Antiepileptics

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Goldfrank's Toxicologic Emergencies, 11e
Chapter 48: Antiepileptics
Suzanne Doyon
HISTORY AND EPIDEMIOLOGY
Epilepsy a ects 6 per 1,000 population in the United States.54 More than 50 distinct epileptic syndromes are identified; they are categorized
into partial (60%) and generalized (40%) epilepsies.31 Partial epileptic seizures arise from localized cortical sites, and generalized epileptic
seizures involve both cerebral hemispheres.31
Historically, seizures were treated by a variety of methods, including ketogenic diets, fluid restriction, and surgical excision of scars or irritable
cortical foci.118 The first truly e ective antiepileptic therapy was introduced in 1857, when the administration of bromides was noted to sedate
patients and significantly reduce their seizures.118 Phenobarbital, a sedative–hypnotic, was first used to treat seizures in 1912. Most of the
subsequently introduced antiepileptics, such as primidone (2-desoxyphenobarbital), had chemical structures similar to that of phenobarbital,
and sedation was erroneously believed to be an essential component of antiepileptic therapy.
The search for nonsedating antiepileptics led to the introduction of phenytoin in 1938 and benzodiazepines, carbamazepine, and valproic acid
(VPA) in the 1960s. These antiepileptics were the only medications available until the 1990s, when second-generation antiepileptics were
introduced: gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, felbamate, vigabatrin, lacosamide, and zonisamide.
Broad-spectrum antiepileptics are e ective in the management of all seizure types. Narrow-spectrum antiepileptics are restricted to patients
who have partial (localized) epilepsy with partial or secondarily generalized seizures.54 Antiepileptics are also currently used for a host of
disorders, including psychiatric illnesses, refractory pain, drug withdrawal syndromes, migraines, cluster headaches, spasms, and chronic
cough. Based on reports, in 2009, the Food and Drug Administration issued a warning about increased risk of suicidal thoughts or actions
following treatment with carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, tiagabine, topiramate, valproic acid, and
zonisamide.25,50,88
Carbamazepine, lamotrigine, oxcarbazepine, and valproic acid are associated with pregnancy complications such as preeclampsia, premature
births, spontaneous abortions, and stillbirths.8,12
This chapter reviews the toxicity and management of overdoses with antiepileptics other than the benzodiazepines and barbiturates, which
are discussed in Chap. 72.
PHARMACOLOGY
The mechanisms of action of antiepileptics include (1) sodium channel blockade; (2) calcium channel blockade; (3) blockade of excitatory
amines; (4) GABA (gamma-aminobutyric acid) potentiation; and (5) binding to synaptic vesicle glycoprotein 2A (SV2A). Some antiepileptics
have multiple mechanisms of action. Table 48–1 and Figs. 48–1 and 48–2 summarize these e ects.
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TABLE 48–1
Comparison of Mechanisms of Action of Antiepileptics
Synaptic
NMDA
Na+ Ca2+ GABA GABA Vesicle Carbonic
GABA AMPA K+ Channel
Channel Channel Transaminase Reuptake Glycoprotein Anhydrase
kainate
2A
Carbamazepine Blocks Potentiates?
Eslicarbazepine acetate Blocks Blocks

(T-type)
Ezogabine Potentiates
Gabapentin Blocks
(N-type)
Lacosamide Blocks
Lamotrigine Blocks Blocks

(N-,
P/Q-
type)
Levetiracetam Blocks Binding

(N-type)
Oxcarbazepine Blocks
Perampanel Blocks
(AMPA)
Phenytoin/Fosphenytoin Blocks
Pregabalin Blocks
(N-type)
Rufinamide Blocks
Stiripentol Potentiates
Tiagabine Blocks
Topiramate Blocks Blocks Potentiates Blocks Blocks

(L-type) (kainate)
Valproic acid Blocks Blocks Blocks

(NMDA)
Vigabatrin Blocks
Zonisamide Blocks Blocks Blocks

(T-type)
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GABA = γ-aminobutyric acid; NMDA = N-methyl-D-aspartate; AMPA = alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate.
FIGURE 48–1.
Excitatory neurons. In presynaptic neurons, carbamazepine, eslicarbazepine, lamotrigine, oxcarbazepine, phenytoin, rufinamide, topiramate,
valproic acid and zonisamide all inhibit the Na+ channel, preventing the release of the excitatory neurotransmitter glutamate. Lacosamide
binds di erently and enhances slow inactivation, i.e. inhibitory e ect. Gabapentin, lamotrigine, levetiracetam, pregabalin, topiramate, and
zonisamide all inhibit the Ca2+ channel, preventing the release of glutamate. In post synaptic neurons, perampanel, topiramate, and valproic
acid each inhibit a di erent excitatory receptor. AMPA=alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA = N-methyl-D-
aspartate. SV2a = Synaptic vesicle protein 2a.
FIGURE 48–2.
Inhibitory neurons. In presynaptic neurons, valproic acid and vigabatrin inhibit GABA metabolism; tiagabine inhibits its transporter; the end
result is increased GABA in the synaptic cle . In post synaptic neurons, stiripentol and topiramate modulate GABAA receptors. GABA = γ-
aminobutyric acid; GABA-T = GABA transaminase; GAT1= GABA transporter; SAS = succinic acid semialdehyde.
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Voltage-gated Na+ channels are fundamental units that evoke action potentials in neurons. These fast channels are large integral membrane
proteins with an important alpha subunit and 2 smaller auxiliary beta subunits which act as modulators. Nine di erent Na+ channels exist (Na+
1.1–1.9), each with a slightly di erent alpha subunit. Alpha subunits have multiple (up to 7) distinct binding sites. Carbamazepine,
eslicarbazepine, lamotrigine, oxcarbazepine, phenytoin, rufinamide, topiramate, VPA, and zonisamide all bind to the batrachotoxin-binding
site (or adjacent area) on alpha subunits of Na+ channels. They close the internal gates, thereby preventing action potential propagation and
decreasing repetitive firing.58,125,198 At therapeutic concentrations, binding of antiepileptics to a Na+ channel is largely selective. At toxic
concentrations, selectivity is lost, and both high-frequency and spontaneous sodium channels are blocked, including those found in cardiac
tissue.22,98,141,176 Lacosamide enhances slow inactivation of Na+ channel (Fig. 48–1).43
Voltage-gated Ca2+ channels are multisubunit complexes that are broadly classified into high- and low-voltage groups. High-voltage Ca2+
channels include the L, N, P/Q, and R-type channels located primarily on presynaptic neurons; low-voltage Ca 2+ include the T-type channels
located on dendrites of thalamic neurons.9 Gabapentin and pregabalin bind to the a2d1 subunit of the high-voltage N-type Ca 2+ channels,
reducing the frequency of calcium fusion of synaptic vesicles to membranes and thereby reducing glutamate exocytosis.60 Levetiracetam also
inhibits N-type Ca2+ channels, but this is not its major mechanism of action.114 Lamotrigine inhibits N- and P/Q-type Ca2+ channels.190
Topiramate inhibits L-type Ca2+ channels; these channels are found on smooth and striated muscle cells, endocrine cells, and, importantly,
cardiomyocytes. Finally, zonisamide inhibits T-type Ca2+ channels, thus reducing the neuronal pacemaker current (Fig. 48–1).179
Several excitatory amine receptors have been identified. They are located on the postsynaptic membrane and are glutamate-activated ligand-
gated ion channels. N-methyl-D-aspartate (NMDA), kainate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) are the
predominant excitatory amine receptors. When activated, these receptors allow for the influx of Na+, K+, and Ca2+ into cells. VPA competitively
inhibits the NMDA receptor.59 Topiramate inhibits the kainate receptor.65 Perampanel, a third-generation antiepileptic, inhibits the AMPA
receptor (Fig. 48–1).23
Synaptic vesicle glycoprotein 2A (SV2A) is a member of the superfamily of proteins called membrane transporters that are an integral part of
secretory vesicles in neuronal tissue. Synaptic vesicular glycoprotein 2A plays an important role in seizure pathophysiology.85 Levetiracetam
binds to SV2A, inducing a conformational change in the protein that leads to inhibition of vesicular exocytosis of glutamate from the
presynaptic neuron (Fig. 48–1).110,116
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γ-Aminobutyric acid is an inhibitory neurotransmitter that is the target of antiepileptics, which o en aim to increase concentrations of GABA in
the synapse. Vigabatrin irreversibly inhibits GABA transaminase, the enzyme primarily responsible for GABA metabolism.34 Valproic acid is
reported to have similar e ects.139 Tiagabine inhibits the GABA transporter GAT-1 (also known as SLC6A1) and thereby prevents reuptake of
GABA into presynaptic neurons.11 Neither gabapentin nor pregabalin, despite their structural similarity to GABA, mimics GABA when
iontophoretically applied to GABA neurons (Fig. 48–2).129
Lastly, ezogabine (retigabine in Europe) is a unique antiepileptic that opens voltage-gated K+ channels and increases the M current, thereby
hyperpolarizing the membrane.117
CARBAMAZEPINE
Carbamazepine is structurally related to the cyclic antidepressants. It is approved for the management of seizures and trigeminal neuralgia
and is a pregnancy category D medication associated with kinked ribs and cle palate.14
Pharmacokinetics and Toxicokinetics
Carbamazepine is lipophilic, with slow and unpredictable absorption a er oral administration and rapid distribution to all tissues. Peak
concentrations can be delayed postingestion up to 100 hours.19,145 It is metabolized primarily by CYP3A4 to carbamazepine 10,11-epoxide,
which is pharmacologically active. This quantifiable metabolite is further degraded by epoxide hydrolase to carbamazepine-diol, a largely
inactive compound.92 Carbamazepine is unique because it induces its own metabolism a er 2 to 4 weeks. The elimination half-life is 25 to 65
hours at initiation of therapy and decreases to 12 to 17 hours with continued dosing.42 Zero-order elimination kinetics are observed following
large overdoses (Tables 48–2 and 48–3).194
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TABLE 48–2
Pharmacokinetics of Antiepileptics A er Oral Administration
Therapeutic Serum
Time to Max Serum Volume of Protein Urinary Elimination
Concentration Active
Concentration Distribution Binding Elimination Half-Life
Metabolite
(hours) (L/kg) (%) Unchanged (%) (hours)
(mg/L) (µmol/L)
Carbamazepine 6–8 IR 4–12 17–51 0.8–1.8 75 1–2 CBZ10–11 Acute 6–20;

