Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs

Abstract

Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P‐glycoprotein) and can reduce the efficacy of co‐administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥200 mg/day) and perampanel (at doses ≥8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen‐containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.

Posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia: Clinical characteristics, risk factors, course, and outcome of disease

“…Dexamethasone has previously been reported to be associated with PRES in cancer treatment, but data are scarce . Several other chemotherapeutic agents used in the treatment of ALL have also been associated with PRES, most likely through cytotoxic mechanisms . Increasing data indicate that hyponatremia might contribute to the pathogenesis of PRES .…”

Anti-Epileptic Drug Combination Efficacy in an In Vitro Seizure Model – Phenytoin and Valproate, Lamotrigine and Valproate

“…In this study we have used an in vitro seizure model to examine the seizure suppressive effects of three commonly used AEDs singly and in combination. This methodology allowed quantitative estimation of seizure inhibition without the potential pharmacokinetic complication of in vivo systems [11]. …”

Poor concordance among drug compendia for proposed interactions between enzyme‐inducing antiepileptic drugs and direct oral anticoagulants

“…Three compendia had instances of extreme internal inconsistency, wherein one EI‐AED was assigned the highest possible interaction severity ranking with a given DOAC, while another EI‐AED (believed to have similar induction properties) was described as not interacting with the same DOAC. While some of these differences could be attributable to heterogeneity in reporting of inductive potential for different EI‐AEDs, this was likely not the primary cause of these discrepancies as AEDs were only included if they had consistent, current classifications as potent P‐gp and CYP3A4 inducers . Previous studies have also proposed that variability among drug compendia may be partially attributable to the dearth of research focused on the impacts of EI‐AEDs on drug transporters like P‐gp compared with drug metabolizing enzymes like CYP3A4 .…”

“…In January 2019, the concordance in interaction reporting and severity rankings for each DOAC with a set of EI‐AEDs were quantified among four leading privately accessible (paid subscription) drug compendia (Clinical Pharmacology powered by ClinicalKey, Drug Facts and Comparisons, Lexicomp, and Micromedex) and four leading publicly accessible (free) drug compendia (Cerner Multum, Epocrates, Medscape, and RxList). As evidence differentiating the inductive potential of EI‐AEDs, particularly relative to P‐gp, is variable and still developing, examined AEDs encompassed only those with consistent evidence supporting potent P‐gp and CYP3A4 induction, including: carbamazepine, phenobarbital, phenytoin, and primidone …”