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

mendelian. The classification of epileptic syndromes guides clinical
assessment and management, and in some instances, selection of
anti-seizure drugs.
NATURE AND MECHANISMS OF
SEIZURES AND ANTI-SEIZURE DRUGS
Partial Epilepsies
More than a century ago, John Hughlings Jackson, the
father of modern concepts of epilepsy, proposed that
seizures were caused by “occasional, sudden, excessive,
rapid and local discharges of gray matter,” and that
a generalized convulsion resulted when normal brain
tissue was invaded by the seizure activity initiated in
the abnormal focus. This insightful proposal provided a
valuable framework for thinking about mechanisms of
partial epilepsy. The advent of the electroencephalogram
(EEG) in the 1930s permitted the recording of
electrical activity from the scalp of humans with
epilepsy and demonstrated that the epilepsies are disorders
of neuronal excitability.
The pivotal role of synapses in mediating communication
among neurons in the mammalian brain
suggested that defective synaptic function might lead
to a seizure. That is, a reduction of inhibitory synaptic
activity or enhancement of excitatory synaptic activity
might be expected to trigger a seizure; pharmacological
studies of seizures support this notion. The neurotransmitters
mediating the bulk of synaptic transmission in the
mammalian brain are amino acids, with γ-aminobutyric
acid (GABA) and glutamate being the principal
inhibitory and excitatory neurotransmitters, respectively
(Chapter 14). Pharmacological studies disclosed
that antagonists of the GABA A
receptor or agonists of
different glutamate-receptor subtypes (NMDA, AMPA,
or kainic acid) (Chapter 14) trigger seizures in experimental
animals in vivo. Conversely, pharmacological
agents that enhance GABA-mediated synaptic inhibition
suppress seizures in diverse models. Glutamatereceptor
antagonists also inhibit seizures in diverse
models, including seizures evoked by electroshock and
chemical convulsants such as pentylenetetrazol.
Such studies support the idea that pharmacological regulation
of synaptic function can regulate the propensity for seizures
and provide a framework for electrophysiological analyses aimed
at elucidating the role of both synaptic and nonsynaptic mechanisms
in seizures and epilepsy. Progress in techniques has fostered the
progressive refinement of the analysis of seizure mechanisms from
the EEG to populations of neurons (field potentials) to individual neurons
to individual synapses and individual ion channels on individual
neurons. Beginning in the mid-1960s, cellular electrophysiological
studies of epilepsy focused on elucidating the mechanisms underlying
the depolarization shift (DS), the intracellular correlate of the
“interictal spike” (Figure 21–1). The interictal (or between-seizures)
spike is a sharp waveform recorded in the EEG of patients with
epilepsy; it is asymptomatic in that it is accompanied by no overt
change in the patient’s behavior. The location of the interictal spike
helps localize the brain region from which seizures originate in a
given patient. The DS consists of a large depolarization of the neuronal
membrane associated with a burst of action potentials. In most
cortical neurons, the DS is generated by a large excitatory synaptic
current that can be enhanced by activation of voltage-gated intrinsic
membrane currents. Although the mechanisms generating the DS
are increasingly understood, it remains unclear whether the interictal
spike triggers a seizure, inhibits a seizure, or is an epiphenomenon
with respect to seizure occurrence in an epileptic brain. While
these questions remain unanswered, the study of the mechanisms of
DS generation set the stage for inquiry into the cellular mechanisms
of a seizure.
During the 1980s, various in vitro models of seizures were
developed in isolated brain slice preparations, in which many synaptic
connections are preserved. Electrographic events with features
similar to those recorded during seizures in vivo have been produced
in hippocampal slices by multiple methods, including altering ionic
constituents of media bathing the brain slices (McNamara, 1994)
such as low Ca 2+ , zero Mg 2+ , or elevated K + . The accessibility and
experimental control provided by these preparations has permitted
mechanistic investigations into the induction of seizures. Analyses of
multiple in vitro models confirmed the importance of synaptic function
for initiating a seizure, demonstrating that subtle (e.g., 20%)
reductions of inhibitory synaptic function could lead to epileptiform
activity and that activation of excitatory synapses could be pivotal in
seizure initiation. Other important factors were identified, including
the volume of the extracellular space as well as intrinsic properties
of a neuron, such as voltage-gated ion channels (e.g., K + , Na + , and
Ca 2+ channels) (Traynelis and Dingledine, 1988). Identification of
these diverse synaptic and nonsynaptic factors controlling seizures
in vitro provides potential pharmacological targets for regulating
seizure susceptibility in vivo.
Additional studies have centered on understanding
the mechanisms by which a normal brain is transformed
into an epileptic brain. Some common forms of
partial epilepsy arise months to years after cortical
injury sustained as a consequence of stroke, trauma, or
other factors. An effective prophylaxis administered to
patients at high risk would be highly desirable. The
drugs described in this chapter provide symptomatic
therapy; that is, the drugs inhibit seizures in patients
with epilepsy. No effective anti-epileptogenic agent has
been identified.
Understanding the mechanisms of epileptogenesis
in cellular and molecular terms should provide a
framework for development of novel therapeutic
approaches. The availability of animal models provides
an opportunity to investigate the underlying
mechanisms.
585
CHAPTER 21
PHARMACOTHERAPY OF THE EPILEPSIES