NP Exam1 Shortened2.docx

Anti-seizure drug pharmacology Epilepsy is characterized by recurrent seizures – episodes of brain dysfunction that result from aberrant synchronous firing of CNS neurons. Seizures are thought to arise in the cerebral cortex (outermost portion of brain). Partial (focal) – arise in a specific loc...

Anti-seizure drug pharmacology Epilepsy is characterized by recurrent seizures – episodes of brain dysfunction that result from aberrant synchronous firing of CNS neurons. Seizures are thought to arise in the cerebral cortex (outermost portion of brain). Partial (focal) – arise in a specific locus Simple partial seizures (focal aware seizure): consciousness is not impaired; person can describe what sensations are associated with the seizure; manifestation will be dependent on which part of cerebral cortex is involved Lasts 20-60 seconds; Precentral/primary motor gyrus See flashes of light, or blurring; hears ringing, hissing, or noises, tingling of contralateral limb, face, or side of body, sweating, flushing EEG: Interictal activity in patient with temporal lobe epilepsy “tingling in my left hand then becomes completely numb” – somatosensory/post-central gyrus Complex partial seizures (focal impaired awareness seizure): consciousness is impaired; will not remember seizure & what went on, but still responsive; often associated with an aura Lasts 30 seconds – 2 minutes Superior temporal gyrus May experience an aura Dreamy state, blank/vacant expression, déjà vu, chewing movements, wetting lips, picking at clothing, dysphasia, bad or unusual smell, hallucinations, hears music etc. “makes a grunting sound… sit up, open eyes and stare… clasp hands together, doesn’t answer” “never answers, odd mouth movements, tastes something, picking lint off shirt, never remembers warning” Partial with secondarily generalized seizures: specific locus where activity starts, then spreads, usually results in tonic-clonic seizure; lasts 1-2 minutes “see a colored ball… becomes like a dream and I don’t feel real… fall to the floor, whole body stiffens for awhile then starts to jerk” “start with tingling in right thumb, thumb starts jerking, whole right hand is jerking, spreads up arm, pass out when it reaches shoulder, can’t remember what happens Generalized (primary generalized) – involve both hemispheres from the start Absence: staring spells, <30 seconds or less “blanks out anywhere from a few seconds to 20 seconds at a time… blinks repetitively, eyes may roll up a bit” Myoclonic: brief, jerk like contractions <1 second; often occur falling asleep or shortly after waking “jumps… arm fly up for a second, drop what I’m holding… mouth my shut for split second” Tonic-clonic seizures: periods of hypertonicity of muscles followed by relaxation (grand-mal); 1-2 minutes; Tonic: stiffening; Clonic: jerking “begins with unnatural shriek… falls and every muscle seems to be activated.. teeth clench.. pale and turns slightly bluish… body starts to jerk” For each drug, know the primary mechanisms of action,the key distinguishing side effects, black box warnings, and general knowledge of teratogenicity. Also, it is important to understand how mechanisms of action produce reduction in neuronal firing. Commonly used drugs: Phenytoin Carbamazepine Valproic acid Ethosuximide Lamotrigine Topiramate Zonisamide Lacosamide Levetiracetam Gabapentin Drugs less commonly used but with novel mechanisms: Ezogabine, Tiagabine, Vigabatrin, Perampanel, Felbamate, Cannabidiol, Fenfluramine Lamotrigine (Lamictal) – multiple MOA so utility in multiple types of seizures, well tolerated, but needs to be titrated so will need time for it to take effect MOA: Inactivation of Na+ channels (somnolence), Low threshold Ca2+ channel blocker (beneficial in absence seizures), Inhibits AMPA, kainate, and NMDA receptors (receptors for glutamate, so blocking excitatory activity) Tab, ODT tab, ER tab, chewable tab *antifolate BUT most evidence for safe use in pregnancy (DOC for pregnancy) Partial seizures or generalized seizures Adjunctive for primary generalized tonic-clonic Can worsen myoclonic epilepsy in infants Adverse effects: dizziness, blurred