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7 Intravenous Secondary Anticonvulsants for Status Epilepticus - #MEDSHED

Updated: Aug 17, 2023

It seems that our IV secondary antiepileptics are as good as a coin flip for seizure termination. Let's talk seven; four "proven" and three additional options -

 

The 2016 American Epilepsy Society Guidelines recommends intravenous (IV) lorazepam and intramuscular (IM) midazolam) as first-line therapy. Underdosed benzodiazepines are a whole discussion for another day. As new anticonvulsants become available, IV administration has been investigated.


The ESETT trial showed that levetiracetem, fosphenytoin, and valproic acid have a similiar safety profile and seizure termination efficacy. Vimpat (lacosamide) and Briviact (brivaracetem) are fairly new to most. Patients with complex epilepy past medical histories may need different mechanisms to terminate seizures. Here are 7 IV secondary antiepileptics for status epilepticus. (no particular order)


Antiepileptic Drug (AED) #1 - Levetiracetem


Mechanism of action

  • Inhibits Synaptic Vesicle Protein 2A, decreasing vesicular priming and neurotransmission

Dosing

  • 60 mg/kg IV (max 4500 mg)

Adverse Drug Reactions (>5% compared to placebo)

  • Somnolence

  • Asthenia

  • Infection

  • Dizziness

Warnings and Precautions

  • Psychiatric reactions

  • Somnolence, fatigue

  • Dermatologic reactions

  • Withdrawal seizures

Insight

  • Without concerns for hepatic impairment/drug-drug interactions, levetiracetem can be given in most patients. May be given IV push. Note vials are 100 mg/mL, 5 mLs each.


Mechanism of action

  • Modulation of voltage-dependent Na/Ca2+ channels of neurons

  • Inhibition of Ca flux across neuronal membranes

Dosing

  • 20 mg/kg phenytoin equivalents (PE) IV (max 1500 mg)

Adverse Drug Reactions

  • Nystagmus

  • Dizziness

  • Hypotension

  • Pruritis

Warnings and Precautions

  • Withdrawal seizures

  • Cardiovascular depression

  • Rash

  • Hepatic injury

  • Hematologic disorders

  • Fetal risk

Contraindicated

  • Phenytoin/fosphenytoin component hypersensitivity

  • Sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome

Insight

  • Phenytoin is a class IB antiarrythmic. The medication has several concerning adverse effects associated with it, especially with rapid IV fosphenytoin infusions. Not my preferred initial agent. Tend to only reach if patient is on it and suspicious for non-adherence.


Mechanism of action

  • Modulation of voltage-dependent Na/Ca2+ channels of neurons

  • Promotes elevations of GABA brain concentrations

Dosing

  • 40 mg/kg IV (max 3000 mg)

Adverse Drug Reactions(>5%): abdominal pain, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness,

nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss (straight from the packaage insert)


Warnings and Precautions

  • Withdrawal seizures

  • Hepatotoxicity

  • Pancreatitis

  • Fetal risk

  • Mood disturbances

  • Hematologic disorders

  • Hyperammonemia

  • Severe skin reactions

Contraindicated

  • Hepatic dysfunction

  • Mitochondrial disorders

  • Suspected POLG-related disorder

  • Known hypersensitivity

  • Urea cycle disorders

Insight

  • Limited by adverse drug reactions. Commonly a part of patient home regimens for mood. May be preferred in patients with behavioral health history.

AED #4 - Lacosamide


Mechanism of action

  • Enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing

Dosing

  • 200 - 600 mg IV push

  • Comes in 200 mg/20 mL vial

Adverse Drug Reactions(>10%)

  • Diplopia, headache, dizziness, nausea

Warnings and Precautions

  • Mood disturbances

  • Cardiac conduction abnormalities/history

  • Withdrawal seizure

Contraindicated

  • Known hypersensitivity

  • No other listed per package insert

Insight

  • Lacosamide does show promise for status epilepticus, but needs more solid evidence. It is unfortuanate that the ESETT trial didn't include lacosamide. Off-label use of lacosamide for status epilepticus puts termination rates around 50%. Prolonged PR intervals warrants concern in those with a cardiac history,.