4–26 ER epoxide chronic 5–
12
Eslicarbazepine 1–4 10–35 2.7 35 1 S- 20–40

licarbazepine
Ezogabine 0.5–2 a a 2–6 80 20 None 8
Gabapentin 2–3 2–20 12–117 0.6–08 0 100 None 5–9
Lacosamide 0.5–4 5–10 20–40? 0.6 15 40 None 12–13
Lamotrigine 1–3 3–15 12–58 0.1–1.4 55 10 None 15–35
Levetiracetam 1–2 10–46 60–240 0.6 0 95 None 6–8
Oxcarbazepine 1–5 1–3 4–12 0.7 67 1 10-hydroxy 1–2

carbazepine
Perampanel 0.5–1.5 a a 77 96 2 None 70–110
Phenobarbital 1–6 15–40 65–172 0.7 35–50 20–50 None 53–140
Phenytoin 5–24 10–20 40–79 0.6 >90 <5 None 6–60
Pregabalin 1–2 2–5 18–52 0.5 0 >90 None 5–7
Rufinamide 5–6 5–35 20–140 0.7–1.1 30 2 None 8–12
Tiagabine 0.5–2 0.02– 0.027– 1–1.3 95 <5 None 5–9

0.2 0.27
Topiramate 2–4 5–20 15–74 0.6–0.8 15 60 None 20–30
Valproic acid 1–24 in overdose 50– 347–832 0.1–0.4 >90b <5 None 5–18
120
Vigabatrin 1–2 0.8–36 155–619 0.8 0 100 None 6–8
Zonisamide 2–5 10–40 47–189 1.45 50 30 None 50–70
IR = immediate release; ER = extended release; CBZ = carbamazepine; aNot yet established; b = saturable.
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TABLE 48–3
Metabolism of Antiepileptics and E ects on CYP Enzymes
Metabolized by Induction Inhibition
Carbamazepine 3A4; 1A2; 2C8; 2C9; 2C9; 3A family None
Eslicarbazepine acetate Hydrolysis; UGT Weak 3A4 2C9, 2C19
Ezogabine N-acetylation None None
Gabapentin None None None
Lacosamide 3A4, 2C9, 2C19 None None
Lamotrigine UGT None None
Levetiracetam None None None
Oxcarbazepine UGT None 2C19, 3A4
Perampanel 3A4; UGT Weak 3A4; 2B6 Weak 2C8; UGT
Phenobarbital 2C9; 2C19, 2E1 3A family None
Phenytoin 2C9; 2C19; 3A4 2C family; 3A family None
Pregabalin None None None
Rufinamide Hydrolysis; UGT None None
Tiagabine 3A4 None None
Topiramate None None 2C19
Valproic acid 2C9; 2C19; UGT None 2C19
Vigabatrin None None None
Zonisamide 3A4; acetylation None None
UGT = uridine-diphosphate-glucuronosyltransferase.
Clinical Manifestations
Acute carbamazepine toxicity is characterized by neurologic and cardiovascular e ects. The neurologic disturbances include nystagmus,
ataxia, seizures, and coma.19,75,115 Status epilepticus is reported.168 Cardiovascular e ects include sinus tachycardia, hypotension,
myocardial depression, and, rarely, cardiac conduction abnormalities such as QRS complex and QT interval prolongation.28,48,64 The toxicity
of carbamazepine in children di ers slightly from that in adults. Children experience a higher incidence of dystonic reactions, choreoathetosis,
and seizures and have a lower incidence of ECG abnormalities.166,175 Chronic carbamazepine overdose can result in headaches, diplopia,
ataxia, and leukopenia.155
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The incidence of carbamazepine-induced hyponatremia ranges from 1.8% to 40%. Increased antidiuretic hormone secretion (SIADH) or
increased sensitivity of peripheral osmoreceptors to antidiuretic hormone are suggested mechanisms (Chap. 12).99,186
Diagnostic Testing
Therapeutic serum concentrations of carbamazepine are 4 to 12 mg/L. Carbamazepine-10,11-epoxide concentrations are 1 to 10 mg/L and can
exceed 10 mg/L with therapeutic use of lamotrigine or VPA, secondary to epoxide hydrolase inhibition (Table 48–4). Electrolytes should be
checked in patients with altered mental status because of the risk of hyponatremia.99,186 Carbamazepine cross-reacts with some toxicology
screening for tricyclic antidepressants (Chap. 68).52
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TABLE 48–4
Antiepileptic Drug Interactions
Increases
Anticonvulsant E ect Decreased Decreases
Toxicity Increased by Concentrations
by Concentrations of
of
Carbamazepine Allopurinol, amiodarone, cimetidine, danazol, Benzodiazepines, felbamate, None Doxycycline,