vision, rashes, SJS Dose related: drowsiness, ataxia, headache, insomnia, sedation, nausea, vomiting, dizziness – titrate slowly to minimize Idiosyncratic: rash (titrate to avoid; HLA-B*1502 testing in asian population); will usually occur w/in first 2 mo of therapy, VPA will increase risk of rash FEWER adverse cognitive effects than carbamazepine or topiramate May cause (RARELY) anxiety, agitation, or insomnia (mostly in patients with autism) NO concerns about cognitive impairment Dose: 25mg QD for 2 weeks, 50mg QD for 2 weeks, 100mg QD for 1-2 week, then 200mg (target) Dosing changes: SIGNIFICANT drug interaction with valproic acid (inhibitor so will decrease metabolism of lamotrigine and will increase serum levels of lamtorigine); Lamotrigine every other 25mg every other day etc. so dose will be half **Dose with VPA: 25mg QOD for 2 weeks, 25mg QD for 2 weeks, 50mg QD for 1 week then 100mg (target dose) CBZ is an inducer so SPEEDS UP metabolism, and reduces serum levels **Dose with CBZ: 50mg QD for 2 weeks, 100mg QD for 2 weeks, 200mg QD for 1-2 weeks then 400mg (target) Oral contraceptives will lower lamotrigine levels (increase seizure activity) Usually the problem is when patient starts placebo week (oral contraceptive no longer lowers lamotrigine, so patient experiences more side effects) Can improve depression associated with bipolar disorder Counseling points: Take at the same time everyday (in the morning or at night) Keep calendar to keep up with titration Valproate/Valproic acid/Divalproex with Salt (Depakote) -- INHIBITOR DR tab, sprinkle caps MOA: Inactivation of Na+ channels (somnolence); Low threshold Ca2+ blocker (absence seizures): Increased GABA levels (enhance inhibitory NT) possibly through increasing synthesis and/or decreasing degradation of GABA Dose: 500mg QD then level 5-7 days later Therapeutic range 50-100mg/L** Adverse effects: drowsiness, dizziness, weight gain**, hair loss** (alopecia- will come back as different texture), polycystic ovarian syndrome**,hirsutism, blurred vision, headache, tremor** (propranolol can help), GI effects** BBW: hepatotoxicity** (esp in kids) – hyperammonemia** (drunken-like behavior), pancreatitis, rash, vision loss, osteoporosis; teratogenicity; do not use in child-bearing age women** Monitor: LFT, pregnancy status, CBC platelets (can cause thrombocytopenia**) Take with food or enteric coating to reduce n/v Hepatic enzyme inducers (carbamazepine, phenytoin, rifampin) may reduce levels significantly Estrogen may reduce VPA Efficacy in bipolar disorder and migraines Topiramate (Topamax) “dopamax” “stupimax” *RA MOA: Inactivation of Na+ channels (somnolence): Activates/enhances GABAA receptor currents; inhibits AMPA/Kainate receptors (glutamate receptors) = basically enhancing inhibition and inhibiting excitation Sprinkle capsules, oral solution, ER caps Carbonic anhydrase inhibitor – soda tastes flat; may contribute to efficacy but also contributes to adverse events: metabolic acidosis Partial and primarily generalized tonic-clonic seizures, atonic seizures Primarily excreted unchanged in urine (renal) 60%; hepatic metabolism 40% Adverse effects: Drowsiness, dizziness, anorexia (not want to eat), changes taste**, weight loss**, metabolic acidosis, paresthesia, impaired concentration, schizophreniform disorder (hallucinations and delusions); COGNITIVE IMPAIRMENT** - word finding difficulties, hyperthermia (can’t sweat - overheat), ataxia Idiosyncratic: acute glaucoma, metabolic acidosis, oligohidrosis, paresthesias (tingling in hands or feet w/in a couple weeks of starting), renal calculi, weight loss, liver failure, hyperthermia, heat stroke May worsen depression/anxiety/emotional lability – NOT a mood stabilizer Titrate slowly to minimize cognitive effects and lethargy **Hyperammonemia +/- encephalopathy (don’t know where they are, can’t think clearly) or +/- hypothermia (increased risk when given with VPA) Monitor: kidney stones*** (d/c) and metabolic acidosis Utility in migraines and obesity Interacts with estrogen containing contraceptives, but only above 200mg** Counseling Points: DRINK LOTS OF WATER Zonisamide (Zonergan) – similar