The document summarizes the treatment of status epilepticus with anti-epileptic drugs. It provides guidelines for first, second, and third line treatment options including benzodiazepines, phenytoin, valproate, levetiracetam, phenobarbital, and anesthetics if needed. It also reviews dosing, mechanisms of action, pharmacokinetics, side effects, and drug-drug interactions of common anti-epileptic drugs used such as phenytoin, valproate, levetiracetam, and phenobarbital. In particular, it notes the interaction between phenytoin and valproate given phenytoin induces liver enzymes while val

1. IV Anti-Epileptic Drug Overview
in Status Epilepticus
Summarized by Yung-Tsai Chu
2019/2

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Drug-Drug Interaction
Focus on Phenytoin and Valproate
(not exhaustive)

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. Drugs Commonly Affected (Apart from AED)
• Cardiovascular agent: Amiodarone, CCB
• Anticoagulants: Warfarin, NOAC
• Antibiotics
• Clopidogrel
• Antidepressant
• Antipsychotic

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. 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. 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.