1. Drugs used in generalized seizures
Domina Petric, MD

2. Ethosuximide I.

3. Ethosuximide
Ethosuximide has an important effect on Ca2+ currents, reducing the low-treshold (T-type) current.
This effect is seen at therapeutically relevant concentrations in thalamic neurons.
The T-type Ca2+ currents provide a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attack.

4. Ethosuximide
Ethosuximide is particularly effective against absence seizures, but has a very narrow spectrum of clinical activity.
Ethosuximide and valproate are the drugs of choice for absence seizures and are more effective than lamotrigine.

5. Pharmacokinetics
Absorption is complete following administration of the oral dosage forms.
Peak levels are observed 3-7 hours after oral administration of the capsules.
Ethosuximide is not protein-bound.
The drug is completely metabolized, principally by hydroxylation, to inactive metabolites.
Very low total body clearance: 0,25 L/kg/day.
Half-life is approximately 40 hours.

6. Dosage
Therapeutic levels of mcg/mL can be achieved in adults with dosages of mg/day.
Ethosuximide has a linear relationship between dose and steady-state plasma levels.
The drug might be administered as a single daily dose, but because of adverse GI effects, twice-a-day dosage is common.

7. Drug interactions
Administration of ethosuximide with valproic acid results in a decrease in ethosuximide clearance and higher steady-state concentrations (inhibition of metabolism).

8. Toxicity
The most common dose-related adverse effects are abdominal pain, nausea and vomiting.
Other dose-related adverse effects are transient lethargy or fatigue and, much less commonly, headache, dizziness, hiccup and euphoria.
Behavioral changes are usually in the direction of improvement.
Idiosyncratic adverse effects of ethosuximide are extremely uncommon.

9. Valproic acid, sodium valproate
II.

10. Valproic acid, sodium valproate
Valproate has effect on Na+ currents.
Blockade of NMDA receptor-mediated excitation is also important.
Valproate has effect to facilitate glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis.
At very high concentrations, valproate inhibits GABA transaminase in the brain, thus blocking degradation of GABA.

11. Valproic acid, sodium valproate
Valproic acid is a potent inhibitor of histone deacetylase and through this mechanism changes the transcription of many genes.

12. Valproic acid, sodium valproate
Valproate is very effective against absence seizures.
It is preferred when the patient has concomitant generalized tonic-clonic attacks.
It can control certain types of myoclonic seizures.
Valproate is effective in tonic-clonic seizures, especially those that are primarily generalized.
Iv. formulations are occasionally used to treat status epilepticus.

13. Pharmacokinetics
Valproate is well absorbed after an oral dose, with bioavailability greater than 80%.
Peak blood levels are observed within 2 hours.
Food may delay absorption.
Decreased toxicity may result if the drug is given after meals.
Valproic acid is 90% bound to plasma proteins.
Valproate is highly ionized and highly protein-bound.

14. Pharmacokinetics
Distribution of valproate is essentially confined to extracellular water.
Volume of distribution is 0,15 L/kg.
Clearance is low and dose dependent.
Its half-life varies from 9 to 18 hours.
Approximately 20% of the drug is excreted as a direct conjugate of valproate.

15. Therapeutic levels of valproate range from 50 to 100 mcg/mL.
Dosage
Dosages of mg/kg/day may be adequate in some patients, but others may require 60 mg/kg/day.
Therapeutic levels of valproate range from 50 to 100 mcg/mL.

16. Drug interactions Valproate displaces phenytoin from plasma proteins.
Valproate inhibits the metabolism of several drugs, including phenobarbital, phenytoin and carbamazepine: higher steady-state concentrations of these agents.
The inhibition of phenobarbital metabolism may cause levels of this barbiturate to rise steeply, causing stupor or coma.
Valproate can dramatically decrease the clearance of lamotrigine.

17. Toxicity
The most common dose-related adverse effects of valproate are nausea, vomiting, abdominal pain and heartburn.
The drug should be started gradually to avoid these symptoms.
Sedation is uncommon, but may be serious when valproate is added to phenobarbital.
A fine tremor is frequently seen at higher levels.

18. Toxicity
Other reversible adverse effects are weight gain, increased appetite and hair loss.
The most important idiosyncratic toxicity is hepatotoxicity.
The risk is greates for patients under 2 years of age and for those taking multiple medications.
Initial aspartate aminotransferase values may not be elevated in susceptible patients.

19. Toxicity
Most fatalities from hepatotoxicity occurred within 4 months after initiation of therapy.
Careful monitoring of liver function!
Iv. L-carnitine as soon as severe hepatotoxicity is suspected.
The hepatotoxicity is reversible in some cases if the drug is withdrawn.

20. Toxicity
Other idiosyncratic response with valproate is thrombocytopenia.
Valproate may cause spina bifida, cardiovascular, orofacial and digital abnormalities in the offspring when used in pregnancy.

21. Benzodiazepines, acetazolamide
III.

22. Benzodiazepines
Diazepam iv. or rectally is highly effective for stopping continuous seizure activity, especially generalized tonic-clonic status epilepticus.
Lorazepam is maybe more effective than diazepam in the treatment of status epilepticus and has longer duration of action than diazepam.
Other benzodiazepines: clonazepam, nitrazepam, clorazepate dipotassium, clobazam.

23. Acetazolamide
Acetazolamide is a diuretic whose main action is the inhibition of carbonic anhydrase.
Mild acidosis in the brain may be the mechanism by which the drug exerts its antiseizure activity.
The depolarizing action of bicarbonate ions moving out of neurons via GABA receptor ion channels may be diminished by carbonic anhydrase inhibition.

24. Acetazolamide Acetazolamide has been used for all types of seizures.
Its use is severly limited by the rapid development of tolerance, with return of seizures usually within a few weeks.
The drug may have a special role in epileptic women who experience seizure exacerbations at the time of menses.
Dosage is 10 mg/kg/day to a maximum of 1000 mg/day.

25. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Literature
Katzung, Masters, Trevor. Basic and clinical pharmacology.