Anticonvulsant Toxicity


First Generation Second Generation
Carbamazepine Felbamate
Ethosuximide Gabapentin
Phenobarbital Lacosamide
Phenytoin Lamotrigine
Primidone Levetiracetam
Valproate Oxcarbazepine
  Pregabalin
  Rufinamide
  Topiramate
  Tiagabine
  Zonisamide
 

Phenytoin and Fosphenytoin

Protein Binding:
  • Phenytoin is extensively (90%) bound to plasma proteins, especially albumin. The free, unbound form is the biologically active moiety responsible for the drug's clinical effect and toxicity.
  • The unbound fraction of the drug is greater in the following groups of patients:
    • neonates; the elderly; pregnant women; individuals with uremia, hypoalbuminemia (cirrhosis, nephrosis, malnutrition, burns, trauma, or cystic fibrosis), and hyperbilirubinemia; and individuals taking drugs that displace phenytoin from binding sites (salicylate, valproate, phenylbutazone, tolbutamide, and sulfisoxazole).
  • Patients with decreased protein binding may have higher levels of free phenytoin and experience a greater biologic effect despite lower levels of total phenytoin. Such patients may show toxicity with total phenytoin levels in the therapeutic range.
  • Free phenytoin levels should be measured in patients who exhibit toxic signs in the therapeutic dosage range.

Metabolism:

  • After absorption and distribution, only 4% to 5% of phenytoin is excreted unchanged in the urine. The remainder is metabolized by hepatic microsomal enzymes.
Phenytoin increases serum levels of  Phenytoin levels are increased by 
  Acetaminophen   Amiodarone
  Acetazolamide   Chloramphenicol
  Amiodarone   Cimetidine
  Oral contraceptives   Disulfiram
  Primidone   Fluconazole
  Zidovudine   Isoniazid
Phenytoin increases toxicity of    Oral anticoagulants
  Carbamazepine   Phenylbutazone*
  Oral anticoagulants   Salicylate (high dose)*
Phenytoin decreases serum levels of    Trimethoprim
  Cyclosporine Phenytoin levels are decreased by 
  Disopyramide   Antineoplastic drugs
  Doxycycline   Calcium
  Ethanol (chronic use)   Ethanol
  Furosemide   Diazepam
  Glucocorticoids   Diazoxide
  Levodopa   Folic acid
  Methadone   Phenobarbital
  Mexiletine   Rifampin
  Quinidine   Sucralfate
  Theophylline   Sulfonamides*
  Valproate   Theophylline
    Tolbutamide*
    Valproate*


Toxicity:

  • The IV administration of phenytoin carries the greatest risk.
  • The most serious reactions after IV administration are cardiovascular (bradycardia, hypotension, and asystole), although tissue necrosis and sloughing after extravasation have been described.
    • Major cardiac toxicity occurs only after parenteral administration; in general, oral overdose does not lead to cardiovascular morbidity.
    • Cardiovascular toxicity is more common in the elderly and those with underlying cardiac disease, but has been described in young healthy patients.
  • Many of the side effects of the oral preparation are dose related and are predictable at higher plasma concentrations.
  • Early toxicity is manifested by vestibular, ocular, or cerebellar signs:
    • nystagmus, dysdiadochokinesia, and ataxia.
    • At higher levels, central nervous system depression and other cognitive effects (confusion, dizziness, and loss of concentration and memory) are seen.
  • Only two areas of the brain normally exhibit spontaneous neuronal burst discharge: the hippocampus and the cerebellum.
    • The ability of phenytoin to suppress these areas may result in impaired memory and balance, respectively.
  • Paradoxically, very high levels of phenytoin may be associated with seizures, although this is, at most, a rare occurrence.
  • Acute oral overdose usually manifests as nystagmus, nausea and vomiting, ataxia, dysarthria, choreoathetosis, opisthotonos, and neurologic depression or excitation.
  • Deaths from oral ingestion of phenytoin are extremely rare, and coingestants are usually involved.
  • The long-term administration of phenytoin is associated with numerous side effects that involve a variety of organ systems. Many of these effects depend on dose and duration, but some are idiosyncratic.
  • Hypersensitivity reactions to phenytoin usually occur within the first few months of therapy and include fever, skin rashes, blood dyscrasia, and, rarely, hepatitis.
  • Deaths have occurred due to a Stevens-Johnson–like syndrome, possibly on a continuum with anticonvulsant hypersensitivity syndrome. Patients with a history of this syndrome should never receive phenytoin again.
  • The adverse and toxic effects of fosphenytoin are the same as those of phenytoin itself.
    • IV fosphenytoin can cause pruritus (most commonly reported in the perineum), although phlebitis and pain at the injection site are much less common than with phenytoin.
    • Paresthesias are common in patients treated with fosphenytoin