diltiazem, fluoxetine, fluvoxamine, gemfibrozil, isotretinoin, phenobarbital, felbamate,
INH, ketoconazole, lamotrigine, macrolides, phenytoin, primidone, haloperidol,
nefazodone, nicotine, propoxyphene, protease succinimides, VPA lamotrigine, OCPs,
inhibitors, stiripentol, verapamil phenytoin,
primidone, tiagabine,
VPA, warfarin
Eslicarbazepine None CBZ, phenobarbital, phenytoin, Phenytoin CBZ, lamotrigine,

topiramate topiramate, VPA
Ezogabine None CBZ, lamotrigine, Phenobarbital Lamotrigine

phenobarbital, phenytoin
Gabapentin Cimetidine Antacids Felbamate None
Lamotrigine Sertraline, VPA CBZ, phenobarbital, phenytoin CBZ epoxide None
Levetiracetam None None Phenytoin None
Oxcarbazepine None CBZ, phenobarbital, phenytoin Phenytoin Lamotrigine, OCPs
Perampanel None CBZ, phenobarbital, phenytoin, Oxcarbazepine CBZ, lamotrigine, VPA

oxcarbazepine, topiramate
Phenytoin Allopurinol, amiodarone, chloramphenicol, Antacids, antineoplastics CBZ, Phenobarbital, Amiodarone, CBZ,
chlorpheniramine, clarithromycin, cloxacillin, calcium, diazepam, diazoxide, primidone, cardioactive steroids,
cimetidine, disulfiram, ethosuximide, ethanol (chronic), folic acid, warfarin corticosteroids,
felbamate, fluconazole, fluorouracil, fluoxetine, influenza vaccine, loxapine, cyclosporine,
fluvoxamine, imipramine, INH, nitrofurantoin, phenobarbital, disopyramide,
methylphenidate, metronidazole, miconazole, phenylbutazone, pyridoxine, dopamine,
omeprazole, phenylbutazone, sulfonamides, rifampin, salicylates, doxycycline,
ticlopidine, trimethoprim, tolbutamide, sulfisoxazole, sucralfate, furosemide,
tolazamide, topiramate, VPA, warfarin theophylline, tolbutamide, VPA, haloperidol, influenza
vigabatrin vaccine, levodopa,
methadone,
mexiletine, OCP,
phenothiazines,
quinidine, tacrolimus,
theophylline,
tiagabine,
tolbutamide, VPA
Pregabalin None Gabapentin, oxcarbazepine None Tiagabine
Rufinamide VPA CBZ, phenobarbital, phenytoin Phenytoin CBZ, lamotrigine,
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Increases
Anticonvulsant E ect Decreased Decreases
Toxicity Increased by Concentrations
by Concentrations of
of
Tiagabine None CBZ, phenobarbital, phenytoin None VPA
Topiramate None CBZ, phenobarbital, phenytoin Phenytoin OCPs, cardioactive

