The long road that takes a medicine to travel in our body
The article is extracted from the journal of the Academy of Veterinary Sciences of Catalonia
This conference was based on the comment of images and diagrams of the cellular structures that the medicines have to cross, the metabolism that they suffer in the liver, the way they are eliminated by the urine or the bile and the mechanism of its therapeutic action on target organ. In total, 55 slides. It is said that a picture is better than a thousand words, therefore it is very difficult to express in writing what was exposed with the support of images. My goal is to expose the basic concepts of the process and to serve as a reflection to appreciate that the application of genomics to customize the medication is the therapeutic of the 21st century. Currently facing pathology is prescribed a treatment based mainly on protocols that expert committees or professional associations recommend in their therapeutic guidelines. But this treatment, which is undoubtedly the right one because according to the experts is the one that obtains the best results, today we are able to personalize it according to the genes of each person; In another words, to pass from the protocol recommended for all, to the treatment also based on the therapeutic guide, but personalized in function of genetic changes of the patient that can modify at individual level the action of the drugs provisionally foreseen, which can range from modifying the dose to change of medication, in order to avoid therapeutic failures or adverse effects.
We take drugs while we are healthy or sick
Taking medicine is a normal part of our lives, whether we are healthy or sick; if we are sick to cure the disease and if we are healthy to improve our health, prevent diseases or simply to "feel better." Our nutritional habits are summarized in eating foods, which we must attempt to provide a balance between the basic nutrients (proteins, fats and carbohydrates); Drinking water, wine, coffee, tea and a great diversity of commercial alcoholic or non- alcoholic drinks, taking nutritional supplements like vitamins or trace elements and revalorizing the consumption of "medicinal" herbs which, as natural products we assume it as a “Good” because we constantly and repeatedly hear – all what is natural is good; However, we remember that “Curare” the poison of the arrows of the South American Indians with which they fought the Spanish conquistadors, comes from plants that are natural products of the families Loganiaceae (Strychnos) and Menispermaceae (Chondrodendron, Curarea and Abuta, among others), as well as strychnine, the poison of old detective novels; Strychnos nux-vomica, a species also of the genus Strychnos and finally we also take medicines.
We take the medicines because they have been prescribed by the doctor. Some of the need a prescription, but for most of them the doctor's prescription is not required and we take them by our own decision based on a recommendation from the pharmacist, because a friend has told us that he takes them "and it is very good" or because we have seen it announced in a magazine or in the "TV". We also base our decision on that as it is a medicine approved by Health organization as a "Good" and it is going to make us a beneficial effect for our health. But all medicines, even if they do not require a prescription, have adverse effects, just read the leaflets and see how many contraindications they mention, and also the interactions with other drugs. My question is do we read it? And if we read it, do we know what it says, when, for example, it stresses that it is incompatible with ISRS? And a more compromised question: did the doctor actually read everything about contraindications and interactions in the brochures of all the medicines prescribed? And is he able memorize them and relate them all to all? Does the doctor consult databases on drug interactions when prescribing them, taking into account not only what he prescribes to the patient, but everything that he is taking prescribed by other doctors or by self-medication?
Our recommendation, after many years of experience is that taking less drugs are better, and always to treat specific pathologies or improve specific aspects of our metabolism and prescribed and controlled by health professionals experts.
Are medicines always beneficial?
It is indisputable that the drugs are very beneficial to health and that thanks to them our quality and quantity of life has improved dramatically in the last 50 years. I am a very strong defender of pharmacological research and the great work being done by pharmaceutical companies that fund research to discover new drugs.
