Page 322 - ILAE_Lectures_2015

Chapter 31

Pharamacokinetic interactions between antiepileptic drugs

PHILIP N. PATSALOS

Institute of Neurology, University College London, The National Hospital for Neurology
and Neurosurgery, Queen Square, London, and Epilepsy Society, Chalfont St Peter,
Buckinghamshire

Classically, a drug interaction is regarded as a modification of the effect of one drug by prior
or concomitant administration of another. Interactions can be divided into two broad types,
namely pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions occur as a
consequence of an effect at the site of drug absorption, plasma protein binding, metabolism
or elimination and are associated with changes in blood concentrations (levels).
Pharmacodynamic interactions occur as a consequence of an effect at the site of action of a
drug, are not associated with any change in blood concentrations and are concluded by
default.

Commonly, drug interactions have been discovered as a result of unexpected changes in the
clinical status of patients upon addition or withdrawal of a drug from existing medication. A
clinically significant drug interaction can be defined as one that results in the need to adjust
dosage regimens in the majority of patients. However, the end result in individual patients
needs also to be considered. For example, a modest or even marked elevation of a low plasma
antiepileptic drug (AED) concentration consequent to an interaction may merely improve
seizure control, and a small elevation of a nearly toxic concentration may precipitate toxicity.
Similarly, a marked interaction in an unusually susceptible individual receiving drug
polytherapy that causes little change in the majority of patients is equally significant.

Table 1 shows the various AEDs and the expected changes in plasma concentrations when
an AED is added to a concomitant AED regimen.

The pharmacokinetic interactions that are most significant clinically can be attributed to
interactions at the metabolic level, and the best examples relate to inhibition or induction of
the hepatic monooxygenase enzyme system (cytochrome P450, CYP) involved in drug
metabolism. Induction involves the synthesis of new enzyme, and requires protein synthesis.
Consequently, it may take many days before induction is complete and results in an increased
drug metabolism, reduced plasma concentrations and an attenuated pharmacological effect
(if no active metabolite is present). The process goes in reverse when the inducer is withdrawn
with an increase in plasma concentrations of the target drug and hence an increased potential
for toxic side effects.

Commonly, inhibition results from competition between drugs for the same active site on an
isoenzyme of CYP, while induction involves production of more isoenzyme and therefore
more binding sites. Circulating concentrations of the inhibited drug increase to a new steady
state between four and six half-lives after the interaction has begun. Consequently, potential
pharmacological effects will occur quickly if a drug has a short half-life and more slowly if
it has a long half-life. The minimum elapsed-time for maximum potentiation is
carbamazepine 4 days, ethosuximide 12 days, phenytoin 14 days, phenobarbitone 20 days,
and valproate 3 days.