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Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e >
Chapter 197: AnticonvulsantsFrank LoVecchio
INTRODUCTION
Anticonvulsants, or antiepileptics, are used to treat acute seizures and prevent convulsions in patients withepilepsy. The first generation of antiepileptics was developed between 1939 and 1980 (Table 197-1). Since1993, 15 additional agents have been introduced into clinical use, termed the "second and third generation"of antiepileptic drugs. In general, these new anticonvulsants have fewer serious adverse side e�ects andfewer drug interactions than the first-generation agents. The first-generation drugs have an establishedtherapeutic range for serum levels that can guide therapy during long-term management and that correlatewith acute toxicity from an overdose. Consistent therapeutic levels have not been established for the secondand third-generation anticonvulsants, and serum levels are not a useful guide to therapy.
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TABLE 197-1
Anticonvulsant Drugs
First Generation
Carbamazepine
Ethosuximide
Phenobarbital
Phenytoin and fosphenytoin
Primidone
Valproate
Second and Third Generation
Eslicarbazepine acetate
Ezogabine or retigabine
Felbamate
Gabapentin
Lacosamide
Lamotrigine
Levetiracetam
Oxcarbazepine
Pregabalin
Rufinamide
Stiripentol
Topiramate
Tiagabine
Vigabatrin
Zonisamide
This chapter reviews the pharmacology, clinical features, and treatment for commonly used anticonvulsants.Disposition recommendations depend on the resolution of clinical toxicity, but patients with intentionaloverdose need mental health evaluation in the ED before discharge.
PHENYTOIN AND FOSPHENYTOIN
Phenytoin is a primary anticonvulsant for partial and generalized tonic-clonic seizures. It is useful in the
treatment of non–drug-induced status epilepticus in conjunction with rapidly acting anticonvulsants.1
Pheny-toin has been used to prevent seizures due to head trauma (in the immediate post-traumatic period)and in the management of some chronic pain syndromes. Serious complications are extremely rare a�erintentional phenytoin overdose if supportive care is provided. Most phenytoin-related deaths have beencaused by rapid IV administration or hypersensitivity reactions.
Phenytoin is available in oral and injecTable forms. Phenytoin has poor solubility in water, so the vehicle forthe parenteral formulation is 40% propylene glycol and 10% ethanol, adjusted to a pH of 12 with sodiumhydroxide. The acute cardiovascular toxicity seen with IV phenytoin infusion has frequently been ascribed tothe propylene glycol diluent. Other limitations with parenteral phenytoin are the irritating nature of thevehicle and a tendency to precipitate in IV solutions. Fosphenytoin (a disodium phosphate ester ofphenytoin) is a prodrug that is converted to phenytoin by phosphatases in the body with a conversion half-
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life of 10 to 15 minutes. The advantage with parenteral fosphenytoin is that it is soluble in aqueous solutions,
is bu�ered to a pH of 8.8, is nonirritating to the tissues, and can be given by IM injection.2
PATHOPHYSIOLOGY
Mechanism of Action
Phenytoin exerts its anticonvulsant e�ect by blocking voltage-sensitive and frequency-dependent sodiumchannels in the neurons, suppressing repetitive neuronal activity, and preventing the spread of a seizure
focus.3 At higher concentrations, phenytoin delays activation of outward potassium currents in nerves andprolongs the neuronal refractory period. It also may exert an anticonvulsant e�ect by influencing calciumchannels and γ-aminobutyric acid receptors or by inhibiting adenosine reuptake.
Pharmacokinetics
Phenytoin is a weak acid with a pKa of 8.3. In the acid milieu of the stomach and even at physiologic pH,
more of the drug is nonionized, and its aqueous solubility is limited. Absorption a�er oral ingestion is slow,variable, and o�en incomplete, especially a�er an overdose. Di�erent phenytoin preparations can possessmajor di�erences in bioavailability. Consequently, it may be necessary to obtain serial measurements ofserum level in suspected overdose to determine peak levels. Peak levels typically occur between 3 and 12hours a�er a single therapeutic oral dose.
A�er absorption, phenytoin is distributed throughout the body, with a volume of distribution of 0.6 to 0.8L/kg. Brain tissue concentrations equal those in plasma within about 10 minutes of IV infusion and arecorrelated with therapeutic e�ects, whereas cerebrospinal fluid and myocardium equilibrate within 30 to 60minutes.
Protein Binding
Phenytoin is extensively (about 90%) bound to plasma proteins, especially albumin. The free, unbound formis the biologically active moiety responsible for the drug's clinical e�ect and toxicity. The unbound fraction ofthe drug is greater in neonates, the elderly, pregnant women, renal failure, hypoalbuminemia (cirrhosis,nephrosis, malnutrition, burns, trauma, or cystic fibrosis), and hyperbilirubinemia. Drugs that displacephenytoin from binding sites (salicylate, valproate, phenylbutazone, tolbutamide, and sulfisoxazole) alsoresult in an increased unbound fraction.
