Interactions of antiepileptic drugs with drugs approved for the treatment of indications other than epilepsy

ABSTRACT

Introduction: Comorbidities of epilepsy may significantly interfere with its treatment as diseases in the general population are also encountered in epilepsy patients and some of them even more frequently (for instance, depression, anxiety, or heart disease). Obviously, some drugs approved for other than epilepsy indications can modify the anticonvulsant activity of antiepileptics.

Areas covered: This review highlights the drug-drug interactions between antiepileptics and aminophylline, some antidepressant, antiarrhythmic (class I–IV), selected antihypertensive drugs and non-barbiturate injectable anesthetics (ketamine, propofol, etomidate, and alphaxalone). The data were reviewed mainly from experimental models of seizures. Whenever possible, clinical data were provided. PUBMED data base was the main search source.Expert opinion: Aminophylline generally reduced the protective activity of antiepileptics, which, to a certain degree, was consistent with scarce clinical data on methylxanthine derivatives and worse seizure control. The only antiarrhythmic with this profile of action was mexiletine when co-administered with VPA. Among antidepressants and non-barbiturate injectable anesthetics, trazodone, mianserin and etomidate or alphaxalone, respectively, negatively affected the anticonvulsant action of some antiepileptic drugs. Clinical data indicate that only amoxapine, bupropion, clomipramine and maprotiline should be used with caution. Possibly, drugs reducing the anticonvulsant potential of antiepileptics should be avoided in epilepsy patients.

KEYWORDS:

• Antiepileptics
• aminophylline
• antidepressants
• antihypertensive drugs
• antiarrhythmic drugs
• non-barbiturate injectable anesthetics
• drug-drug interactions
• epilepsy
• seizures

Article highlights

• Comorbidities of epilepsy and their treatment may affect the efficacy of antiepileptic drugs. Both an enhancement or reduction of their anticonvulsive activity may be encountered.

• Aminophylline (theophylline₂^.ethylenediamine) is still applied for pulmonary reasons (obturatory lung diseseases), theophylline (a methylxanthine derivative) being its active component.

• The anticonvulsive activity of various conventional (carbamazepine, phenobarbital, phenytoin, valproate) or newer (lamotrigine, topiramate) was significantly reduced by aminophylline given in subconvulsive doses in mice challenged with MES-induced convulsions. Gabapentin (a newer antiepileptic drug) was resistant to aminophylline. Thus, preclinical and also some of very limited clinical data indicate that methylxanthine derivatives should be avoided in epilepsy patients.

• Depression is a frequent comorbidity of epilepsy (reaching even 30% in patients with drug-resistant seizures), so co-administration of antiepileptic and antidepressant drugs may often be the case.

• Preclinically, chronic bupropion, fluoxetine, milnacipran, reboxetine, tianeptine, or venlafaxine potentiated the anticonvulsive activity of a number of antiepileptic drugs against MES-induced convulsions in mice. However, at higher doses acute bupropion produced convulsions in mice. Clinical data confirm this effect in overdosed patients and indicate that also amoxapine, clomipramine or maprotiline need to be administered with caution in epilepsy patients. Evidently, mianserin and trazodone reduced the protective potential of some AEDs but there are no clinical data on this issue.

• Generally, antiarrhythmic drugs remained neutral or enhanced the anticonvulsive action of antiepileptic drugs. Mexiletine was an exception with probable involvement of pharmacokinetic events when combined with valproate. Its co-administration with other antiepileptic drugs seems safe in epilepsy patients.

• As regards antihypertensive drugs, none of them reduced the protective activity of antiepileptic drugs.

• Among non-barbiturate injectable anesthetics, only etomidate and alphaxalone negatively affected the anticonvulsant activity of some antiepileptic drugs.

• Angiotensin II receptor antagonists positively interacted with valproate and lamotrigine without evident pharmacokinetic mechanisms. Other antihypertensive drugs were generally neutral in combinations with AEDs. Basing upon clinical data, antihypertensive drugs do not seem to possess any negative potential for the interactions with antiepileptic drugs.

• Clinical data are scarce in terms of the above-mentioned interactions. Case reports confirm the negative interactions between caffeine (closely related to aminophylline) and antiepileptic drugs. Some pharmacokinetic data are available for the concomitant use of antidepressants and antiepileptics. Possibly, drugs negatively affecting the anticonvulsant efficacy of AEDs in animal studies need to be avoided in epilepsy patients.

Declaration of interest

S.J. Czuczwar has received financial support from Bayer, GlaxoSmithKline, Janssen, Novartis, Sanofi-Aventis for lecturing. He is also a recipient of an unrestricted grant from GlaxoSmithKline. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.