasting five minutes or more, or two or more discrete seizures between which there is incomplete recovery of consciousness • International League Against Epilepsy (ILAE) has proposed it is a condition which can lead to abnormally prolonged seizures • These prolonged seizures can have long-term consequences, which include neuronal death, neuronal injury, and modifications of neuronal networks Ease Seizure Pathogenesis Excitatory NT as Glutamate, aspartate, norepinephrine Inhibitory NT as GABA Incidence of Epilepsy between imbalance them Diagnosis and Seizure Classification • Seizure is only a symptom in epilepsy. Epilepsy : 1. Two or more seizures not provoked by specific events as trauma, infection, fever or chemical changes occurring greater than 24 hours apart. 2. One unprovoked ( or reflex) seizure and a probability of further seizures similar to the general occurrence risk ( at least 60%) after 2 unprovoked seizures, occurring over the next 10 years. 3. Diagnosis of an epilepsy syndrome Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure free for the last 10 years , with no seizure medicines for the last 5 years. Post-ictal period : the time immediately following a seizure. Epilepsy is a clinical diagnosis ( based on medical signs and patient reported symptoms, rather than one diagnostic test. Fyi Basedonlocation t Classification: Seizure part g star Classification is based on 3 questions : 1-Where in the brain the seizure originates 2- Patient’s level of awareness during a seizure 3- Other features of the seizure It as International Seizure Classification • PARTIAL SEIZURES ( Focal/Local) Simple partial – awareness, not mentally impaired Complex partial or “psychomotor”-mentally impaired Partial + secondarily generalized • PRIMARY GENERALIZED SEIZURES Absence or “petit mal” Myoclonic or “minor motor” Clonic or “grand mal” Tonic or “grand mal” Tonic-clonic or “grand mal” Atonic or “akinetic/drop/minor motor” Commission on Classification & Terminology of the international League Against Epilepsy. Epilepsia 1981:22: 489-501. Summary of New Basic Seizure Classification • Epilepsy is classified into one of four categories: • Focal Epilepsy with only focal-onset seizure • Generalized epilepsy with only generalizedonset seizures • Combined generalized and focal epilepsy • Unknown • Gold standard for diagnosing epilepsy is electroencephalogram (EEG). This Photo by Unknown Author is licensed under CC BY-SA-NC General Treatment Approach “when and how” When to treat ? After single isolated seizure answer would be 1- Treat , 2-Possbily treat, 3- Don’t treat Probability of recurrent seizure increases with certain factors (cerebral palsy, stroke, trauma, EEG abnormalities, nocturnal seizure). Most clinicians start treatment after second unprovoked seizure. How to select therapy ? 6 main factors 1. ASM efficacy to seizure type 2. Treating other comorbid conditions 3. ASM based on adverse events, patient-specific factors (age, gender, etc …) 4. Interactions with other medications 5. Adherence and economic burden 6. Do we need to reach therapeutic level quickly? When to suggest polytherapy ? Polytherapy is reserved for unsatisfactory control of seizure ( despite optimizing dose, ruling out other factors as nonadherence). Follow the algorithm for treatment , always evaluate the regimen at each visit. Treatment Goal Main goal is to stop the seizures. Minimize adverse events and improve quality of life (QOL) Goals of therapy may change over time. Things to remember : ASMs are symptomatic treatment only , non are curative. Surgery is the only possible curative therapy ( only for a select number of patients) Epilepsy is a chronic disease , patients are on lifelong ASM therapy. There is 20-35% of patients can’t reach seizure freedom and at that point a balance with QOL goals is necessary ( balance of side effects, number of episodes, cost of treatment, etc …). We aim for monotherapy > polytherapy. ASM Therapy Algorithm An algorithm for ASM therapy. (ASM, antiseizure medication; VNS, vagal nerve stimulation.) Citation: Chapter 75 Epilepsy, DiPiro JT, Yee GC, Michael Posey LL, Haines ST, Nolin TD, Ellingrod VL. DiPiro: Pharmacotherapy A Pathophysiologic Approach, 12e; 2021. Available at: https://westcoastuniversity.authn.worldcat.org/ Accessed: August 02, 2022 Copyright © 2022 McGraw-Hill Education. All rights reserved General Treatment Approach When to stop and how? When a drug is least effective in a polytherapy regimen. The American Academy of Neurology (AAN) has issued guidelines for discontinuing ASDs in seizure-free patients .After assessing the risks and benefits to both the patient and society, ASD withdrawal can be considered in a patient meeting the following profile: 1. Seizure free for 2 to 5 years 2. A history of a single type of focal seizure or primary generalized seizures 3. A normal neurologic exam and normal IQ, and 4. An EEG that has normalized with treatment ASM withdrawal should be done gradually. Withdrawal seizures are of concern specially with barbiturates, and benzodiazepines. Tapering slowly over a period of months may be necessary. enzymes ind g BEEF as Madditionto Otterred mirin venypotent neuropathies pain Toorearlyuse