Patients with decreased protein binding have higher levels of free phenytoin and experience a greaterbiologic e�ect despite lower levels of total phenytoin. Free phenytoin concentrations are more useful inpredicting toxicity. Corrected serum phenytoin levels (the concentration that would be present if a patient'sserum albumin level were normal) can be calculated as follows: corrected phenytoin concentration =(measured phenytoin concentration × 4.4)/(albumin concentration), with phenytoin concentration measuredin micrograms/mL and the albumin concentration measured in grams/dL.
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Metabolism
A�er absorption and distribution, only 4% to 5% of phenytoin is excreted unchanged in the urine. Theremainder is metabolized by hepatic microsomal enzymes, primarily hydroxylated through a series ofinactive compounds. The metabolism of phenytoin is capacity limited (dose dependent). At plasmaconcentrations of <10 micrograms/mL, elimination is first-order kinetics (a fixed percentage of drugmetabolized per unit of time). At higher concentrations, including those in the therapeutic range of 10 to 20micrograms/mL, the metabolic pathways may become saturated, and the elimination may change to zero-order kinetics (a fixed amount metabolized per unit of time). With zero-order kinetics, small increases inmaintenance doses may saturate the enzyme systems, markedly prolonging the half-life of phenytoin, andresult in a disproportionate increase in the plasma level. Thus incremental dose increases should be limitedto 30 to 50 milligrams at a time, and levels should be carefully monitored when it is necessary to raisephenytoin doses above 300 milligrams (or above 5 milligrams/kg) per day.
Concomitant use of drugs that inhibit or enhance hepatic microsomal activity may result in an increase ordecrease of phenytoin level, respectively. Phenytoin also a�ects the metabolism of various other agents(Table 197-2).
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*These drugs displace phenytoin from its protein-binding sites, thus increasing the free phenytoin fraction, although
the total phenytoin level may decrease.
TABLE 197-2
Phenytoin Drug Interactions (Partial List)
Phenytoin increases serum levels of
Acetaminophen
Acetazolamide
Amiodarone
Oral contraceptives
Primidone
Zidovudine
Phenytoin increases toxicity of
Carbamazepine
Oral anticoagulants
Phenytoin decreases serum levels of
Cyclosporine
Disopyramide
Doxycycline
Ethanol (chronic use)
Furosemide
Glucocorticoids
Levodopa
Methadone
Mexiletine
Quinidine
Theophylline
Valproate
Phenytoin levels are increased by
Amiodarone
Chloramphenicol
Cimetidine
Disulfiram
Fluconazole
Isoniazid
Oral anticoagulants
Phenylbutazone*
Salicylate (high dose)*
Trimethoprim
Phenytoin levels are decreased by
Antineoplastic drugs
Calcium
Ethanol
Diazepam
Diazoxide
Folic acid
Phenobarbital
Rifampin
Sucralfate
Sulfonamides*
Theophylline
Tolbutamide*
Valproate*
Propylene Glycol and Ethanol Diluents
Propylene glycol is a potent myocardial depressant and vasodilator and also enhances vagal tone. Thischemical can cause coma, seizures, circulatory collapse, ventricular dysrhythmias, atrioventricular node
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depression, and hypotension in experimental animals.4 Other toxic e�ects from propylene glycol include
hyperosmolality, hemolysis, and lactic acidosis.5 The ethanol diluent fraction of parenteral phenytoin mayprecipitate a reaction in patients taking disulfiram.
CLINICAL FEATURES
Central Nervous System Toxicity
As toxic phenytoin levels are reached, inhibitory cortical and excitatory cerebellar and vestibular e�ectsbegin to occur. The initial sign of toxicity is usually nystagmus, which is seen first on forced lateral gaze and
later becomes spontaneous (Table 197-3).6 Vertical, bidirectional, or alternating nystagmus may occur withsevere intoxication. A decreased level of consciousness is common, with initial sedation, lethargy, ataxic gait,
and dysarthria.6 This may progress to confusion, coma, and even apnea in a large overdose. Nystagmus maydisappear as the level of consciousness decreases, and complete ophthalmoplegia and loss of cornealreflexes may occur. Therefore, absence of nystagmus does not exclude severe phenytoin toxicity. Nystagmusreturns as serum drug levels decrease and coma lightens.
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TABLE 197-3
Clinical Features of Phenytoin Toxicity
Central nervous
system
Dizziness, tremor (intention), visual disturbance, horizontal and vertical nystagmus,
diplopia, miosis or mydriasis, ophthalmoplegia, abnormal gait (bradykinesia, truncal
ataxia), choreoathetoid movements, irritability, agitation, confusion, hallucinations,
fatigue, coma, encephalopathy, dysarthria, meningeal irritation with pleocytosis, seizures
(rare)
Peripheral
nervous system
Peripheral neuropathy, urinary incontinence
Hypersensitivity
(anticonvulsant
hypersensitivity
syndrome)
Eosinophilia, rash, pseudolymphoma (di�use lymphadenopathy), systemic lupus
erythematosus, pancytopenia, hepatitis, pneumonitis
Gastrointestinal Nausea, vomiting, hepatotoxicity
Dermatologic Hirsutism, acne, rashes (including Stevens-Johnson syndrome)
Other organs Fetal hydantoin syndrome, gingival hyperplasia, coarsening of facial features,
hemorrhagic disease of the newborn, hyperglycemia, hypocalcemia
Parenteral
toxicity
May cause hypotension, bradycardia, conduction disturbances, myocardial depression,
ventricular fibrillation, asystole, and tissue necrosis from infiltration
Paradoxically, very high levels of phenytoin may be associated with seizures, although this is a rareoccurrence, and such phenytoin-induced seizures are usually brief and generalized and almost always are
preceded by other signs of toxicity, especially in acute overdose.7
Cerebellar stimulation and alterations in dopaminergic and serotonergic activities may cause acutedystonias and movement disorders, such as opisthotonos and choreoathetosis. Hyperactive deep tendonreflexes, clonus, and extensor toe responses also may be elicited. Chronic neurologic toxicity includesperipheral neuropathy and cerebellar degeneration with ataxia.
