INTRODUCTION

Ethosuximide is succinimide compound that is effective in the

treatment of absence seizures. It is the product of an intense
structure-activity research effort to find an specific agent to
suppress absence seizures with a relatively low side effect
profile. While the exact mechanism of action is not known, the
antiepileptic effect of ethosuximide is thought to result from
its ability to decrease low-threshold calcium currents in
thalamic neurons. The thalamus has a key role in the
production of 3-Hz spike-wave rhythms that are a hallmark of
absence seizures. Ethosuximide may also inhibit the sodium-
potassium ATPase system and NADPH-linked aldehyde
reductase.
THERAPEUTIC AND TOXIC CONCENTRATIONS

The therapeutic range for ethosuximide is defined

by most laboratories as 40100 g/mL, although
some clinicians suggest drug concentrations as high
as 150 g/mL with appropriate monitoring of
serum concentrations and possible side effects.5
The most common adverse effects of ethosuximide
are gastric distress, nausea, vomiting, and anorexia,
but these gastrointestinal problems appear to be
caused by local irritation of gastric mucosa.
 Generally, administration of smaller doses and more
frequent dosing of the drug produce relief from these
side effects. In the upper end of the therapeutic range
(>70 g/mL) some patients will begin to experience the
concentration-dependent adverse effects of
ethosuximide treatment: drowsiness, fatigue, lethargy,
dizziness, ataxia, hiccups, euphoria, and headaches.
Idiosyncratic side effects that are independent of
concentration include rash, systemic lupus-like
syndromes, and blood dyscrasias (leukopenia,
pancytopenia).
 CLINICAL MONITORING PARAMETERS
The goal of therapy with anticonvulsants is to reduce seizure
frequency and maximize quality of life with a minimum of
adverse drug effects. While it is desirable to entirely abolish all
seizure episodes, it may not be possible to accomplish this in
many patients. Patients should be monitored for
concentration-related side effects (drowsiness, fatigue,
lethargy, dizziness, ataxia, hiccups, euphoria, headaches) as
well as gastrointestinal upset associated with local irritation of
gastric mucosa (gastric distress, nausea, vomiting, anorexia).
Serious, but rare, idiosyncratic side effects include systemic
lupus-like syndromes, leukopenia, and pancytopenia.
 Ethosuximide serum concentrations should be measured
in most patients. Because epilepsy is an episodic disease
state, patients do not experience seizures on a
continuous basis. Thus, during dosage titration it is
difficult to tell if the patient is responding to drug therapy
or simply is not experiencing any abnormal central
nervous system discharges at that time. Ethosuximide
serum concentrations are also valuable tools to avoid
adverse drug effects. Patients are more likely to accept
drug therapy if adverse reactions are held to the absolute
minimum.
 BASIC CLINICAL PHARMACOKINETIC PARAMETERS

Ethosuximide is eliminated primarily by hepatic metabolism (7080%)

via hydroxylation and then conjugated to inactive metabolites. About
2030% of an ethosuximide dose is recovered as unchanged drug in
the urine. Ethosuximide is not significantly bound to plasma proteins.
At concentrations exceeding 100 g/mL, the drug may follow
nonlinear pharmacokinetics, presumably owing to Michaelis-Menten
(concentration dependent or saturable) metabolism. Because an
intravenous form of the drug is not commercially available, the
absolute bioavailability in humans is not known. However, based on
animal studies, ethosuximide oral bioavailability of capsules (250 mg)
and syrup (250 mg/5 mL) is assumed to be 100%. The typical
maintenance dose for ethosuximide is 20 mg/kg/d for pediatric
patients (<12 years old) and 15 mg/kg/d for older patients.
 EFFECTS OF DISEASE STATES AND CONDITIONS
ON PHARMACOKINETICS AND DOSING
Ethosuximide oral clearance rate (Cl/F) for older children (12 years
old) and adults is 12 mL/h/kg and for younger children is 16
mL/h/kg. Ethosuximide volume of distribution (V/F) equals 0.7 L/kg,
and its half life averages 30 hours in children and 60 hours in adults.
Although studies in patients with hepatic disease are not available,
7080% of the drug is eliminated by hepatic metabolism. Because of
this, patients with liver cirrhosis or acute hepatitis may have
reduced ethosuximide clearance because of destruction of liver
parenchyma. This loss of functional hepatic cells reduces the
amount of enzymes available to metabolize the drug and decreases
clearance. An index of liver dysfunction can be gained by applying
the Child-Pugh clinical classification system to the patient (Table 14-
2).
 DRUG INTERACTIONS
Unlike other antiepileptic drugs, ethosuximide
is not a hepatic enzyme inducer or inhibitor,
and appears to cause no clinically important
drug interactions. Valproic acid can inhibit
ethosuximide metabolism and increase
steady-state concentrations, especially when
ethosuximide serum concentrations are in the
upper end of the therapeutic range.
 INITIAL DOSAGE DETERMINATION
METHODS
Several methods to initiate ethosuximide therapy are
available. The pharmacokinetic dosing method is the most
flexible of the techniques. It allows individualized target serum
concentrations to be chosen for a patient, and each
pharmacokinetic parameter can be customized to reflect
specific disease states and conditions present in the patient.
Literature-based recommended dosing is a very commonly
used method to prescribe initial doses of ethosuximide. Doses
are based on those that commonly produce steady-state
concentrations in the lower end of the therapeutic range,
although there is a wide variation in the actual concentrations
for a specific patient.
 Pharmacokinetic Dosing Method
The goal of initial dosing of ethosuximide is to compute the
best dose possible for the patient given their set of disease
states and conditions that influence ethosuximide
pharmacokinetics and the epileptic disorder being treated. In
order to do this, pharmacokinetic parameters for the patient
will be estimated using average parameters measured in other
patients with similar disease state and condition profiles
(CLEARANCE ESTIMATE, VOLUME OF DISTRIBUTION ESTIMATE,
HALF-LIFE AND ELIMINATION RATE CONSTANT ESTIMATE,
SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL AND
EQUATIONS).
 Ethosuximide follows a one-compartment pharmacokinetic model.
When oral therapy is required, ethosuximide has good
bioavailability (F = 1), and once or twice dosing provides a relatively
smooth serum concentration/time curve that emulates an
intravenous infusion. Because of this, a very simple pharmacokinetic
equation that computes the average ethosuximide steady-state
serum concentration (Css in g/mL = mg/L) is widely used and
allows maintenance dosage calculation: Css = [F(D/)] / Cl or D = (Css
Cl ) / F, where F is the bioavailability fraction for the oral dosage
form (F = 1 for oral ethosuximide products), D is the dose of
ethosuximide in milligrams, Cl is ethosuximide clearance in liters per
hour, and is the dosage interval in hours.