Why are my brain drugs not working? The answer may be in your genetics

Pharmacology is the auxiliary science of medicine that has helped us fight disease, pain and all kind of problems, but it has always encountered a problem: every person is quite unique from a genetic point of view, and that usually don’t represent a problem at all, most of the truly important differences are well known by physicians and are extremely rare from a statistical point of view; but in the last years we have got to know something we were previously ignoring completely: medication doesn’t work the same in everybody, that’s why a new branch of pharmacology has surged: Pharmacogenetics is the study of why does drugs don’t work, works in another ways, and in what efficiency in patients based solely on their genes, today we will explore the case of Phenytoin (Dilantin,) a very common antiseizure drug in order to understand better how this will affect how we treat medication.

The actual reasons of why some medication will not work for some people

Science advances (and changes, a lot) almost daily, but the effect that it has on our day-to-day life is something truly remarkable, now after a long time we have stopped using simple tags such as race in biomedical research and are now focusing on the specific ancestors of a person, a spectrum rather than a “closed genetic box” that ultimately, didn’t have that much weight. This changes a lot about how we do clinical trials and tests, and how do we get to the bottom of why certain medication doesn’t work for you at all, is less effective than average or does a completely different thing. We, humans, have a certain degree of genetic variability that gives possibility to something we call pathogenic variants, previously known as mutations, those are very specific genetic changes that may cause different reactions, a variable degree of sensibility or metabolism regarding medication, or in the worst of cases, inheritable disorders or diseases.

Phenytoin and the problem of “too long, too short, too little, too much”

Phenytoin is a commonly used antiseizure drug known by one of its commercial names, Dilantin. If you are epileptic there is a good chance that your neurologist has prescribed or that you have been administered with it on more than one occasion.

Phenytoin is of common use to treat seizures, but it has some really undesirable side effects such as nausea, sedation and dancing eyes. As a merely illustrative example for you to get an idea: overdose can and will produce a coma if the blood concentration reaches more than 2.3 milligrams for every pound. A dose of phenytoin must be closely controlled and measured to have the desired effect. This is known as the therapeutic window, it happens when a medication doesn’t follow the logic of “double the dose, double the effect” (which your physician knows as a Michaelis Menten kinetics) So, it must be administered in a certain range.

The true culprit may be closer than you think, your liver

Now, the specific enzyme responsible for the metabolism of the phenytoin is the CYP2C9 (which does 90% of the work or 100% most of the times) and the CYP2C19 which does the leftover 10% or none of the work, as it is auxiliary to the main enzyme, meaning that it only starts to work when the liver is oversaturated with phenytoin. This little enzyme can have different alleles, if you happen to have the “bad metabolizer” variable (polymorphism) then something unexpected can happen and that is the occurrence of the drug accumulating over time and producing harming effects. The contrary can happen if you got the “fast metabolizer” when the drug doesn’t have any effect at all because it has not been given enough time to act.

Render of the CYP2C19 and CYPC9 enzymes. Original creation, 2026.

What will be changing now

Finally, we can sum it up with the most significative change you will be noticing if you’re a user of this drug is the testing, the so called pharmacogenetic neurological panel, a test in which an analysis of your specific variations of certain genes will give your physician an idea of how you may react to phenytoin and a variety of another drugs. This is just a little example of pharmacogenetics helping us more and more nowadays, reducing the risk of complications or toxicity.

Our genes, finally, aren’t destiny. They are an instruction book we are finally learning how to read correctly.

Sources

Franco, Valentina, and Emilio Perucca. “CYP2C9 Polymorphisms and Phenytoin Metabolism: Implications for Adverse Effects.” Expert Opinion on Drug Metabolism & Toxicology, ahead of print, 2015. https://doi.org/10.1517/17425255.2015.1053463.

Lewis, Anna C. F., Santiago J. Molina, Paul S. Appelbaum, et al. “Getting Genetic Ancestry Right for Science and Society.” Science 376, no. 6590 (2022): 250–52. https://doi.org/10.1126/science.abm7530.

“Pharmacogenetics and Pharmacogenomics.” In Medical and Health Genomics. Academic Press, 2016. https://doi.org/10.1016/B978-0-12-420196-5.00010-1.

Assessed and Endorsed by the MedReport Medical Review Board