irreversiblevision lost Summary of Anti-epileptic drugs First generation ASMs : • Very efficacious • Cons: complex pharmacokinetics, drug interactions, and increased incidence of adverse events, which make them hard to manage. Second generation ASMs: mostof temare • Used as first-line agents in monotherapy • Similar efficacy to 1st generation • Fewer drug-drug interactions (DDIs) Third generation ASMs: iontrolledmed• Approved for very specific indications only • Reserved for use after other ASMs failed • Used as off-label in refractory epilepsy after failure of first line ASMs. Éresistence orgy absence gychonal ethoor valporic Selection of ASM for important SOAPnotes • Factors that play a role in selecting an appropriate treatment: • ASM efficacy to seizure type • Treatment of other comorbid conditions (migraine, bipolar disorder, neuropathic pain, etc.….) • Tolerability : ASM adverse events, patientspecific factors (age, gender, etc …) • Interactions with other medications • Adherence and economic burden É • my There are different guidelines for drug treatment: • National Institute for Health and Care Excellence (NICE 2020) • International League Against Epilepsy (ILAE 2013) • American Academy of Neurology (AAN 2018) Seizure type and Drugs of Choice Summary of guidelines Seizure Type Focal Onset Seizure (NEWLY DIAGNOSED) Focal Onset Seizure (Refractory MONOTHERAPY) Focal Onset Seizure (Refractory Adjunct) First line ASM Adults: Carbamazepine , Gabapentin, Oxcarbazepine, Phenytoin, phenobarbital, topiramate, valproic acid, levetiracetam, zonisamide Children: Oxcarbazepine Elderly: Lamotrigine, Gabapentin, Oxcarbazepine Lamotrigine, Oxcarbazepine,Topiramate , Eslicarbazepine Adults: Gabapentin, Lamotrigine, Levetiracetam, oxcarbazepine, Tiagabine, Topiramate, Zonisamide , lacosamide, eslicarbazepine, Topiramate ER., pregabalin, perampanel. Children: Gabapentin, Topiramate, Lamotrigine, Oxcarbazepine Generalized Seizure Absence Lamotrigine, Ethosuximide, Valproic acid (NEW) Generalized Tonic-Clonic Topiramate Juvenile Myoclonic Epilepsy Valproic Acid Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy. Neurology Jul 2018;81:74-81. Selection of ASM : Case 1 Yangs Ethozor Navid no onset seizures. ST is an 18-year-old female with a history of generalized • Her seizures began in childhood and manifest as extremely brief episodes (13 seconds) where she blanks out and may have “staring spells”. Her semiology is deemed consistent with absence epilepsy. • Which of the following AEDs is considered the gold standard for treatment of absence epilepsy? • Clobazam • Ethosuximide • Rufinamide • Vigabatrin ASMs Adverse Reactions • Individual ASMs have unique adverse effect profile, please refer to the handout. • Common adverse events are mostly dose dependent, not life threatening, yet may happen within therapeutic ranges. • Usually, slow titration of dose help with managing these side effects. • These may include CNS side effects ( dizziness , diplopia, ataxia, somnolence, cognitive impairment). wa Wise two • Uncommon side effects are usually idiosyncratic ( not concentration dependent) can be serious and life threatening. • Most recognized is skin rashes that progress to SJS • Blood dyscasias • Chronic adverse events associated with ASMs : • Osteomalacia and osteoporosis (hypothesized that PHT , PB, CBZ, OXC, VPA may interfere with vitamin D metabolism • Supplementation of vitamin D, Calcium and bone mineral density are warranted. softeninof me Eboyes • Suicidal thoughts warning is present with all ASMs. It is still low but higher than placebo ( 0.5% vs 0.24%) • Patients and caregivers should be informed that ASMs may increase the risk of suicidal thoughts. med thephasnoneedol Case 2 : Kordporic • A 34-year-old female diagnosed with grand mal epilepsy (Tonic clonic) two years ago was suffering from recurrent seizures until she was started on levetiractem keptwith dose titration to 1500 mg twice a day. She has been seizure free for the last 6 months. Today she in the clinic for routine follow-up and labs show a subtherapeutic levetiracetam drug level (lower than the level last year). What is the best next step ? A. B. C. D. Increased dose of levetiracetam to 2000 mg twice daily Continue same dose Change to another broad-spectrum seizure medication Repeat levetiracetam level in few days and if still low, increase the dose. monitorig tending duginteract Theonsuer Nbannesee 35 5 gidl pagglyat Notenough pays Optimizing dose and drug as.at monitoring Anti-epileptic Drug bombeconelted d Therapeutic druge level (mcg/mL) Load 15-20 mg/kg 10 - 20 (normal albumin >20 mcg/ mL Nystagmus level) may occur Maintenance 4-6 mg/kg/day 1-2.5 (free phenytoin) Load 20-40 mg/kg Valproic Acid Maintenance 10-15 mg/kg/day Load 15-20mg/kg Phenobarbital Maintenance 1.5-2 mg/kg/day (not in liver impairment) Carbamazepine Ethosuximide gentles Dose Phenytoin • Treat the patient not the level ! • Start low and go slow ( slower especially with lamotrigine or topiramate or in general when treating an elderly patient) . • If patient is experiencing multiple seizures, then may need to titrate rapidly ( in such cases a loading dose oral or intravenous can be administered). • Optimal dose = Effective dose to control seizure + tolerable side effect profile grapaticangmonitor 400 mg daily up to 1600 mg max daily dose (adult) 500 mg /day to a max of 1500 mg /day In a case if levalofphenytoinis or TDM clinical pearl >30 mcg/mL Ataxia slurred speech IIImat > 75 mcg/mL Lethargy, 50 - 100 (levels as high ataxia as 175 are used in RSE) > 100 mcg/ mL tremor, >175mcg/mL coma 30s CNS depression, 10 - 40 (higher levels respiratory depression is may be utilized in RSE) dose -related side effect >60mcg/mL 4-12 mcg/mL 40-100 mcg/mL >15-25 mcg/mL associated with seizures , hallucinations and coma >150 mcg/mL associated with dizziness, drowsiness and anorexia notbadbutit'sahighproteinbound chronickidneydiseasesaskfroghenotyin teal orderthetest dAlbumire morefreephenytointyosoodforpt Anti-Epileptic drugs Refer to the Epilepsy handout on canvas mangier Phenytoin • Indications: Generalized tonic-clonic seizures, • Drug interactions: prevention and treatment post neurosurgery. • It is a drug inducer (CYP • Mode of action: blocks sodium channels 450 and UGT) • Highly protein bound • Brand name : Dilantin®, Phenytek® (interact with medications • Common side effects: causing displaced • Gingival hyperplasiasongagovergrow (reversible) phenytoin increase level. 3 • Facial hair growth, enlarged facial features • CNS : Nystagmus ,usedation (dose dependent) •sTeratogenic (fetal hydantoin syndrome) Bodebesomeweed • Metabolic: Osteoporosis (chronic use) disease • Serious Side effects: Purple glove syndrome,a seriousskin DRESS Morash • Warning : causes hypotension, arrhythmia (IV) mas Phenytoin lostgoveryfast inchildren specially we • Warnings • Boxed warning – cardiovascular events with IV infusion >50 mg/min (or 50 mg/min, whichever is slower) • Pediatrics – should not exceed 1-3 mg/kg/min (or 50 mg/min, whichever is slower) to decrease risk of severe hypotension, cardiac arrhythmias • SJS, TEN – ten-fold increased risk in Asian descent • Test for HLA-B*1502 allele, avoid if positive • • • • • Blood dyscrasias Hepatic injury Bradycardia and cardiac arrest reported Angioedema Exacerbation of porphyria • Renal or hepatic impairment, hypoalbuminemia • Hyperglycemia • Chronic use associated with decrease bone mineral density, fractures • Teratogenicity • Sustained phenytoin serum levels above therapeutic range may produce confusional states including delirium, psychosis, encephalopathy, or rarely, irreversible cerebellar dysfunction and/or cerebellar atrophy After 3gMglday on bby t If youwentto Ithedosehavetobecareful Phenytoin 3Efuausegong • Phenytoin goes through complex kinetic • Phenytoin is metabolized in the liver by CYP450 enzymes and displays Michaelis–Menten phenytoin’s metabolism is generally linear in most patients. • A metabolizing enzymes and a small change in dose can result in a disproportionally large increase in serum concentrations, potentially leading to toxicity. • P increase by 30mg increments instead of 100mg. ifHLA B note phenytoin sumpto tidy 1 Pharmacokinetics of ASMs First Generation Pharmacokinetics Drug Bioavailability Binding % Clearance Half-life (hrs) Causes PK Interaction? CBZ 80 75-85 100% H* 6 - 15 Yes PB 100 50 75% H 72 - 124 Yes PHT 95 90 100 % H** 12 - 60 Yes VPA 100 75-95% 100% H 6 - 18 Yes Some Second Generation Pharmcokinetics Drug Absorption Binding % GABA 60% 0% Elimination 100% R Half-life (hrs) 5-7 Causes Interaction ? No LAMO 100% 55% 100% H 18 - 30* No LEVE TIAG ~100 % ~ 100 % < 10 % 96% 66% R 100 % H 15% 30-55 % R 20 - 30 Yes/ No 40-60% 40% 50-70 % H 100 % H 50 - 80 5 - 11 No Yes / No Phat TOP ZON OXC 80-100% 100% 4-8 5 - 13 No No R = Renal H = Hepatic *Depends if combined with enzyme inducer or in combination with valproic acid ** Dose-dependent saturable ASM Drug Interactions: • ASMs are known for their drug -drug interaction : • CYP 450 interaction • Pharmacodynamic interaction • Protein binding • • • • • Clinically significant with drugs >90% protein bound ASM: valproate, phenytoin, tiagabine, perampanel Non-ASMs: warfarin, digoxin. Potent CYP 450 inducers include : CBZ, PHT, PB. Highly protein bound ASMs : PHT, VPA, CBZ. • Some clinically important interactions : • • ASM Drug Interactions: ASM Interactions with common drugs Drug Affected Medications Effect Enzyme inducers: PHT,PB,CBZ, FLB,TOP,OXC Amitriptyline,bupropion, haloperidol, olanzapine, simvastatin, oral contraceptives Decreased level , consider COC (estrogen >50mcg) PB, CBZ, PHT Warfarin Decreased level and , monitor VPA Warfarin, Simvastatin,Amitriptyline Increased level and effect, monitor VPA LTG Start at lower dose, titrate folds) Erythromycin , clarithromycin VPA azithromycin recommended as an alternative Case 3 : KS is a 35-year-old male with who presents to the ED with a witnessed seizure x2. His PMH is notable for an extensive psychiatric history including mood lability with anger problems, PTSD, and depression. sieve If the doctors decide to treat KS for epilepsy with an AED, which of the following AEDs should be avoided? (Select all that apply) A.Clonazepam B.Levetiracetam C.Oxcarbazepine D.Perampanel is Fey AED : Anti-epileptic drug Xx peronp Special populations : Children , Elderly needs as I a Neonates and children: cower dose • For