Cardiovascular Toxicity
Cardiovascular complications have been almost entirely limited to cases of IV administration, in large part
due to the constituents of the parenteral vehicle, or in rare cases of chronic oral toxicity.8 Cardiac toxicity
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Abbreviation: PE = phenytoin equivalents.
*For simplicity, the pharmaceutical concentration and dose of fosphenytoin is expressed in PE, with 150 milligrams
fosphenytoin = 100 milligrams PE.
†Unlike with IV loading, not all patients will reach a therapeutic level with oral loading.
a�er oral phenytoin overdose in an otherwise healthy patient has not been reported and, if observed, is due
to other causes (e.g., hypoxia and other drugs).8
Reported cardiovascular complications include hypotension with decreased peripheral vascular resistance,bradycardia, conduction delays progressing to complete AV nodal block, ventricular tachycardia, primaryventricular fibrillation, and asystole. ECG changes include increased PR interval, widened QRS interval, andaltered ST segments and T waves. Cardiovascular toxicity is more common in the elderly, those withunderlying cardiac disease, and the critically ill. Guidelines for parenteral phenytoin administration stress aslow rate of infusion and constant monitoring (Table 197-4).
TABLE 197-4
Guidelines for Phenytoin or Fosphenytoin Loading
IV Loading dose is 18 milligrams/kg as phenytoin or fosphenytoin PE.*
Mix total dose in 150–200 mL of normal saline.
Keep phenytoin concentration <6 milligrams/mL or fosphenytoin PE concentration <25
milligrams/mL.
Administer phenytoin through Millipore filter using an infusion pump.
Rate of administration should not exceed 25–50 milligrams/min of phenytoin or 150 milligrams/min
of fosphenytoin PE.
Use a slower rate of infusion in patients with cardiovascular disease.
Monitor the blood pressure and cardiac rhythm continually during the infusion.
In the event of complications, immediately stop the infusion and administer isotonic crystalloid
and other treatment as indicated.
IM Administer 15 milligrams/kg fosphenytoin PE preparation in one or multiple IM sites.
PO† Loading dose is 20 milligrams/kg.
Phenytoin tablets or suspension may be used.
Patient must be conscious with an intact gag reflex and not actively seizing or vomiting.
Administer the total amount in one dose.
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Even though fosphenytoin does not contain the propylene glycol diluent, cardiovascular toxicity can occurwith IV administration. Hypotension is seen in about 8%, and rare cases of bradycardia, AV nodal block, and
asystole have been observed.2,10,11
Vascular and So� Tissue Toxicity
IM injection of phenytoin may result in localized crystallization of the drug with hematoma, sterile abscess,and myonecrosis at the injection site. IV extravasation may produce skin and so� tissue necrosis,compartment syndrome, and limb gangrene. Delayed bluish discoloration of the a�ected extremity ("purpleglove syndrome") followed by erythema, edema, vesicles, bullae, and local tissue ischemia has been
described.12
Hypersensitivity Reactions
Hypersensitivity reactions usually occur within 1 to 6 weeks of beginning phenytoin therapy and can presentas a febrile illness with skin changes (erythema multiforme, toxic epidermal necrolysis or Stevens-Johnsonsyndrome) and internal organ involvement (hepatitis, rhabdomyolysis, acute interstitial pneumonitis, renalfailure, lymphadenopathy, leukopenia and/or disseminated intravascular coagulation). Patients with ahistory of previous hypersensitivity reactions should not receive phenytoin, and because of similar reactionsto phenobarbital, lamotrigine, felbamate, and carbamazepine, these anticonvulsants should also beavoided.
Miscellaneous E�ects
Gingival hyperplasia is relatively common and is associated with poor dental hygiene (gingivitis and dentalplaques). Because of the risk of fetal hydantoin syndrome, oral phenytoin therapy should never be initiatedin a pregnant patient without consultation with and close follow-up by a neurologist and obstetrician.
DIAGNOSIS
The therapeutic phenytoin serum level is 10 to 20 micrograms/mL (40 to 80 micromoles/L), which generally
corresponds to a free phenytoin level of 1 to 2 micrograms/mL.13 Although 50% of patients achieve reductionin seizure frequency below these levels, some patients require levels as high as 20 micrograms/mL foradequate control. The ratio of toxic dose to therapeutic dose for phenytoin is rather low, and there is wideindividual variability in the levels required to cause adverse e�ects. In general, toxicity is correlated withincreasing plasma levels (Table 197-5).
