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

600 explain lamotrigine’s actions on partial and secondarily generalized
seizures. However, as mentioned in the subsequent “Therapeutic
Use” section, lamotrigine is effective against a broader spectrum of
seizures than phenytoin and carbamazepine, suggesting that lamotrigine
may have actions in addition to regulating recovery from inactivation
of Na + channels. The mechanisms underlying its broad
spectrum of actions are incompletely understood. One possibility
involves lamotrigine’s inhibition of glutamate release in rat cortical
slices treated with veratridine, a Na + channel activator, raising the
possibility that lamotrigine inhibits synaptic release of glutamate by
acting at Na + channels themselves.
Pharmacokinetics. Lamotrigine is completely absorbed from the gastrointestinal
tract and is metabolized primarily by glucuronidation.
The plasma t 1/2
of a single dose is 24-30 hours. Administration of
phenytoin, carbamazepine, or phenobarbital reduces the t 1/2
and
plasma concentrations of lamotrigine. Conversely, addition of valproate
markedly increases plasma concentrations of lamotrigine, likely
by inhibiting glucuronidation. Addition of lamotrigine to valproic acid
produces a reduction of valproate concentrations by ~25% over a few
weeks. Concurrent use of lamotrigine and carbamazepine is associated
with increases of the 10,11-epoxide of carbamazepine and clinical
toxicity in some patients.
Therapeutic Use. Lamotrigine is useful for monotherapy and addon
therapy of partial and secondarily generalized tonic-clonic
seizures in adults and Lennox-Gastaut syndrome in both children
and adults. Lennox-Gastaut syndrome is a disorder of childhood
characterized by multiple seizure types, mental retardation, and
refractoriness to anti-seizure medication.
Lamotrigine monotherapy in newly diagnosed partial or generalized
tonic-clonic seizures is equivalent to carbamazepine or
phenytoin, monotherapy (Brodie et al., 1995; Steiner et al., 1999).
A double-blind, placebo-controlled trial of addition of lamotrigine to
existing anti-seizure drugs further demonstrated effectiveness of
lamotrigine against tonic-clonic seizures and drop attacks in children
with the Lennox-Gastaut syndrome (Motte et al., 1997).
Lamotrigine was also found to be superior to placebo in a doubleblind
study of children with newly diagnosed absence epilepsy
(Frank et al., 1999).
Patients who are already taking a hepatic enzyme–inducing
anti-seizure drug (such as carbamazepine, phenytoin, phenobarbital,
or primidone, but not valproate) should be given lamotrigine initially
at 50 mg/day for 2 weeks. The dose is increased to 50 mg twice
per day for 2 weeks and then increased in increments of 100 mg/day
each week up to a maintenance dose of 300-500 mg/day divided into
two doses. For patients taking valproate in addition to an enzymeinducing
anti-seizure drug, the initial dose should be 25 mg
every other day for 2 weeks, followed by an increase to 25 mg/day
for 2 weeks; the dose then can be increased by 25-50 mg/day every
1-2 weeks up to a maintenance dose of 100-150 mg/day divided into
two doses.
SECTION II
NEUROPHARMACOLOGY
Toxicity. The most common adverse effects are dizziness, ataxia,
blurred or double vision, nausea, vomiting, and rash when lamotrigine
was added to another anti-seizure drug. A few cases of Stevens-
Johnson syndrome and disseminated intravascular coagulation
have been reported. The incidence of serious rash in pediatric
patients (~0.8%) is higher than in the adult population (0.3%).
Levetiracetam
Levetiracetam (KEPPRA, others) is a pyrrolidine, the
racemically pure S-enantiomer of α-ethyl-2-oxo-1-
pyrrolidineacetamide and is FDA-approved for adjunctive
therapy for myoclonic, partial-onset, and primary
generalized tonic-clonic seizures in adults and children
as young as 4 years old.
Pharmacological Effects and Mechanism of Action. Levetiracetam
exhibits a novel pharmacological profile insofar as it inhibits partial
and secondarily generalized tonic-clonic seizures in the kindling
model, yet is ineffective against maximum electroshock- and
pentylenetetrazol-induced seizures, findings consistent with clinical
effectiveness against partial and secondarily generalized tonic-clonic
seizures. The mechanism by which levetiracetam exerts these antiseizure
effects is unknown. No evidence for an action on voltagegated
Na + channels or either GABA- or glutamate-mediated synaptic
transmission has emerged. The correlation between binding affinity
of levetiracetam analogs and their potency toward audiogenic
seizures suggests that a synaptic vesicle protein, SV2A, mediates
the anticonvulsant effects of levetiracetam (Rogawski and Bazil,
2008). Uncertainty as to the function of SV2A limits insights into
how binding of levetiracetam to SV2A might affect cellular function
or neuronal excitability.
Pharmacokinetics. Levetiracetam is rapidly and almost completely
absorbed after oral administration and is not bound to plasma proteins.
Ninety-five percent of the drug and its inactive metabolite are
excreted in the urine, 65% of which is unchanged drug; 24% of the
drug is metabolized by hydrolysis of the acetamide group. It neither
induces nor is a high-affinity substrate for CYP isoforms or glucuronidation
enzymes and thus is devoid of known interactions with
other anti-seizure drugs, oral contraceptives, or anticoagulants.
Therapeutic Use. Double-blind, placebo-controlled trials of adults
with either refractory partial seizures or uncontrolled generalized
tonic-clonic seizures associated with idiopathic generalized epilepsy
revealed that addition of levetiracetam to other anti-seizure medications
was superior to placebo. Levetiracetam also has efficacy as
adjunctive therapy for refractory generalized myoclonic seizures
(Andermann et al., 2005). Insufficient evidence is available about its
use as monotherapy for partial or generalized epilepsy.
Toxicity. Levetiracetam is well tolerated. The most frequently
reported adverse effects are somnolence, asthenia, and dizziness.
Tiagabine
Tiagabine (GABITRIL) is a derivative of nipecotic acid
and approved by the FDA as adjunct therapy for partial
seizures in adults.