neonates and infants, an increase in the total body water to fat ratio and a decrease in serum elimination half-life. • activity before 2 years of age). • Children require higher doses than adults. ( robust hepatic activity by 2 to 3 years of age). • Adverse events of concern are cognitive side effects , there is an increased risk of oligohydrosis with zonisamide and topiramate. Geriatric population: • On multiple medications increase the risk of sensitivity to neurocognitive effects. • Increased risk of drug-drug interactions ( CBZ, PHT, VA ). • Higher risk of hypoalbuminemia and reduced kidney or liver function warranting dose adjustment. • Lamotrigine is considered drug of choice based on a Veterans Affairs cooperative study ( equal efficacy to CBZ , gabapentin , better tolerated). Special populations : Females • Estrogen has slight proconvulsant effect. owz.sk • Catamenial seizures happen around menstruation and at the time of ovulation, which is believed to be due to a slight increase in estrogen relative to progesterone. • VPA affect sex hormone concentration causing hyperandrogenism and polycystic changes. • Enzyme inducing ASMs can cause treatment failure in patients taking OCs. • Higher estrogen containing OCP >50 mcg is advisable . • Twice the normal dose of emergency contraception is advisable. Special populations : Pregnancy, lactation Pregnancy: • ASMs levels may decrease in pregnancy ( protein binding may change). • Lamotrigine have been found to undergo 40% decrease causing deterioration in seizure control. • Monitoring, increasing the dose during pregnancy and decreasing in post partum period is warranted. • Folic acid supplementation is recommended ( no clear evidence , but may decrease teratogenic impact of ASMs) • Vitamin K supplementation for PHT pregnant patients to avoid hemorrhagic disorder. Lactation : • Even when ASM level can be measured in breast milk , argument of health benefits and avoiding abrupt withdrawal of ASM to continue breast feeding. • Special caution with phenobarbital or benzodiazepines. Clinical Pearls • To date, no single AED or combination of AEDs has been shown to be ideal as first-line therapy. • Nonadherence to AEDs is a major barrier to successful treatment of epilepsy. • Initiate ASMs at the lowest possible dose. 1. Titrate AEDS slowly to the lowest possible dose that is expected to provide seizure control. 2. Increase and/or adjust doses as needed if seizures are not controlled and/or patient develops adverse effects. • When initiating an AED, assess for possible drug interactions with other medications that the person is taking. 1.If seizures are not controlled after initial monotherapy, after excluding nonadherence to AEDs, consider switching to another monotherapy. 2.If seizures are not controlled after trial of second AED as monotherapy, consider dual therapy, then polytherapy. ( Titration up, and titration down of old agent) Three non-pharmacological options for seizure treatment Vagal nerve stimulation (VNS) Ketogenic diet • Reduced seizure frequency, relatively safe, mechanisms unknown • High in fat and low in carbohydrates and protein, and it leads to acidosis and ketosis • Positive effect on mood and behavior • No sugar is allowed. Vitamins and minerals are supplemented. • Common AE: hoarseness, pharyngitis, dyspnea, dyspepsia, and nausea. • Serious AE: infection, nerve paralysis, urinary retention Surgery Refractory focal epilepsy, especially seizures originating from the temporal lobe • Fluids are also controlled • Poorly tolerated. Kidney stones, bone fractures, and adverse effects on growth Evaluation of Clinical Outcome • Clinical response should be evaluated based on patient reported seizure frequency, severity and any reported adverse events that may compromise QOL. • Period screening for comorbid neuropsychiatric disorders. • Counselling on ASM side effects, addressing any issues related to QOL improvement as driving , forming relationship, epilepsy safety measures, etc… aboveEmin seizure MY Imedependent g yes Status Epilepticus: • Status epilepticus (SE) is a neurologic emergency that may be associated with significant morbidity and mortality. • SE is defined as: 1. Any seizure lasting longer than 30 minutes whether or not consciousness is impaired or 2. Recurrent seizures without an intervening period of consciousness between seizures. • SE is considered an emergency and aggressive treatment is necessary for any seizures last 5 minutes or more ( regarded as continuous seizure activity). Status Epilepticus Classification: I ok Convulsive SE includesmuscles • Generalized SE (Grand mal) • Tonic-Clonic • Tonic • Clonic • Myoclonic • Erratic • Secondary generalized SE • Tonic • Partial with secondary generalized Non-convulsive SE • • • • • Absence ( Petit mal) Partial SE Simple Somatomotor Complex partial Case A: novalporic 2 TEFhomusdestiffnees for • A 25-year-old female had her roommate witnessed generalized tonic clonic seizure at dorms around 7 pm and called 911. Patient never gained back consciousness and continued to seize until EMS arrived. EMS gave her 5 mg midazolam, but she continue to seize. She was transported to ED on ventilation, and she is still seizing its 