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

602 Pharmacological Effects and Mechanisms of Action. Felbamate
is effective in both the maximal electroshock and pentylenetetrazol
seizure models. Clinically relevant concentrations of felbamate
inhibit NMDA-evoked responses and potentiate GABA-evoked
responses in whole-cell, voltage-clamp recordings of cultured rat
hippocampal neurons (Rho et al., 1994). This dual action on excitatory
and inhibitory transmitter responses may contribute to the wide
spectrum of action of the drug in seizure models.
Therapeutic Use. An active control, randomized, double-blind protocol
demonstrated the efficacy of felbamate in patients with poorly
controlled partial and secondarily generalized seizures (Sachdeo et al.,
1992). Felbamate also reduced seizures in patients with Lennox-
Gastaut syndrome (Felbamate Study Group in Lennox-Gastaut
Syndrome, 1993). The clinical efficacy of this compound, which
inhibits responses to NMDA and potentiates those to GABA, underscores
the potential value of additional anti-seizure agents with similar
mechanisms of action.
SECTION II
NEUROPHARMACOLOGY
Zonisamide
Zonisamide (ZONEGRAN, others) is a sulfonamide derivative
that is FDA approved as adjunctive therapy of partial
seizures in adults.
Pharmacological Effects and Mechanism of Action. Zonisamide
inhibits the T-type Ca 2+ currents. In addition, zonisamide inhibits the
sustained, repetitive firing of spinal cord neurons, presumably by prolonging
the inactivated state of voltage-gated Na + channels in a manner
similar to actions of phenytoin and carbamazepine.
Zonisamide inhibits tonic hind limb extension evoked by
maximal electroshock and inhibits both partial and secondarily generalized
seizures in the kindling model, results predictive of clinical
effectiveness against partial and secondarily generalized tonic-clonic
seizures. Zonisamide does not inhibit minimal clonic seizures
induced by pentylenetetrazol, suggesting that the drug will not be
effective clinically against myoclonic seizures.
Pharmacokinetics. Zonisamide is almost completely absorbed after
oral administration, has a long t 1/2
(~63 hours), and is ~40% bound
to plasma protein. Approximately 85% of an oral dose is excreted in
the urine, principally as unmetabolized zonisamide and a glucuronide
of sulfamoylacetyl phenol, which is a product of metabolism
by CYP3A4. Phenobarbital, phenytoin, and carbamazepine
decrease the plasma concentration/dose ratio of zonisamide, whereas
lamotrigine increases this ratio. Conversely, zonisamide has little
effect on the plasma concentrations of other anti-seizure drugs.
Therapeutic Use. Double-blind, placebo-controlled studies of
patients with refractory partial seizures demonstrated that addition of
zonisamide to other drugs was superior to placebo. There is insufficient
evidence for its efficacy as monotherapy for newly diagnosed
or refractory epilepsy.
Toxicity. Overall, zonisamide is well tolerated. The most common
adverse effects include somnolence, ataxia, anorexia, nervousness,
and fatigue. Approximately 1% of individuals develop renal calculi
during treatment with zonisamide, which may relate to its ability to
inhibit carbonic anhydrase. Post-marketing experience indicates that
zonisamide can cause metabolic acidosis in some patients. Patients
with predisposing conditions (e.g., renal disease, severe respiratory
disorders, diarrhea, surgery, ketogenic diet) may be at greater risk.
The risk of zonisamide-induced metabolic acidosis also appears to
be more frequent and severe in younger patients. Measurement of
serum bicarbonate prior to initiating therapy and periodically thereafter,
even in the absence of symptoms, is recommended.
Lacosamide
Lacosamide (VIMPAT) is a functionalized amino acid that
was approved by the FDA in 2008 as adjunctive therapy
for partial-onset seizures in patients 17 years of age and
older. An injectable formulation is available for short
term use when oral administration is not feasible.
LACOSAMIDE
Pharmacological Effects and Mechanism of Action. Lacosamide
enhances slow inactivation of voltage-gated Na + channels and limits
sustained repetitive firing, the neuronal firing pattern characteristic
of partial seizures. Lacosamide also binds collapsin response
mediator protein 2 (crmp-2), a phosphoprotein involved in neuronal
differentiation and axon outgrowth. Its anti-seizure mechanism of
action is more likely mediated by its enhancing slow inactivation of
Na + channels.
Therapeutic Use. Double-blind, placebo-controlled studies of adults
with refractory partial seizures demonstrated that addition of
lacosamide to other drugs was superior to placebo.
Rufinamide
Rufinamide (BANZEL) is a triazole derivative structurally
unrelated to other marketed anti-epileptic drugs. It was
approved by the FDA in 2008 for adjunctive treatment
of seizures associated with Lennox-Gastaut syndrome
in children 4 years and older and adults.
RUFINAMIDE
Pharmacological Effects and Mechanism of Action. Rufinamide
enhances slow inactivation of voltage gated Na + channels and limits
sustained repetitive firing, the firing pattern characteristic of partial
seizures. Whether this is the mechanism by which rufinamide suppresses
seizures is presently unclear.