Epilepsy, generalized seizures, antiseizure drugs, clinical pharmacology

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 60-100 mcg/mL can
be achieved in adults with dosages of 750-
1500 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. Dosage
Dosages of 25-30 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. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.