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TABLE 197-5
Correlation of Plasma Phenytoin Level and Toxic E�ects
Total Plasma Level (micrograms/mL) Toxic E�ects
<10 Usually none
10–20 Occasional mild nystagmus
20–30 Nystagmus
30–40 Ataxia, slurred speech, nausea and vomiting
40–50 Lethargy, confusion
>50 Coma, seizures
TREATMENT
The initial treatment of severe oral phenytoin overdose is similar to that for ingestion of other drugs. Correctacidosis (respiratory or metabolic) to decrease the active free phenytoin fraction. Multidose activatedcharcoal may decrease drug half-life but does not decrease time to recovery and does not change outcome in
overdose patients.14 Seizures may be treated with IV benzodiazepines or phenobarbital, with the cautionthat seizures are uncommon in phenytoin overdose. For patients with severe and persistent toxicity,
hemodialysis and hemoperfusion can produce substantial improvement in neurologic toxicity.15,16,17
Cardiac monitoring a�er isolated oral ingestion is unnecessary. Atropine and temporary cardiac pacing maybe used for symptomatic bradyarrhythmias associated with IV phenytoin. Hypotension that occurs during IVadministration of phenytoin or fosphenytoin usually responds to discontinuation of the infusion andadministration of isotonic crystalloid.
DISPOSITION AND FOLLOW-UP
Phenytoin has a long and erratic absorption phase a�er oral overdose, so the decision to discharge ormedically clear a patient for psychiatric evaluation cannot be based on one serum level. A�er acuteingestions, serum level should be measured every few hours. Patients with serious complications a�er anoral ingestion (seizures, coma, altered mental status, or significant ataxia) should be admitted for furtherevaluation and treatment. Those with mild symptoms should be observed in the ED and discharged once
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their levels of phenytoin are declining and they are clinically well. Mental health or psychiatric evaluationshould be obtained, as indicated, in cases of intentional overdose.
Patients with symptomatic chronic intoxication should be admitted for observation unless signs are minimal,adequate care can be obtained at home, drug levels are decreasing, and 6 to 8 hours have elapsed since thepatient's last therapeutic dose. Phenytoin therapy should be stopped in all cases, and if toxicity continues toresolve, serum level may be reassessed in 2 to 3 days to guide resumption of therapy. Surgical consultationshould be obtained for patients with significant extravasation of IV phenytoin or with other signs of localvascular or tissue toxicity a�er infusion.
CARBAMAZEPINE
Carbamazepine is a primary anticonvulsant used in the treatment of partial and tonic-clonic seizures. Otheruses include trigeminal neuralgia, chronic pain disorders, manic disorder, and bipolar disorder.
PATHOPHYSIOLOGY
Carbamazepine inhibits sodium channels and interferes with muscarinic acetylcholine receptors, nicotinic
acetylcholine receptors, N-methyl-d-aspartate receptors, and central nervous system adenosine receptors.3
Carbamazepine may relieve neuropathic pain through blockade of synaptic transmission in the trigeminalnucleus. Carbamazepine also possesses anticholinergic, antiarrhythmic, antidepressant, sedative, andneuromuscular-blocking properties. It has central antidiuretic e�ects, which may lead to the syndrome ofinappropriate antidiuretic hormone secretion. Carbamazepine is a potent cytochrome P-450 enzyme inducerand enhances its own metabolism over time.
Carbamazepine is an iminostilbene derivative that is chemically and structurally similar to imipramine.Gastrointestinal absorption is slow, and peak serum concentrations usually occur within 8 hours but may be
as late as 12 hours a�er ingestion. A therapeutic carbamazepine concentration is 4 to 12 micrograms/mL.18
Carbamazepine has a protein binding of about 80% and a volume of distribution of 0.8 to 1.2 L/kg. It ismetabolized by liver cytochrome P-450 isoenzymes to an active metabolite (10,11-epoxide). The epoxideconcentration comprises 15% of the parent compound in adults and slightly higher in children. The epoxidemetabolite is responsible for much of the neurotoxicity seen in overdose. Autoinduction of the enzymes thatmetabolize carbamazepine occurs with about 1 month of continuous use. Because of this, the drug's half-lifeshortens over time: the half-life a�er an isolated carbamazepine dose is about 35 hours, much longer than
the 10 to 20 hour half-life at steady state a�er 3 to 5 weeks of continuous therapy.17
CLINICAL FEATURES
A�er an overdose, the delayed and erratic absorption due to anticholinergic properties (which delaygastrointestinal motility) and low water solubility can cause delayed clinical deterioration or a crescendo-
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decrescendo clinical course.19 Manifestations of acute toxicity include mental status depression, ataxia,nystagmus, ileus, hypertonicity with increased deep tendon reflexes, dystonic reactions, and an
anticholinergic toxidrome.19,20,21 Paradoxical seizures can occur in patients with high carbamazepineconcentrations and an underlying seizure disorder. There are sporadic reports of le� ventricular dysfunctionwith heart failure and transient heart block (without hemodynamic compromise). Cardiac arrhythmias arerarely seen, but carbamazepine is one of the few drugs that can potentially cause both a wide QRS intervaland seizures. Laboratory abnormalities seen with acute overdose include hyponatremia, hyperglycemia, andtransient elevation of serum liver enzyme levels.