to Topamax MOA Inactivation of Na+ channels; high threshold Ca2+ channel blocker Carbonic anhydrase inhibitor Renally excreted Adjunctive for partial seizures Also used in infantile spasms, myoclonic, generalized, absence Dose related AE: dizziness, somnolence, confusion, anorexia, diarrhea, weight loss, irritability Idiosyncratic AE: metabolic acidosis, oligohidrosis, paresthesias, renal calculi, SJS, psychosis, aplastic anemia, agranulocytosis DO NOT give if sulfa allergy CI: kidney stones** Phenytoin (Dilantin) – poor tolerability - *Michaelis Menten MOA: inactivation of Na+ channels Increase in GABA response, decrease in repetitive firing Partial and secondarily generalized tonic-clonic Target range: 10-20 mcg/mL and 1-2 mcg/mL free drug** Loading dose often needed Highly bound to albumin; free level is preferred Low albumin will affect phenytoin level if albumin >4, indicates patient is malnourished and need to calculate corrected phenytoin (normal can actually be toxic if albumin is low) Max infusion rate: 50mg/min in adults Dilute in normal Saline not less than 5mg/mL Phenytoin: absorption is highly dependent on formulation; lipophilic so accumulates in brain, liver, and fat; elimination of phenytoin is dose-dependent (1st order), metabolism is saturable; induces microsomal enzymes DI: Warfarin Adverse Effects: Drowsiness, Involuntary movement of the eyes (nystagmus**), diplopia, Loss of muscle coordination (ataxia**), cognitive dysfunction, peripheral neuropathy Idiosyncratic: Gingival hyperplasia (20% of chronic therapy), anemia, hirsutism**, lymphadenopathy, osteoporosis, hepatitis, lupus-like syndrome Pregnancy risk Stevens-Johnson Syndrome (SJS)/Toxic epidermal necrolysis (TEN) HLA-B*1502 testing Irreversible neurotoxicity associated with acute or chronically high levels** Long term: osteoporosis (induces Vit D) IV: rate-related hypotension and cardiac arrhythmias, Purple Glove Syndrome (IV) – must be administered slowly; VERY alkaline, injection site reactions, phlebitis, and tissue necrosis if extravasated Avoid IM (poor absorption and tissue injury) Fosphenytoin (Cerebyx) is preferred for parenteral use (1mL fosphenytoin = 50mg phenytoin equivalents); can be given at faster rate (150mg phenytoin equivalent) Rate related AE: itching and paresthesias Hepatic metabolism Reduces efficacy of oral contraceptives, need EE >50mcg Carbamazepine (Tegretol) CBZ – INDUCER (speeds up metabolism, drug levels go down) MOA: Inactivation of Na+ channels Tab, chewable tab, extended-release DOC for focal temporal lobe epilepsy; good for partial and secondarily generalized tonic-clonic May make absence or myoclonic seizures worse DOC in trigeminal neuralgia (severe pain) – tic douloureaux Benefit in bipolar disorder – good mood stabilizer Therapeutic range 4-12 mg/L**; titrate to target over 3-4 weeks ER products may be better tolerated (lower peaks) Adverse effects: dizziness, ataxia, rash, nausea/vomiting, hyponatremia, bone marrow suppression, hematologic effects Dose related: Diplopia, drowsiness, nausea, sedation – titrate slowly to minimize Cognitive effects can impair learning Idiosyncratic: hyponatremia** (risk factors: elderly, diuretic, SSRI), leukopenia, partial or complete heart block BBW: agranulocytosis, aplastic anemia, SJS/TEN (HLA-B*1502 testing in asian population)**, hepatotoxicity (very rare but monitor CMP), bone marrow suppression (so monitor CBC)** Long term (bc speeds up metabolism of vitamin D): osteoporosis, and osteopenia Modulates sodium channels and affects white blood cells Monitor: blood count (CBC) for WBC and CMP for sodium levels** and liver function test*** Pregnancy risk Auto-inducer (speeds up own metabolism) – numerous drug interactions; ex. oral contraceptives Induces microsomal enzymes: single dose half-life: 36 hours; continuous therapy: 8-12 hours Case example: given with Cimetidine and Erythromycin – both inhibitors so were increasing CBZ levels; when inhibitors go away, SDC will decrease bc autoinduction effect would increase VPA can increase metabolite of CBZ, CBZ epoxide (which is what gives cognitive side effects) Levels may decrease over the