Serum Levels and Range of Toxicity:

Plasma Level (micrograms/mL) Side Effects
<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

Clinical Features of Phenytoin Toxicity:

Central nervous system effects Dizziness, tremor (intention), visual disturbance, horizontal and vertical nystagmus, diplopia, miosis or mydriasis, ophthalmoplegia, abnormal gait (bradykinesia, truncal ataxia), choreoathetoid movements, vomiting, dysphagia, irritability, agitation, confusion, hallucinations, fatigue, coma, encephalopathy, pseudodegenerative disease, dysarthria, meningeal irritation with pleocytosis, seizures (rare)
Peripheral nervous system effects Peripheral neuropathy, urinary incontinence
Hypersensitivity reactions (anticonvulsant hypersensitivity syndrome) Eosinophilia, rash, pseudolymphoma (diffuse lymphadenopathy), systemic lupus erythematosus, pancytopenia, hepatitis, pneumonitis
GI effects Nausea and vomiting, hepatotoxicity
Dermatologic effects Hirsutism, acne, rashes (including Stevens-Johnson syndrome)
Other effects Fetal hydantoin syndrome, gingival hyperplasia, coarsening of facial features, hemorrhagic disease of the newborn, hyperglycemia, hypocalcemia
Parenteral toxicity May cause


Treatment

  1. Initial treatment of severe oral phenytoin overdose is establishment of IV access and airway management.
  2. Acidosis (respiratory or metabolic) should be corrected to decrease the active free phenytoin fraction.
  3. Multiple doses of oral activated charcoal (1 gram/kg) within the first 24 hours may be of benefit, as demonstrated in volunteers.
  4. Seizures may be treated with IV benzodiazepines with the caution that seizures are not common in phenytoin overdose and other causes should be considered.
  5. Cardiovascular toxicity is extremely rare in oral overdose and should suggest other causes.
  6. Unfortunately, phenytoin has high protein binding, so hemodialysis removes only minute amounts and is almost never clinically useful.
  7. Cardiac monitoring after isolated oral ingestion is unnecessary.
  8. Atropine and temporary cardiac pacing may be used for symptomatic bradyarrhythmias associated with IV phenytoin.
  9. Hypotension that occurs during IV administration of phenytoin or fosphenytoin usually responds to discontinuation of the infusion and administration of isotonic crystalloid

Disposition and Follow-Up:

  • Given the long and erratic absorption phase of phenytoin after oral overdose, the decision to discharge or medically clear a patient for psychiatric evaluation cannot be based on one serum level.
  • After acute ingestions, serum level should be measured every few hours.
  • Patients with serious complications after an oral ingestion (seizures, coma, altered mental status, or significant ataxia) should be admitted for further evaluation and treatment.
  • Those with only mild symptoms may be observed in the ED and discharged once their levels of phenytoin are declining.
  • Mental health or psychiatric evaluation should be obtained, as indicated, in cases of intentional overdose.
  • Prolonged observation and frequent assessment of drug levels are not practical in many EDs. Thus, patients with continuing symptoms may need to be admitted or followed in an observation unit.
  • 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 the patient's last therapeutic dose.
  • Phenytoin therapy should be stopped in all cases, and if toxicity continues to resolve, serum level may be reassessed in 2 to 3 days to guide resumption of therapy.
  • Patients with significant or persistent complications after the IV administration of phenytoin or fosphenytoin should be admitted.
  • Appropriate surgical consultation should be obtained for patients with any significant extravasation of IV phenytoin or other signs of local vascular or tissue toxicity after infusion.
  • Those with transient effects, such as hypotension, may safely be discharged