Adverse e�ects occur in 25% of patients receiving long-term carbamazepine therapy. Mild transientleukopenia may occur during the first month of treatment. This is unrelated to the more serious side e�ect ofaplastic anemia, which has a reported incidence of 1 to 5 per million patient-years, approximately 11 timeshigher than in the normal population. Mild liver enzyme elevation occurs in up to 10% of patients on long-term therapy. Stevens-Johnson syndrome and toxic epidermal necrolysis are reported with about the samefrequency as aplastic anemia.
DIAGNOSIS
Serum carbamazepine concentrations are not linearly correlated with poisoning severity. However, serumconcentrations of >40 micrograms/mL are associated with an increased risk of serious complications such as
seizures, respiratory failure, coma, and cardiac conduction defects.22 Serum concentrations higher than 60 to80 micrograms/mL may be fatal. The seriousness of toxicity should be judged by the clinical status of the
patient, not by the serum concentration.20,21,22
Because the chemical structure of carbamazepine is related to imipramine, carbamazepine can cause a false-
positive tricyclic antidepressant result on a urine drug screen.23 Both carbamazepine and epoxidemetabolite are measured by the standard enzyme-multiplied immunoassay to determine serum levels.
TREATMENT
Activated charcoal may be considered if the patient is not obtunded and presents within 1 hour of ingestion,
because delayed absorption is possible.14 Multidose activated charcoal may decrease drug half-life but does
not decrease time to recovery or change outcome in overdose patients.24 In patients with severe toxicity and
multiorgan dysfunction, hemodialysis, hemoperfusion, or hemodiafiltration is e�ective.25–31 Althoughcardiac conduction delays are rare, if conduction delay is noted on the electrocardiogram, sodiumbicarbonate treatment seems reasonable.
DISPOSITION AND FOLLOW-UP
Patients can be medically cleared from the ED if at least two carbamazepine measurements obtained a fewhours apart show decreasing levels (preferably below 15 micrograms/mL) and the patient is awake,
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ambulatory, and free of cardiac conduction abnormalities.
VALPROATE
Valproate (or valproic acid) is used to treat tonic-clonic seizures, absence seizures, partial complex seizures,and post-traumatic epilepsy. Valproate is also used in migraine headache prophylaxis, to control manicepisodes in bipolar disorder, and to treat neuropathic pain.
PATHOPHYSIOLOGY
Valproate a�ects neurotransmitters and the function of electrically exciTable cells.3 Valproate increases γ-aminobutyric acid concentrations, reduces release of γ-hydroxybutyrate, and blocks N-methyl-d-aspartate
receptors.32 Valproate prolongs recovery of inactivated sodium channels, enhances potassium conductance,and reduces T-type calcium current firing.
With standard preparations at therapeutic doses, peak serum concentrations occur within 4 hours a�eringestion. If the enteric-coated or controlled-release formulation has been ingested, peak serum
concentration may be delayed for 12 to 17 hours.33
Valproate is metabolized by the liver by glucuronic acid conjugation and mitochondrial beta oxidation.Valproate enters mitochondria by using L-carnitine as a cofactor. Protein binding is extensive and influencedby serum concentration, with 90% of the drug protein bound at concentrations of 40 micrograms/mL.Valproate is an eight-carbon fatty acid and has a small volume of distribution of 0.13 to 0.23 L/kg. The half-life
of valproate is 8 to 21 hours but may be two or three times longer a�er overdose.33,34,35,36
CLINICAL FEATURES
A�er an overdose with acute toxicity, the most frequent sign is CNS depression, ranging from drowsiness to
coma.35 Other findings include respiratory depression, hypotension, hypoglycemia, hypocalcemia,hypernatremia, hypophosphatemia, and anion gap metabolic acidosis that may persist for days. Toxicity tothe liver produces elevated serum levels of aminotransferases, ammonia, and lactate. Pancreatitis may occur,
and thrombocytopenia may be clinically significant and severe.35
Valproate increases renal ammonia production and blocks hepatic ammonia metabolism. Hyperammonemiain the absence of liver failure has been reported following valproate overdose and during long-term
therapy.37,38 Cerebral edema has been seen in acute overdose.34,35 During long-term therapeutic use,increased serum liver enzyme levels occur in >50% of patients with therapeutic valproate serumconcentrations. Liver enzyme levels typically normalize with dosage reduction or discontinuation of thedrug. Hepatic failure, histologically evident as microvesicular steatosis, occurs in about 1 in 20,000 patients
receiving long-term therapy.39,40,41 Valproate-induced hepatotoxicity may be either intrinsic and benign(reversible, reproducible, and dose dependent) or idiosyncratic and fatal (unpredictable, not dose
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dependent, with a long latent period). Children <3 years of age who are receiving multiple antiepilepticagents and have additional medical problems are at highest risk for fatal hepatotoxicity, with an incidence ofabout 1 in 500. Serum levels of transaminases and ammonia should be checked in children on valproatetherapy who demonstrate somnolence or lethargy.