first month after initiation or dosage increase Counseling point: DO NOT store in bathroom, humidity can affect the medication Decreases efficacy of oral contraceptives*** want >50mcg EE Oxcarbazapine (Trileptal) MOA: Inactivation of Na+ channels Initial dose 150mg BID, can titrate up (Don’t monitor serum levels like we do in CBZ) Temporal lobe epilepsy, partial, secondarily generalized seizures May worsen myoclonic and absence Adverse effects: cognitive impairment, rarely SJS and TENS, schizophreniform disorder Dose related: ataxia, diplopia, drowsiness, dizziness, nausea, vomiting Idiosyncratic: hyponatremia** (more common than CBZ), 30% cross reactivity with CBZ* hypersensitivity, rash still a concern, bone marrow suppression (RARE, does not occur like it does in CBZ) HLA-B*1502 testing Asian population Hyponatremia risk factors: elderly, diuretic or SSRI use Long term: osteoporosis Monitoring parameters: sodium (hyponatremia** can occur) NO autoinduction, less DI Drug interaction with estrogen containing OC – MAKE SURE TO COUNSEL (use >50mcg EE) Benefit in bipolar disorder Lacosamide (Vimpat) CV *RA – ST will not ask MOA: Increased number of Na+ channels in the SLOW inactivation state Tab, injection, oral solution (can be expensive); dose BID Oral and IV forms (equal dose) Partial-onset seizures (37%); adjunctive for tonic-clonic seizures (60-93%) – not a first line agent Adverse effects: headache, fatigue What adverse effect is NOT present that is with fast inactivation state drugs? Somnolence Dose related: dizziness, ataxia, vomiting, diplopia, nausea, vertigo, blurred vision – titrate slowly to minimize Idiosyncratic: neutropenia, anemia, palpitations, depressed mood DRESS – abnormal eosinophil rash Slowed cardiac conduction, monitor PR interval** Low DDI Drugs that inhibit low threshold (T-type) voltage-gated Ca2+ channels (useful in treating absence seizures) Overactive Low t-type in thalamus (sensory relay) in absence seizures; so they are activated more readily with calcium influx, causes thalamic neurons to fire and causes seizure activity in the cortex; low threshold bc activated by low/small depolarizations – hypersensitive in patients who have absence seizures ethosuximide, zonisamide, valproate, lamotrigine Ethosuximide (Zarontin) MOA: Low threshold Ca2+ channel inhibitor DOC: absence seizures only Pregnancy risk Adverse effects: gastric distress (nausea, pain), fatigue, rare but serious agranulocytosis and aplastic anemia Dose related: ataxia, sedation, N/V, HA, hiccups, behavioral changes, psychosis Divide dose to minimize n/v and sedation; usually resolves with continued use, but temporary dose reduction may be needed Idiosyncratic: hepatotoxicity, neutropenia, rash Hepatic metabolism Drugs that inhibit high voltage-activated Ca2+ channels High threshold voltage gated calcium channels get activated by huge changes in membrane potential (action potential); blocking this will block release of excitatory NT like glutamate Levetiracetam, gabapentin, pregabalin (analogs of GABA, but don’t act directly on GABA receptors), lamotrigine, carbamazepine, oxcarbazepine, phenobarbital, topiramate, zonisamide, phenytoin?, felbamate Levetiracetam (Keppra) “divorce-drug” *RA Oral (tab, ER tab, soln, susp) and IV forms (for status epilepticus) MOA: Targets a synaptic vesicle protein (SV2A) (decrease release of excitatory NT) Dose: 500mg BID for 2 weeks, 1000mg BID for 2 weeks then target dose: 1500mg BID Partial, primary generalized tonic-clonic, myoclonic, Lennox-Gastaut, absence Adverse effects: respiratory tract inflammation (stuffy nose, etc.) Dose related: drowsiness, weakness, dizziness, vertigo, flu-like symptoms, headache, behavioral abnormalities -aggression, hostility, irritability, hallucinations, psychosis Low incidence of cognitive effects Idiosyncratic: depression LEAST risk for drug interactions, well tolerated Gabapentin (Neurontin) *RA MOA: High threshold Ca2+ channel blocker – may decrease release of glutamate Start at low doses, titrate slowly Adjunctive therapy for partial and secondarily generalized seizures; can be used as monotherapy Can exacerbate myoclonic seizures