steroids
Valproic acid Cimetidine, felbamate, ranitidine Antacids, CBZ, chitosan, Felbamate, CBZ, tiagabine
chlorpromazine, felbamate, INH, lamotrigine,
methotrexate, phenobarbital, phenobarbital,
phenytoin, primidone, primidone
salicylates
Vigabatrin None None None Phenytoin
Zonisamide None CBZ, phenobarbital, phenytoin ?CBZ -CBZ
CBZ = carbamazepine; INH = isoniazid; OCP = oral contraceptive pill; VPA = valproic acid.
Management
Rigorous supportive care underlies management. Multiple-dose activated charcoal is associated with improved outcomes in several studies
and is recommended for to patients presenting with large overdoses, if there are no contraindications.13,70,115 Seizures should be treated with
benzodiazepines. Vasopressors should be used for hypotension that is refractory to fluids. Sodium bicarbonate is recommended if the QRS
complex duration exceeds 100 milliseconds (ms).48 Serial serum concentrations should be obtained owing to delays in peak concentrations.
Extracorporeal drug removal is reasonable in cases of severe poisonings associated with intractable seizures or life-threatening
dysrhythmias.62 Intermittent hemodialysis (HD) is preferred.62
ESLICARBAZEPINE ACETATE
Eslicarbazepine acetate is a third-generation antiepileptic that belongs to the dibenzazepine family, which includes carbamazepine (first-
generation) and oxcarbazepine (second-generation). It is a prodrug that is presystemically metabolized in the liver to S(+)-licarbazepine (95%)
and R(–)-licarbazepine (5%).162 S(+)-Licarbazepine is also the pharmacologically active metabolite of oxcarbazepine (Tables 48–2 and 48–
3).162 Eslicarbazepine is expected to be more e ective than oxcarbazepine and is further discussed in the oxcarbazepine section.162
EZOGABINE
Ezogabine (Retigabine in Europe) is a recently approved antiepileptic. Hepatic hydrolysis/N-acetylation followed by glucuronidation are
responsible for 50% to 65% of its metabolism. Uridine-diphosphate-glucuronosyltransferase (UGT1A4) is the principal isoenzyme involved.200
It is associated with bluish skin discoloration (6%), maculopathy, urinary disorders, and QT prolongation (Tables 48–2 and 48–3).127
GABAPENTIN
Gabapentin is a narrow-spectrum antiepileptic approved for the management of seizures, postherpetic neuralgia, chronic neuropathic pain,
migraine headaches, and restless leg syndrome.54 Gabapentin can be misused and abused.45 It is a category C medication with limited human
data in pregnancy.14
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The bioavailability of gabapentin is approximately 60% in the therapeutic dose range. Absorption kinetics are dose-dependent, with
decreasing bioavailability at increased dosage because of saturation of the L-amino acid transport system.15,185 It has high water solubility but
poor lipid solubility.15 Dosage adjustments are necessary in patients with creatinine clearance or estimated glomerular filtration rate (eGFR) of
60 mL/min or less.140 It is not metabolized by and does not a ect the CYP450 system and has no significant interactions with other
antiepileptics (Tables 48–2 and 48–3).200
Sedation, ataxia, movement disorders, slurred speech, and gastrointestinal (GI) symptoms are reported a er acute gabapentin
overdose.78,95,193 Gabapentin withdrawal is characterized by agitation, confusion, tachycardia, and possibly seizures.128
Diagnostic Testing
Therapeutic serum concentrations of gabapentin are 2 to 20 mg/L. Because of its large therapeutic index, monitoring of serum gabapentin
concentrations is not routinely necessary.97
Management
Treatment is largely supportive. Saturation of the transporter system limits GI absorption and movement across the blood–brain barrier.15,185
Hemodialysis and hemoperfusion are not generally necessary, but up to 35% is removed by HD in anuric patients.39,78 Gabapentin withdrawal
does not respond well to administration of benzodiazepines and should be treated with tapering doses of gabapentin.128
LACOSAMIDE
Lacosamide is a functionalized amino acid with high water solubility.97 It is a category C medication with limited data in human pregnancy.14
Lacosamide is almost 100% bioavailable orally. It is predominantly excreted unchanged in the urine and 30% metabolized in liver (2C19).82
Enzyme inducers such as carbamazepine and phenytoin can significantly reduce serum lacosamide concentrations (Tables 48–2 and 48–3).82
Diagnostic Testing
Lacosamide’s therapeutic serum concentration is 5 to 10 mg/L.82 Monitoring of concentration is not routinely recommended in overdose.
Gastrointestinal e ects, QRS complex prolongation, dysrhythmias, intractable hypotension, and death are reported following acute
overdose.26,119 Prolongation of the QRS complex is reported following overdose of a mix of lacosamide and other Na+ channel blockers.37,142
Management
Electrocardiographic monitoring and supportive care are recommended. QRS complex prolongation responds to administration of sodium
bicarbonate, and hypotension responds to administration of vasopressors making these reasonable therapeutics.26,119
LAMOTRIGINE
Lamotrigine is a phenyltriazine antiepileptic also approved for maintenance treatment of bipolar mood disorder.82 It is a category C
medication with limited human data in pregnancy.14
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The bioavailability of lamotrigine approaches 100%.82 It is predominantly glucuronidated to lamotrigine-2-N-glucuronide.82 The elimination
half-life is approximately 25 hours but can be significantly reduced (12 hours) in the presence of phenytoin and carbamazepine.199 The half-life
is doubled by VPA, an enzyme inhibitor. Significantly reduced clearance of lamotrigine occurs in patients with Gilbert syndrome (syndrome of
defective glucuronidation) (Tables 48–2 and 48–3).198
Neurologic and cardiovascular manifestations predominate following lamotrigine overdose. In large case series, seizures, central nervous
system depression, agitation, myoclonus, and hyperreflexia were present.134 Status epilepticus is reported.109,141 Tachycardia, hypertension,
and tachypnea are also frequently present along with QRS complex prolongation, Brugada-like ECG abnormalities, and third-degree heart
block.22,134,141,176 Chronic supratherapeutic dosing resulted in oculogyric crises in 4 patients.188
Diagnostic Testing
Therapeutic serum concentrations of lamotrigine are 2 to 15 mg/L.82 Monitoring of concentration is not routinely recommended in overdose.
Management
Supportive care and cardiac monitoring should be provided. Lamotrigine-induced seizures respond to benzodiazepines.134,191 Data on HD
and hemoperfusion are not available. Intravenous lipid emulsion is not recommended owing to toxicity based on limited data (Antidotes in
Depth: A23).22,134
LEVETIRACETAM
Levetiracetam is an enantioselective isomer (S) piracetam analogue antiepileptic that may also be e ective in the treatment of traumatic brain
injury.71,82 It is a category C medication with limited human data in pregnancy.14
The bioavailability of levetiracetam approaches 100%. The major metabolic pathway involves enzymatic hydrolysis of the acetamide group.
This reaction occurs in the blood and is not dependent on hepatic CYP450 activity.82 There are no active metabolites.82 Dosage adjustments
are necessary in patients with creatinine clearances or eGFR of 80 mL/min or less (Tables 48–2 and 48–3).91,173
Mild central nervous system (CNS) depression and ataxia were reported in one large case series.104 Respiratory depression requiring
intubation was occurred in one case report.7 Chronic therapy is not associated with behavioral problems in adults but is associated with
aggression and agitation in up to 20% of children.73,123
Diagnostic Testing
Therapeutic serum concentrations of levetiracetam are 12 to 46 mg/L. Because of its large therapeutic index, routine monitoring of serum
levetiracetam concentrations is not necessary.82
Management
Supportive care should be provided. Extracorporeal removal treatment is not recommended.
OXCARBAZEPINE
Oxcarbazepine is an analog of carbamazepine that functions as a prodrug of licarbazepine, also known as monohydroxycarbazepine.162 It is a
category C medication with limited data in human pregnancy.14
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Pharmacokinetics, Toxicokinetics
Oxcarbazepine has 100% bioavailability. Rate-limited presystemic ketoreduction rapidly metabolizes oxcarbazepine to licarbazepine, also
known as monohydroxycarbazepine. Metabolism is skewed toward formation of S(+)-licarbazepine (80%), which is pharmacologically
active.162 Plasma elimination half-life of oxcarbazepine is 2 hours, and licarbazepine, 8 to 15 hours.146 Oxcarbazepine minimally inhibits
CYP3A4 but increases glucuronidation.146,199 Licarbazepine concentrations are reduced by 25% in the presence of enzyme inducers such as
carbamazepine and phenytoin (Tables 48–2 and 48–3).146,200
Central nervous system e ects (lethargy, nystagmus, dizziness) and cardiovascular e ects (tachycardia, hyper/hypotension) are reported a er
overdose.148,170 In severe cases, coma, respiratory depression and seizures are noted.170 The rate-limited enzymatic conversion to the active
metabolite may limit toxicity; in some cases, serum concentrations of oxcarbazepine were very high (10-fold), while concentrations of S(+)-
and R(–)-licarbazepine were low (2-fold).56,148,187 In one large case series of acute overdoses, electrolyte abnormalities were rarely
reported.170 Oxcarbazepine is associated with drug-induced liver injury.77
Diagnostic Testing
Therapeutic serum concentrations of oxcarbazepine are 10 to 35 mg/L. Licarbazepine (monohydroxycarbazepine) serum concentrations are 3
to 35 mg/L.112 Monitoring of concentrations is not routinely recommended in overdose. Electrolytes should be checked in patients with
altered mental status because of the risk of hyponatremia (<135 mmol/L).112
Management
Rigorous supportive care underlies management. Hemodialysis (HD) does not increase the clearance of oxcarbazepine/10-
hydroxycarbazepine, so HD is not recommended.56
PERAMPANEL
Perampanel is a recently approved antiepileptic with a unique mechanism of action. It is a noncompetitive (allosteric) AMPA receptor
antagonist.10 It has a favorable pharmacokinetic profile and an extremely long elimination half-life of 70 hours.10 Perampanel’s metabolism is
induced by carbamazepine and phenytoin.10 Therapeutic serum concentrations have not yet been established.82 Lethargy and slurred speech
were observed for 48 hours following one case report of a large overdose.76 Supportive care and monitoring of mental status are
recommended in overdose (Tables 48–2 and 48–3).
PHENYTOIN AND FOSPHENYTOIN