DIAGNOSIS
Therapeutic valproate concentrations are 50 to 100 micrograms/mL. Although serum concentration does notcorrelate well with either seizure control or toxicity, adverse side e�ects increase as concentrations riseabove 150 micrograms/mL, and coma may occur with levels above 800 micrograms/mL. When serumvalproate concentrations are measured, the enzyme-multiplied immunoassay technique yields higher valuesthan gas-liquid chromatography, so a consistent analytic methodology should be used when monitoringtreatment. Serum ammonia and glucose concentrations should be measured with suspected valproatetoxicity. Valproate is eliminated partly as ketone bodies and may cause a positive test result for ketones inthe urine or blood.
TREATMENT
Single-dose activated charcoal alone is su�icient for the vast majority of patients with a valproate overdose.Consider multidose activated charcoal and/or whole-bowel irrigation a�er ingestion of enteric-coated,delayed-release preparations to prevent the ongoing absorption that may occur from delayed capsule or
tablet dissolution.14,42 Because of delayed peak serum levels a�er an overdose, serial concentrations shouldbe measured.
Administration of high-dose naloxone has been reported to reverse valproate-induced neurologicdepression, possibly by reversal of valproate-induced release of endogenous opioids or reversal of valproate-
induced blockade of γ-aminobutyric acid uptake.43,44 Because the serious toxic e�ects of valproate involvemore than just these two mechanisms, naloxone is unlikely to be helpful in the management of a comatosepatient a�er valproate overdose.
Overdose patients have been given L-carnitine in an attempt to increase valproate metabolism by betaoxidation, and this therapy appears to hasten the resolution of coma, prevent hepatic dysfunction, and
reverse mitochondrial metabolic abnormalities in patients with acute valproate intoxication.45,46,47
Administration of L-carnitine 100 milligrams/kg IV initially followed by infusions of 50 milligrams/kg every 8hours is recommended in cases of valproate toxicity with lethargy, coma, hyperammonemia, and hepatic
dysfunction.46 For patients receiving long-term valproate therapy, oral carnitine administration reversescarnitine deficiency, decreases elevated ammonia levels, and reduces lethargy.
Hemoperfusion and hemodiafiltration have been used to treat severe valproate overdose.48,49,50,51,52
Although valproate should not be amenable to dialysis due to significant protein binding, unbound (free)drug is markedly increased in overdose, and removal of valproate from this pool appears beneficial. During
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hemoperfusion and hemodiafiltration treatment, elimination half-life ranges from 1.7 to 3 hours comparedwith 4.8 to 21 hours in patients before and a�er extracorporeal therapy. Clinical comparison of extracorporeal
detoxification with supportive care reports a benefit to extracorporeal removal.53
DISPOSITION AND FOLLOW-UP
Assess valproate levels every few hours until a decline in the level is noted and the patient is asymptomatic.
SECOND- AND THIRD-GENERATION ANTICONVULSANTS
As a group, the second- and third-generation anticonvulsants are less toxic in acute overdose than the first-
generation agents, and most of the serious complications reported occur in cases of mixed ingestion.54 Somespecific acute toxic e�ects are noTable (Table 197-6).
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TABLE 197-6
Unique Aspects of Overdose With Second- and Third-Generation Anticonvulsants
Drug
(Generation)E�ects
Eslicarbazepine
acetate (3rd)*
Vertigo, ataxia, hemiparesis
Ezogabine or
retigabine (3rd)
Agitation, irritability, aggressive behavior
Felbamate (2nd) Crystalluria, hematuria, aplastic anemia, liver failure
Gabapentin (2nd) Drowsiness, ataxia, nausea, vomiting
Lacosamide (3rd) Limited experience; serious toxicity unlikely
Lamotrigine
(2nd)
Drowsiness, vomiting, ataxia, and dizziness; serious neurologic and cardiovascular
toxicity with co-ingestants; "Stevens-Johnson syndrome"
Levetiracetam
(2nd)
Lethargy, coma, respiratory depression
Oxcarbazepine
(2nd)
Little toxicity from isolated oxcarbazepine overdose
Pregabalin (2nd) Drowsiness and depressed level of consciousness
Rufinamide (2nd) Limited experience; serious toxicity unlikely
Stiripentol (2nd)* No information
Tiagabine (2nd) Rapid onset of lethargy, coma, seizures, and status epilepticus; myoclonus, muscular
rigidity, and delirium
Topiramate (2nd) Somnolence, vertigo, agitation, and mydriasis; seizures and status epilepticus;
metabolic acidosis
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*Not available in the United States as of March 2012.
Drug
(Generation)E�ects
Vigabatrin (2nd) Drowsiness, unconsciousness, coma
Zonisamide (2nd) Little toxicity from isolated zonisamide overdose
ESLICARBAZEPINE ACETATE
Eslicarbazepine acetate is a prodrug drug for eslicarbazepine, an anticonvulsant that stabilizes sodium-
dependent channels in their inactivated state.55,56 Eslicarbazepine acetate has a half-life of 10 to 20 hoursand possesses modest and possible clinically relevant drug interactions with phenytoin, carbamazepine, and
oral contraceptives.55,56,57 Symptoms of vertigo, ataxia, and hemiparesis have been observed a�eraccidental overdose. Eslicarbazepine acetate is available in Europe but not in the United States as of March2012.
