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

Unfortunately, such a study has not been performed. Many
of the studies referenced in description of newer drugs did compare
a new with an older anti-seizure drug, but study design did not permit
declaring a clearly superior drug; moreover, differences in study
design and patient populations preclude comparing a new drug with
multiple older drugs or with other new drugs. The use of recently
introduced anti-seizure drugs for newly diagnosed epilepsy was analyzed
by subcommittees of the American Academy of Neurology
and the American Epilepsy Society (French et al., 2004a; French
et al., 2004b); the authors concluded that available evidence supported
the use of gabapentin, lamotrigine, and topiramate for newly
diagnosed partial or mixed seizure disorders. None of these drugs,
however, has been approved by the FDA for either of these indications.
Insufficient evidence was available on the remaining newly
introduced drugs to permit meaningful assessment of their effectiveness
for this indication.
Absence Seizures
Ethosuximide and valproate are considered equally effective in the
treatment of absence seizures (Mikati and Browne, 1988). Between
50% and 75% of newly diagnosed patients are free of seizures following
therapy with either drug. If tonic-clonic seizures are present or
emerge during therapy, valproate is the agent of first choice. French
and others concluded that available evidence indicates that lamotrigine
is also effective for newly diagnosed absence epilepsy despite the
fact that lamotrigine is not approved for this indication by the FDA.
Myoclonic Seizures
Valproic acid is the drug of choice for myoclonic seizures in the syndrome
of juvenile myoclonic epilepsy, in which myoclonic seizures
often coexist with tonic-clonic and absence seizures. Levetiracetam
also has demonstrated efficacy as adjunctive therapy for refractory
generalized myoclonic seizures.
Febrile Convulsions
Two to four percent of children experience a convulsion associated
with a febrile illness. From 25-33% of these children will have
another febrile convulsion. Only 2-3% become epileptic in later
years, a 6-fold increase in risk compared with the general population.
Several factors are associated with an increased risk of developing
epilepsy: preexisting neurological disorder or developmental delay,
a family history of epilepsy, or a complicated febrile seizure (i.e.,
the febrile seizure lasted > 15 minutes, was one-sided, or was followed
by a second seizure in the same day). If all of these risk factors
are present, the risk of developing epilepsy is ~10%.
The increased risk of developing epilepsy or other neurological
sequelae led many physicians to prescribe anti-seizure drugs
prophylactically after a febrile seizure. Uncertainties regarding the
efficacy of prophylaxis for reducing epilepsy combined with substantial
side effects of phenobarbital prophylaxis (Farwell et al.,
1990) argue against the use of chronic therapy for prophylactic purposes
(Freeman, 1992). For children at high risk of developing recurrent
febrile seizures and epilepsy, rectally administered diazepam at
the time of fever may prevent recurrent seizures and avoid side
effects of chronic therapy.
Seizures in Infants and Young Children
Infantile spasms with hypsarrhythmia (abnormal inter-ictal high
amplitude slow waves and multifocal asynchronous spikes on EEG)
are refractory to the usual anti-seizure agents. Corticotropin or the
glucocorticoids are commonly used and repository corticotropin (H.P.
ACTHAR GEL) was designated as an orphan drug for this purpose in
2003. A randomized study found vigabatrin (γ-vinyl GABA; SABRIL)
to be efficacious in comparison to placebo (Appleton et al., 1999).
Constriction of visual fields has been reported in a high percentage of
patients treated with vigabatrin (Miller et al., 1999). The potential for
progressive and permanent vision loss has resulted in vigabatrin being
labeled with a black-box warning and marketed under a restrictive
distribution program. The drug received orphan drug status for the
treatment of infantile spasms in the U.S. in 2000 (and was FDAapproved
in 2009 as adjunctive therapy for adults with refractory
complex partial seizures). Ganaxolone also has been designated as
an orphan drug since 1994 for the treatment of infantile spasms and
completed a phase II clinical trial for uncontrolled partial-onset
seizures in adults in 2009.
The Lennox-Gastaut syndrome is a severe form of epilepsy
which usually begins in childhood and is characterized by cognitive
impairments and multiple types of seizures including tonic-clonic,
tonic, atonic, myoclonic, and atypical absence seizures. Addition of
lamotrigine to other anti-seizure drugs resulted in improved seizure
control in comparison to placebo in a double-blind trial (Motte et al.,
1997), demonstrating lamotrigine to be an effective and welltolerated
drug for this treatment-resistant form of epilepsy.
Felbamate also was found to be effective for seizures in this syndrome,
but the occasional occurrence of aplastic anemia and hepatic
failure have limited its use (French et al., 1999). Topiramate has also
been demonstrated to be effective for Lennox-Gastaut syndrome
(Sachdeo et al., 1999).
Status Epilepticus and Other Convulsive Emergencies
Status epilepticus is a neurological emergency. Mortality for adults
approximates 20% (Lowenstein and Alldredge, 1998). The goal of
treatment is rapid termination of behavioral and electrical seizure
activity; the longer the episode of status epilepticus is untreated, the
more difficult it is to control and the greater the risk of permanent
brain damage. Critical to the management is a clear plan, prompt
treatment with effective drugs in adequate doses, and attention to
hypoventilation and hypotension. Since hypoventilation may result
from high doses of drugs used for treatment, it may be necessary to
assist respiration temporarily. Drugs should be administered by the
intravenous route only. Because of slow and unreliable absorption,
the intramuscular route has no place in treatment of status epilepticus.
To assess the optimal initial drug regimen, a double-blind, multicenter
trial compared four intravenous treatments: diazepam
followed by phenytoin; lorazepam; phenobarbital; and phenytoin
alone (Treiman et al., 1998). The treatments had similar efficacies,
with success rates ranging from 44-65%. Lorazepam alone was significantly
better than phenytoin alone. No significant differences
were found with respect to recurrences or adverse reactions.
Anti-Seizure Therapy and Pregnancy
Use of anti-seizure drugs has diverse implications of
great importance for the health of women. Issues include
interactions with oral contraceptives, potential teratogenic
effects, and effects on vitamin K metabolism in
pregnant women (Pack, 2006). Guidelines for the care
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CHAPTER 21
PHARMACOTHERAPY OF THE EPILEPSIES