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Intravenous anti epileptic drug review

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Overview of intravenous anti-epileptic drugs, including benzodiazepine(BZD), phenytoin, valproate, levetiracetam, phenobarbital, lacosamide and general anesthetics.

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Intravenous anti epileptic drug review

  1. 1. IV Anti-Epileptic Drug Overview in Status Epilepticus Summarized by Yung-Tsai Chu 2019/2
  2. 2. Treatment Algorithm 1st BZD 2nd AED 3rd Anesthetics Lorazepam Midazolam (IM) Diazepam Phenobarbital Phenytoin Levetiracetam Valproate Phenobarbital Lacosamide? Midazolam Propofol Pentobarbital Reference: • Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol. 2015 Jun;14(6):615-24. • Tracy Glauser et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016 Jan-Feb; 16(1): 48–61. Stabilization Vital signs Monitor (if hypoglycemia) 100mg Thiamine 50ml D10W
  3. 3. Benzodiazepine • Lorazepam 0.1mg/kg(max = 4mg) IV, may repeat once • Midazolam 10mg IM, once • Alternatives: IV diazepam 0.15-0.2mg/kg(max 10mg), rectal diazepam • IV Phenobarbital 15mg/kg, once • The rate of respiratory depression in SE treated with BZD is lower than in SE treated with placebo • Respiratory problems are an important consequence of SE • No substantial difference exists between BZD and phenobarbital in the occurrence of cardiorespiratory adverse events Tracy Glauser et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016 Jan-Feb; 16(1): 48–61.
  4. 4. General Comparison Loading dose Maintenance dose Therapeutic range(mg/L) Mechanism Metabolism P450 enzyme Protein binding Side effect Interaction Other Phenytoin 15-20mg/kg 100mg Q8H 10~20 Na(fast) Liver, Non-linear Inducer High Arrhythmia, hypotension, extravasation Most experience Valproate 20-40mg/kg 10-15 mg/kg/day (Q6-8H) 50~100 Multiple, Ca, Na, GABA, NMDA? Liver Inhibitor High NH3, Thrombocytopenia, pancreatitis Better efficacy? Levetiracetam 20-60mg/kg 10-15 mg/kg Q12H N/A SVA2, GABA, Ca? Renal nil Behavior issue, psychosis minimal Slightly worse efficacy? Phenobarbital 15-20mg/kg 50-100 mg Q12H 15~40 GABA, glu? Liver Inducer Cardio-respiratory inhibition, sedation Lacosamide 200-400mg 200-300 mg Q12H N/A Na(slow) Renal nil Bradycardia, AV block minimal Limited evidence,
  5. 5. AED • Efficacy • Phenytoin: most experience • Valproate: might be better than phenytoin? • Levetiracetam: Less effective at dose of 20mg/kg • Alternatives • Phenobarbital • Lacosamide: newer AED, introduced in 2008, less evidence, not approved by FDA Reference: Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol. 2015 Jun;14(6):615-24.
  6. 6. Phenytoin Dosing and Administration Mechanism Pharmacokinetic Side Effect Loading dose: 15-20mg/kg, 50mg/min Maintenance: 100mg Q8H Target range: 10-20 mg/L Solvent: basic solution  risk of extravasation Inhibit fast-activating Na channel Risk of arrhythmia, hypotension BP, EKG monitor P450 enzyme inducer Non-linear kinetics (metabolism is saturable) High protein binding (Compete with VPA)
  7. 7. Valproate Dosing and Administration Mechanism Pharmacokinetic Side Effect Loading dose: 20-40mg/kg Maintenance: (different versions…) 10-15mg/kg/day(Q6-8H) Target range: 50-100mg/L in normal setting, up to 175 in RSE Inhibit T-type Ca, Na channel, GABA potentiation, NMDA antagonist? Liver toxicity, Hyperammonemia, mitochondria dysfunction pancreatitis, thrombocytopenia Enzyme-inhibitor High protein binding (Compete with phenytoin)