     

Carbamazepine

1

Valproate

1

Second-Generation Anticonvulsants

Drug Effects
Felbamate Crystalluria, hematuria, and possibly acute renal failure
Gabapentin Drowsiness, ataxia, nausea, vomiting
Lacosamide Limited experience; serious toxicity unlikely
Lamotrigine Drowsiness, vomiting, ataxia, and dizziness; serious neurologic and cardiovascular toxicity with coingestants
Levetiracetam Lethargy, coma, respiratory depression
Oxcarbazepine Little toxicity from isolated oxcarbazepine overdose
Pregabalin Drowsiness and depressed level of consciousness
Rufinamide Limited experience; serious toxicity unlikely
Tiagabine Rapid onset of lethargy, coma, seizures, and status epilepticus; myoclonus, muscular rigidity, and delirium
Topiramate Somnolence, vertigo, agitation, and mydriasis; seizures and status epilepticus; metabolic acidosis
Zonisamide Little toxicity from isolated zonisamide overdose

Felbamate was the first of the second-generation antiepileptics and was introduced in 1993. The proposed mechanism of action of felbamate is inhibition at -aminobutyric acid receptors and excitation at N-methyl-d-aspartic acid receptors. Felbamate has a half-life of 14 to 24 hours and shows drug interactions with some other antiepileptics, namely, phenytoin, valproate, carbamazepine, and gabapentin. Serious side effects observed during therapeutic use include aplastic anemia and hepatic failure. 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.46–48 Treatment with IV hydration has been reported to be successful.

Gabapentin is, as its name suggests, an agent that increases -aminobutyric acid levels in the brain. It also has indirect effects on calcium channels located on the postsynaptic terminal. Gabapentin has a short half-life, around 5 to 9 hours. Gabapentin has reported drug interactions with cimetidine and antacids, but no significant serious adverse effects have been seen during therapeutic use. With an overdose, gabapentin produces little toxicity—usually drowsiness, ataxia, nausea, and vomiting that resolve in about 10 hours.49,50 Depressed level of consciousness has been described in a patient with end-stage renal disease who ingested multiple doses of gabapentin over 2 days without intervening hemodialysis; hemodialysis was associated with rapid recovery.

Lacosamide affects voltage-gated sodium channels in the central nervous system. Lacosamide has a half-life of 15 to 24 hours and appears not to have any significant drug interactions. During therapeutic use, adverse reactions are usually mild to moderate and typically include dizziness, headache, nausea, and diplopia. There is limited clinical experience with lacosamide overdose, but serious toxicity after an isolated overdose would not be expected to occur.

Lamotrigine inhibits sodium channels in the central nervous system neurons and likely has the same effect in the heart. Lamotrigine has a half-life of 15 to 35 hours and interacts with most first-generation antiepileptics, including phenytoin, valproate, carbamazepine, and phenobarbital. During therapeutic use, lamotrigine has been associated with autoimmune reactions, such as Stevens-Johnson syndrome. With an overdose, the clinical course is usually benign, and the most common effects are drowsiness, vomiting, ataxia, and dizziness. However, serious neurologic and cardiovascular toxicity has been reported following lamotrigine overdose, usually with coingestants. Neurologic toxicity can include provoking of seizures, status epileptics, and coma.60 Cardiac toxicity can include QRS-complex widening and QT-interval prolongation.61 Acute pancreatitis has been reported in association with a lamotrigine overdose. Treatments used in lamotrigine overdose include sodium bicarbonate for QRS-complex widening, magnesium sulfate for QT-interval prolongation, and IV lipid emulsion to remove active drug from binding sites and sequester it in a lipid sink.