Phenytoin was first synthesized in 1908 but its antiepileptic properties were not discovered until 1938. It is a pregnancy category D medication,
associated with the fetal hydantoin syndrome and cerebral hemorrhage in neonates.14
Fosphenytoin is a water-soluble phosphate ester prodrug of phenytoin. Advantages include more rapid administration, availability for
intramuscular (IM) administration, and low potential for tissue injury at injection sites.57
Phenytoin is rapidly distributed to all tissues following a 2-compartment model. Oral loading doses of 20 mg/kg yield therapeutic (>10 mg/L)
serum concentrations at 5.6 ± 0.2 hours.180 In cases of very large oral overdoses, GI absorption is altered and peak serum concentrations can
be delayed for days.24,29,61 Additionally, phenytoin occasionally forms concretions in the GI tract.24,29
Phenytoin is extensively bound to serum proteins, mainly albumin. Only the unbound free fraction is pharmacologically active. A significant
fraction of phenytoin remains unbound in neonates, uremic patients, and other patients with hypoalbuminemia, such as patients in ICUs.36
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Phenytoin is predominantly metabolized by CYP enzymes (2C9 and 2C19) to inactive metabolites, less than 1% is excreted unchanged in the
urine. Its rate of elimination varies as a function of its concentration (ie, rate is nonlinear; Michaelis–Menten kinetics).152 At phenytoin
concentrations below 10 mg/L, elimination usually is first-order, and half-life is 6 and 24 hours. At higher concentrations, zero-order
elimination occurs because of saturation of the hydroxylation reaction, and the apparent half-life increases to 20 to 105 hours (Chap. 9) (Tables
48–2 and 48–3).46
Fosphenytoin is metabolized by tissue and blood phosphatases to phenytoin, phosphate, and formaldehyde. The half-life of conversion of
fosphenytoin to phenytoin is 7 to 15 minutes.51 Although molar conversion is equivalent, di erences in molecular mass necessitate a 1.5:1
conversion factor from fosphenytoin–phenytoin; for example, 1.5 g fosphenytoin sodium = 1 g phenytoin sodium.113
Acute phenytoin toxicity produces predominantly neurologic dysfunction, a ecting the cerebellar and vestibular systems. Phenytoin
concentrations greater than 15 mg/L are associated with nystagmus; concentrations greater than 30 mg/L are associated with ataxia and poor
coordination; and concentrations exceeding 50 mg/L are associated with lethargy, slurred speech, and pyramidal and extrapyramidal
manifestations.29,131 Ophthalmoplegia, opsoclonus, and other focal neurologic deficits are also reported.174 Cardiovascular instability, de
novo seizures, and death following oral overdoses are rare.174,197
Intravenous overdose produces the same symptoms as oral overdose, with the addition of cardiotoxicity, hypotension, and dysrhythmias.
These manifestations are usually attributed to the diluents propylene glycol (40%) and ethanol (10%).41,46,67,132
Metabolism of fosphenytoin releases phosphate and formaldehyde. Iatrogenic overdoses of fosphenytoin are associated with
hyperphosphatemia, hypocalcemia, bradycardia, hypotension, and asystole.90,102,124,154
The purple glove syndrome is a serious complication of IV phenytoin or fosphenytoin administration whose incidence ranges from 1% to 6%.57
Pathophysiology is unclear but appears to be related either to micro-extravasation or an unidentified procoagulant mechanism. Symptoms
begin 2 to 12 hours a er administration and include discoloration and edema distal to the site of administration.18 Mild symptoms typically
resolve over days, but when severe, lead to necrosis, possibly necessitating amputation.57 The risk of purple glove syndrome associated with
fosphenytoin is lower because of its water solubility.57
Chronic therapy results in gingival overgrowth in up to 20% of patients.133 It is also associated with decreased ADH, osteomalacia,
hepatotoxicity, and megaloblastic anemia.161
Diagnostic Testing
Serum phenytoin concentrations are 10 to 20 mg/L. Because of zero-order elimination, very high serum phenytoin concentrations o en take
days to return to the therapeutic range.29,47,111
Measurement of free phenytoin concentration is helpful in neonates, elderly, hypoalbuminemic, and uremic patients because it compares
more reliably with the cerebrospinal fluid concentration.36,69 Therapeutic free phenytoin concentrations are 1.0 to 2.1 mg/L.
Management
The treatment of patients with oral phenytoin overdoses is largely supportive. Oral multidose activated charcoal (MDAC) is recommended in
severe overdoses presenting with profound coma.5,165 Hemodialysis, charcoal hemoperfusion, plasmapheresis, and other extracorporeal
techniques such as molecular adsorbents recirculating systems (MARS) is reasonable in severe cases with life-threatening cardiovascular
instability or profound neurologic impairment.5 All patients admitted to the hospital for oral phenytoin overdose require frequent neurologic
assessments; routine cardiac monitoring is not necessary because of the low risk of cardiac toxicity following oral overdose.44,197 Phenytoin-
induced agranulocytosis can be treated successfully with administration of granulocyte colony–stimulating factor.178
Intravenous phenytoin is associated with hypotension, cardiac dysrhythmias, and dyskinesias. These are usually transient and resolve in 60
minutes. Stopping the phenytoin infusion for a few minutes and administering a bolus of 250 to 500 mL of 0.9% sodium chloride solution
generally is su icient to treat the hypotension. Restarting the infusion at half the initial rate is recommended.
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Fosphenytoin IV overdose is associated with QT interval prolongation due to hyperphosphatemia and hypocalcemia. Electrolytes should be
corrected immediately; HD may be required.124 Dysrhythmias are reported and require prolonged periods of cardiopulmonary
resuscitation.102,154
The management of extravasation is discussed in Special Considerations: SC8.
PREGABALIN
Pregabalin is an antiepileptic developed as a more potent analog of gabapentin. It is indicated in the management of seizures and neuropathic
pain.157 Pregabalin is abused and misused.45,72,177 It is a category C medication with limited human data in pregnancy.14
Pregabalin, unlike gabapentin, does not have a saturable GI transporter protein and is highly bioavailable, with rapid absorption. It is not
protein-bound, and more than 90% is excreted unchanged in the urine.151,199 Dose adjustments are necessary in patients with GFR less than
60 mL/min.195 Pregabalin has no significant interactions with other antiepileptics except perhaps increasing the steady-state concentrations of
tiagabine (Tables 48–2 and 48–3).15
Cerebellar dysfunction (including dizziness, ataxia, and nystagmus), tremors, twitching, and seizures are described a er
overdose.83,130,143,164,195 Third-degree atrioventricular block, QT interval prolongation, encephalopathy, and respiratory failure are
observed.2,101,195 Peripheral edema, weight gain, and decompensated congestive heart failure occur with chronic therapy.135
Diagnostic Testing
Therapeutic concentrations of pregabalin are 2.8 to 8.3 mg/L.82 Monitoring of concentration is not routinely recommended in overdose.
Management
Rigorous supportive care underlies management.2,101,195 Cardiac monitoring is recommended. It is reasonable to utilize HD in patients with
severe CKD.
RUFINAMIDE
Rufinamide is a recently approved antiepileptic. Therapeutic serum concentrations are 10 to 35 mg/L and metabolism is induced by
carbamazepine and phenytoin (Tables 48–2 and 48–3). In clinical trials, the most frequently reported adverse events at high doses included
lethargy, aggravated seizures, vomiting, and rashes.192 There are no data on overdose.
TIAGABINE
Tiagabine inhibits GABA reuptake and is a category C medication with limited data in human pregnancy.14
Tiagabine is quickly absorbed and has 90% bioavailability.146 It is predominantly (98%) metabolized in the liver, via CYP3A4.146 The
elimination half-life is 8 hours and can be shortened to 2 to 3 hours in the presence of carbamazepine, phenytoin, or phenobarbital (Tables 48–
2 and 48–3).82
In a large case series, lethargy, confusion, and tachycardia were observed following acute overdose.171 Facial myoclonus (grimacing) and
seizures are also reported.21,169,171
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Diagnostic Testing
Therapeutic tiagabine concentrations are 0.02 to 0.2 mg/L.82 Monitoring of concentration is not routinely recommended in overdose.
Management
Supportive care should be provided. Seizures respond to administration of benzodiazepines.55,84,89,144 Status epilepticus resistant to
benzodiazepines should be treated with barbiturates or propofol. Posturing and grimacing are treated with benzodiazepines.21 Hemodialysis
will likely not be e ective because of very high protein binding.
TOPIRAMATE
Topiramate is an antiepileptic approved for mood stabilizing and migraine prophylaxis.54 Its sulfamate moiety weakly inhibits carbonic
anhydrase, specifically the II and IV isoforms, present in the kidneys and CNS.38 Topiramate is a pregnancy category D medication because of
the risk of oral cle s.14
Topiramate is 80% bioavailable.146 Approximately 50% is excreted unchanged by the kidneys and the rest is metabolized in the liver, using yet-
to-be identified CYP enzymes.146 Elimination half-life is 20 to 30 hours (Tables 48–2 and 48–3).120,146
Lethargy, ataxia, nystagmus, myoclonus, hallucinations, coma, seizures, and status epilepticus are all reported following topiramate
overdose.100,193 Abnormal speech patterns and disturbances in verbal fluency appear at high concentrations.121 In some overdoses, e ects
last for days.107 Hyperchloremic non–anion gap metabolic acidosis results from inhibition of renal cortical carbonic anhydrase (lowest
reported bicarbonate concentration, 12 mEq/L) along with hypocitraturia and high urine pH leading to formation of calcium phosphate
stones.66,86 The hyperchloremic metabolic acidosis typically appears within hours of ingestion and can persist for days.27,49,149,184
Chronic topiramate therapy is associated with acute bilateral secondary acute angle-closure glaucoma, acute bilateral myopia, and other
visual problems in the first 2 weeks of therapy.53 Additionally, chronic topiramate is associated with a risk of kidney stone in up to 1.5% of
patients.86
Diagnostic Testing
Therapeutic concentrations of topiramate are 5 to 20 mg/L. Electrolytes should be evaluated for the presence of a hyperchloremia and
metabolic acidosis.86 Monitoring of concentration is not routinely recommended in overdose.
Management
Meticulous supportive care should be provided. Severe hyperchloremic metabolic acidosis (pH <7.2) should be treated with sodium
bicarbonate 1 to 2 mEq/kg bolus intravenously and an infusion. Sodium bicarbonate impairs the antiepileptic e ect of topiramate.27,49
Intermittent HD can increase topiramate clearance 12-fold.16,120 It is reasonable to consider intermittent HD in patients with life-threatening
topiramate toxicity presenting with significant neurologic impairment, intractable electrolyte abnormalities, or anuria. Calcium phosphate
stones should be treated with fluids, restriction of sodium intake, and possible supplementation with potassium citrate.86
VALPROIC ACID
Valproic acid (di-n-propylacetic acid {VPA}) is a simple branched-chain carboxylic acid antiepileptic that is also approved for treatment of
mania associated with bipolar disorder and in migraine prophylaxis.54 It is a category D drug in pregnancy and is associated with neural tube
and facial defects.14
Pharmacokinetics, Toxicokinetics, and Pathophysiology