EZOGABINE
Ezogabine (generic name in the United States) or retigabine (generic name in Europe) activates voltage-gated
potassium channels in the brain, a unique mechanism among the anticonvulsants.55,56,58 Ezogabine has ahalf-life of 6 to 10 hours and possesses drug interactions with phenytoin, carbamazepine, and
lamotrigine.55,56,57 Side e�ects seen with ezogabine therapy include dizziness, fatigue, confusion, tremor,
and ataxia.58 Increased rate of urinary retention and slight increase in QT interval have been reported. Thereis limited experience with overdose, but agitation, irritability, and aggressive behavior have been noted.
FELBAMATE
Felbamate was the first of the second-generation antiepileptics.54 However, shortly a�er its introduction in1993 it received a "black box warning" because of the association with aplastic anemia (with an incidence100 times higher than in the general population) and hepatic failure. Hence it is only recommended whenother treatment regimens have failed. The proposed mechanism of action of felbamate is inhibition at γ-aminobutyric acid receptors and excitation at N-methyl-d-aspartic acid receptors. Felbamate has a half-life of
20 to 23 hours and possesses drug intersections with the first-generation anticonvulsants and oralcontraceptives. In overdose, the symptoms are usually mild, but in large ingestions, felbamate can crystallize
in the kidney, producing crystalluria, hematuria, and possibly acute renal failure.59,60,61 Treatment issupportive.
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GABAPENTIN
Gabapentin, as its name suggests, increases γ-aminobutyric acid levels in the brain. It also has indirecte�ects on calcium channels located on the postsynaptic terminal. Gabapentin has a half-life of 5 to 9 hoursand possesses drug interactions with cimetidine and antacids. With an overdose, gabapentin produces little
toxicity, usually drowsiness, ataxia, nausea, and vomiting that resolve in about 10 hours.62 Depressed level ofconsciousness has been described in a patient with end-stage renal disease who ingested multiple doses ofgabapentin over 2 days without intervening hemodialysis; hemodialysis was associated with rapid
recovery.63 The only reported suicide from gabapentin overdose is controversial.64
LACOSAMIDE
Lacosamide a�ects voltage-gated sodium channels in the central nervous system.65 Lacosamide has a half-
life of 12 to 16 hours and has no significant drug interactions.56,57 During therapeutic use, adverse reactions
are usually mild to moderate and typically include dizziness, headache, nausea, and diplopia.65 There islimited clinical experience with lacosamide overdose, but serious toxicity a�er an isolated overdose wouldnot be expected to occur.
LAMOTRIGINE
Lamotrigine inhibits sodium channels in CNS neurons and likely has the same e�ect in the heart.55
Lamotrigine has a half-life of 15 to 35 hours and interacts with the first-generation antiepileptics.57
Autoimmune reactions, such as Stevens-Johnson syndrome, have occurred during therapeutic use. With anoverdose, the clinical course is usually benign, and the most common e�ects are drowsiness, vomiting,
ataxia, and dizziness.66,67 Serious neurologic and cardiovascular toxicity is rare, but has been reported a�er
lamotrigine overdose, sometimes with coingestants.68,69,70,71,72 Neurologic toxicity includes oculogyric
crisis, provoking of seizures,70,74,75,76,77 status epilepticus, and coma. Cardiac toxicity includes QRS complex
widening,78 AV nodal block,79 and cardiovascular collapse.72,77 Acute pancreatitis has been reported in
association with a lamotrigine overdose.80 Treatments used in lamotrigine overdose include activated
charcoal to reduce absorption,81 sodium bicarbonate for QRS complex widening, magnesium sulfate for QTinterval prolongation, and IV lipid emulsion to remove active drug from binding sites and sequester it in a
lipid sink.82,83
LEVETIRACETAM
The mechanism of action of levetiracetam is not known. Levetiracetam has a half-life of 6 to 8 hours andpossesses drug interaction only with phenytoin. During therapeutic use, the major side e�ect is somnolence,
usually seen during the initial 4 weeks of therapy.84 There are few reports of levetiracetam overdose, and the
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most common symptom is lethargy that can progress to coma and respiratory depression.85,86,87,88
Recovery is usually rapid with supportive care alone.
OXCARBAZEPINE
Oxcarbazepine inhibits voltage-sensitive sodium channels in the nervous system.89 Oxcarbazepine has a
half-life of 8 to 15 hours and interacts with phenytoin, lamotrigine, and oral contraceptives.56,57 Duringtherapeutic use, hyponatremia and drug rash can be seen. There appears to be little toxicity from isolatedoxcarbazepine overdose; most of the serious neurologic depression has been seen with mixed
ingestions.90,91,92,93
PREGABALIN
Pregabalin has a mechanism of action similar to that of gabapentin, increasing γ-aminobutyric acid levels inthe brain in addition to having indirect e�ects on calcium channels located on the postsynaptic terminal.Pregabalin has a half-life of 5 to 7 hours and possesses drug interactions with ethanol, lorazepam, and
oxycodone.56,57 During long-term therapeutic use, the most commonly reported side e�ects are somnolenceand dizziness; serious adverse e�ects are rare. There is little reported experience with pregabalin overdose;
depressed level of consciousness appears to be the major symptom.94,95 Similar to the experience withgabapentin, toxicity from pregabalin has been reported in patients with end-stage renal failure but resolves
with dialysis.96
RUFINAMIDE
Rufinamide inhibits the activity of sodium channels, prolonging their inactive state.97 Rufinamide has a half-life of 6 to 10 hours and has drug interactions with other anticonvulsants—phenytoin, carbamazepine,
valproate, phenobarbital, and lamotrigine—as well as with oral contraceptives.56,57 During long-termtherapy, commonly reported adverse reactions include headache, dizziness, fatigue, and somnolence. Thereis limited clinical experience with rufinamide overdose, but given the lack of symptoms seen with doses ofmore than six times the recommended amount, toxicity would not be expected a�er an isolated overdose.