7:15pm. spieth • PMH : PCOS • Social History : • 1-2 alcoholic drinks / week • Non-smoker , non-drug user • Allergies : None • Medications : Tylenol 325 mg every 6 hours as needed Case A: 1. What is the Diagnosis? A. B. C. D. Tonic Clonic Seizure Generalized convulsive Status Epilepticus Alcohol intoxication Generalized non convulsive Status Epilepticus Etiology and Pathophysiology: • Etiology in infants : • Infants born to addicted mothers • Pyridoxine deficiency • Metabolic disorders • Etiology in young children: • Viral illness , fever • Etiology in Adults : • Cerebrovascular disease • Rapid anti-convulsant withdrawal • Prescription, over the counter, recreational drugs proeneralizedsonvulsivestatusepticas Pathophysiology and GCSE phases: Two main phases of GCSE: 1. Phase I : (first 30 minutes) • • • 2. Phase II : ( > 30 minutes) • Decompensation • • Hypotension • Hyperthermia , hypoxia Tempretare lessoggen GCSE four phases: 1. Stabilization (0-5minutes) 2. Initial therapy (0-20 minutes) • Impending GCSE 3. Secondary therapy(20-40mins) • Established GCSE 4. Third therapy • Refractory GCSE : 40-60 minutes • Super-refractory : >24 hours Treatment goals, Seizure first aid • Due to the associated increase in mortality and morbidity with time lapsed , short term goal is rapid termination of clinical and electrical seizure • Prehospital care is important. • Caregiver education is essential : • • 3• a• 5• Clear the area from anything sharp or hard Put something soft , flat under the head I I the seizing patient Never restrain Time the seizure Call 911 if it last longer than 5 minutes Treatment Algorithm: Pre-hospital Care a. Airway and vitals are critical (ventilation) OROV b. Rectal Diazepam (VALIUM) can help c. IN or IM midazolam (VERSED) can be used d. Some SE seizures can be contained without a hospital wit admission! BI SE Benzodiazepine2doses thentothenextthing Stabilization phase : In-hospital care a. Stabilize the patient (ABCs) b. Time seizure from the onset/monitor vital signs c. Assess oxygenation (i.e., give face mask with nasal cannula) d. Initiate ECG monitoring e. Finger stick blood glucose .If glucose is less than < 60 mg/dL, treat with 100 mg IV thiamine & 50 mL IV D5W f. Obtain IV access to obtain CBC + differential, CMP, and toxicology screen Case A continued: 1. What is the first step in treating this patient? A. Give IV lorazepam 0.1 mg / kg B. Talk to the room mate to collect information C. Give Thiamine and Dextrose 50 D. Secure the airways, circulation and breathing for this patient as Case A continued: MrBenyo Patient were given midazolam by EMS , it is 20 minutes, ED team secured airways , she is still seizing , what would be an appropriate medication to administer : A. Another IM dose of midazolam 0.2mg/ kg B. IV Phenytoin 18 mg /kg over 20 mins C. IV Levetiracetam 40 mg / kg D. 50 mL of 50% glucose if glucose > 60 mg/ dL Initial Phase : 5-20 min • Benzodiazepine - Level A Evidence • Equivalent First-line Agents IM Midazolam 10 mg > 40 kg or 5 mg 13-40 kg, single dose Second Therapy Phase: Established GSCE 20- 40 min No Evidence-based Preferred Choice (please refer to established GSCE chart) Equal efficacy with each ASM but more deaths with levetiracetam; more hypotension & intubation with fosphenytoin IV Lorazepam 0.1 mg/kg/dose, max 4 mg/dose, may repeat once IV Diazepam 0.15 - 2 mg/kg/dose, max 10 mg/dose, may repeat once Bothsaving Benzodiazepines: its when it dispense never wesyringe): • DIASTAT (Diazepam Rectal • Need to know: • Syringes must be DIALED to the right dose and LOCKED before dispensing. • Syringes come in 2.5, 10, and 20 mg • Instructions of locking are in the box. • Lock dose for BOTH syringes and only dispense if the green ring with ready sign is shown. locked NI syfy Benzodiazepines: Diazepam nasal spray (Valtoco) and Midazolam (Nayzilam) • Nasal spray is indicated for acute treatment of intermittent frequent seizure activity. • One dose in one nostril (not the same nostril) • No need to breath deeply Treatment consideration: Phenytoin vs. Fosphenytoin Medication Max Infusion rate Compatible with Normal Saline Compatible with 5% Dextrose Need for a filter Time to check serum level after IV admin. Can be given IM Side effect profile 80 N du Phenytoin 50 mg /min Yes No , precipitate Yes (0.22 micron) Fosphenytoin cere but 150 mg PE/ min faster e Yes Yes as No 1 hour post 2 hours post No (Erratic Absorption) precipitate Hypotension, arrhythmias Pruritis Yes Hypotension (less than PHT) Pruritis ( face, groin) Third Phase 40-60 mins No Evidence-based Preferred Choice Repeat second-line therapy Anesthetic doses PLUS continuous EEG monitoring Midazolam Phenobarbital Propofol Treatment consideration: Monitor vital signs , ECG changes with all IV infusion of benzodiazepines or ASMs. Wernicke’s encephalopathy can develop in alcoholics, and adults should receive IV thiamine (100 mg) prior to glucose Overview of GCSE Treatment Algorithm Case B y NOVA A 22-year-old female is brought to the emergency department with involuntary jerky movements of the whole body for approximately 7-8 minutes in her office. The client has impaired mental status at present. While the providers are assessing the client, the client