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Valproic acid is well absorbed from the GI tract with a bioavailability of 90%. Peak concentrations usually are reached in 6 hours, except for
enteric-coated and extended-release preparations, where peak concentrations can be delayed up to 24 hours.46,93 Valproic acid is 90% protein
bound at therapeutic concentrations. Protein binding can decrease to 15% when VPA concentrations increase as a result of saturation of
binding sites (Tables 48–2 and 48–3).63
Valproic acid is predominantly metabolized in the liver, with less than 3% excreted unchanged in the urine.183 Glucuronidation (50%), β-
oxidation (40%), and ω-oxidation (10%) account for most of the hepatic metabolism of VPA.160 β-Oxidation occurs in the mitochondrial matrix
and starts with passive di usion of VPA across the mitochondrial membrane and ends with the transport of metabolites in the opposite
direction using acetyl-CoA and carnitine as transporters (Fig. 48–3 and Table 48–5).106,181
FIGURE 48–3.
Valproic acid (VPA) metabolism by the hepatocyte. Valproic acid is linked to coenzyme A (CoA) by acyltransferase I and subsequently
transferred to carnitine. Valproylcarnitine (VPA-carnitine) is shuttled into the mitochondrion, where, a er transfer back to CoA by
acyltransferase II, it undergoes β-oxidation, yielding several metabolites. These metabolites sequester CoA, preventing its use in the β-
oxidation of other fatty acids. This process may lead to a Reyelike syndrome of hepatic steatosis. Alternatively, valproylcarnitine may di use
from the cell and be renally eliminated, or it may inhibit cellular uptake of carnitine. In either case, the cellular depletion of carnitine shi s
valproate metabolism toward microsomal ω-oxidation, which occurs in the endoplasmic reticulum. This pathway forms 4-en-valproate, a
putative hepatotoxin. ω-Oxidation products and reduced N-acetylglutamate also interfere with carbamoylphosphate synthase I (CPS I), the
initial step in the urea cycle, resulting in hyperammonemia.
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TABLE 48–5
Adverse Events Associated With Therapy
DRESS
Common Serious
Syndrome
Carbamazepine Dizziness, sedation, blurred vision, ataxia, weight gain, Agranulocytosis (1/200,000), aplastic anemia Yes
nausea, leukopenia (1/500,000), rash (10%), SJS (rare),
hyponatremia (1.8%–40%)
Eslicarbazepine Dizziness, sedation, nausea, ataxia, diplopia Rash Yes
Ezogabine Skin and nail discoloration, dizziness, sedation, ataxia Maculopathy, urinary disorders, QT interval No
prolongation
Gabapentin Sedation, dizziness, mild weight gain, ataxia, behavioral None No