AED #5 - Ketamine


Mechanism of action

  • Antagonism of N-methyl-D-aspartate in central nervous system

Dosing

  • 1 - 4 mg/kg IV push

Adverse Drug Reactions

  • Associated with hypertension and tachycardia, may cause bradycardia and hypotension

  • Emergence reactions (>12%) - treat with benzodiazepines

  • Hypersalivation

  • Nausea/vomiting

  • Tonic movements

Warnings and Precautions

  • Cardiovascular instability

  • May induce apnea and laryngeal-spasm

  • Intraocular pressures

Contraindicated

  • Known hypersensitivity

Insight

  • The use specifically in status epilepticus on as secondary IV anticonvulsant is not common. More evidence supports use in refractory and super refractory status epilepticus, in addition to a continuous infusion. Glutamate reduction may be beneficial as an adjunct therapy in certain patients.



Mechanism of action

  • Inhibits Synaptic Vesicle Protein 2A, decreasing vesicular priming and neurotransmission

Dosing

  • 200 mg (50 - 400 mg) IV over 15 minutes

Adverse Drug Reactions(>5%)

  • Somnolence/sedation, dizziness, fatigue, and nausea/vomiting

Warnings and Precautions

  • Suicidal bevhavior

  • Psychiatric disturbance

  • Hypersensitivity, including bronchospasm and angioedema

  • Withdrawal seizure

Contraindicated

  • Known hypersensitivity

Insight

  • Recently introduced to the market in 2016. Brivaracetem is should theoretically be levetiracetem with a higher affinity for the same receptor. There has been increased chronic use in patients. With more evidence in the future, brivaracetem may have an indication for status epilepticus.


Mechanism of action

  • Prolongs opening of Cl- channels (enhances GABA)

  • Antagonism of NMDA receptor

Dosing

  • 15 mg/kg IV push

Adverse Drug Reactions: Dizziness, headache, "hangover" confusion especially in the elderly, paradoxical excitation, exacerbation of pre-existing pain, nausea, vomiting, epigastric pain, hypotension, facial edema, skin rash with bullae and vesicles, purpura, erythema multiforme, exfoliative dermatitis (rare), megaloblastic anemia, agranulocytosis and thrombocytopenia.


Warnings and Precautions

  • Drug-drug interactions

Contraindicated

  • Known hypersensitivity

  • Porphyria

  • New borns

Insight

  • Go-To: Alcohol withdrawal seizures and delirium tremens (DTs).

Maximize BZDs at Guideline-Recommended Doses Before Secondary Anticonvulsants


Status epilepticus is associated with significant morbidity and mortality. Benzodiazepines are first line therapy. We have several secondary IV AEDs, but it appears that they're as good as a coin flip for seizure termination. Keep these 7 agents in mind; levetiracetem, fosphenytoin, valproic acid, lacosamide, ketamine, brivaracetem, and phenobarbital. Rather than finding the best secondary agent, I cannot emphasize enough how important it is to maximize benzodiazepines at guideline-recommended doses.


Mark Nguyen, PharmD, BCEMP



References

  1. Contreras-Garcia et al. Levetiracetam Mechanisms of Action: From Molecules to Systems. Pharmaceuticals (Basel). 2022 Apr 13;15(4):475. doi: 10.3390/ph15040475.

  2. Santamarina et al. Intravenous lacosamide (LCM) in status epilepticus (SE): Weight-adjusted dose and efficacyEpilepsy Behav. 2018 Jul;84:93-98. doi: 10.1016/j.yebeh.2018.04.025

  3. Hofler J, Trinka E. Intravenous ketamine in status epilepticus. Epilepsy Beha. 2018 Jul;84:93-98. doi: 10.1016/j.yebeh.2018.04.025.

  4. Aicua-Rapun et al. Intravenous brivaracetam in status epilepticus: Correlation between loading dose, plasma levels and clinical response. Epilepsy Behav. 2018 Jul;84:93-98. doi: 10.1016/j.yebeh.2018.04.025.

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