STIRIPENTOL
Stiripentol inhibits the reuptake of γ-aminobutyric acid into the presynpatic neuron, thereby increasing γ-aminobutyric acid concentrations in the synaptic cle� and promoting γ-aminobutyric acid activity.Stiripentol has a half-life of 5 to 13 hours and possesses modest drug interactions with valproate and
clobazam.56,57 Side e�ects during therapeutic use include drowsiness, ataxia, tremor, anorexia, nausea, andvomiting. Transient aplastic anemia and leukopenia have occurred. There is no information on clinicaloverdose with this medication. Stiripentol is available in Europe and Canada, but not in the United States asof March 2012.
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TIAGABINE
Tiagabine inhibits the reuptake of γ-aminobutyric acid into the presynpatic neuron, thereby increasing γ-aminobutyric acid concentrations in the synaptic cle� and promoting γ-aminobutyric acid activity. Tiagabinehas a half-life of 5 to 8 hours and interacts with most of the first-generation antiepileptics, including
phenytoin, valproate, carbamazepine, phenobarbital, and primidone.56,57 In overdose, tiagabine can cause
the rapid onset of neurologic toxicity, including lethargy, coma, and seizures.98,99,100,101 Tiagabine overdose
can provoke status epilepticus, even in patients without an underlying seizure disorder.102,103,104,105 Other
signs seen in tiagabine overdose include myoclonus, muscular rigidity, and delirium.98 Recovery usuallyoccurs in about 24 hours.
TOPIRAMATE
Topiramate inhibits γ-aminobutyric acid receptors in addition to a�ecting sodium channels in the brain.Topiramate has a half-life of 20 to 30 hours and possesses drug interactions with other anticonvulsants—phenytoin, valproate, carbamazepine, phenobarbital, and primidone—as well as with oral
contraceptives.56,57 Adverse e�ects observed during therapeutic use include promotion of renal stoneformation and glaucoma. In overdose, topiramate can produce somnolence, vertigo, agitation, and
mydriasis.106,107,108 Seizures and status epilepticus have been reported.109,110 A unique aspect of
topiramate overdose is the production of a non-anion gap metabolic acidosis.111,112,113 The cause isinhibition of renal carbonic anhydrase, and because of the long half-life of topiramate, metabolic acidosiscan last up to 7 days. However, this e�ect is completely reversible, and no permanent sequelae have beenseen.
VIGABATRIN
Vigabatrin is a structural analog of γ-aminobutyric acid that increases brain concentrations of thisneurotransmitter. Vigabatrin has a half-life of 5 to 7 hours and has a modest drug interaction with
phenytoin.56,57,114 During chronic therapy, vigabatrin may worsen mood and exacerbate psychosis.Sedation, headache, and weight gain are common side e�ects. A�er acute overdose, drowsiness,
unconsciousness, and coma are described in the majority of cases.115
ZONISAMIDE
Zonisamide inhibits voltage-sensitive sodium channels in CNS - neurons.116 Zonisamide has a long half-life,50 to 70 hours, and possesses drug interactions with most of the first-generation antiepileptics, including
phenytoin, valproate, carbamazepine, phenobarbital, and primidone.56,57 Serious adverse e�ects duringtherapeutic use include the promotion of renal stone formation and a drug-induced rash. Isolated
zonisamide overdose is associated with lethargy.117,118 A death ascribed to zonisamide overdose was
actually a mixed ingestion that included mirtazapine, diphenhydramine, and ca�eine.119
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USEFUL WEB RESOURCES
American Association of Poison Control Centers—http://www.aapcc.org/DNN/
American Academy of Clinical Toxicology—http://www.clintox.org/index.cfm
European Association of Poisons Centres and Clinical Toxicologists—http://www.eapcct.org/
Asia Pacific Association of Medical Toxicology—http://www.asiatox.org/
South Asian Clinical Toxicology Research Collaboration—http://www.sactrc.org/
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TOXBASE: The primary clinical toxicology database of the National Poisons Information Service (free accessfor UK National Health Service hospital departments and general practices, and National Health Servicedepartments of public health and health protection agency units; available to hospital EDs in Ireland bycontract; available to European poison centers whose sta� are members of the European Association ofPoisons Centres and Clinical Toxicologists; overseas users may be allowed access on payment of a yearlysubscription, subject to the approval of the Health Protection Agency)—http://www.toxbase.org/
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