e ect (children)
Lamotrigine Dizziness, blurred vision, insomnia, headache Rash, SJS (1–3/1,000), hypersensitivity (rare), Yes
hepatotoxicity (rare)
Lacosamide Dizziness, sedation, ataxia, nausea Rash No
Levetiracetam Fatigue, irritability, anxiety, asthenia Psychosis (rare) Yes
Oxcarbazepine Fatigue, dizziness, ataxia, diplopia, nausea, headache Rash, SJS or TEN (0.5–6/million), hyponatremia Yes
(2.5%), anaphylaxis (rare)
Perampanel Dizziness, sedation, ataxia Psychiatric and behavioral problems No
Phenytoin Fatigue, dizziness, ataxia, nausea, headache, gingival Rash, SJS or TEN (2–4/10,000), megaloblastic Yes
hypertrophy,hirsutism, osteopenia anemia (rare), hepatotoxicity (rare), lupuslike
syndrome
Pregabalin Sedation, weight gain, peripheral edema Peripheral edema No
Rufinamide Sedation, dizziness, nausea, headache, diplopia Rash Possible
Tiagabine Fatigue, dizziness, ataxia, somnolence, anxiety Seizures No
Topiramate Sedation, ataxia, word-finding di iculty, slowed speech, Metabolic acidosis (3%), nephrolithiasis (1.5%), No
di iculty concentrating, anorexia, weight loss, paresthesias, acute glaucoma (rare), heat stroke
oligohidrosis (children)
Valproic acid Sedation, ataxia, weight gain, nausea, tremor, hair loss Hepatotoxicity (1/20,000), pancreatitis (1/3,000), No
thrombocytopenia, hyperammonemia, aplastic
anemia (rare)
Vigabatrin Fatigue, headache, dizziness, weight gain Peripheral vision loss, psychosis No
Zonisamide Sedation, ataxia, di iculty concentrating, irritability, nausea, Aplastic anemia, nephrolithiasis (0.2%–4%), No
headache rash (1%–2%), SJS or TEN (rare), heat stroke
(rare)
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DRESS = Drug Reaction with Eosinophilia and Systemic Symptoms; SJS = Stevens–Johnson syndrome; TEN = toxic epidermal necrolysis.
Mitochondrial β-oxidation of VPA depletes carnitine stores through various mechanisms. First, VPA increases carnitine excretion via formation
of valproylcarnitine, which is renally excreted. Second, valproylcarnitine inhibits the adenosine triphosphate (ATP)–dependent carnitine
transporter located on the plasma membrane. Third, VPA metabolites trap mitochondrial CoA. Mitochondrial CoA trapping decreases ATP
production, which in turn negatively a ects the carnitine transporter.106,160,181 Reduced mitochondrial CoA activity decreases the formation
of N-acetylglutamate, an obligatory cofactor for carbamoylphosphate synthetase I (CPSI). CPSI is the primary enzyme responsible for
incorporation of ammonia into the urea cycle. The result is failure to metabolize ammonia and hyperammonemia. Hyperammonemia can
injure muscle and brain tissue.6,188
Mitochondrial dysfunction, inhibition of β-oxidation, depletion of carnitine, depletion of acetyl-CoA, and possibly depletion of glutathione
stores impair lipid metabolism and lead to fatty acid accumulation, steatosis, lysosomal leakage, formation of reactive oxygen species, and
cytotoxicity histologically similar to Reye syndrome.150,160
Valproic acid toxicity is associated with neurologic symptoms and metabolic disturbances. Ataxia and lethargy are common.63 In one large
case series, patients with serum VPA concentrations greater than 850 mg/L manifested coma, respiratory depression, and hypotension.167
Hypernatremia, hypocalcemia, and hyperammonemia are reported.46,163,167 Anion gap metabolic acidosis is a poor prognostic sign. It results
from accumulation of ketoacids, carboxylic, and propionic acid.3,32,70 Bone marrow suppression occurs 3 to 5 days a er acute massive
overdoses and is characterized by pancytopenia.3,167 Pancreatitis, hepatotoxicity, and acute kidney injury are rare manifestations of acute
toxicity.3,32,94
Chronic VPA therapy may lead to hepatotoxicity and microvesicular steatosis secondary to the aforementioned metabolic aberration in fatty
acid metabolism.17,40 Clinical findings vary from asymptomatic elevation of aminotransferase concentrations to fatal hepatitis.
Valproate-induced hyperammonemic encephalopathy is characterized by impaired consciousness with lethargy, focal or bilateral neurologic
signs, and aggravated seizures. It is not always accompanied by elevated VPA concentrations or hepatotoxicity. The etiology is uncertain, but
elevated ammonia concentrations coupled with elevated concentrations of some of the more neurotoxic VPA metabolites are likely
responsible.20,47,189
Diagnostic Testing
Therapeutic serum concentrations of VPA are 50 to 100 mg/L.82 Electrolytes should be monitored because of the risk of hypernatremia,
hypocalcemia, elevated serum lactate, and hyperammonemia.160
Management
Rigorous supportive care should be provided. Activated charcoal is recommended in the initial management. Repetitive doses are reasonable
in massive overdoses.
L-Carnitine is recommended to treat hyperammonemia or hepatotoxicity.87,105,181 L-Carnitine depletion results in an accumulation of toxic
metabolites and hyperammonemia. L-Carnitine loading dose is 100 mg/kg IV over 30 minutes (maximum, 6 g) followed by 15 mg/kg IV over 10
to 30 minutes every 4 hours until clinical improvement occurs. Whereas IV L-carnitine is preferred in symptomatic patients, oral carnitine is
su icient in asymptomatic patients (Antidotes in Depth: A10). Extracorporeal drug removal is recommended in cases of severe intoxication
associated with VPA serum concentrations greater than 900 mg/L, coma, respiratory depression requiring intubation, or pH <7.1.63
Intermittent HD is preferred.63,163
VIGABATRIN
Vigabatrin, or vinyl GABA, is a stereospecific irreversible inhibitor of GABA-transaminase.54 It is a category C medication in pregnancy.14
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Vigabatrin is rapidly absorbed and has a 60% to 80% bioavailability.14 Duration of action is 24 hours.146 It is completely excreted unchanged in
the urine.146 Dosage adjustments are necessary in patients with creatinine clearance or eGFR less than 80 mL/min.156 Drug interactions are
not common (Tables 48–2 and 48–3).146
Agitation, coma, and psychosis are reported following acute ingestion.33,103 Chronic toxicity may result in dizziness, tremor, depression, and
psychosis.103 The use of vigabatrin is associated with a risk of retinopathy and irreversible peripheral field defects, and permanent visual loss
in up to 44% of patients.82,158
Diagnostic Testing
Therapeutic serum concentrations of vigabatrin are 0.8 to 36 mg/L.82 Monitoring of concentration is not routinely recommended in overdose.
Management
Supportive care should be provided. Benzodiazepines are recommended for severe agitation. Visual defects may be irreversible.82 Cases of
mild vigabatrin-induced psychosis resolve on withdrawal of the medication.103
ZONISAMIDE
Zonisamide is a sulfonamide derivative. Similarly to topiramate, zonisamide inhibits carbonic anhydrase enzymes.82 It is a category C
medication in pregnancy.14
Zonisamide is 65% bioavailable.82 It is primarily metabolized by the liver via CYP3A4.82 The elimination half-life is 60 hours.82 Metabolism is
increased by enzyme inducers such as carbamazepine and phenytoin (Tables 48–2 and 48–3).200
Symptoms include lethargy, coma, seizures, and hyperchloremic metabolic acidosis.126 QT prolongation, hypotension, and cardiac arrest are
reported.74,126,182
Diagnostic Testing
Therapeutic serum concentrations of zonisamide are 10 to 40 mg/L.82 Low serum bicarbonate is occasionally present.30,126 Monitoring of
concentration is not routinely recommended in overdose.
Management
Supportive care is the mainstay of management.126 Zonisamide is cleared via HD in chronically hemodialyzed patients.81 There are no data in
overdose and HD is not recommended.
DRUG-INDUCED HYPERSENSITIVITY SYNDROME (DIHS)
Drug-induced hypersensitivity syndrome (DIHS) is a severe adverse drug event first described in 1950.79 Previously known as the
anticonvulsant hypersensitivity syndrome or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), there exists no current
consensus on nomenclature. Drug-induced hypersensitivity syndrome is characterized by fever, morbilliform cutaneous eruption, and
multiorgan manifestations.79 The syndrome occurs in approximately one of every 1,000 to 10,000 uses of antiepileptics. The most commonly
implicated antiepileptics are carbamazepine, phenytoin, phenobarbital, and lamotrigine but oxcarbazepine, levetiracetam, and rufinamide
are also involved (Fig. 17–9).68,136,153 The etiology of DIHS remains unknown but data suggest a genetic defect in drug metabolism (HLA-
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A*3101 in Northern Europeans and Japanese individuals) or epigenetic disruption leading to reactivation of T cells that harbor latent
herpesviruses (particularly HHV-6).35,147
Drug-induced hypersensitivity syndrome occurs most frequently within the first 2 months of therapy and is not related to dose or serum
concentration. The pathophysiology is related to the accumulation of reactive arene oxide metabolites resulting from decreased epoxide
hydrolase enzyme activity. These metabolites bind to macromolecules and cause cellular apoptosis and necrosis. They also form neoantigens
that trigger T cell–mediated delayed (type IV) hypersensitivity reactions. Interestingly, the same metabolite is believed to cause other serious
dermatologic reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis (Chap. 17 and Fig. 17–6).172
Initial symptoms include fever (38°C–40°C) for 1 to 2 weeks followed by a di use, pruritic macular exanthem that spreads from face to trunk to
extremities. Facial edema is common.1 Mucositis is present in 30%, and tender lymphadenopathy in 75% of cases.4,80 Multiorgan involvement
usually occurs 1 to 2 weeks into the syndrome. The liver is the most frequently a ected organ (>80% of cases), although involvement of the
CNS (encephalitis), heart (myocarditis), lungs (pneumonitis), kidney (nephritis), and thyroid are possible. Liver disturbances range from mildly
elevated aminotransferase concentrations to fulminant hepatic failure.80 Eosinophilia (>2.0 × 109 eosinophils per L) and mononucleosis-type
atypical lymphocytosis are common.79,147 This syndrome is commonly mistaken for sepsis.79 Fatality rates are reportedly as high as 5% to
10%.80,136
Skin biopsies reveal dense perivascular lymphocytic infiltration, with extravasated erythrocytes, eosinophils, and dermal edema.79 Lymph
node histology reveals benign hyperplasia or pseudolymphoma.79 Other laboratory abnormalities include positive rheumatoid factor,
antinuclear antibodies, anti–double-stranded DNA smooth muscle antibodies, cold agglutinins, and hypo- or hypergammaglobulinemia.80
There is no reliable standard for the diagnosis of this syndrome, and separate diagnostic criteria have been developed by the European
Registry for Severe Cutaneous Adverse Reaction and the Japanese Research Committee on Severe Cutaneous Adverse Reaction.79 Prompt
discontinuation of the o ending antiepileptic is essential and benzodiazepines should be used temporarily to control seizures. Patients should
be admitted to the intensive care or burn unit for fluid replacement, correction of electrolytes, warming environment, high caloric intake diet,
prevention of bacterial or viral suprainfection, and appropriate skin care. Topical steroids should be applied for symptomatic relief.137
Methylprednisolone 30 mg/kg is recommended. Intravenous immunoglobulin 2 g/kg over 5 days is recommended if patient fails to respond
quickly to methylprednisolone.80,122 Corticosteroids should be gradually tapered over 3 to 6 months.35 Extracorporeal membrane
oxygenation (ECMO), intraaortic balloon pump, and le ventricular–assist devices can be used to treat myocarditis, and organ transplantation
is recommended in cases of intractable liver or heart failure.35,108 The major cause of death is hepatic necrosis.80
In one case series, 90% of patients with this syndrome showed in vitro cross-reactivity to other aromatic antiepileptics.96 Based on this
evidence, avoidance of phenytoin, carbamazepine, phenobarbital, primidone, lamotrigine, levetiracetam, oxcarbazepine, and rufinamide is
recommended; benzodiazepines, VPA, gabapentin, topiramate, and tiagabine are safe alternatives. Clinicians should report all cases of DIHS
to the US Food and Drug Administration Adverse Event Reporting System (FAERS)
(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugE ects/ucm115894.htm).
SUMMARY
All antiepileptics produce CNS symptoms in overdose; therefore, di erentiation based on clinical findings is di icult. Lethargy, sedation,
ataxia, and nystagmus occur a er overdoses of almost all the antiepileptics.
Coma occurs a er substantial overdose of all antiepileptics with perhaps the exception of gabapentin. Seizures are possible following
carbamazepine, lamotrigine, pregabalin, and zonisamide overdoses.
Hemodynamic instability and abnormal ECGs are rare findings. Carbamazepine, lamotrigine, and possibly topiramate can cause QRS complex
prolongation.
Except for VPA overdoses, there are no specific antidotes or overdoses of antiepileptics. Supportive care alone usually yields beneficial
outcomes.
Patients with severe VPA overdoses or VPA-induced hyperammonemia should be treated with L-carnitine. Extracorporeal drug removal is rarely
necessary.
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Antiepileptics

