Ethosuximide

Article Author:
Brian Hanrahan
Article Editor:
Robert Carson
Updated:
10/3/2019 2:25:10 PM
PubMed Link:
Ethosuximide

Indications

Ethosuximide is FDA approved for the management of absence seizures in patients over 3 years of age. Currently, there are no off label uses for ethosuximide, however, there is some evidence it may have some analgesic effects. Specifically, several studies have suggested value in the management of neuropathic pain.[1][2][3]

Ethosuximide has level A evidence for childhood absence seizures and has been known to be an effective medication in the management of absence seizures in humans since the 1960s and 1970s.[4][5] A landmark trial in 2010 showed that ethosuximide and valproic acid were more effective than lamotrigine for the management of childhood absence seizures[6]. Seizure freedom rates for ethosuximide and valproic acid were 53% and 58% respectively. These patients were then followed for 12 months to evaluate their long term outcomes. This data was published in 2013, showing that ethosuximide had better tolerability than valproic acid.[7] Similar data has been found in adolescents.[8] Due to its effectiveness and relatively limited side effect profile as outlined above, ethosuximide is considered the first line therapy for absence epilepsy. If a patient continues to be refractory to ethosuximide monotherapy, valproic acid can to added to increase the likelihood of seizure control. 

While ethosuximide is effective for absence seizures, it otherwise has a very narrow therapeutic profile. It has no benefit in symptomatic epilepsies or other generalized epilepsies. If a patient has concurrent generalized tonic-clonic (GTC) seizures, valproic acid is recommended over ethosuximide as initial monotherapy since ethosuximide does not control GTC seizures and can potentially exacerbate them. 

Mechanism of Action

Ethosuximide (3-ethyl-3-methyl pyrrolidine-2,5-dione) is one of three succinimides known to have anticonvulsant properties. The other two succinimides, phensuximide and methsuximide, have worse side effect profiles and are less effective than ethosuximide.[9] Studies of this class of organic compounds first took place in the 1950s in mouse models. 

Thalamocortical neurons are hypothesized to be generators of the classic 3 Hz spike-and-wave discharges seen with absence seizures and rely heavily on low threshold T-type calcium channels to do so. Ethosuximide is able to lower the threshold of T-type calcium currents and disrupt the oscillatory activity of thalamocortical circuitry by blocking T-type calcium channels.

Administration

Ethosuximide administration is via 250mg capsules or a 250mg/5mL oral suspension. The oral suspension has a faster absorption rate than the capsules. 

Dosing should start at 125mg BID for children between ages 3-6. Children above the age of 6 and adults can start at 250 mg BID. Dosing can then be increased by 250mg every 4 to 7 days to 20 mg/kg/day divided BID. Serum concentrations of ethosuximide follow linear kinetics with increasing doses. The maximum dose is 1500 mg/day. Patients on hemodialysis may require additional doses before or after their treatments to maintain therapeutic levels. When being discontinued, it should be tapered off slowly as abrupt withdrawal may precipitate absence status epilepticus.

Ethosuximide has excellent bioavailability (over 90%). It has negligible protein binding once it enters the bloodstream and readily crosses the blood-brain barrier.[10] It is hepatically metabolized (80%) primarily by CYP3A4 into inactive metabolites. About 10 to 20% may be excreted unchanged in the urine. It has a relatively long half-life; 30 hours in children and 50 to 60 hours in adults. Because of its long half-life, ethosuximide can take several days (7 to 10) to reach a steady state. 

Adverse Effects

The overall rate of adverse side effects with ethosuximide use is less than most other AEDs (26 to 46%). Gastrointestinal side effects (nausea, vomiting, diarrhea, and anorexia) are a common initial side effect which often diminishes after 1 to 2 weeks. Other common side effects include drowsiness, lethargy, insomnia, and hiccups. Headache can occur in 14% of children on ethosuximide. 

Reports exist of rare idiosyncratic reactions Stevens-Johnson syndrome, agranulocytosis, aplastic anemia, and systemic lupus erythematosus.[11][12] Discontinuation of ethosuximide is necessary if any idiosyncratic reactions occur. Recovery may take time but usually occurs with discontinuation. 