For example, new non-chemotherapeutic drugs against cancer are greatly improving the quality of life of patients, further lengthen their life and in many cases cure cancer. As an example, a specific data on breast cancer, which affects about 22,000 women in Spain a year; currently the survival is almost 80%, when about 50 years ago almost 80% were deaths. In summery our quality of life, as far as health is concerned, is at a very high level thanks to the use of medicines, but what we try to communicate is not to abuse and use them more adequate ones and especially personalized. To make clear the position above mentioned I will present some data that show that all the questions discussed above in most cases are left without answers. In the United States according to data from the Center for Disease Control and Prevention (CDC), it is assumed that there are around 100,000 deaths per year in the country due to adverse drug reactions and more than 90% of these deaths at the individual level correspond to correctly medicated patients according to protocols. EU data from Pharmacovigilance Commission assume that in the EU there are 197,000 deaths from adverse drug reactions per year (data from 2008). All processes involved the attention of urgencies, hospitalization, intensive care, etc. Including the death amount which cost to the health system about 79,000 million euros. All this without counting how much the life of the deceased is worth for themselves, for their relatives and for the society. If we extrapolate to Spain the figure is between 15,000-20,000 deaths a year due to adverse drug reactions. We recall that in Spain in 2015 according to data from the DGT there were 1,126 deaths in traffic accidents and according to data from the Ministry of Labor 608 deaths from work accidents. This is discussed periodically; data are analyzed in the media and in publications of the respective ministries, and a lot of money is spent on public awareness campaigns to avoid them through the TV and other media. All this for a total of 1,734 deaths a year, and no one speaks or says anything about the 15,000-20,000 who die from interactions and adverse drug reactions.
What is the cause of this tragedy in countries of advanced health systems?
First of all for a socioeconomic reason, since there is a high consumption of medicines because there is the perception that the more the better, and if we visit a doctor and his recommendation is for example to lower cholesterol, change our life habits (food and physical inactivity) and does not prescribe any medication, we consider it as he has not treated us good enough. Going to the doctor is synonymous of leaving the consultation with a prescription of taking a few pills a day that will improves or solves our problem; If there is no prescription there is frustration and if our diet is changed and the doctor advices to exercise, stop smoking and drink a little less, then there is not only frustration but also there is anger … and "I will not go back to that doctor, because he has not prescribed anything to improve my health." Secondly there are the technical answers that we are going to deal with. The first one, which should be taken into account in the 99.9% of the cases, is not taken into account: the patient's genetics, and then the adverse effects of drugs or interactions between all medications, Nutritional supplements, herbal etc, taken by the patient and many of them, even though they are outlined in the leaflets are ignored, or not keeping them in memory and not having done what is appropriate, which is to consult specialized databases and look in the interactions of everything that the patient is taking. The interactions between drugs known by clinical data can be found – if we look for them – in the pamphlets and in specialized databases, but in the 21st century, that the human genome has already been decoded, we must add the adverse effects due to Genetics changes in the patient. Nowadays this is already possible to know it for the majority active principles of the market. In the USA it is mandatory to review the medication booklets. Fortunately the EMA also requires it for new registrations and the AEMPS also starts to demand it, so that in the brochures of new medicines in our country we speak directly or indirectly of pharmacogenetics concepts. In summary, for a correct and personalized prescription it should be applied Pharmacogenetics, which is the science that studies the interactions between the patient's polymorphisms and the drugs to be prescribed as well as the interactions between the whole medication.
The perception is that we take the drug, and an intelligent molecule in it already knows where to go inside of our body to have beneficial effect, such as lowering tension, lowering cholesterol, improving headache this is a very simple way. But have we ever thought about the route the medicine makes since we take it until it gives us the therapeutic effect? Do we know what obstacles it has to overcome until to reach the target point? If we are all genetically different, are we sure that we all will have the same effect? Have we ever considered that the medicine that a friend advises us because it had a good effect on him, may not have the same effect or maybe have a side effect that will damage my health because I am genetically different? Here we will try to answer these questions conceptually.
What happens when we take a medicine?
There is a process in general when we take pills; it begins with their absorption by the small intestine, its transport by the blood to the target cell in the target organ, its metabolization in the liver and its elimination by the urine or by bile.
