Some of the traditional AEDs, including
Phenobarbital, Phenytoin and Carbamazepine are
metabolized in the liver and are potent inducers of the
cytochrome P450 (CYP450) system. These drugs act
by blocking voltage-dependent sodium channels pre-venting the repetitive and uncontrolled neuronal dis-charges seen in epilepsy. Phenobarbital, in addition,
enhances GABA mediated inhibition, which further
acts to prevent the repetitive neuronal firing.
25
In the
developed world, Phenobarbital is now prescribed
rarely due to its sedative side effect profile. However
due to its relatively low cost it is regularly prescribed
in developing countries. All of the drugs described
above induce hepatic enzymes and decrease the
serum concentration of additional AEDs that may be
prescribed. As a consequence of this effect, each drug
may impede the other, by preventing effective serum
concentrations being reached.
22
It is therefore advised
that the combination of an enzyme-inducing AED with
another AED which is metabolized in the liver requires
particular caution. Interactions with other medications
should also be considered when prescribing hepatic
enzyme inducing drugs, particularly in patients taking
exogenous contraceptive hormones, immunosuppres-sant therapy, a number of corticosteroids and some
antineoplastic chemotherapeutic agents, all of which
can be the subject of enzyme- induction. Physicians
should also be aware of the additional adverse effects
that enzyme-inducing drugs can produce, includ-ing secondary hyperparathyroidism, reduced serum
testosterone concentrations, menstrual irregularities
and elevated cholesterol levels, which may impact on
a patient’s cardiovascular disease risk. Consequently,
it has been suggested that the older, enzyme-inducing
AEDs should not be considered as first-line treat-ment options for patients with refractory seizures.26
Among older AEDs, Valproate is characterized by a
number of mechanisms of action, including sodium
channel blockade and potentiation of GABA medi-ated inhibition. It is also metabolized by the liver, but
has no enzyme-inducer properties.