DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

596 Oxcarbazepine is a prodrug that is almost immediately
converted to its main active metabolite, a 10-monohydroxy
derivative, which is inactivated by glucuronide conjugation
and eliminated by renal excretion.
SECTION II
NEUROPHARMACOLOGY
Its mechanism of action is similar to that of carbamazepine.
Oxcarbazepine is a less potent enzyme inducer than carbamazepine.
Substitution of oxcarbazepine for carbamazepine is associated with
increased levels of phenytoin and valproic acid, presumably because
of reduced induction of hepatic enzymes. Oxcarbazepine does not
induce the hepatic enzymes involved in its own degradation.
Although oxcarbazepine does not appear to reduce the anticoagulant
effect of warfarin, it does induce CYP3A and thus reduces
plasma levels of steroid oral contraceptives. It has been approved for
monotherapy or adjunct therapy for partial seizures in adults, as
monotherapy for partial seizures in children ages 4-16, and as
adjunctive therapy in children 2 years of age and older with epilepsy.
SUCCINIMIDES
Ethosuximide
Ethosuximide (ZARONTIN, others) is a primary agent for
the treatment of absence seizures.
Structure-Activity Relationship. The structure-activity relationship
of the succinimides is in accord with that for other anti-seizure
classes. Methsuximide (CELONTIN) has phenyl substituents and is
more active against maximal electroshock seizures. It is no longer in
common use. Discussion of its properties can be found in previous
editions of this book. Ethosuximide, with alkyl substituents, is the
most active of the succinimides against seizures induced by
pentylenetetrazol and is the most selective for absence seizures.
Pharmacological Effects. The most prominent characteristic of
ethosuximide at nontoxic doses is protection against clonic motor
seizures induced by pentylenetetrazol. By contrast, at nontoxic doses
ethosuximide does not inhibit tonic hind limb extension of electroshock
seizures or kindled seizures. This profile correlates with
efficacy against absence seizures in humans.
Mechanism of Action. Ethosuximide reduces low threshold Ca 2+
currents (T-type currents) in thalamic neurons (Coulter et al., 1989).
The thalamus plays an important role in generation of 3-Hz spikeand-wave
rhythms typical of absence seizures (Huguenard and
McCormick, 2007). Neurons in the thalamus exhibit large-amplitude
T-type currents that underlie bursts of action potentials and likely
play an important role in thalamic oscillatory activity such as 3-Hz
spike-and-wave activity. At clinically relevant concentrations, ethosuximide
inhibits the T-type current, as is evident in voltage-clamp
recordings of acutely isolated, ventrobasal thalamic neurons from
rats and guinea pigs. Ethosuximide reduces this current without
modifying the voltage dependence of steady-state inactivation or the
time course of recovery from inactivation. By contrast, succinimide
derivatives with convulsant properties do not inhibit this current.
Ethosuximide does not inhibit sustained repetitive firing or enhance
GABA responses at clinically relevant concentrations. Inhibition of
T-type currents likely is the mechanism by which ethosuximide
inhibits absence seizures.
Pharmacokinetic Properties. Absorption of ethosuximide appears
to be complete, with peak concentrations in plasma within ~3 hours
after a single oral dose. Ethosuximide is not significantly bound to
plasma proteins; during long-term therapy, its concentration in the
CSF is similar to that in plasma. The apparent volume of distribution
averages 0.7 L/kg.
Approximately 25% of the drug is excreted unchanged in the
urine. The remainder is metabolized by hepatic microsomal
enzymes, but whether CYPs are responsible is unknown. The major
metabolite, the hydroxyethyl derivative, accounts for ~40% of
administered drug, is inactive, and is excreted as such and as the glucuronide
in the urine. The plasma t 1/2
of ethosuximide averages
between 40 and 50 hours in adults and ~30 hours in children.
Toxicity. The most common dose-related side effects are gastrointestinal
complaints (nausea, vomiting, and anorexia) and CNS effects
(drowsiness, lethargy, euphoria, dizziness, headache, and hiccough).
Some tolerance to these effects develops. Parkinson-like symptoms
and photophobia also have been reported. Restlessness, agitation,
anxiety, aggressiveness, inability to concentrate, and other behavioral
effects have occurred primarily in patients with a prior history
of psychiatric disturbance.
Urticaria and other skin reactions, including Stevens-Johnson
syndrome, as well as systemic lupus erythematosus, eosinophilia,
leukopenia, thrombocytopenia, pancytopenia, and aplastic anemia
also have been attributed to the drug. The leukopenia may be transient
despite continuation of the drug, but several deaths have
resulted from bone marrow depression. Renal or hepatic toxicity has
not been reported.
Plasma Drug Concentrations. During long-term therapy, the plasma
concentration of ethosuximide averages ~2 μg/mL per daily dose of
1 mg/kg. A plasma concentration of 40-100 μg/mL usually is
required for satisfactory control of absence seizures.
Therapeutic Uses. Ethosuximide is effective against absence
seizures but not tonic-clonic seizures.
An initial daily dose of 250 mg in children (3-6 years old)
and 500 mg in older children and adults is increased by 250-mg
increments at weekly intervals until seizures are adequately controlled
or toxicity intervenes. Divided dosage is required occasionally
to prevent nausea or drowsiness associated with once-daily
dosing. The usual maintenance dose is 20 mg/kg per day. Increased
caution is required if the daily dose exceeds 1500 mg in adults or
750-1000 mg in children. The therapeutic use of ethosuximide is discussed
further at the end of the chapter.
VALPROIC ACID
The anti-seizure properties of valproic acid (DEPAKENE,
others) were discovered serendipitously when it was
employed as a vehicle for other compounds that were
being screened for anti-seizure activity.