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Mitzi Payne, MD Pediatric Neurology Hoops Family Childrens Hospital at Cabell Huntington Hospital Marshall University Department of Neuroscience

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Fewest possible seizures Limit side effects Monotherapy Minimal dosing schedules (once, twice, three times a day) Limit need for blood tests 2

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70% of patients are seizure-free with one medication With careful monitoring and adjustment 5% to 10% of patients are seizure free with two or more drugs 20% of patients STILL HAVE FREQUENT SEIZURES 3

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Use the right drug for the correct seizure type Use one drug and increase the dose until a therapeutic effect is achieved or side effects occur May need to check blood levels If needed, a second drug is added. 4

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If one medication fails, use two medications Add a third medication IF necessary Balance frequency of seizures with side effects of medications Dose Effect of seizures on daily life Side effects patients may experience 5

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For a medication to be effective, it must be taken as prescribed! Non-compliance is a common factor Patients must be involved in decisions of medications This helps compliance 6

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Dont understand why they are taking it Poor memory Poor understanding of how to take the medication SIDE EFFECTS IMPRACTICAL dose schedules Poor tasting medications 7

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Frequent seizures, need to adjust meds Recurrence of seizures, need to adjust meds Side effects ensure patient is not toxic and abrupt or inpatient weaning needs to occur Assessment of compliance Document a good level for that patient Changes to medication regimens, concern for medication interactions (AEDs, abx, etc) 8

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Blood concentrations are guide only Doctor / Mom / Patient: Dont worry, the level is in the NORMAL RANGE, says the physician / nurse / receptionist. 9

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TROUGH levels need to be drawn. PEAK levels are not a good consistent assessment. Mom, the level we drew today in the ER was high. So, even though your son had a seizure at school today, your neurologist has dosed him too high and you need to lower his dose. 10

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Never look at the blood level in isolation In the pediatric population (and sometimes adult), the dosage is based on weight Doses will change if multiple seizure medications are used and thus interact with each other A PERFECT blood level for a particular patient: Minimal side effects Low seizure frequency 11

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A neuron fires, leads to an action potential. This action potential spreads and involves the brain by excitatory neurotransmitters (glutamate) Imbalance of excitatory and inhibitory signals more excitatory than inhibitory 12

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A neuron fires, leads to an action potential. Stop action potential from occuring Sodium channel blocker or modulator Potassium channel opener This action potential spreads and involves the brain by excitatory neurotransmitters (glutamate) Stop this transmission or Encourage inhibitory neurotransmitters (GABA) GABA uptake inhibitor GABA mimics 13

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Target for many medications Sodium channels give way to the action potential in excitatory neurons 14 Phenytoin Carbamazepine Oxcarbazepine Lamotrigine

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End neuronal excitability, but bring neuron back to its normal resting potential Involved in length of action potential 15

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Inhibitory neurotransmitters GABA A post -synaptic; 7 classes Dependent upon chloride and bicarbonate ions GABA B pre- and post -synaptic 16

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Barbiturates phenobarbital Benzodiazepines Clobazam, clonazepam, diazapam Tiagabine Vigabatrin 17

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Main excitatory transmitter Mainly intracellular Three receptor types: NMDA Associated with sodium and calcium ions Magnesium ions block Other messengers act at NMDA site AMPA and kainate receptors metabotropic 18

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Valproic acid Gabapentin Piracetam Levetiracetam 19

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Valproate, vigabatrin, tiagabine increase GABA by inhibiting reuptake (2) and preventing breakdown within the cell (3) Benzodiazepines bind to GABA receptors (4) Phenobarbital opens chloride channels (4) Topiramate blocks sodium channels and is a GABA agonist at some sites (4) 20

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Gabapentin, has similar structure to GABA Phenytoin,carbamazepine,oxcarbazepine, lamotrigine, act on sodium channels Ethosuximide, reduces calcium currents Levetiracetam, has neuroprotective effect Topiramate, acetazolamide, are carbonic anhydrase inhibitors Zonisamide has weak carbonic anhydrase activity 22

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Seizure typeDrug of choiceAlternatives Simple & complex partial Carbamazepine Phenytoin Valproate Lamotrigine Gabapentin Levetiracetam Topiramate Tiagabine Oxcarbazepine Phenobarbital 23

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Seizure typeDrug of choiceAlternatives Generalized tonic clonic Carbamazepine Phenytoin Valproate Lamotrigine Topiramate Phenobarbital AbsenceEthosuximide Valproate Lamotrigine Clonazepam Atypical absence Atonic, myoclonic ValproateClonazepam 24