Contraindications

Patients with hypersensitivity to succinimides should avoid taking ethosuximide.  Its use requires caution in patients with hepatic and renal disease.

Monitoring

There are no guidelines for therapeutic drug monitoring of ethosuximide. Dosing can be adjusted purely on the patient's clinical response to a particular dose and electroencephalogram (EEG). Ethosuximide levels checking is done as a trough. The therapeutic range for ethosuximide is between 40 to 100 mcg/ml. Higher levels than 100 mcg/ml are usually tolerable without toxicity. Patients in absence status epilepticus may need serum concentrations higher than 120 mcg/ml to achieve seizure control.[10] Complete blood counts (CBC) and liver function tests (LFT) can also be checked intermittently to monitor for severe but rare hematologic dyscrasias (pancytopenia, agranulocytosis, leukopenia) despite no evidence that this is sufficient to alert physicians about this potential serious idiosyncratic reaction.

Enzyme-inducing antiepileptic drugs (AEDs) such as phenytoin, carbamazepine, and phenobarbital can reduce serum concentrations of ethosuximide by accelerating its elimination.[13] The effect of valproic acid on ethosuximide concentrations can be variable.[14][15][16][17] Ethosuximide may increase phenytoin levels, but it has no enzyme-inducing properties. 

Isoniazid may reduce ethosuximide metabolism, while rifampicin can increase ethosuximide clearance.[18][19]

Toxicity

Mouse models suggest symptoms of ethosuximide toxicity begin with incoordination and can progress to dyspnea, respiratory failure, and death.[20] Comparably, overdose in humans can lead to coma and respiratory depression. Recommendations are that patients with an acute overdose of ethosuximide should be observed in an emergency room or inpatient setting, with supportive care if needed.[21] Hemodialysis can be a safe and effective way to rapidly clear ethosuximide from the body.[22]

Ethosuximide is a category C drug (possibly unsafe in pregnancy) that is known to cross the placenta; Serum concentrations of ethosuximide in neonates are comparable to that of the mothers.[23] Recommendations are that during pregnancy, ethosuximide should be used as monotherapy with the lowest effective dose when possible. Levels could be checked pre-pregnancy and then monitored intermittently during pregnancy. Ethosuximide can be excreted in breastmilk at concentrations comparable to maternal serum. Because of this, breastfeeding while on ethosuximide is considered potentially hazardous.

Enhancing Healthcare Team Outcomes

Primary care physicians commonly are the first medical care providers to be informed about staring episodes or poor school performance suggesting absence seizures, prompting a referral to neurology. After making a diagnosis of absence epilepsy, and initiating ethosuximide, primary care physicians and neurologists should both monitor for clinical benefit from ethosuximide therapy. If a patient remains seizures free for over two years while on ethosuximide, and if the patient's EEG has normalized, one could consider slowly tapering the medication off over weeks to see if the patient developed terminal remission. 