1. We have to absorb it through the small intestine, so that it passes into the blood. But to cross the epithelium of the intestine it can do it in several ways. Some enter through passive diffusion, others through the so-called ion channels and others by inflow conveyor proteins (transport the medicine from the outside to the inside), but in the membrane of the enterocyte epithelium there are also efflux transporter proteins (in another words it return to the intestinal lumen) and in this case energy is needed through systems that provide ATP. In these cases the amount of the medicine that will pass into the blood to bind to the target organ will be that which results from the activity of the inflow and efflux proteins.
2. Once in the blood it will be transported to the target organ, which is where it should effect, but to effect it must be attached to receptors, which are generally proteins of cells’ membrane, which captures it and after the union with them is triggered, by complex biochemical reactions, its therapeutic effect.
3. About 30% of some medicines are removed directly by the urine without any transformation, but to reach the urine they have to pass through the renal tubule membrane and they can do so, as we have already mentioned, by passive diffusion, ion channels or by transporter proteins in this case efflux ones.
4. Approximately 70% of the medicines through the blood get into the liver – crossing the hepatocyte membrane and generally facilitated by inflow transporter proteins – and in the hepatic parenchyma there is a set of enzymes (families of cytochromes or CYP) that will transform them into more hydrophilic compounds (Phase I of hepatic detoxification) so that they can more easily be removed by urine or conjugated with other molecules (methylation, acetylation, Glucuronidation, conjugation with glutathione, among others) in the so-called Phase II to form non-toxic compounds, which are very water soluble and can also be easily removed by urine. A small group of medicines which are very lipid soluble are eliminated by bile by mechanisms that we call Phase II.
Proteins are the main in the whole process
If we observe what occurs in the four points discussed above, we see that the whole process is ruled by the action of proteins. Transporter proteins, inflow or efflux proteins through membranes, the receptors in the target organ are also of a protein nature and finally their metabolization in the liver with the synchronization of the so-called Phase I and Phase II which are performed by enzymes are also proteins. After that raises a question the so-called "million Dollar question": Do all people have an identical structure of all these proteins that ensure that these processes are the same for all? This can only happen with monozygotic twins, but all the others – even dizygotic twins – are genetically different. The dose and effect of the medicine has been based on clinical trials in thousands of people and accepting the average data, but the results as a whole are distributed according to a Gaussian function, in which we say for example 80% of the population will get the expected effects with the recommended doses, but at the extremes of the function we will have (approximately and variable in each case) a 10% without therapeutic effect and in the other extreme a 10% that will have produced a side effect of toxicity. In the final decisions of the clinical trials these extremes are "discarded" and the appropriate posology (which is in the booklet of medicine) is accepted according to the data of the central 80% of the function in which was obtained the desired therapeutic effect, but in medical practice let’s say 20% of "discarded" people exists in this proportion of entire real population who go to consult with a doctor, so they will be prescribed the medicines according to the dosage of the booklet and therefore some will get an effect and others will get side effects due to toxicity and we are talking about 20-30% of the population, that is many millions of people. The key to knowing it is in the genes.
The functionality of a transporter protein, an enzyme or a receptor depends on its three-dimensional protein structure. We remember that in the subject of Biochemistry we were told (at least I explained it so) that the union of the enzyme with the substrate is made by chemical links between both structures of the "key with the lock", and that small modifications in the structure of the lock (the enzyme) can cause the key to fail to open the door, in another words assigned function is not performed correctly, and regarding the enzymatic reaction modifications of structure in the protein (lock) can cause that the medication (the key) fails the expected therapeutic effect (open the door); This concept can be extended to the transport through a membrane by means of a transporter protein, or the union of the medicine with its receptor that in general also is a protein. Therefore changes in the structure of proteins will be the cause on an individual level of whether a medicine does or does not have the expected effect according to the clinical trials obtained for the "majority" (not all) population. The structure of each protein is encoded by a gene and is synthesized by a process of different stages whereby from DNA t are synthesized complementary RNA molecules (transcription process) containing a base sequences (codons) which by the translation process will encode the sequence of amino acids that will configure the protein. Certain triplet bases encode different amino acids (genetic code), so genetic polymorphisms that change a base can change an amino acid and this change can modify the functionality of the protein.