Assessing a pharmacodynamic interaction between two drugs requires a valid quantitative measurement of a specific drug effect for the two drugs individually, as well as a quantitative measurement of the effect of the two drugs administered together. The isobolographic analysis is widely used to determine the various types of pharmacodynamic interaction in experimental animal models, in particular for antiepileptic drugs. Besides the isobolographic analysis, various other methods have been used to assess pharmacodynamic interactions. One of them is the fractional effective concentration (FEC) index. The difficulties encountered in the assessment of pharmacodynamic interactions in experimental animals are compounded when interactions are to be studied clinically in patients, especially for antiepileptic drugs. The discussion on designs of clinical trials to study pharmacodynamic interactions between antiepileptic drugs is based on the assumption that the studies are to be clinically relevant.

This chapter addresses the clinical impact of pharmacodynamic (PD) interactions of antiepileptic drugs (AEDs) and the strategies that have been used to discover these interactions. It outlines trials that have provided, or have attempted to provide, relevant data on PD interactions that impact on efficacy. The most common studies of additive effects of AEDs are the randomized placebo-controlled add-on studies of the new AEDs. Negative-PD interactions, also called supra-additivity for side effects, may occur when two drugs with similar side-effect profiles exceed the threshold for that side effect in combination but not individually. Several studies of specific AED combinations have demonstrated an increase in side effects. PD interactions may also increase the likelihood of non-dose-related side effects and serious idiosyncratic reactions. To date, the best data for a potentially supra-additive effect on efficacy are for the combination of lamotrigine and valproate (VPA).

This chapter discusses the clinical data concerning pharmacodynamic (PD) interactions of antiepileptic drugs (AEDs) with antidepressants (ADs), antipsychotics (APs), central nervous system (CNS) stimulants, anesthetic agents, analgesics and anti-inflammatory drugs. Experimental and clinical data suggest that AEDs and ADs have similar mechanisms of action which could result in favorable and/or unfavorable PD interactions depending on the particular agents involved. AP and AEDs are frequently co-administered and PD interactions concerning their effects on psychosis and seizure threshold are possible. At low doses, stimulants are co-administered with AEDs in the epileptic patient and seem to have beneficial PD interactions. Among anesthetic agents, lidocaine is of particular interest. Treatment of anesthetic-induced convulsions can be particularly difficult because of many possible unfavorable PD interactions. AEDs, analgesics and anti-inflammatory drugs can often be co-administered for the treatment of some forms of pain.

Pharmacodynamic interactions consist of the quantitative or qualitative alterations of any effect of a drug on any organ when these alterations are caused by the presence of another drug in the body. In order for two drugs to have a pharmacodynamic interaction, they have to share at least one common pharmacodynamic property or they have to share an identifiable clinical effect. Whenever a patient takes two or more medications simultaneously, there is the potential for some type of pharmacodynamic interaction. There can be doubt that one of the main disadvantages of antiepileptic combination therapy is an increase in the intensity or number of side effects. This chapter discusses the clinical significance of pharmacodynamic interactions and their advantages and disadvantages. A literature review of data in animals and in humans was used to determine whether appropriate antiepileptic drugs (AED) combinations can be selected on the basis of their mechanism of action.