References

[1] Flatters SJ,Bennett GJ, Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain. 2004 May;     [PubMed PMID: 15082137]
[2] Dogrul A,Gardell LR,Ossipov MH,Tulunay FC,Lai J,Porreca F, Reversal of experimental neuropathic pain by T-type calcium channel blockers. Pain. 2003 Sep;     [PubMed PMID: 14499432]
[3] Hamidi GA,Ramezani MH,Arani MN,Talaei SA,Mesdaghinia A,Banafshe HR, Ethosuximide reduces allodynia and hyperalgesia and potentiates morphine effects in the chronic constriction injury model of neuropathic pain. European journal of pharmacology. 2012 Jan 15;     [PubMed PMID: 22134003]
[4] Weinstein AW,Allen RJ, Ethosuximide treatment of petit mal seizures. A study of 87 pediatric patients. American journal of diseases of children (1960). 1966 Jan;     [PubMed PMID: 4954419]
[5] Browne TR,Dreifuss FE,Dyken PR,Goode DJ,Penry JK,Porter RJ,White BG,White PT, Ethosuximide in the treatment of absence (peptit mal) seizures. Neurology. 1975 Jun;     [PubMed PMID: 805382]
[6] Glauser TA,Cnaan A,Shinnar S,Hirtz DG,Dlugos D,Masur D,Clark PO,Capparelli EV,Adamson PC, Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. The New England journal of medicine. 2010 Mar 4;     [PubMed PMID: 20200383]
[7] Glauser TA,Cnaan A,Shinnar S,Hirtz DG,Dlugos D,Masur D,Clark PO,Adamson PC, Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia. 2013 Jan;     [PubMed PMID: 23167925]
[8] Brigo F,Igwe SC, Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents. The Cochrane database of systematic reviews. 2017 Feb 14;     [PubMed PMID: 28195639]
[9] GOLDENSOHN ES,HARDIE J,BOREA ED, Ethosuximide in the treatment of epilepsy. JAMA. 1962 Jun 9;     [PubMed PMID: 13899742]
[10] Patsalos PN,Berry DJ,Bourgeois BF,Cloyd JC,Glauser TA,Johannessen SI,Leppik IE,Tomson T,Perucca E, Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008 Jul;     [PubMed PMID: 18397299]
[11] Glauser TA, Idiosyncratic reactions: new methods of identifying high-risk patients. Epilepsia. 2000;     [PubMed PMID: 11092609]
[12] Teoh PC,Chan HL, Lupus-scleroderma syndrome induced by ethosuximide. Archives of disease in childhood. 1975 Aug;     [PubMed PMID: 812426]
[13] Giaccone M,Bartoli A,Gatti G,Marchiselli R,Pisani F,Latella MA,Perucca E, Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients. British journal of clinical pharmacology. 1996 Jun;     [PubMed PMID: 8799524]
[14] Bauer LA,Harris C,Wilensky AJ,Raisys VA,Levy RH, Ethosuximide kinetics: possible interaction with valproic acid. Clinical pharmacology and therapeutics. 1982 Jun;     [PubMed PMID: 6804151]
[15] Pisani F,Narbone MC,Trunfio C,Fazio A,La Rosa G,Oteri G,Di Perri R, Valproic acid-ethosuximide interaction: a pharmacokinetic study. Epilepsia. 1984 Apr;     [PubMed PMID: 6423377]
[16] Mattson RH,Cramer JA, Valproic acid and ethosuximide interaction. Annals of neurology. 1980 Jun;     [PubMed PMID: 6776874]
[17] Battino D,Cusi C,Franceschetti S,Moise A,Spina S,Avanzini G, Ethosuximide plasma concentrations: influence of age and associated concomitant therapy. Clinical pharmacokinetics. 1982 Mar-Apr;     [PubMed PMID: 6802548]
[18] Bachmann KA,Jauregui L, Use of single sample clearance estimates of cytochrome P450 substrates to characterize human hepatic CYP status in vivo. Xenobiotica; the fate of foreign compounds in biological systems. 1993 Mar;     [PubMed PMID: 8498093]
[19] van Wieringen A,Vrijlandt CM, Ethosuximide intoxication caused by interaction with isoniazid. Neurology. 1983 Sep;     [PubMed PMID: 6684262]
[20] CHEN G,WESTON JK,BRATTON AC Jr, Anticonvulsant activity and toxicity of phensuximide, methsuximide and ethosuximide. Epilepsia. 1963 Mar;     [PubMed PMID: 14020499]
[21] McCrea S, Antiepileptic drug overdose. Emergency nurse : the journal of the RCN Accident and Emergency Nursing Association. 2002 Feb;     [PubMed PMID: 11845727]
[22] Marbury TC,Lee CS,Perchalski RJ,Wilder BJ, Hemodialysis clearance of ethosuximide in patients with chronic renal disease. American journal of hospital pharmacy. 1981 Nov;     [PubMed PMID: 7304633]
[23] Kuhnz W,Koch S,Jakob S,Hartmann A,Helge H,Nau H, Ethosuximide in epileptic women during pregnancy and lactation period. Placental transfer, serum concentrations in nursed infants and clinical status. British journal of clinical pharmacology. 1984 Nov;     [PubMed PMID: 6508976]