Adverse effects Dose related (CNS): drowsiness, sedation, ataxia, fatigue, nystagmus, blurred vision, confusion Idiosyncratic: peripheral edema, weight gain, movement disorder, behavioral changes Used for chronic neuropathic pain, anxiety, and migraine DOES NOT induce or inhibit hepatic enzymes Few DDI Pregabalin (Lyrica) CV *RA MOA: High threshold Ca2+ channel blocker – may decrease release of glutamate Start at low doses, titrate slowly Adjunct for partial seizures; not useful for absence or myoclonic Adverse effects: weight gain, drowsiness, dizziness (dose-dependent), dry mouth, ataxia, blurred vision, confusion Idiosyncratic: peripheral edema, weight gain, myoclonus PR prolongation, angioedema, myopathy, decreased platelet count Used for chronic neuropathic pain, pain, generalized anxiety Few DDI Taper over 1 week (actually longer) when discontinuing Drugs that enhance GABA action Diazepam, clobazam, phenobarbital, vigabatrin, valproate, tiagabine, felbamate, topiramate, zonisamide, lamotrigine, cannabidiol (CBD)?, stiripentol, ganaxolone Benzodiazepines (BZD): diazepam (Valium) and clobazam (Onfi) MOA: Increase frequency of GABAA receptor channel opening, increasing amplitude of IPSP (GABAA allosteric modulators - positive) Pregnancy risk Adverse effects: Sedation, tolerance, dependence, withdrawal DO NOT abruptly withdraw – will cause seizures Diastat AcuDial single-dose syringe in 10mg or 20mg – pharmacist must lock the syringe to prescribed dose before dispensing Clonazepam (Klonopin) MOA: Enhance GABA activity Used for myoclonic, atonic, and absence seizures Not as effective as ethosuximide or valproic acid Typically an add-on Hepatic metabolism Dose related AE: ataxia, memory impairment, sedation, slowed thinking NO idiosyncratic AE Phenobarbital (Luminal) – poor tolerability MOA: Increase duration of GABAA receptor channel opening, increasing duration of IPSP; AMPA antagonist (decrease glutamate) Adverse Events Dose related: ataxia, diplopia, somnolence, dizziness, sedation, cognitive dysfunction Idiosyncratic: rash, agranulocytosis, thrombocytopenia, anemia Pregnancy risk Hepatic metabolism Primidone (Mysoline) is metabolized into phenobarbital; poor tolerability Depresses cerebral cortex, hepatic metabolism, Also used for essential tremor Adverse events – dose related: diplopia, dizziness, sedation, cognitive dysfunction Idiosyncratic: rash agranulocytosis, thrombocytopenia, anemia Cannabidiol (Epidiolex) CV – not considered to be psychoactive MOA: GPR55 antagonist; GPR55 normally binds to LPI to increase excitation and decrease inhibition not a good thing if we are having seizures; CBD blocks binding of LPI to GPR55; highly expressed in hippocampus (extension of temporal cortex) found pre-synaptically (bind GluR which enhances excitation) and post synaptically (decrease activity of GABAA RECEPTORS so reduces inhibition) 32,500 cost per year Midazolam (Nayzilam) Dose: 5mg (one spray) into one nostril (>12 yo). Repeat if needed in other nostril in ten minutes if not excessively sedated or having breathing difficulties. Do not use for more than one episode every 3 days or more than 5 episodes per month Metabolism of AEDs Many have major effects on CYP enzymes (inducers and inhibitors) Also may induce or inhibit phase 2 enzymes- which ones in particular? UGT What do those enzymes do? makes molecules more soluble to be eliminated renally CYP3A4: Carbamazepine, Phenobarbital, Phenytoin, Primidone decreases efficacy of OC Teratogenicity of Anti-seizure drugs Valproate (BBW), 1st gens, 2nd gens-choice is lamotrigine (but remember it is an anti-folate so recommend folic acid supplement) Supplement folate to reduce neural tube defects Key points: Inducers: Carbamazepine, Phenobarbital, Phenytoin, (Primidone) Use zonisamide, topiramate, or levetiracetam cautiously in mood disorders If patient does not response to a medication, might also fail with medications with similar MOA Renally adjust: gabapentin, lacosamide, levetiracetam, pregabalin, topiramate Phenytoin in uremic patients or patients with low albumin: free phenytoin is best Complications Dose-related – occur mainly when the dose is