  8. 8. Levetiracetam Dosing and Administration Mechanism Pharmacokinetic Side Effect Loading dose: up to 60mg/kg (1000-3000mg, max = 4500mg) Maintenance: 10-15mg/kg Q12H (500-1500mg) Target range: could not be measured in clinical setting Inhibit synaptic vesicle membrane protein SV2A, HVA(high voltage activated Ca channel, GABA potentiation Behavior issue, Psychosis Renal Excretion Minimal drug-drug interaction ***Some studies reported it is less effective than phenytoin and valproate at dose of 20mg/kg
  9. 9. Phenobarbital Dosing and Administration Mechanism Pharmacokinetic Side Effect Loading dose: 15-20mg/kg Maintenance dose: 50-100mg Q12H Target range: 15-40 mg/L GABA-A receptor Inhibit block HVA Ca channels? inhibit glutamate receptors? Cardiopulmonary depression Strong sedation Metabolized in the liver Long half-life (80-100 hours) P450 Enzyme inducer
  10. 10. Lacosamide Dosing and Administration Mechanism Pharmacokinetic Side Effect Dose: 200-400 mg IV loading Maintenance: 200-300 mg Q12H Inhibit slow Na channel 1st AV block, Bradycardia  EKG monitor Renal Excretion Minimal drug-drug interaction Not approved by FDA in SE, limited evidence May be used as adjunctive therapy
  11. 11. General Anesthetics • Midazolam • Loading: 0.2 mg/kg at 4 mg/min bolus • then infusion of 0.2-0.6 mg/kg/h • Propofol • load 1-2 mg/kg • then infusion 2–5 mg/kg/h • Pentobarbital • load 5 mg/kg • infusion 1–5 mg/kg/h Reference: Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol. 2015 Jun;14(6):615-24.
  12. 12. Drug-Drug Interaction Focus on Phenytoin and Valproate (not exhaustive)
  13. 13. General Consideration • Phenytoin, Phenobarbital (also Carbamazepine) • Enzyme inducer • May decrease serum level of other drugs • Valproate • Enzyme inhibitor • May increase serum level of other drugs
  14. 14. Drugs Commonly Affected (Apart from AED) • Cardiovascular agent: Amiodarone, CCB • Anticoagulants: Warfarin, NOAC • Antibiotics • Clopidogrel • Antidepressant • Antipsychotic
  15. 15. Phenytoin • ↓ Lamotrigine, oxcarbazepine, pregabalin, topiramate, zonisamide, valproate • ↓ Amiodarone, diltiazem, verapamil, NOAC, antidepressants and antipsychotics • ↓ Doxycycline, metronidazole • ↓ Fentanyl • ↓ Immunosuppressant (cyclosporine, tacrolimus, corticosteroids) • Clopidogrel, Diltiazem, Amiodarone, Fluoxetine, sertraline, trazodone increase phenytoin level Farrokh, S., Tahsili-Fahadan, P., Ritzl, E. K., Lewin, J. J., & Mirski, M. A. (2018). Antiepileptic drugs in critically ill patients. Critical care (London, England), 22(1), 153.
  16. 16. Valproate • ↑ Phenytoin, carbamazepine, ethosuximide, lamotrigine, phenobarbital • ↑ Amitriptyline, nortriptyline, paroxetine • ↑ Nimodipine, warfarin • Carbapenem, methotrexate decrease serum level of valproate Farrokh, S., Tahsili-Fahadan, P., Ritzl, E. K., Lewin, J. J., & Mirski, M. A. (2018). Antiepileptic drugs in critically ill patients. Critical care (London, England), 22(1), 153.
  17. 17. Reference • Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol. 2015 Jun;14(6):615-24. • Tracy Glauser et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016 Jan-Feb; 16(1): 48–61. • Farrokh, S., Tahsili-Fahadan, P., Ritzl, E. K., Lewin, J. J., & Mirski, M. A. (2018). Antiepileptic drugs in critically ill patients. Critical care (London, England), 22(1), 153. • Abou-Khalil BW. Antiepileptic Drugs. Continuum (Minneap Minn). 2016 Feb;22(1 Epilepsy):132-56.
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    Nov. 17, 2020
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    Aug. 16, 2019

Overview of intravenous anti-epileptic drugs, including benzodiazepine(BZD), phenytoin, valproate, levetiracetam, phenobarbital, lacosamide and general anesthetics.

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