Levetiracetam does not have an understood mechanism of action for its anticonvulsant properties. Levetiracetam has a short half-life, 6 to 8 hours, and has a drug interaction only with phenytoin. During therapeutic use, the major side effect is somnolence, usually seen during the initial 4 weeks of therapy. There are few reports of levetiracetam overdose, and the most common symptom is lethargy that can progress to coma and respiratory depression.64–66 Recovery is usually rapid with supportive care alone.

Oxcarbazepine inhibits voltage-sensitive sodium channels in the nervous system.67 Oxcarbazepine has a half-life of 8 to 15 hours and interacts with phenytoin, lamotrigine, and oral contraceptives. During therapeutic use, hyponatremia and drug rash have been seen. There appears to be little toxicity from isolated oxcarbazepine overdose; most of the serious neurologic depression has been seen with mixed ingestions.

Pregabalin has a mechanism of action similar to that of gabapentin, increasing -aminobutyric acid levels in the brain in addition to having indirect effects on calcium channels located on the postsynaptic terminal. Pregabalin has a short half-life of 5 to 7 hours and shows drug interactions with ethanol, lorazepam, and oxycodone. During long-term therapeutic use, the most commonly reported side effects are somnolence and dizziness; serious adverse effects are rare. There is little reported experience with pregabalin overdose; depressed level of consciousness appears to be the major symptom. Similar to the experience with gabapentin, toxicity from pregabalin has been reported in patients with end-stage renal failure but resolves with dialysis.

Rufinamide inhibits the activity of sodium channels, prolonging their inactive state. 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. During long-term therapy, commonly reported adverse reactions include headache, dizziness, fatigue, and somnolence. There is limited clinical experience with rufinamide overdose, but given the lack of symptoms seen with doses of more than six times the recommended amount, toxicity would not be expected to occur after an isolated overdose.

Tiagabine inhibits the reuptake of -aminobutyric acid into the presynpatic neuron, thereby increasing -aminobutyric acid concentrations in the synaptic cleft and promoting -aminobutyric acid activity. Tiagabine has a short half-life, 5 to 8 hours, and interacts with most of the first-generation antiepileptics, including phenytoin, valproate, carbamazepine, phenobarbital, and primidone. In overdose, tiagabine has the ability to cause the rapid onset of neurologic toxicity, including lethargy, coma, and seizures. Tiagabine overdose can provoke status epilepticus, even in patients without an underlying seizure disorder.80–83 Other signs seen in tiagabine overdose include myoclonus, muscular rigidity, and delirium.76 Recovery usually occurs in about 24 hours.

Topiramate inhibits -aminobutyric acid receptors in addition to affecting sodium channels in the brain. Topiramate has a relatively long half-life of 20 to 30 hours and has drug interactions with other anticonvulsants—phenytoin, valproate, carbamazepine, phenobarbital, and primidone—as well as with oral contraceptives. Serious adverse effects observed during therapeutic use include promotion of renal stone formation and glaucoma. In overdose, topiramate can produce somnolence, vertigo, agitation, and mydriasis. Seizures and status epileptics have been reported.87 A unique aspect of topiramate overdose is the production of a metabolic acidosis.88–91 The cause appears to be inhibition of renal carbonic anhydrase, which creates a non–anion gap metabolic acidosis that, because of the long half-life of topiramate, can last up to 7 days. However, this effect is completely reversible, and no permanent sequelae have been seen.

Zonisamide inhibits voltage-sensitive sodium channels in central nervous system neurons. Zonisamide has a long half-life, 50 to 70 hours, and shows drug interactions with most of the first-generation antiepileptics, including phenytoin, valproate, carbamazepine, phenobarbital, and primidone. Serious adverse effects during therapeutic use include the promotion of renal stone formation and a drug-induced rash. There is little reported experience with zonisamide overdose, and the one reported death ascribed to zonisamide overdose was actually a mixed ingestion that included mirtazapine, diphenhydramine, and caffeine.
 
 

 

 

 

 

 





Source: Tintinalli ED 7th.