Page 443 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 24 Antiseizure Drugs 429

H H
N N N N
O O O O O O O O
* * *

Ethosuximide Phensuximide Methsuximide

N
O O
O

Trimethadione

Mechanism of Action 15–40 mg/kg/d. In older children and adults, the initial dose is
250 or 500 mg/d, increasing in 250-mg increments to clinical
Ethosuximide is thought to act by inhibition of low-voltage- response to a maximum of 1500 mg/d. While dosing is based
activated T-type calcium channels in thalamocortical neurons on titration to maximal seizure control with acceptable toler-
that underlie the 3-Hz spike-wave discharges of generalized ability, the accepted therapeutic serum concentration range is
absence seizures. Other ion channels affected include voltage- 40–100 mcg/mL (although plasma levels up to 150 mcg/mL may
gated sodium channels, calcium-activated potassium channels, be necessary and tolerated in some patients). There is a linear
and inward rectifier potassium channels; these actions may con- relationship between ethosuximide dose and steady-state plasma
tribute to the efficacy of ethosuximide in absence epilepsy.
levels. While the long half-life could allow once-daily dosing, eth-
osuximide is generally administered in two or even three divided
Clinical Uses doses to minimize adverse gastrointestinal effects.
Studies in the mid-1970s provided evidence that monotherapy
with ethosuximide is effective in the treatment of childhood Drug Interactions & Toxicity
generalized absence seizures. There is also evidence that it is effec- Administration of ethosuximide with valproic acid results in a
tive in the treatment of atypical absence and epileptic negative decrease in ethosuximide clearance and higher steady-state con-
myoclonus, a rare seizure type characterized by interruption of centrations owing to inhibition of ethosuximide metabolism. No
ongoing electromyographic activity contralateral to a lateralized other important drug interactions have been reported. The most
spike-and-wave discharge. If ethosuximide in monotherapy does common dose-related adverse effect of ethosuximide is gastric
not lead to seizure control, the drug can be used in combination distress, including pain, nausea, and vomiting. When an adverse
with valproate or other agents such as benzodiazepines.
effect does occur, temporary dosage reductions may allow adapta-
tion. Other dose-related adverse effects are transient lethargy or
Pharmacokinetics fatigue and, much less commonly, headache, dizziness, hiccup,

Absorption is complete following administration of the oral dosage and euphoria. Behavioral changes are usually in the direction of
forms. Peak levels are observed 3–7 hours after oral administration improvement. Non-dose-related or idiosyncratic adverse effects of
of the capsules. Ethosuximide is not protein bound. During long- ethosuximide are extremely uncommon.
term administration, approximately 20% of the dose is excreted
unchanged by the kidney. The remaining drug is metabolized in the
liver, principally by CYP3A hydroxylation, to inactive metabolites. TRIMETHADIONE
Ethosuximide has a very low total body clearance (0.25 L/kg/d).
This corresponds to a half-life of approximately 40 hours, although Trimethadione is an oxazolidinedione antiseizure drug introduced
values from 18 to 72 hours have been reported. in 1945. It is no longer marketed in the USA but is available
elsewhere. Trimethadione is effective in the treatment of general-
ized absence seizures and was the drug of choice for this seizure
Therapeutic Levels & Dosage type until the introduction of ethosuximide. Trimethadione has
In children, a common starting dose is 10–15 mg/kg/d, with numerous dose-related and idiosyncratic side effects, including
titration according to clinical response to a maintenance dose of hemeralopia (day blindness). Because of the high propensity for