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

590 The cellular electrophysiological consequences of these
mutations can inform on the mechanisms of seizures and anti-seizure
drugs. For example, generalized epilepsy with febrile seizures
(GEFS+) is caused by a point mutation in the β subunit of a voltage-gated
Na + channel (SCN1B). As described previously, several
anti-seizure drugs act on Na + channels to promote their inactivation;
the phenotype of the mutated Na + channel appears to involve defective
inactivation (Wallace et al., 1998).
Spontaneous mutations in SCN1A (encoding the α subunit of
the major voltage-gated Na + channel in neurons) that result in truncations
and presumed loss of Na + channel function have been identified
in a subset of infants with a catastrophic severe myoclonic
epilepsy of infancy. An intriguing clue as to how this genotype may
lead to an epileptic phenotype has emerged from the study of SCN1A
knock-out mice (Yu et al., 2006). Heterozygote mice have only one
functional allele and provide a mouse model of this epileptic syndrome.
Because activation of voltage-gated Na + channels depolarizes
and activates a neuron, it seemed odd that a loss of function mutation
of SCN1A would result in increased excitability of networks of
neurons and epilepsy. This led to the discovery of impaired firing of
inhibitory interneurons, but not excitatory principal neurons, in
SCN1A heterozygous mice (Yu et al., 2006). These findings suggest
that loss of function mutations of SCN1A may cause epilepsy as a
consequence of reduced firing of inhibitory interneurons. Because
interneurons effect inhibition by releasing GABA, this suggests that
drugs acting to enhance GABA-mediated inhibition may be effective
anticonvulsants in SCN1A mutant mice and infants with these mutations.
Consistent with this hypothesis, preliminary findings reveal
that an experimental anti-seizure drug that increases the duration of
GABA A
receptor channel open times (Quilichini et al., 2006) was
beneficial in children with severe myoclonic epilepsy of infancy
(Chiron, 2007). If confirmed, this would provide the first instance
of rational use of anti-seizure drugs in that insight into the cellular
mechanism of the epilepsy would guide selection of drugs acting by
a given mechanism.
SECTION II
NEUROPHARMACOLOGY
ANTI-SEIZURE DRUGS: GENERAL
CONSIDERATIONS
History. The first anti-epileptic drug was bromide, which was used
in the late 19th century. Phenobarbital was the first synthetic organic
agent recognized as having anti-seizure activity. Its usefulness, however,
was limited to generalized tonic-clonic seizures, and to a lesser
degree, simple and complex partial seizures. It had no effect on
absence seizures. Merritt and Putnam developed the electroshock
seizure test in experimental animals to screen chemical agents for
anti-seizure effectiveness; in the course of screening a variety of
drugs, they discovered that diphenylhydantoin (later renamed phenytoin)
suppressed seizures in the absence of sedative effects. The electroshock
seizure test is extremely valuable, because drugs that are
effective against tonic hind limb extension induced by electroshock
generally have proven to be effective against partial and tonic-clonic
seizures in humans. Another screening test, seizures induced by the
chemoconvulsant pentylenetetrazol, is most useful in identifying
drugs that are effective against myoclonic seizures in humans. These
screening tests are still used. The chemical structures of most of the
drugs introduced before 1965 were closely related to phenobarbital.
These included the hydantoins and the succinimides. Between 1965
and 1990, the chemically distinct structures of the benzodiazepines,
an iminostilbene (carbamazepine), and a branched-chain carboxylic
acid (valproic acid) were introduced, followed in the 1990s by a
phenyltriazine (lamotrigine), a cyclic analog of GABA (gabapentin),
a sulfamate-substituted monosaccharide (topiramate), a nipecotic acid
derivative (tiagabine), and a pyrrolidine derivative (levetiracetam).
Therapeutic Aspects. The ideal anti-seizure drug would
suppress all seizures without causing any unwanted
effects. Unfortunately, the drugs used currently not only
fail to control seizure activity in some patients, but frequently
cause unwanted effects that range in severity
from minimal impairment of the CNS to death from
aplastic anemia or hepatic failure. In 2009, all manufacturers
of anti-seizure drugs were required to update
their product labeling to include a warning about an
increased risk of suicidal thoughts or actions and to
develop information targeted at helping patients understand
this risk. The risk applies to all anti-seizure drugs
used for any indication. Details are online at the FDA
website.
The clinician who treats patients with epilepsy is
faced with the task of selecting the appropriate drug or
combination of drugs that best controls seizures in an
individual patient at an acceptable level of untoward
effects. As a general rule, complete control of seizures
can be achieved in up to 50% of patients, while another
25% can be improved significantly. The degree of success
varies as a function of seizure type, cause, and
other factors.
To minimize toxicity, treatment with a single drug
is preferred. If seizures are not controlled with the initial
agent at adequate plasma concentrations, substitution
of a second drug is preferred to the concurrent
administration of another agent. However, multipledrug
therapy may be required, especially when two or
more types of seizure occur in the same patient.
Measurement of drug concentrations in plasma
facilitates optimizing anti-seizure medication, especially
when therapy is initiated, after dosage adjustments, in
the event of therapeutic failure, when toxic effects
appear, or when multiple-drug therapy is instituted.
However, clinical effects of some drugs do not correlate
well with their concentrations in plasma, and recommended
concentrations are only guidelines for therapy.
The ultimate therapeutic regimen must be determined
by clinical assessment of effect and toxicity.
The individual agents are introduced in the next
sections, followed by a discussion of some general principles
of the drug therapy of the epilepsies.