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Antiepileptics

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Goldfrank's Toxicologic Emergencies, 11e

HISTORY AND EPIDEMIOLOGY

Carbamazepine Blocks Potentiates?

Eslicarbazepine acetate Blocks Blocks

Lamotrigine Blocks Blocks

Levetiracetam Blocks Binding

Topiramate Blocks Blocks Potentiates Blocks Blocks

Valproic acid Blocks Blocks Blocks

Zonisamide Blocks Blocks Blocks

GABA = γ-aminobutyric acid; NMDA = N-methyl-D-aspartate; AMPA = alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate.

Pharmacokinetics and Toxicokinetics

Carbamazepine 6–8 IR 4–12 17–51 0.8–1.8 75 1–2 CBZ10–11 Acute 6–20;

Eslicarbazepine 1–4 10–35 2.7 35 1 S- 20–40

Ezogabine 0.5–2 a a 2–6 80 20 None 8

Gabapentin 2–3 2–20 12–117 0.6–08 0 100 None 5–9

Lacosamide 0.5–4 5–10 20–40? 0.6 15 40 None 12–13

Lamotrigine 1–3 3–15 12–58 0.1–1.4 55 10 None 15–35

Levetiracetam 1–2 10–46 60–240 0.6 0 95 None 6–8

Oxcarbazepine 1–5 1–3 4–12 0.7 67 1 10-hydroxy 1–2

Perampanel 0.5–1.5 a a 77 96 2 None 70–110

Phenobarbital 1–6 15–40 65–172 0.7 35–50 20–50 None 53–140

Phenytoin 5–24 10–20 40–79 0.6 >90 <5 None 6–60

Pregabalin 1–2 2–5 18–52 0.5 0 >90 None 5–7

Rufinamide 5–6 5–35 20–140 0.7–1.1 30 2 None 8–12

Tiagabine 0.5–2 0.02– 0.027– 1–1.3 95 <5 None 5–9

Topiramate 2–4 5–20 15–74 0.6–0.8 15 60 None 20–30

Vigabatrin 1–2 0.8–36 155–619 0.8 0 100 None 6–8

Zonisamide 2–5 10–40 47–189 1.45 50 30 None 50–70

Metabolized by Induction Inhibition

Carbamazepine 3A4; 1A2; 2C8; 2C9; 2C9; 3A family None

Eslicarbazepine acetate Hydrolysis; UGT Weak 3A4 2C9, 2C19

Ezogabine N-acetylation None None

Gabapentin None None None

Lacosamide 3A4, 2C9, 2C19 None None

Lamotrigine UGT None None

Levetiracetam None None None

Oxcarbazepine UGT None 2C19, 3A4

Perampanel 3A4; UGT Weak 3A4; 2B6 Weak 2C8; UGT

Phenobarbital 2C9; 2C19, 2E1 3A family None

Phenytoin 2C9; 2C19; 3A4 2C family; 3A family None

Pregabalin None None None

Rufinamide Hydrolysis; UGT None None

Tiagabine 3A4 None None

Topiramate None None 2C19

Valproic acid 2C9; 2C19; UGT None 2C19

Vigabatrin None None None

Zonisamide 3A4; acetylation None None

Carbamazepine Allopurinol, amiodarone, cimetidine, danazol, Benzodiazepines, felbamate, None Doxycycline,

Eslicarbazepine None CBZ, phenobarbital, phenytoin, Phenytoin CBZ, lamotrigine,

Ezogabine None CBZ, lamotrigine, Phenobarbital Lamotrigine

Gabapentin Cimetidine Antacids Felbamate None

Lamotrigine Sertraline, VPA CBZ, phenobarbital, phenytoin CBZ epoxide None

Levetiracetam None None Phenytoin None

Oxcarbazepine None CBZ, phenobarbital, phenytoin Phenytoin Lamotrigine, OCPs

Perampanel None CBZ, phenobarbital, phenytoin, Oxcarbazepine CBZ, lamotrigine, VPA

Pregabalin None Gabapentin, oxcarbazepine None Tiagabine

Rufinamide VPA CBZ, phenobarbital, phenytoin Phenytoin CBZ, lamotrigine,

Tiagabine None CBZ, phenobarbital, phenytoin None VPA

Topiramate None CBZ, phenobarbital, phenytoin Phenytoin OCPs, cardioactive

Vigabatrin None None None Phenytoin

Zonisamide None CBZ, phenobarbital, phenytoin ?CBZ -CBZ

Pharmacokinetics and Toxicokinetics