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Dose Start 10-20 mg/kg/day Therapeutic plasma concentration 4 to 12 micrograms per ml Poor correlation between dose and plasma level in children Widely distributed in tissues, found in placenta and breast milk (40% plasma level) t MAX 4 to 8 hours Indicated for All forms of seizures except absence and myoclonic seizures 25

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Common side effects Headache, drowsiness, dizziness, ataxia, double vision, Serious effects Osteomalacea, folate deficency, peripheral neuropathy, water retention, hyponatraemia, rash, blood dyscrasias-leucopaenia Comments Many drug interactions as enzyme inducer Can make myoclonus worse or appear to cause it 26

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Dose Start 20-30 mg/kg/day Therapeutic plasma concentration Indicated for Partial seizures with or without secondarily generalised tonic clonic seizures Common side effects As for carbamazepine less severe Comments Fewer drug interactions than carbamazepine 27

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Dose 0.5 to 8 mg a day Therapeutic plasma concentration Indicated for Refractory absence and myoclonic seizures Sleep Irritability 28

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Common side effects Sedation, ataxia, behaviour problems, hyperactivity Comments Half life 18 to 50 hours Tolerance develops in 30% 29

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Dose 10 to 60mg a day Indicated for Refractory seizures Cluster seizures Common side effects As for clonazepam 30

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Dose Start 10-15 mg/kg/day Therapeutic plasma concentration 300 -700 micromoles/L 50 -100 micrograms/L Indicated for Simple absence seizures NOT convulsive seizures 31

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Common side effects Gastro intestinal upset, nausea, drowsiness, headache, behavioural changes, hiccups, skin rashes Comments Half life 50 to 60 hours in adults 30 to 40 hours in children 32

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Dose Start 5 mg/kg/day Therapeutic plasma concentration Not clinically relevant Indicated for All forms of seizures 33

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Common side effects Dizziness, ataxia, double vision, nausea, somnolence Rash (worse in children) less if slow escalation Comments Complex interaction with valproate very slow escalation needed Indicated for partial seizures and secondarily generalised tonic clonic seizures Half life 25 hours shorter with enzyme inducers Excreted in breast milk Reasonably safe in overdose (10x) 34

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Dose Start 20-30 mg/kg/day Therapeutic plasma concentration Not relevant Indicated for Partial seizures, Generalized seizures Common side effects Irritability, nausea, drowsiness, rash, Comments No drug interactions described 35

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Dose Start 3-4 mg/kg/day Therapeutic plasma concentration 15 to 40 micrograms/ml Indicated for All forms of seizures except absence seizures 36

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Common side effects Sedation (tolerance develops), headache, hyperkinesia (old & young) slurred speech, skin reactions, cognitive impairment Comments Dependency; needs very, very slow withdrawal Interactions - increases valproate effect; -enzyme inducer, reduces effects of many other drugs - Half life 2 to 7 days - Can cause folate deficiency - Concern for developmental delays! 37

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Dose Start 15 mg/kg/day Therapeutic plasma concentration 50 to 100 micrograms/ml Indicated for All forms of epilepsy 38

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Common side effects Nausea, gastrointestinal irritation, drowsiness, ataxia, weight gain & also anorexia, alopecia. Rare but serious impaired liver function thrombocytopenia Comments Half life 10 to 20 hours, reduced with polytherapy GI upset reduced by enteric coating Interacts with lamotrigine and phenobarbital 39

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Dose Start 5 mg/kg/day Therapeutic plasma concentration Not clinically relevant Indicated for Adjunctive treatment for refractory partial seizures Common side effects Nausea, abdominal pain, anorexia, cog. impairment, mood disorders (can be aggressive in LD) 40

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Comments Watch for weight loss and depressive psychosis Ensure adequate hydration; increased risk of kidney stones. Avoid carbonic anhydrase inhibitors e.g. acetazolamide Half life 18 to 30 hours reduced where given with enzyme inducing drugs 41

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Rectal valium Syringes: 2.5 mg, 10 mg, 20 mg Locked to prescribed dose by pharmacist Package of two syringes

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USUALLY prescribed to be given once a seizure has lasted for 4-5 minutes Exceptions: Prolonged seizures Depending on patient, perhaps 2-3 seizures within a certain period of time

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Ages 2-5 years: 0.5 mg/kg Ages 6-11 years: 0.3 mg/kg Age 12 + years: 0.2 mg/kg

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Often used for seizure clusters Dosing 0.025-0.1 mg/kg May be given orally in between seizures