escalated for greater control Sedation, ataxia (walking drunk), diplopia (double vision) Idiosyncratic – not dose or concentration related and will always result in stopping the drug Rash, hepatotoxicity, and hematologic toxicities Thought to be immunologic – cross reactivity Chronic Adverse Reactions Peripheral neuropathy Cerebellar atrophy Weight gain Osteoporosis Comorbid Disease States -- Think about drug interactions; Does the anticonvulsant drug cause the problem (headaches, depression)? Can you kill two birds with one stone? Hepatic Disease: Avoid valproic acid Kidney Stones: Avoid topiramate or zonisamide Hyponatremia: Avoid carbamazepine or oxcarbazepine HIV, organ-transplant, cancer: Avoid enzyme inducing drugs Partial complete heart block: Avoid carbamazepine Blood dyscrasias: Avoid carbamazepine Thrombocytopenia: Avoid Valproic acid Weight gain: caused by gabapentin, pregabalin, valproic acid Weight loss: Felbamate, topiramate, zonisamide Switching drugs Taper up and down at the same time Be aware of new and old drug interactions when starting or stopping a drug Stopping therapy – d/c least effective or most AE first No seizures for 2-5 years Normal neuro exam Normal IQ Single type of partial or generalized seizure Normal EEG with treatment Slow (at least 6 months) discontinuation should be encouraged 61% chance of remaining seizure free Drug Interactions Absorption: tube feedings and antacids Metabolism: CYP450 Protein binding Special Populations Pregnancy – inherent risk of increased rate of birth defects even without anticonvulsants Reduced fertility PCOS Lower IQ scores in children whose mothers took VPA Teratogenicity: neural tube defects with VPA and CBZ (spina bifida) AED + hormonal contraceptives: topiramate, carbamazepine, oxcarbazepine, phenobarbital, phenytoin Need higher EE: >50mcg or other forms of birth control AED during Pregnancy 1-4mg of folic acid per day** (normal is 0.4mg) If seizure free for 9 months prior to pregnancy, 84-92% remain seizure free during pregnancy Use monotherapy when possible; lamotrigine or levetiracetam have lowest risk Use lowest effective dose BEFORE PREGNANCY Stay on effective medication Monitor serum concentrations at baseline then EVERY TRIMESTER (metabolism and Vd increases); then reduce dose at delivery (metabolism decreases) Vit K in 8th month to those taking inducers CBZ, DPH, PB, and Lamotrigine (they speed up metabolism of VitK); then Vit K to baby Monitor postpartum Avoid VPA Children Developmental changes occur rapidly Control seizures ASAP Choose drugs less likely to interfere with cognitive function and development Metabolic rates are higher Doses are higher on mg/kg basis Drug levels are used more extensively Epilepsy decreases fertility, increases PCOS (which decreases fertility) Evaluation of therapeutic outcomes: Clinical response Diary: severity and frequency of seizures Question patients and family regularly about seizures Monitor long-term Comorbid conditions DI QOL: including anxiety and depression Adherence Factors favoring withdrawal: Seizure free for 2-4 years Complete seizure control within 1 year of onset Onset after age 2 but before 35 years of age Normal neurologic exam and EEG Factors with poor prognosis of withdrawal History of high frequency of seizures Repeated episodes of status epilepticus Combination of seizure types Abnormal mental functioning TBL Notes: Need 2 unprovoked seizures for diagnosis; don’t usually treat after first seizure Counseling points: Restriction after a seizure: Can’t drive 6 months after a seizure Avoid heights Avoid using large machinery Some things that can mimic epilepsy: syncope (fainting), dehydration from alcohol, alcohol decreases seizure threshold, alcohol withdrawal, sleep deprivation can induce seizures (have a good sleep schedule!) CBC can tell us about an infection (meningitis, encephalitis) CMP vs BMP: looks at electrolytes, glucose BMP does not include liver function test Other tests to order: EEG (other than witness describing the event, this is the only definitive way to get diagnosis, but in between seizures, this can look very normal), UDS (looking mainly for