It is a complete lottery when your doctor chooses medicine for you if your genes are slightly different from average. No – we don’t talk about skin color or anything else that can be seen on the outside. We are talking about the enzymes that break down the drug so that it gives you the effect expected and does not cause too many side effects.
I read the results from quite a few clinical trials; the tests done with new medicines before the medicine can be approved by the authorities. There are specific rules for how these tests should be conducted. There should be a control group so that we can see how large the placebo effect is, there must be subjects of both sexes, of different ages, a substantial number of participants and the drug has to be tested in 2 or more doses.
But – in my opinion – one important variable is missing. There is no requirement that the drug be tested on people who are slow metabolizers or ultra rapid metabolizers of the enzymes that break down the drug.
The majority of medicines are broken down by a handful of different liver enzymes. They can be recognized by their name beginning with the letters CYP followed by a series of numbers and letters. CYP3A4 and CYP2D6 are the two enzymes that break down the majority of our common drugs. In addition, some triptans are metabolized by the enzyme MAO-A, which some readers may recognize as the enzyme that also breaks down tyramine. Tyramine is the most common cause for food migraine..
Enzyme activity varies from person to person
Here are three examples of how the enzyme activity of a single enzyme determines the effect of the medicines we are offered by the doctor. The text continues below the stories from three women.
Vivi has migraines many days every month. She has tried virtually every form of acute and preventative treatment.
The triptans (except Almotriptan) worked fine. But the doctor thinks she should take preventative treatment.
She has already tried Propranolol, Amitriptyline and Flunarizin. They gave her only side effects.
The explanation is that her CYP2D6 enzyme works slowly. So Propranolol, Amitriptyline, Flunarizine and Naproxen stay in her body for much longer than expected. This means that the amount of active medicine in her body exceeds what is expected, resulting in side effects.
About 7% of Europe’s population has this problem. See https://europepmc.org/article/med/15669884
Carla has many migraine days each month, too. She loves her triptans, and doesn’t think she needs preventative medicine. However, she did not benefit from Almotriptan and Eletriptan when she tried them.
But her doctor is pushing her to try more preventatives. If she does, Carla will find that Metoprolol, Topiramate and Naproxen have no effect.
Carla breaks down these medications so quickly that they fail to give her an effect. Her CYP3A4 works ultra fast. https://doi.org/10.1515/dmpt-2016-002
Lise gets migraine from eating chocolate – and many other things she eats. During periods she has many migraine days, in others only a few.
She is fine with taking Sumatriptan, and has also tried Rizatriptan and Zolmitriptan. All three worked fine. She has not tried any preventatives – because they is not necessary when she stays away from alcohol and chocolate.
Migraine triggered by chocolate suggests that Lise is a somewhat slow metabolizer of the enzyme MAO-A. It breaks down tyramine, which is a well-known migraine trigger. MAO-A also breaks down Sumatriptan, Rizatriptan, Naratriptan and partly also Zolmitriptan. So these triptans (like tyramine from her diet) stay a little longer in Lise’s body than expected and, if she is not burdened by the side effects of her medication, the triptans also work fine.
Lise’s MAO-A has an ‘intermediate’ activity – i.e. is slightly more active than a slow metabolizer. Sometimes Lise’s MAO-A is called “down-regulated”.
Around one third of the European population is considered to have reduced MAO activity. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058761/
These examples mention the effect of only a single enzyme for each person: Vivi is a slow degrader of CYP2D6. Carla is an ultra rapid metabolizer of CYP 3A4 and Lise is an intermediate (i.e., slightly slow) metabolizer of MAO-A. We assume that all their other enzymes, like those of the majority, break down the medications as the majority of the population.
Enzyme activity varies from person to person. As a rule of thumb, a small group breaks down medicine very slowly another small group that breaks down the drug super fast and a large group that – with minor variations – breaks down the medication pretty much as the pharmaceutical company expected. This latter group consists of the extensive metabolizers (the majority) and those who have a slightly reduced metabolism – the intermediate metabolizers. The results for the clinical tests of new medicines consist mostly of results from the extensive and the intermediate metabolizers.. The two other groups will have virtually no benefit from the medicine, will have side effects (those that break down the drug ultra fast) or will have an extremely good effect, but also quite a few side effects (those that are slow metabolizers and take a long time to the break down the medication).
