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

606 of women with epilepsy have been published by the
American Academy of Neurology (Morrell, 1998).
SECTION II
NEUROPHARMACOLOGY
The effectiveness of oral contraceptives appears to be
reduced by concomitant use of anti-seizure drugs. The failure rate
of oral contraceptives is 3.1/100 years in women receiving antiseizure
drugs compared to a rate of 0.7/100 years in non-epileptic
women. One attractive explanation of the increased failure rate
is the increased rate of oral contraceptive metabolism caused by
anti-seizure drugs that induce hepatic enzymes (Table 21–2); particular
caution is needed with anti-seizure drugs that induce
CYP3A4.
Teratogenicity. Epidemiological evidence suggests that anti-seizure
drugs have teratogenic effects (Pack, 2006). These teratogenic effects
add to the deleterious consequences of oral contraceptive failure.
Infants of epileptic mothers are at 2-fold greater risk of major congenital
malformations than offspring of non-epileptic mothers (4-8%
compared to 2-4%). These malformations include congenital heart
defects, neural tube defects, cleft lip, cleft palate, and others. Inferring
causality from the associations found in large epidemiological studies
with many uncontrolled variables can be hazardous, but a causal
role for anti-seizure drugs is suggested by association of congenital
defects with higher concentrations of a drug or with polytherapy compared
to monotherapy. Phenytoin, carbamazepine, valproate, lamotrigine,
and phenobarbital all have been associated with teratogenic
effects. Newer anti-seizure drugs have teratogenic effects in animals
but whether such effects occur in humans is yet uncertain. One consideration
for a woman with epilepsy who wishes to become pregnant
is a trial free of anti-seizure drug; monotherapy with careful attention
to drug levels is another alternative. Polytherapy with toxic levels
should be avoided. Folate supplementation (0.4 mg/day) has been
recommended by the U.S. Public Health Service for all women of
childbearing age to reduce the likelihood of neural tube defects, and
this is appropriate for epileptic women as well.
Anti-seizure drugs that induce CYPs have been associated
with vitamin K deficiency in the newborn, which can result in a
coagulopathy and intracerebral hemorrhage. Treatment with vitamin
K 1
, 10 mg/day during the last month of gestation, has been recommended
for prophylaxis.
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