The role of heat-not-burn, snus and other nicotine-containing products as interventions for epileptic patients who take phenytoin and smoke cigarettes.

Background: Cigarette smoke increases the metabolism of phenytoin, a widely used anti-epileptic agent, by inducing cytochrome P450 enzymes in the liver. Therefore, cigarette smoke may reduce the clinical effect of phenytoin. Switching from cigarettes to smoke-free products (e.g., heat-not-burn, snus and e-cigarettes) is likely to have an impact on phenytoin metabolism. The absence of tobacco combustion in these smoke-free products reduces the production of the chemicals that induce the metabolism of phenytoin. Objectives: The primary objective was to determine whether smoke-free products have a role to play in epileptic patients who take phenytoin and continue to smoke cigarettes. The secondary objectives were to assess: (1) the influence of cigarette smoke on phenytoin metabolism including the metabolic pathways involved, (2) the influence of nicotine on phenytoin metabolism including the metabolic pathways involved, if any, and (3) the influence of nicotine on epilepsy in humans, if any. Methods: The literature review was conducted in 2019 and 2020 using a structured search to identify relevant articles. The potential mechanisms underlying the effects of cigarette smoke and nicotine on phenytoin metabolism and the pathways for phenytoin metabolism were evaluated to determine overlapping mechanisms/pathways. The key methodological deficiencies in the studies were recorded, where applicable. Results: Thirty-five studies were reviewed. The literature showed that cigarette smoke influenced the metabolism of phenytoin by increasing the maximum metabolism rate of phenytoin by an average of 16% in humans. Cigarette smoke is known to contain several polycyclic aromatic hydrocarbons (PAHs), which can lead to faster elimination of numerous medicines, including phenytoin. There is no literature assessing the direct influence of nicotine on phenytoin metabolism in humans and animals. The metabolic pathways of phenytoin and nicotine do not overlap indicating that nicotine does not influence the metabolism of phenytoin. Hence, complete switching to smoke-free products with similar nicotine concentrations to cigarettes, may reduce the influence smoking has on phenytoin metabolism in epileptic patients who take phenytoin and smoke. There was also no evidence to demonstrate that nicotine has the potential to trigger epilepsy in humans. Conclusion: The literature showed that the increase in metabolic rate of phenytoin due to tobacco smoke is probably attributable to PAHs and not nicotine. The similar nicotine content between smoke-free products and cigarettes and the reduced levels of PAHs in smoke-free products indicate that there is a role for smoke-free products in epileptic patients who take phenytoin and smoke.