Epilepsy ethosuximide

Phenobarbitone was the first AED and was introduced in 1912. It was largely replaced in 1932 by phenytoin for the management of tonic-xilonic seizures and partial and secondary epilepsy. Carbamazepine followed, then ethosuximide for absence seizures and valproic acid. These remained, apart from the introduction of the benzodiazepines, the mainstay of therapy until the last decade. They were introduced solely on their ability to control experimentally induced seizures. Their mechanisms of action were unknown and no thought was given to the possibility of NT modification and in fact subsequent research has shown that with the exception of the benzodiazepines none of them work primarily through NT manipulation. They act directly on neuronal excitability. 

Figure 16.7 The structure of some established antiepileptic drugs (AEDs) and some newer ones. Note that while the structures of phenytoin and ethosuximide are similar and also close to that of phenobarbitone, they are effective in different forms of epilepsy. Vigabatrin, progabide and gabapentin are clearly related to GABA. Muscimol is a GABAa agonist but is not an effective antiepileptic drug...

Calcium channels have been shown to play a role in epilepsy as well [23]. Currently used antiepileptic drugs exhibit a wide spectrum of activity, including modulation of voltage-gated sodium and calcium channels. T-type calcium channels have been demonstrated to play an important role in absence epilepsy, a specific form of epilepsy characterized by brief lapses in consciousness correlated with spike-and-wave discharges in the electroencephalogram [14,24-28]. Ethosuximide 1 has been shown to block T-type calcium channels and is used clinically to treat absence epilepsy [25]. Several selective small-molecule T-type calcium channel antagonists have demonstrated efficacy in rodent epilepsy models (vide infra). 

FIGURE 37-4 Antiseizure mediated reduction of IT. Certain antiseizure drugs reduce the flow of calcium through T-type Ca2+ channels (ethosuximide, valproate), thereby reducing the pacemaker current that underlies spike-wave discharges of generalized absence epilepsy. 

Ethosuximide is an anticonvulsant drug that is used in minor forms of epilepsy. It is also prescribed under the name aximide, suxilene, rontone, and pyknolepsinum. 

It is now generally accepted that the specific antiepileptic action of ethosuximide (and the older agent tri-methadione, no longer employed) against absence epilepsy is its ability to reduce the low-threshold calcium current (LTCC) or T (transient) current. These currents underlie the 3-Hz spike wave discharges that are characteristic of absence epilepsy. A blockade of... 

The only clinical use for ethosuximide (Zarontin) is in the treatment of absence epilepsy. If absence attacks are the only seizure disorder present, ethosuximide alone is effective. If other types of epilepsy are present, ethosuximide can be readily combined with other agents. 

Ethosuximide is most commonly used antiepileptic agent in the treatment of petitmal epilepsy. It acts on thalamocortical system by selectively suppressing T current without affecting other types of Ca " or Na" currents. It is completely absorbed from gastrointestinal tract and present in plasma in free form and approximately 20% is excreted unchanged in urine and remaining portion is metabolized in liver. 

It is similar to ethosuximide and used along with the other drugs in the treatment of temporal lobe epilepsy. 

It is a benzodiazepine useful in the treatment of petitmal epilepsy, myoclonic seizures and infantile spasms. It is used in the treatment of petitmal epilepsy not responding to ethosuximide and sodium valproate. Clonazepam and diazepam act by increasing the effectiveness of the inhibitory neurotransmitter GABA, within the central nervous system. 

Ethosuximide is effective in absence seizures, but not other types of epilepsy. It may even precipitate tonic-clonic seizures in susceptible patients. 

Both forms of absence seizure often occur as part of one of the recognized epilepsy syndromes. Typical absence seizures respond fairly well to AEDs ethosuximide and valproate are first-choice drugs. Clonazepam is effective but sedating, and tolerance to the antiabsence effects may develop. Lamotrigine may be useful. Treatment of atypical absence seizures with AEDs Is less successful. 

Moderate social drinking does not appear to affect the serum levels of carbamazepine, ethosuximide or phenytoin. Some small changes are seen in the serum levels of phenobarbital and sodium valproate, but no changes in the control of epilepsy seem to occur. No pharmacokinetic interaction was detected between tiagabine and alcohol, and tiagabine did not alter the cognitive effect of alcohol. The adverse effects of both alcohol and antiepileptics, such as enhanced sedation, may be additive. 

Salke-Kellermann RA May T, Boenigk HE. Influence of ethosuximide on valproic acid serum concentrations. Epilepsy Res (1991) 26, 345-349. 

Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Capparelli EV, Adamson PC Childhood Absence Epilepsy Study Group. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 2010 362(9) 790-9. 

A woman with refractory absence epilepsy at age 8 years developed arthritis with an increase in anti-double-strand DNA antibodies while taking ethosuximide and carbamazepine. Both drugs were withdrawn and the symptoms were ascribed to carbamazepine. At age 24, because of numerous absence seizures, ethosuximide 1000 mg/day was again prescribed and 1 month later she had arthralgia and fever and the antinuclear antibody concentration was were 80 Ul/ml. Ethosuximide was continued and 3 weeks later the antinuclear antibodies were 640 Ul/ml and the anti-double-strand DNA antibodies were 33 lU/ml. Ethosuximide was withdrawn and the antibodies normalized and the arthralgia and fever abated. 

Nervous system An 11-year-old girl with typical childhood absence epilepsy was reported to have an EEG conversion from 3 Hz spike-and-wave to right centrotemporal and centroparietal spikes after starting ethosuximide. The authors suggested that this may have been a drug-induced conversion however, whetiier this is possible remains controversial [65 ]. 

---