The two extreme groups constitute around 5 and 20% of the population for most medicines – so their test results are well hidden in the average values that are the results of the clinical trial.
Between 5 and 20% of the population does not get the expected effect of the triptans they are offered. They are the ones who metabolize medicine very quickly or very slowly.
In the real world, when the drug is approved by the authorities and marketed, the two extreme groups suddenly become more visible. A minority of drug users does not get the expected effect – just as the genetics indicate and another minority has serious side effects, but usually also a super nice effect if they can withstand the side effects. But there is normally very little help from the doctor – you are just unlucky.
What happens when we take triptans?
|Enzymes that metabolizer triptans|
A migraineur who is a slow MAO-A metabolizer will typically get migraines from food that contains tyramine (for example strong cheese), but Naratriptan, Sumatriptan, Rizatriptan and Zolmitriptan will help with their migraine, although there will probably also be some side effects. A migraineur who breaks down MAO-A quickly will have no effect from Naratriptan, Rizatriptan, Sumatriptan and Zolmitriptan, but can eat very strong cheese without getting migraines.
Zolmitriptan is metabolized by two enzymes (CYP1A2 and MAO-A). If the migraineur is a slow metabolizer of MAO-A, this can, at least partially, be offset by the enzyme CYP1A2, so the side effects may not be too bad.
Similarly, a migraineur who is a slow metabolizer of CYP3A4 will have a nice effect from Almotriptan and Eletriptan, most likely with some side effects. However, a migraineur who is an ultra rapid metabolizer of CYP3A4 will have no effect (nor any side effects) of these two triptans.
Fortunately, there is a little more variation than shown here. Each enzyme’s activity is determined by more than one piece of DNA, so the information here is a little too simple. Only the major (strongest) genes that determine enzyme activity are discussed here. The lucky 80% or more of migraineurs who belong to the middle groups of triptan metabolizers will have a reasonably good effect and limited side effects from the triptans.
Did the medical industry forget to take the minorities into account?
It could not possibly have escaped the attention of the pharmaceutical companies that the two extreme groups will be dissatisfied with the medicines. However, as long as no one mentions the problem, there is probably no reason to invest in marketing the medicine in smaller doses (for those who break down the medicine slowly) or perhaps in larger doses than average (for those who break the medicine faster than the average).
We have these three classic scenarios:
- the triptan has neither effect nor side-effects = the patient is an ultra rapid metabolizer
- the triptan has the expected effect and mild side effects = the largest group of migraineurs
- the triptan has a fine effect, but the side effects are unbearable = the patient is a slow metabolizer and gives up using the triptan.
That is not satisfactory for the triptan users – up to 20% of the users cannot use triptans!
Preventive medicine (the most commonly used medicines)
As for triptans, there are some migraineurs who get a great help from the classic preventive agents (beta-blockers, epilepsy drugs or antidepressants). However, they are also distributed to migraineurs based on the effects and side effects of the average population.
Many migraineurs must try a number of different preventive medications before – perhaps – finding one that reduces their migraine. These, pretty much random, choices of preventive medicines cause periods with unnecessary side effects and disappointments. We now have a fairly good knowledge of the genes that control the activity of the enzymes that break down the preventive agents, so it should be possible to avoid some of the redundant preventatives.
|Preventive migraine medicine often used||Liver enzymes that metabolize the preventive medicine|
|Metoprolol||3A4, 2B6, 2C9|
|Topiramate||3A4 , 2C19|
|Flunarizine||2D6, 2C9, 2B6, 1A1, 1A2, 2A6|
|Naproxen||1A2, 2C9, 3A4, 2C19|
We cannot change our genetics. But we can find out whether we are slow or rapid metabolizers of the enzymes that break down our medicine. With this knowledge we could get a suitable medicine in the first attempt and don’t need to make ourselves into a one person test population.
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