Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs

Abstract

Summary: Development of tolerance (i.e., the reduction in response to a drug after repeated administration) is an adaptive response of the body to prolonged exposure to the drug, and tolerance to antiepileptic drugs (AEDs) is no exception. Tolerance develops to some drug effects much more rapidly than to others. The extent of tolerance depends on the drug and individual (genetic?) factors. Tolerance may lead to attenuation of side effects but also to loss of efficacy of AEDs and is reversible after discontinuation of drug treatment. Different experimental approaches are used to study tolerance in laboratory animals. Development of tolerance depends on the experimental model, drug, drug dosage, and duration of treatment, so that a battery of experimental protocols is needed to evaluate fully whether tolerance to effect occurs. Two major types of tolerance are known. Pharmacokinetic (metabolic) tolerance, due to induction of AED-metabolizing enzymes has been shown for most firstgeneration AEDs, and is easy to overcome by increasing dosage. Pharmacodynamic (functional) tolerance is due to "adaptation" of AED targets (e.g., by loss of receptor sensitivity) and has been shown experimentally for all AEDs that lose activity during prolonged treatment. Functional tolerance may lead to complete loss of AED activity and cross-tolerance to other AEDs. Convincing experimental evidence indicates that almost all first-, second-, and third-generation AEDs lose their antiepileptic activity during prolonged treatment, although to a different extent. Because of diverse confounding factors, detecting tolerance in patients with epilepsy is more difficult but can be done with careful assessment of decline during long-term individual patient response. After excluding confounding factors, tolerance to antiepileptic effect for most modern and old AEDs can be shown in small subgroups of responders by assessing individual or group response. Development of tolerance to the antiepileptic activity of an AED may be an important reason for failure of drug treatment. Knowledge of tolerance to AED effects as a mechanism of drug resistance in previous responders is important for patients, physicians, and scientists.

Effect of Aqueous Extract Withania somnifera on Tolerance to Antiepileptic Effect of Phenobarbitone in Mice

“…conventional as well as the newer agents both in experimental and clinical studies. 24 Tolerance may lead to drug resistance. Thus we decided that strategies ameliorating tolerance development and would prevent development of drug resistance.…”

Drug Resistance and Resistance Mechanisms in Epilepsy

“…van Vliet ve ark.nın çalışmasındaki fenitoin ve tariquidar ile gözlenen geçici etki ise fenitoin etkinliğini azaltabilecek başka faktörlerin varlığını akla getirmiştir. [42] AEİ'ye tolerans gelişimi bunlardan biri olabilir.…”

“…Bu durum uzun süreli tedavi boyunca tüm AEİ'ler için deneysel olarak gösterilmiştir. [42] Tablo 1'de AEİ farmakogenetiği ile ilişkili genler ve fonksiyonları görülmektedir.…”

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

“…These results illustrate the complex role of the functioning of the blood-brain barrier as a determinant of the target exposure. Indeed, upregulation of the efflux transporter Pgp has been indicated as one of the possible explanations for the development of apparent tolerance [30]. Whereas active transport processes may determine tissue distribution, high variability in drug exposure can exist even between closely located areas in the brain.…”