stimulants), ask about BZDs (alprazolam, clonazepam), pregnancy test Factors that increase risk of reoccurrence Abnormal EEG Neurologic event in the past (ex. stroke) Or evidence of partial onset Before adding a medication: Check serum concentration levels Ask about adherence (What is the average number of doses you miss in a week?) Side effect (if none, can increase dose) – goal is monotherapy! Status Epilepticus – neurologic emergency, if not stopped, can cause brain damage or death – seizure that lasts more than 5 minutes, up to 30 minutes = permanent damage Midazolam nasal spray or diazepam rectally if seizure lasts longer than 5 minutes All patients will get thiamine 100mg IV,pyridoxine for babies; thiamine is a cofactor in dextrose metabolism or Wernicke’s Encephalopathy BZD to stop seizures: Lorazepam > Diazepam; Diazepam is very lipophilic, will go immediately to brain but redistributes out quickly; quick onset, but also short duration of action (half-life in CNS: 30 minutes). Lorazepam will not re-distribute so will prevent recurrent seizures Another option is midazolam continuous infusion. To stop recurrence: Phenytoin or Fosphenytoin IV, VPA, Keppra IV Phenytoin HAS to be diluted in normal saline (base is propylene glycol) Have to have cardiac monitoring bc cardiac arrhythmias Limited in how fast you can administer: 50mg/min (slow) Very alkaline (lots of pain and burning) – phlebitis and necrosis and purple glove syndrome! Fosphenytoin is water soluble, no rate limiting effect; dose equivalent WAIT 2 HOURS before checking levels (checking phenytoin levels) AE: warmth in groin region 2nd line: phenobarb or lacosamide Refractory (>2 hrs) – continuous EEG, check hydration, cerebral perfusion, After 120 minutes = coma; midazolam nonstop and propofol Some things that can mimic epilepsy: syncope (fainting), dehydration from alcohol, alcohol decreases seizure threshold, alcohol withdrawal, sleep deprivation can induce seizures (have a good sleep schedule!) CBC can tell us about an infection (meningitis, encephalitis) CMP vs BMP: looks at electrolytes, glucose BMP does not include liver function test Other tests to order: EEG (other than witness describing the event, this is the only definitive way to get diagnosis, but in between seizures, this can look very normal), UDS (looking mainly for stimulants), ask about BZDs (alprazolam, clonazepam), pregnancy test Factors that increase risk of reoccurrence Abnormal EEG Neurologic event in the past (ex. stroke) Or evidence of partial onset Before adding a medication: Check serum concentration levels Ask about adherence (What is the average number of doses you miss in a week?) Side effect (if none, can increase dose) – goal is monotherapy! Status Epilepticus – neurologic emergency, if not stopped, can cause brain damage or death – seizure that lasts more than 5 minutes, up to 30 minutes = permanent damage Midazolam nasal spray or diazepam rectally if seizure lasts longer than 5 minutes All patients will get thiamine 100mg IV,pyridoxine for babies; thiamine is a cofactor in dextrose metabolism or Wernicke’s Encephalopathy BZD to stop seizures: Lorazepam > Diazepam; Diazepam is very lipophilic, will go immediately to brain but redistributes out quickly; quick onset, but also short duration of action (half-life in CNS: 30 minutes). Lorazepam will not re-distribute so will prevent recurrent seizures Another option is midazolam continuous infusion. To stop recurrence: Phenytoin or Fosphenytoin IV, VPA, Keppra IV Phenytoin HAS to be diluted in normal saline (base is propylene glycol) Have to have cardiac monitoring bc cardiac arrhythmias Limited in how fast you can administer: 50mg/min (slow) Very alkaline (lots of pain and burning) – phlebitis and necrosis and purple glove syndrome! Fosphenytoin is water soluble, no rate limiting effect; dose equivalent WAIT 2 HOURS before checking levels (checking phenytoin levels) AE: warmth in groin region 2nd line: phenobarb or lacosamide Refractory (>2 hrs) – continuous EEG, check hydration, cerebral perfusion, After 120 minutes = coma; midazolam nonstop and propofol

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