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

588
Open
Inactivated
Na + Na +
vigabatrin
GABA
GABA-T
SECTION II
NEUROPHARMACOLOGY
I
A
Na +
carbamazepine
phenytoin
topiramate
Na +
lamotrigine
valproate
zonisamide
Figure 21–2. Anti-seizure drug-enhanced Na + channel inactivation.
Some anti-seizure drugs (shown in blue text) prolong the
inactivation of the Na + channels, thereby reducing the ability of
neurons to fire at high frequencies. Note that the inactivated
channel itself appears to remain open, but is blocked by the inactivation
gate I. A, activation gate.
known to be effective at limiting seizures in humans
(Rogawski and Loscher, 2004). Inhibition of the highfrequency
firing is thought to be mediated by reducing
the ability of Na + channels to recover from inactivation
(Figure 21–2). That is, depolarization-triggered
opening of the Na + channels in the axonal membrane
of a neuron is required for an action potential; after
opening, the channels spontaneously close, a process
termed inactivation. This inactivation is thought to
cause the refractory period, a short time after an action
potential during which it is not possible to evoke
another action potential. Upon recovery from inactivation,
the Na + channels are again poised to participate
in another action potential. Because firing at a slow
rate permits sufficient time for Na + channels to recover
from inactivation, inactivation has little or no effect on
low-frequency firing. However, reducing the rate of
recovery of Na + channels from inactivation would limit
the ability of a neuron to fire at high frequencies, an
effect that likely underlies the effects of carbamazepine,
lamotrigine, phenytoin, topiramate, valproic
acid, and zonisamide against partial seizures.
Insights into mechanisms of seizures suggest that
enhancing GABA-mediated synaptic inhibition would
reduce neuronal excitability and raise the seizure
threshold. Several drugs are thought to inhibit seizures
by regulating GABA-mediated synaptic inhibition
through an action at distinct sites of the synapse
(Rogawski and Loscher, 2004). The principal postsynaptic
receptor of synaptically released GABA is
termed the GABA A
receptor (Chapters 14 and 17).
Activation of the GABA A
receptor inhibits the postsynaptic
cell by increasing the inflow of Cl – ions into the
A
I
valproate
tiagabine
GABA
GAT-1
benzodiazepines
succinic
semialdehyde
succinic
semialdehyde
dehydrogenase
metabolites
GABA binding site
cell, which tends to hyperpolarize the neuron. Clinically
relevant concentrations of both benzodiazepines and
barbiturates enhance GABA A
receptor–mediated inhibition
through distinct actions on the GABA A
receptor
(Figure 21–3), and this enhanced inhibition probably
underlies the effectiveness of these compounds against
partial and tonic-clonic seizures in humans. At higher
concentrations, such as might be used for status epilepticus,
these drugs also can inhibit high-frequency firing
of action potentials. A second mechanism of enhancing
GABA-mediated synaptic inhibition is thought to
underlie the anti-seizure mechanism of tiagabine;
tiagabine inhibits the GABA transporter, GAT-1, and
reduces neuronal and glial uptake of GABA (Rogawski
and Loscher, 2004).
Generalized-Onset Epilepsies:
Absence Seizures
In contrast to partial seizures, which arise from localized
regions of the cerebral cortex, generalized-onset
Cl –
barbiturates
Figure 21–3. Enhanced GABA synaptic transmission. In the presence
of GABA, the GABA A
receptor (structure on left) is
opened, allowing an influx of C1 − , which in turn increases membrane
polarization (Chapter 14). Some anti-seizure drugs (show
in larger blue text) act by reducing the metabolism of GABA.
Others act at the GABA A
receptor, enhancing C1 − influx in
response to GABA. As outlined in the text, gabapentin acts
presynaptically to promote GABA release; its molecular target is
currently under investigation. GABA molecules, GABA-T,
GABA transaminase; GAT-1, GABA transporter.