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

clonazepam at any dosage. The initial dose of clonazepam for adults
should not exceed 1.5 mg per day and for children 0.01-0.03 mg/kg
per day. The dose-dependent side effects are reduced if two or three
divided doses are given each day. The dose may be increased every
3 days in amounts of 0.25-0.5 mg per day in children and 0.5-1 mg
per day in adults. The maximal recommended dose is 20 mg per day
for adults and 0.2 mg/kg per day for children. Clonazepam intranasal
spray is designated as an orphan drug for recurrent acute repetitive
seizures.
While diazepam is an effective agent for treatment of status
epilepticus, its short duration of action is a disadvantage, leading to
the more frequent use of lorazepam. Although diazepam is not useful
as an oral agent for the treatment of seizure disorders, clorazepate
is effective in combination with certain other drugs in the treatment
of partial seizures. The maximal initial dose of clorazepate is 22.5 mg
per day in three portions for adults and children > 12 years and 15 mg
per day in two divided doses in children 9-12 years of age.
Clorazepate is not recommended for children under the age of 9.
OTHER ANTI-SEIZURE DRUGS
Gabapentin and Pregabalin
Gabapentin (NEURONTIN, others) and pregabalin (LYRICA)
are anti-seizure drugs that consist of a GABA molecule
covalently bound to a lipophilic cyclohexane ring or
isobutane, respectively. Gabapentin was designed to be a
centrally active GABA agonist, with its high lipid solubility
aimed at facilitating its transfer across the blood-brain
barrier. The structures of gabapentin and pregabalin are:
H 2 N
PREGABALIN
COOH
Pharmacological Effects and Mechanisms of Action. Gabapentin
inhibits tonic hind limb extension in the electroshock seizure model.
Interestingly, gabapentin also inhibits clonic seizures induced by
pentylenetetrazol. Its efficacy in both these tests parallels that of valproic
acid and distinguishes it from phenytoin and carbamazepine.
Despite their design as GABA agonists, neither gabapentin nor pregabalin
mimics GABA when iontophoretically applied to neurons
in primary culture. These compounds bind with high affinity to a
protein in cortical membranes with an amino acid sequence identical
to that of the Ca 2+ channel subunit α2δ-1 (Gee et al., 1996). It has
been speculated that the anticonvulsant effects of gabapentin are
mediated by α2δ-1 protein, but whether and how the binding of
gabapentin to the α2δ-1 regulates neuronal excitability remains
unclear. Pregabalin binding is reduced but not eliminated in mice
carrying a mutation in the α2δ-1 protein (Field et al., 2006).
Analgesic efficacy of pregabalin is eliminated in these mice; whether
the anticonvulsant effects of pregabalin are also eliminated was not
reported. It is unclear whether the anticonvulsant and analgesic
effects of gabapentin and pregabalin are mediated by affecting Ca 2+
currents and, if so, how.
Pharmacokinetics. Gabapentin and pregabalin are absorbed after
oral administration and are not metabolized in humans. These compounds
are not bound to plasma proteins and are excreted
unchanged, mainly in the urine. Their half-lives, when used as
monotherapy, approximate 6 hours. These compounds have no
known interactions with other anti-seizure drugs.
Therapeutic Uses. Gabapentin and pregabalin are effective for partial
seizures, with and without secondary generalization, when used
in addition to other anti-seizure drugs.
Double-blind placebo-controlled trials of adults with refractory
partial seizures demonstrated that addition of gabapentin or pregabalin
to other anti-seizure drugs is superior to placebo (Sivenius et
al., 1991; French et al., 2003). A double-blind study of gabapentin
(900 or 1800 mg/day) monotherapy disclosed that gabapentin was
equivalent to carbamazepine (600 mg/day) for newly diagnosed partial
or generalized epilepsy (Chadwick et al., 1998). Gabapentin also
is being used for the treatment of migraine, chronic pain, and bipolar
disorder.
Gabapentin usually is effective in doses of 900-1800 mg daily
in three doses, although 3600 mg may be required in some patients
to achieve reasonable seizure control. Therapy usually is begun with
a low dose (300 mg once on the first day), which is increased in daily
increments of 300 mg until an effective dose is reached.
Toxicity. Overall, gabapentin is well tolerated with the
most common adverse effects of somnolence, dizziness,
ataxia, and fatigue. These effects usually are mild to
moderate in severity but resolve within 2 weeks of onset
during continued treatment. Gabapentin and pregabalin
are listed in pregnancy category C.
Lamotrigine
Lamotrigine (LAMICTAL, others) is a phenyltriazine derivative
initially developed as an antifolate agent based on
the incorrect idea that reducing folate would effectively
combat seizures. Structure-activity studies indicate that
its effectiveness as an anti-seizure drug is unrelated to its
antifolate properties (Macdonald and Greenfield, 1997).
Pharmacological Effects and Mechanisms of Action. Lamotrigine
suppresses tonic hind limb extension in the maximal electroshock
model and partial and secondarily generalized seizures in the
kindling model, but does not inhibit clonic motor seizures induced
by pentylenetetrazol. Lamotrigine blocks sustained repetitive firing
of mouse spinal cord neurons and delays the recovery from inactivation
of recombinant Na + channels, mechanisms similar to those of
phenytoin and carbamazepine (Xie et al., 1995). This may well
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CHAPTER 21
PHARMACOTHERAPY OF THE EPILEPSIES