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

Pharmacotherapy
of the Epilepsies
James O. McNamara
The epilepsies are common and frequently devastating
disorders, affecting ~2.5 million people in the U.S. alone.
More than 40 distinct forms of epilepsy have been identified.
Epileptic seizures often cause transient impairment
of consciousness, leaving the individual at risk of bodily
harm and often interfering with education and employment.
Therapy is symptomatic in that available drugs
inhibit seizures, but neither effective prophylaxis nor cure
is available. Compliance with medication is a major
problem because of the need for long-term therapy
together with unwanted effects of many drugs.
The mechanisms of action of anti-seizure drugs
fall into three major categories.
1. The first mechanism is to limit the sustained,
repetitive firing of neurons, an effect mediated
by promoting the inactivated state of voltageactivated
Na + channels.
2. A second mechanism appears to involve
enhanced γ-aminobutyric acid (GABA)–mediated
synaptic inhibition, an effect mediated
either by a presynaptic or postsynaptic action.
Drugs effective against the most common forms
of epileptic seizures, partial and secondarily generalized
tonic-clonic seizures, appear to work by
one of these two mechanisms.
3. Drugs effective against absence seizure, a less common
form of epileptic seizure, work by a third
mechanism, inhibition of voltage-activated Ca 2+
channels responsible for T-type Ca 2+ currents.
Although many treatments are available, much
effort is being devoted to elucidating the genetic causes
and the cellular and molecular mechanisms by which
a normal brain becomes epileptic, insights that promise
to provide molecular targets for both symptomatic
and preventive therapies.
TERMINOLOGY AND EPILEPTIC
SEIZURE CLASSIFICATION
The term seizure refers to a transient alteration of
behavior due to the disordered, synchronous, and rhythmic
firing of populations of brain neurons. The term
epilepsy refers to a disorder of brain function characterized
by the periodic and unpredictable occurrence of
seizures. Seizures can be “non-epileptic” when evoked
in a normal brain by treatments such as electroshock or
chemical convulsants, or “epileptic” when occurring
without evident provocation. Pharmacological agents
in current clinical use inhibit seizures, and thus are
referred to as anti-seizure drugs. Whether any of these
prevent the development of epilepsy (epileptogenesis)
is uncertain.
Seizures are thought to arise from the cerebral
cortex, and not from other central nervous system
(CNS) structures such as the thalamus, brainstem, or
cerebellum. Epileptic seizures have been classified into
partial seizures, those beginning focally in a cortical
site, and generalized seizures, those that involve both
hemispheres widely from the outset (Commission on
Classification and Terminology, 1981). The behavioral
manifestations of a seizure are determined by the functions
normally served by the cortical site at which the
seizure arises. For example, a seizure involving motor
cortex is associated with clonic jerking of the body part
controlled by this region of cortex. A simple partial
seizure is associated with preservation of consciousness.
A complex partial seizure is associated with
impairment of consciousness. The majority of complex
partial seizures originate from the temporal lobe.
Examples of generalized seizures include absence,
myoclonic, and tonic-clonic. The type of epileptic
seizure is one determinant of the drug selected for