develops a similar episode in the emergency department. What would comprehend as the first-line drug of choice to terminate the client's seizure? Bento A. Phenytoin B. Carbamazepine C. Lorazepam D. Valproic acid Phenytoin (Dilantin ®,Phenytek®) AS M Ta b le 1 : Firs t Ge n e ra tio n AS Ms In d ic a tio n (s ) MO A GTC Volta ge de pe nde nt comple x pa rtia l se izure blocka de of Na + pre ve ntion/tre a tme nt of cha nne l a ctiva tion se izure s following ne urosurge ry Phenobarbital (schedule IV) titanceuse AYEE Foca l a nd ge ne ra lize d (not FDA a pprove d) Binds to GABAA modula te s Cl conducta nce C o mmo n S id e e ffe c ts *Gingiva l hype rpla sia (re ve rsible upon d/c) Wa rn in g s Hypote nsion, Arrhythmia whe n give n IV [BBW] Se ve re de rma tologic re a ction DDI Induce r of CYP450 a nd UGT CNS: Nysta gmus fa tigue , se da tion (dose de pe nde nt) Blood dyscra sia s (idiosyncra tic) Ma ny DDIs Highly prote in bound (displa ce d phe nytoin ca use s le ve l) Highly prote in bond 4-Fosphe nytoin (Ce re byx®) is wa te r soluble prodrug use d IV, IM for SE. Te ra toge nicity (fe ta l hyda ntoin syndrome ) Fre e phe nytoin (unbound) = Active 5- Phe nytoin ma y be ora lly or IV loa de d in pt. who re quire ste a dy sta te Me ta bolic bone dise a se : oste oporosis. (chronic) Ca ution with low prote in sta tus pts. (ESRD, critica lly ill) (a djuste d e qua tion to ca lcula te le ve l) 1-Inte lle ctua l blunting 2- Slow ta pe ring whe n d/c 6- Vita min K supple me nta tion for pre gna nt wome n (to de cre a se risk of ble e ding) Fa cia l ha ir growth, lympha de nopa thy , e nla rge d fa cia l fe a ture s S e rio u s b u t Ra re SJS, DRESS, purple glove syndrome in IV Blood dyscra sia s ( lowe r with fosphe nytoin) CNS: Nysta gmus, SJS, DRESS fa tigue , se da tion, Re spira tory de pre ssion, dizzine ss, a ta xia . me ga lobla stic a ne mia . pa roxysma l e ffe cts (e xcite me nt, irrita bility in olde r a dults , childre n) (dose de pe nde nt) Primidone Carbamazepine (Tegretol®) (Carbatrol®) (Equetro®) I Prodrug to phe noba rbita l CNS e ffe cts (a ta xia , nysta gmus, diplopia , hype rirrita bility) Re comme nde d to use 2-Monitor se rum phe nytoin, LFTs,CBC non-hormona l OCP with with diffe re ntia l chronic phe nytoin use Pote nt Induce r of CYP450 a nd UGT PB SJS, DRESS, blood dyscra sia s Inte lle ctua l blunting, be ha viora l cha nge s Enha nce fa st ina ctiva tion of volta ge ga te d Na + cha nne l CBZ spe cia l *Ra sh* 2-Use ful in pts with e sse ntia l tre mor SJS, DRESS, Apla stic a ne mia Avoid in pt if prior ra sh with othe r ASM, or in pt. with hx of bone ma rrow de pre ssion, not within 14 da ys of MAO inhibitor Induce r a nd Autoinduce r CBZ le vothyroxine , wa rfa rin, OCP Te ra toge ne city autoindayganged induceit's 1- Tole ra nce , de pe nde nce 3- Contra indica te d in porphyria races to Loredema Hypona tre mia (SIADH) CNS e ffe cts: (a ta xia , nysta gmus, diplopia ). 1-Additive CNS de pre ssion ma y ca use fa ta l re spira tory de pre ssion 2- Monitor LFTs, CBC with diffe re ntia l OCP le ve l Induce r of CYP450 Me ta bolic bone dise a se s (Oste oporosis) Monothe ra py/ a djunctive the ra py for foca l onse t a nd TC se izure s 3-Exhibit Micha e lis-Me nte n Kine tics 3-Tole ra nce , de pe nde nce Oste oporosis (chronic) Monothe ra py/ a djunctive the ra py for foca l onse t a nd TC se izure s Th in g s to kn o w 1-Aggre va te Abse nce se izure Ca n't be use d with NNRTIs ( nonnucle oside re ve rse tra nscripta se inhibitors) 1- Avoid in Abse nce Se izure 2-BBW: Apla stic Ane mia , Agra nulocytosis, incre a se d risk of SJS/TEN with HLA-B*1502 a lle le 3-Use ful in Bipola r disorde r a nd trige mina l ne ura lgia 4- Monitor : CBC, diffe re ntia l, pla te le ts,LFT,Na +, re na l function (ba se line , 3-5 da ys a fte r initia tion a nd 4 we e ks a fte r) Clona ze pa m (Klonopin®) (s c he dule IV) AS M Ta ble 1: Firs t Ge ne ra tion AS Ms (~Continue d) Indica tion (s ) MO A Common S ide e ffe cts S e rious but Ra re Monotherapy/ Binds to GABAa CNS: cognitive Blood dyscrasias adjunctive therapy receptor impairment, ataxia Hepatomegaly LGS (petit-mal), akinetic, absence 3-Withdrawal may cause SE Ethos uximide (Za rontin®) Absence Seizure Va lproic a c id/ Diva lproa te ( De pa ke ne ®) (De pa kote ®) Wa rnings DDI Things to know BBW: Concomitant use May PHT level. 1- Useful when a long acting BDZ is with opioids may result May be affected by needed in respiratory enzyme inducing drugs depression 2- De pe nde nce may occur Inhibition of T-type Ca channels 1-GI side effects: Nausea/Vomiting (dose dependent) Blood dyscrasias Worsen TC seizures VPA may level of ETS Drug of choice for Absence seizure 2-CNS : night terror Monotherapy & adjunctive therapy for complex partial, simple partial seizures, complex absence seizures; adjunctive for multiple seizure types including absence seizures Increases GABA, blocks sodium channels, inhibits T type Ca channels CNS: Nystagmus, fatigue, sedation, dizziness, ataxia Hyperammonemia (chronic use) Polycystic ovary syndrome Blood: Neutropenia Alopecia** (Idiosyncratic) Weight gain (chronic) 1- Hepatotoxicity especially Not recommended in Inhibitor CYP2C9(weak) Valproate (Depacon®) IV, can be used for children <2 years [BBW] childbearing age group Valproic acid is highly for SE. Monitor protein bound so will affect other protein bound medications, phenytoin level DR and ER formulations are not increased. bioequivalent. (from DR to ER total 2-Fetal risk including neural tube defects, other major malformations, and decreased IQ [BBW] 3- Pancreatitis including fatal hemorrhagic pancreatitis (Idiosyncratic) [BBW] VPA PB, PHT, warfarin, zidovudine Also used for bipolar disorder and migraines Salicylates VPA (displace protein binding) VPA LTG Monitor LFTs (baseline, frequently in first 6 months) Estrogen OCP VPA Monitor CBC with differential and platelet Topira ma te (Topa ma x®) La motrigine (La micta l®) Ga ba pe ntin (Ne urontin®, Gra lise ®,Horiza nt®) Fosphe nytoin (Ce re byx®) Ta b le 2 : Se c o n d Ge n e ra tio n ASMs In d ic a tio n (s ) MO A 2nd ge ne ra tion ASM IV &IM txt of GTC SE a nd pre ve ntion a nd tre a tme nt of se izure s occurring during ne urosurge ry C o m m o n Sid e e ffe c ts Se rio u s b u t Ra re phospha te e ste r Infusion ra te -de pe nde nt Infusion ra te >150mg PE prodrug of phe nytoin pruritus (phe nytoin e quiva le nt) (sa me MOA) incre a se risk of hypote nsion a nd ca rdia c a rrhythmia (BBW) Binds to pre syna ptic Adjunctive the ra py for 1-CNS: Ata xia , dizzine ss, foca l onse t se izure s with somnole nce , fa tigue , a nd without TC se izure s in cha nne ls with unknown irrita bility (a cute ) pa tie nts 3 ye a rs a ntise izure e ffe ct None Wa rn in g s Confusing dose conve rsion (che ck via l volume a nd PE milligra m) (1PE = 1 mg phe nytoin = 1.5 mg fosphe nytoin) None DDI Th in g s to kn o w Strong induce r CYPs a nd high prote in bound ( inte ra ction with displa cing prote in binding me dica tions) 1-Compa tible with common IV solutions Not significa nt 1-Ne a rly 100% re na lly e limina te d (dose a djustme nt wa rra nte d) 2-Ra pid IV infusion (ma x 150mg/min) 3-Ca n be store d a t room te mpe ra ture for 24 hours 2-We ight ga in (chronic) Adjunctive the ra py in foca l onse t a nd TC se izure s, ge ne ra lize d se izure s of LGS in pa tie nts 2 ye a rs of a ge ; monothe ra py in pa tie nts with foca l-onse t se izure s 16 ye a rs of a ge Enha nce s fa st ina ctiva tion of volta ge ga te d Na + cha nne ls, inhibits gluta ma te Monothe ra py/ a djunctive the ra py for foca l onse t se izure s or prima ry ge ne ra lize d TC se izure s in pa tie nts 2 ye a rs of a ge ; a djunctive the ra py for pa tie nts with LGS 2 ye a rs of a ge Anta gonize s volta ge ga te d sodium cha nne l; binds to GABAA re ce ptor a nd a ugme nts GABAe rgic tra nsmission, a nta gonize s AMPA/ka ina te gluta ma te re ce ptor, we a k ca rbonic a nhydra se inhibitor heworkson 3-Be ha vior proble ms (Idiosyncra tic) 4- Pe da l e de ma (idiosyncra tic) 1-Ra sh (SJS) a nd be nign 1-DRESS ra sh* (idiosyncra tic) (BBW) 2-Use in ne uropa thic pa in (post he rpe tic ne ura lgia ) Ra sh (HLH) a ppe a rs in 3- Significa nt with 4 we e ks a nd ca n va lproa te progre ss to SJS 2-CNS : Diplopia , dizzine ss 2-Blood dyscra sia s CBZ, PHT, PB LTG (by 40%) 3-Infe ction: a se ptic me ningitis (HA, fe ve r, stiff ne ck) (a cute ) 4- Alope cia , N/V NgondsABIatate 1-CNS: Be ha viora l cha nge s, irrita bility, cognitive proble ms (WORD 1-Re na l stone s FINDING) , a ta xia , fa tigue (a cute ) 2-We ight loss (dose 2-Gla ucoma de pe nde nt, chronic) 3-Myopia , se conda ry a ngle 3-Hype ra mmone mia closure gla ucoma (Idiosyncra tic) 4-Me ta bolic a cidosis (should be a voide d with ke toge nic die t) 1-SLOW titra tion to a void SJS ( 2 diffe re nt sta rte r kits a va ila ble , lowe r dose if combine d with VPA, a nd highe r dose kit if combining with CBZ, PHT, PB) 2-Ra sh incre a se if give n with va lproa te Monitor de cre a se d swe a ting a nd incre a se d body te mpe ra ture (e spe cia lly childre n) We a k inhibitor (CYP2C19) Induce r of CYP3A4 TOP INR (pt on wa rfa rin) TOP OCP PHT, CBZ, VPA, LTG TOP Avoid in pa tie nts with pre e xisting cognitive issue s Migra ine prophyla xis Monitor re na l function, hydra tion sta tus, e ye e xa m ( gla ucoma , intra ocula r pre ssure ), e le ctrolyte s. dose with CrCl < 70 ml/min atonal very Zonisa mide Dia ze pa m ( Va lium®, Va ltoco® Oxca rba ze pine (Trile pta l®) (Zone gra n®) (ZNS) Na sa l , Dia sta t® re cta l ge l) 0 Le ve tira ce ta m (Ke ppra ®) ASM Ta b le 2 : Se c o n d Ge n e ra tio n ASMs (~C o n tin u e d ) In d ic a tio n (s ) MO A C o m m o n Sid e e ffe c ts Binds to a nd se le ctive ly 1-CNS: Somnole nce , Childre n: Adjunctive the ra py for foca l onse t inhibits syna ptic ve sicle hostility, a ggre ssion SV2A prote in the re by se izure s in pa tie nts >14 (e spe cia lly in childre n) months, Adults: myoclonic pre ve nting ne urotra nsmitte r se izure s in pa tie nts with re le a se JME 12 ye a rs of a ge , a nd ge ne ra lize d TC se izure s in pa tie nts 6 ye a rs of a ge with ge ne ra lize d e pile psy Monothe ra py/ a djunctive the ra py for foca l onse t se izure s in pa tie nts 4 ye a rs of a ge ; a djunctive the ra py for foca l onse t se izure s in pa tie nts 2 ye a rs of a ge Enha nce s fa st ina ctiva tion of volta ge ga te d Na + cha nne ls