Since antiepileptic drugs (AEDs) being commonly prescribed for long periods, even in a lifetime, many patients with concomitant conditions usually present with side effects of drug interactions resulting from treatment of these conditions. First-generation AEDs such as phenytoin, carbamazepine, primidone as well as phenobarbital are known to be potent inducers of hepatic enzymes. Inductions of the hepatic enzymes result in the reduction in plasma levels of other drugs such as antimicrobial, cardiovascular, psychotropic and immunosuppressant drugs (Patsalos & Perucca, 2003).
However, even AEDs can have pharmacokinetic impacts on other AEDs, either inducing their metabolism or inhibit their metabolism. Pharmacokinetic interactions between AEDs mainly involve inhibition or induction of the cytochrome P450. Commonly administered, enzyme-inducing AEDs, primidone, phenytoin, carbamazepine, and phenobarbital induce the metabolism of other AEDs when concurrently administered. Stimulation of the metabolism of valproic acid by the action of carbamazepine leads to significant increase in the dose of valproic acid to compensate for its fast clearance. In addition, AEDs interact with each other to cause an increase in serum levels of the affected drug. Valproic acid, an AED, is known to inhibit the metabolism of phenobarbital and lamotrigine leading to an increase in the latter serum concentration. Unlike AEDs interaction that leads to decreased serum levels of the affected drug, serum concentration leads to toxicity leading to life-threatening skin rashes. Valproic acid co-administration with carbamazepine also leads to the latter serum concentration since it inhibits enzyme epoxide hydrolase. Felbamate also increases plasma levels of phenobarbital, valproic acid, and phenytoin. Stiripentol interact with other AEDs including phenobarbital, carbamazepine, valproic acid, and phenytoin by increasing their plasma concentration. Other pharmacodynamic interactions of AEDs include the reciprocal interactions at the site of action affecting the tolerability and efficacy of a drug. The concurrent pharmacokinetic interactions of lamotrigine and valproic acid is known to circumvent the potential adverse effects in managing seizures that are unresponsive to maximum tolerated doses of either of the AEDs (Zaccara & Perucca, 2014).
The interactions of AEDs and other drugs such as antimicrobials have been documented in antihelminthic and antibiotic drugs. Carbamazepine and phenytoin interact with praziquantel, an antihelminthic drug, significantly increasing its first-pass metabolism leading to the low plasma level of the drug. The reduction in the plasma concentration of praziquantel may result in therapeutic failure of the antihelminthic drug the mechanism of action of increased metabolism of antihelminthic drugs including albendazole occurs through the stimulation of the CYP3A4 pathway by the AEDs. On the other hand, antituberculosis drugs such as isoniazid are known to inhibit the metabolism of AEDs including phenytoin, carbamazepine, and ethosuximide. The result of this antibiotic-mediated inhibition is an increase in these AEDs plasma concentration leading to toxicity. Inhibition of first-generation AEDS is also observed in other classes of antibiotics such as macrolides and sulfonamides (Patsalos & Perucca, 2003).
Valproic acid interacts with other drugs such as lopinavir and zidovudine with the potential of inhibiting their activity leading to their increased serum concentration. Such interactions have the potential of causing toxicity especially when valproic acid is co-administered with antineoplastic agents. Warfarin dose adjustment is required when felbamate, an AED, is co-administered to minimize the risk of excessive anticoagulation (Zaccara & Perucca, 2014). Drug-drug interactions involving chemotherapeutic drugs and anticonvulsants have also been documented. The result of these interaction leads to inadequate tumor therapy or even drug toxicity. Valproic acid accelerates thrombopenia caused by chemotherapeutic drugs through its effect on the bone marrow (Bénit & Vecht, 2016).
- Bénit, C. P., & Vecht, C. J. (2016). Neuro-Oncology Practice Seizures and cancer: drug interactions of anticonvulsants with chemotherapeutic agents, tyrosine kinase inhibitors and glucocorticoids. Neuro-Oncology Practice, 3(4), 245–260. https://doi.org/10.1093/nop/npv038
- Patsalos, P. & Perucca, E. (2003). Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. The Lancet Neurology, 2(8), 473-481. https://doi.org/10.1016/S1474-4422(03)00483-6 .
- Zaccara, G., & Perucca, E. (2014). Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs. In Epileptic Disorders, 16, 409–431. https://doi.org/10.1684/epd.2014.0714