Ethosuximide

Ethosuximide (α-ethyl-α-methyl-succinimide) is the main survivor of the succinimides. It was first introduced in clinical practice in the early 1950s for the treatment of ‘petit mal’.

Authorised indications

UK-SmPC: primarily useful in absence seizures. When GTCSs and other forms of epilepsy co-exist with absence seizures, ethosuximide may be administered in combination with other AEDs.

FDA-PI: control of absence (petit mal) epilepsy.

Clinical applications

Ethosuximide is still a valuable AED for the treatment of typical absence seizures and has a 70% seizure-free success rate as monotherapy.¹ It is recommended in childhood absence epilepsy (monotherapy) and IGEs with intrac table absence seizures (adjunctive therapy).

Ethosuximide is also useful as adjunctive treatment in negative myoclonus,² drop attacks³ and certain types of myoclonic epilepsy.⁴ An anecdotal view that ethosuximide does not control GTCS has recently been challenged.⁵

Dosage and titration

Titrate slowly to avoid ADRs, mainly gastrointestinal disturbances.

Adults and children over 12 years: start treatment with 250 mg/day and increase slowly in 250 mg increments every 4–7 days, to up to 750–1500 mg.

Children under 12 years: start with 5–10 mg/kg/day and increase slowly to 20–35 mg/kg/day.

Dosing: two or three times daily.

TDM: mostly not needed.

Reference range: 40–100 mg/l (300–700 μmol/l).

Main ADRs

Common and/or serious: gastrointestinal symptoms include anorexia, vague gastric upset, nausea and vomiting, cramps, epigastric and abdominal pain and diar rhoea. Drowsiness, weight loss photophobia, euphoria, hiccups, headache and, less often, behavioural and psychotic disturbances may occur.

Severe: haemopoietic complications (aplastic anaemia), Stevens–Johnson syndrome, renal and hepatic impairment, and systemic lupus erythema tosus.

Considerations in women

Pregnancy: category C.

Interaction with hormonal contraception: none.

Main mechanisms of action

Ethosuximide exerts its anti-absence effect by either reducing thalamic low threshold calcium currents, probably by a direct channel-blocking action that is voltage dependent,⁶ or through a potent inhibitory effect in the perioral region of the primary somatosensory cortex.⁷

Pharmacokinetics

Oral bioavailability: 90–100%. Protein binding: 85%. Metabolism: hepatic oxidation and then conjugation. Elimination half-life: 30–60 hours.

Drug interactions

Commonly, there are no clinically significant drug–drug interactions. Ethosuximide may raise the plasma concentration of phenytoin. Valproate has been reported to both increase and decrease ethosuximide levels.

Main disadvantages

• Narrow spectrum of anti-epileptic activity.
• It sometimes exhibits severe adverse idiosyncratic reactions.
• Abrupt withdrawal in patients with absences may precipitate absence status epilepticus.

Other available succinimides

Methsuximide is a broader spectrum drug than ethosuximide (but with a weaker action) and is also effective in focal seizures. ADRs are more frequent and may be more serious than with ethosuximide.

Phensuximide is rarely used because its effect is inferior to other succinimides.

References

1. Panayiotopoulos CP. Treatment of typical absence seizures and related epileptic syndromes. Paediatr Drugs 2001;3:379–403.
2. Oguni H, Uehara T, Tanaka T, Sunahara M, Hara M, Osawa M. Dramatic effect of ethosuximide on epileptic negative myoclonus: implications for the neurophysiological mechanism. Neuropediatrics 1998;29:29–34.
3. Snead OC, III, Hosey LC. Treatment of epileptic falling spells with ethosuximide. Brain Dev 1987;9:602–4.
4. Wallace SJ. Myoclonus and epilepsy in childhood: a review of treatment with valproate, ethosuximide, lamotrigine and zonisamide. Epilepsy Res 1998;29:147–54.
5. Schmitt B, Kovacevic-Preradovic T, Critelli H, Molinari L. Is ethosuximide a risk factor for generalised tonic-clonic seizures in absence epilepsy? Neuropediatrics 2007;38:83-7.
6. Coulter DA. Antiepileptic drug cellular mechanisms of action: where does lamotrigine fit in? J Child Neurol 1997;12 Suppl 1:S2–9.
7. Manning JP, Richards DA, Leresche N, Crunelli V, Bowery NG. Cortical-area specific block of genetically determined absence seizures by ethosuximide. Neuroscience 2004;123:5–9.