Acute tre a tme nt of inte rmittme nt, ste rotypic fre que nt se izure s ( se izure cluste rs) Binds GABAA re ce ptor a nd pote ntia te s GABA by modula ting chloride conducta nce Se rio u s b u t Ra re Psychosis, ha llucina tion 2-Blood dyscra sia s Re spira tory de pre ssion + + Monitor Na le ve l (Na < 125 mmol/L is clinica lly significa nt) Pts a t highe r risk + concomita nt use of diure tics. Monohydroxy de riva tive (MHD) is the a ctive me ta bolite BBW: Concomita nt Opioid use , re spira tory de pre ssion Inhibitor of Use ful in bipola r disorde r CYP2C19, induce r of CYP3A4 (ma y incre a se la motrigine le ve l) No a utoinduction Dose conve rsion 1.2 to 1.5 da ily dose of CBZ Monitor a ctive me ta bolite le ve l (MHD) Wa tch for Not for ma inte na nce the ra py bre a thing Incre a se risk of suicida l thoughts 2- Na sa l spra y: na sa l discomfort, runny nose Adjunctive the ra py for foca l onse t se izure s in a dults Enha nce s fa st ina ctiva tion of volta ge ga te d Na + cha nne ls; inhibits T-type Ca cha nne ls; we a k ca rbonic a nhydra se inhibitor 1-CNS : Se da tion, dizzine ss, cognitive impa rime nt (a cute ) 2-We ight loss (chronic) 3-Kide ny stone s (Idiosyncra tic) 4-Oligohidrosis (Idio) 5-Ra sh (sulfa de riva tive ) Th in g s to kn o w Must a djust dose in re na l fa ilure / dia lysis Pre gna ncy ca te gory C 1- Highe r incide nce of 1-SJS, TEN hypona tre mia ( tha n CBZ) but milde r 2-CNS: dizzine ss, diplopia , nysta gmus 1-CNS: Se da tion, he a da che Wa rn in g s DDI Ma y worse n de pre ssion, Minima l a nxie ty inte ra ction Re cta l ge l (for incre a se d se izure s e pisode s 2 ye a rs a nd a bove a ge group) 1- SJS 2-Blood dyscra sia s 3-Me ta bolic a cidosis 1-SULFONAMIDE CYP3A4 de riva tive , ra sh , DRESS inhibitors a nd induce rs ma y la te r ZON le ve ls 2-Wa rning re ga rding oligohydrosis a nd he a t stroke Use ful in Tre mor Once a da y dosing Cloba za m Ca nna bidiol Pe ra mpa ne l Eslica rba ze pine (Onfi®) (Epidiole x®) (CBD) (not (Fycompa ®) (Sche dule (Aptiom®) (ESL) Sche dule IV sche dule d) III) (PER) Pre ga ba lin (Lyrica ®) (Sche dule V) Briva ra ce ta m (Brivia ct®) AS M Ta b le 3 : Th ird Ge n e ra tio n AS Ms In d ic a tio n (s ) MO A Monothe ra py/Adj. the ra py Inhibit syna ptic ve sicle Inje cta ble a pprove d 16 SV2A prote in ye a rs of a ge Use ma inly in drug re sista nt se izure s. Adjunctive the ra py for foca l onse t se izure s in pa tie nts 4 ye a rs of a ge cha nne ls S e rio u s b u t Ra re Angioe de ma Bronchospa sm Wa rn in g s Dose a djustme nt in he pa tic impa irme nt DDI CBZ, PHT, PB Briv. Th in g s to kn o w It ma y be conside re d in conve rting we llcontrolle d pa tie nts on le ve tira ce ta m with intole ra ble psychia tric a dve rse re a ctions. 100 % re na l e limina tion Nonsignifica nt Use ful for ne uropa thic pa in BBW: Aggre ssion, hostility, homicida l ide a tion CBZ, PHT, PB, TP PER Avoid in a ctive psychosis Avoid in se ve re he pa tic, re na l impa irme nt or he modia lysis He ma tologic a bnorma litie s CNS: dizzine ss, Misuse pote ntia l with opia te s somnole nce , blurre d vision, difficulty with conce ntra tion a nd a tte ntion. Dry mouth; e de ma We ight ga in (chronic) Tre a tme nt/ a djunctive tre a tme nt pa rtia l-onse t se izure s with or without se conda ry ge ne ra lize d ( 4, 12 ye a rs a s a djunctive ) Non-compe titive AMPA CNS e ffe cts including dizzine ss, somnole nce , gluta ma te re ce ptor a nta gonist fa tigue , fa lls, ve rtigo, a ta xia , he a da che , Monothe ra py or a djunctive the ra py for foca l onse t se izure s in pa tie nts 4 ye a rs of a ge Se le ctive ly e nha nce s fa st ina ctiva tion of volta ge -ga te d Na + cha nne ls Indica te d for the tre a tme nt of se izure s a ssocia te d with LGS, Dra ve t syndrome , tube rous scle rosis comple x 1 yrs. Old Unknown DRESS GI e ffe cts including na use a , we ight ga in, vomiting, a bdomina l pa in PER OCP le ve ls we ight ga in CNS: dizzine ss, diplopia , a ta xia CNS: dizzine ss, diplopia , a ta xia Hypona tre mia (SIADH) Avoid concomita nt use ESL OCP with CBZ, OXC e stroge n le ve l Dose a djustme nt in re na l fa ilure Hypona tre mia (SIADH) we p Binds to pre syna ptic C o m m o n S id e e ffe c ts CNS: he a da che , somnole nce , irrita bility. formsesemisition lift Binds GABAA re ce ptor a nd pote ntia te s GABA by modula ting chloride conducta nce Adjunctive the ra py for pa tie nts with LGS 2 ye a rs of a ge CNS: somnole nce , fa tigue , He pa totoxicity sle e ping disorde r. GI de cre a se d a ppe tite , dia rrhe a Sle e pine ss, tire dne ss, fe ve r, drooling, a ggre ssive be ha vior, irrita bility, la ck of coordina tion. t Sefton steepness Conside r dose a djustme nt or d/c if 3 time s norma l tra nsa mina se e le va tions CBZ, PHT, PB ESL le ve l. CBD LTG Use ful in non-a dhe re nt ca se s ( once a da y) • Monitor Ba se line , 1 month, 3 months, 6 months, &pe riodica lly: AST, ALT, a nd tota l bilirubin. CBD CLB a ctive me ta bolite Ra sh (SJS, TEN); a ne mia ; live r Concomita nt use with CBZ, Avoid a brupt d/c ( ca use s withdra wa l e nzyme e le va tions; re spira tory opioids incre a se s risk of fe lba ma te , PHT, syndrome ) de pre ssion de a th (BBW) PB CLB