- USES: Succinimide derivatives are anticonvulsants used to control absence (petit mal) seizures. PHARMACOLOGY: Succinimides suppress activity associated with lapses of consciousness by depressing the motor cortex and elevating the CNS threshold to convulsive stimuli. TOXICOLOGY: Methsuximide toxicity may follow a biphasic profile with extended CNS depression. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours. The accumulation of the active metabolite N-desmethylmethsuximide may be responsible for the recurrence of coma. EPIDEMIOLOGY: Overdose is rarely reported. MILD TO MODERATE TOXICITY: Mild to moderate toxicity may cause nausea and vomiting. SEVERE TOXICITY: Severe effects of acute toxicity include CNS depression, respiratory depression, and coma. ADVERSE EFFECTS: COMMON: The most frequent effects with succinimide use include nausea, vomiting, anorexia, diarrhea, weight loss, epigastric pain, abdominal pain, drowsiness, ataxia, and dizziness. ADVERSE EFFECTS: LESS COMMON AND RARE: Less common and rare adverse effects include: leukopenia, agranulocytosis, pancytopenia (with or without bone marrow suppression), eosinophilia, monocytosis, psychosis, depression or suicidal behavior, aggressiveness, Stevens-Johnson syndrome, and sleep disturbances. Gum hypertrophy, tongue swelling, night terrors, lack of concentration, hirsutism, vaginal bleeding, hematuria and systemic lupus erythematosus have been reported with the use of ETHOSUXIMIDE. Auditory hallucinations, blurred vision, headache, photophobia, proteinuria, hyperemia, and periorbital edema have been reported with METHSUXIMIDE use.
Range of Toxicity:
- TOXICITY: Toxic doses are variable depending on the particular agent. Specific toxic doses have not been determined. A 10-year-old boy developed psychiatric symptoms including headaches, insomnia, visual hallucinations, paranoia, and suicidal thoughts following 2 weeks of ETHOSUXIMIDE at 750 mg twice daily. THERAPEUTIC DOSE: ETHOSUXIMIDE: 6 YEARS OF AGE AND OLDER: Initial dose is 500 mg/day orally. The dose may be increased in small increments (eg, 250 mg every 4 to 7 days) until desired control is achieved. Dose should not exceed 1.5 g daily without strict physician supervision. PEDIATRIC: 3 TO 6 YEARS OF AGE: The optimal dose for the pediatric population is 20 mg/kg/day orally. METHSUXIMIDE: ADULT: Therapy must be individualized by trial based on response. A suggested dose for the initial week of therapy is 300 mg/day orally. The dose may be increased by 300 mg/day every week for 3 weeks to a maximum of 1.2 g/day. PEDIATRIC: 10 to 20 mg/kg/day; adjust as necessary to achieve therapeutic drug levels. PHENSUXIMIDE: ADULT: 500 to 1000 mg orally 2 to 3 times daily, titrated to response.
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. MANAGEMENT OF SEVERE TOXICITY: Treatment is symptomatic and supportive. Methsuximide toxicity may follow a biphasic profile with extended CNS depression. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours. Monitor mental status. Perform early intubation in patients with a declining level of consciousness. Patients with mixed types of epilepsy or abrupt withdrawal of these agents can precipitate seizures. Treat seizures with IV benzodiazepines, barbiturates.
- Decontamination: PREHOSPITAL: GI decontamination is not recommended because of the risk of CNS depression and aspiration. HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is alert and able to maintain airway.
- Airway management: Ensure adequate ventilation and perform endotracheal intubation early in patients with serious toxicity or significant CNS or respiratory depression.
- Antidote: None.
- Seizure: The use of these agents in patients with mixed types of epilepsy can increase the frequency of grand mal seizures or abrupt withdrawal of these agents may precipitate petiti mal seizures. Administer benzodiazepines, barbiturates.
- Myelosuppression: Severe neutropenia: filgrastim 5 mcg/kg/day IV or SubQ or sargramostim 250 mcg/m(2)/day IV infused over 4 hours. Monitor serial CBC with differential. Transfusions as needed for severe thrombocytopenia, bleeding.
- Monitoring of patient: Monitor mental status and vital signs. CNS depression and coma may develop. Methsuximide toxicity may follow a biphasic profile with extended CNS depression. Following an initial comatose state, patients have awakened and then relapsed into a coma within 24 hours. Serum concentrations of these drugs are not readily available. Obtain a CBC with differential , particularly if signs or symptoms of infection (eg, sore throat or fever) develop. Monitor urinalysis for proteinuria or hematuria. Monitor liver enzymes serum electrolytes and renal function in symptomatic patients.
- Enhanced elimination procedure: ETHOSUXIMIDE: Early hemodialysis would be expected to effectively clear ethosuximide. METHSUXIMIDE: Charcoal hemoperfusion may effectively remove the N-desmethyl metabolite of methsuximide. Exchange transfusions and forced diuresis are unlikely to be effective for removing ETHOSUXIMIDE or the N-desmethyl metabolite of METHSUXIMIDE.
- Patient disposition: HOME CRITERIA: Children with inadvertent ingestion of up to the therapeutic pediatric dose, and adults with inadvertent ingestion of an extra dose who have minimal symptoms can be managed at home. OBSERVATION CRITERIA: Patients with deliberate overdose, those with more than mild symptoms, and children who have ingested more than a therapeutic dose for age should be sent to a healthcare facility for evaluation. ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted. Patients who develop CNS depression after methsuximide overdose should be admitted as recurrent CNS depression may develop. CONSULT CRITERIA: Consult a Poison Center for assistance in managing patients with severe toxicity or for whom the diagnosis is unclear.