Table 1.

First- and second-line anti-seizure medications (ASMs)

Medication	Dose [11, 49]	Pharmacokinetics and other considerations [11, 38, 49, 111]	Mechanism of action [49, 111]	Serious adverse effects [11, 49]	Rational polytherapy—synergistic action tested in animal or human studiesa
Benzodiazepines			Positive allosteric modulator of GABAA receptor—once bound BZD locks the GABAA receptor into a conformation where GABA has higher affinity for GABAA receptor. This increases the frequency of associated Cl channel opening, thus hyperpolarizing the membrane and potentiating an inhibitory effect of available GABA	Respiratory depression, hypotension, sedation, dizziness, weakness, unsteadiness	Animal studies: Diazepam-ketamine-valproate: P [100] Midazolam-ketamine: P [112] Diazepam-perampanel: P [113] Diazepam-levetiracetam: P [114] Diazepam-brivaracetam: P [115] Human studies: BZD (diazepam or clonazepam)-fosphenytoin: P [108] Lorazepam vs diazepam-phenytoin combination: N [116]
Diazepam	2–5 years: 0.5 mg/kg (rectal) 6–11 years: 0.3 mg/kg (rectal) > 12 years: 0.2 mg/kg (rectal) Max dose of 20 mg	Lipophilic: rapidly penetrates blood–brain barrier leading to rapid onset of action. This also leads to rapid redistribution from brain to other lipophilic tissues in the body, and therefore a short duration of action
Lorazepam	0.1 mg/kg IV up to 4 mg/dose May repeat once in 5–10 min	Less lipophilic than diazepam; therefore, slower onset of action and longer anticonvulsant action than diazepam
Midazolam	0.2 mg/kg, max dose of 10 mg (IM) 0.2 mg/kg, max dose of 10 mg (IN) 0.2–0.5 mg/kg, max dose of 10 mg (buccal)	Short half-life after a single dose, significantly increased half-life with infusion; Renal elimination; Metabolized by cytochrome P450 (3A4 and 3A5), levels can be affected by enzyme inducing or inhibiting medications
Levetiracetam	20–60 mg/kg IV (max dose of 4500 mg)	Minimal drug interactions; Not hepatically metabolized; does not affect cytochrome P450 enzymes; Good tolerability profile	Modulates synaptic neurotransmitter release through binding to the synaptic vesicle protein SV2A		Human studies: Clonazepam-levetiracetam: N [106]
Valproate	20–40 mg/kg IV (max dose of 3000 mg)	Cytochrome P450 inhibitor, thus interacts with many medications	Prolongs sodium channel inactivation, attenuates calcium mediated transient currents and augments GABA	Hyperammonemia, acute hemorrhagic pancreatitis, hepatotoxicity, thrombocytopenia; Use with caution in patients with traumatic head injury; May be dangerous in patients with mitochondrial disease (POLG mutation)	Human studies: Valproate-lamotrigine: P [103, 104]
Fosphenytoin	15–20 mg/kg (max dose of 1500 mg) May give additional dose of 5–10 mg/kg 10 min after loading infusion	Cytochrome P450 inducer with several drug–drug interactions; Especially with phenytoin, cardiac and blood pressure monitoring is needed [117]	Blocks voltage gated sodium channels	Hypotension, bradycardia, arrythmias (sino-atrial block and atrio-ventricular block); Phenytoin should be administered slower due to risk for severe tissue necrosis after paravenous infusion	Animal studies: Phenobarbital-phenytoin-pregabalin: P [102] BZD (diazepam or clonazepam)-fosphenytoin: P [108]
Topiramate	No pediatric dosing established Start with 1 mg/kg/day divided twice a day [118]	No IV formulation available; Caution with topiramate-valproate combination due to risk of hyperammonemic encephalopathy	Enhances GABA-mediated inhibition, inhibits Na+, K+, L-type Ca2+ channels, decrease of glutamatergic transmission, and inhibition of carbonic anhydrase	Metabolic acidosis [119], nephrolithiasis, anhidrosis
Lacosamide	No pediatric dose is established. Typically dose of 2–4 mg/kg is used [120], also higher doses of 8–10 mg/kg have been used in some studies [121–123]	Cardiac monitoring is needed. Minimal drug interactions, limited experience in treatment of SE	Enhances slow inactivation of voltage-gated sodium channels	PR prolongation (therefore use with caution in patients with AV block, atrial fibrillation), hypotension
Phenobarbital	20 mg/kg IV, may give additional boluses of 5–10 mg/kg	Strong enzyme inducer, which increases the rate of metabolism of several drugs		Hypotension, respiratory depression	Animal studies: Phenobarbital-phenytoin-pregabalin: P [102] Diazepam-phenobarbital-scopolamine: P [124]

AV atrioventricular, BZD benzodiazepine, Ca2+ calcium, Cl chloride, GABA gamma-aminobutyric acid, IM intramuscular, IN intranasal, IV intravenous, K+ potassium, POLG DNA polymerase gamma, SE status epilepticus, SV2A synaptic vesicle glycoprotein 2A

^aN no additional benefit with polytherapy, P polytherapy had better outcomes