Concomitant treatment
Where do the side effects of drugs come from and how do they threaten us
Slava Gomenyuk, N+1
"I Googled, ****** [was surprised] and did not take it" — this is how a Russian-speaking Twitter user describes her story of acquaintance with the instructions for favipiravir, which doctors prescribe to people with a positive test for coronavirus. Others call it "a drug that kills the fetus in pregnant women" and suggest calling the police at home together with doctors. We will not talk in detail about favipiravir itself — we have already written about it. We'll talk about the side effects of this and other medications. Why are they prescribed to people if it is dangerous? And if they are actually safe, where do the long lists of side effects in the instructions come from?
What is a side effect?
What we used to call a "side effect" goes a long way to get this status. At the beginning of a clinical trial, there are only "adverse events". This is the name of any adverse events from a medical point of view that the organizers of the tests notice in the patient after using the drug.
But an undesirable phenomenon can also occur by itself, outside of connection with taking medication. This connection has yet to be found. And only if doctors have proved that it exists, the undesirable phenomenon is renamed into an "undesirable reaction".
Doctors divide these reactions into two groups according to the degree of influence on health: undesirable and serious undesirable. In order for the reaction to be recorded as "serious", it is necessary that it, regardless of the dose of the drug:
- led to death,
- created a threat to life,
- sent the patient to the hospital,
- led to persistent or significant disability or disability,
- it was a congenital anomaly or malformation.
If something from this list happened in the first three phases of the trial, and the doctors were convinced that this effect was definitely caused by the drug, then such a drug will definitely not get the green light for further research, and even more so for use.
So, for example, in 2016, a painkiller based on cannabis was tested in France. Five participants had serious neurological disorders that required hospitalization, and another participant died. The French Ministry of Health has launched an investigation into the incident. It turned out that the laboratory that conducted the tests did not violate any rules — however, the test was interrupted, and this medicine never reached the shelves.
If you use medications incorrectly — for example, take too large a dose (how much is actually needed, they find out just during phase II trials) — then even the most harmless of them can lead to death. This is well known for drugs affecting the central nervous system. So, among the undesirable reactions to diazepam, seemingly frivolous "lethargy, drowsiness, increased fatigue" are listed. But with an overdose, they turn into depression of the central nervous system up to coma.
Therefore, when a serious adverse reaction occurs, doctors pay attention to the dose at which it occurred. Even if a very small dose causes serious adverse reactions, such a drug will definitely not be missed in the next phases of the study. If serious adverse reactions occur only with a high dose of the drug, they will be included in the instructions in the "Overdose" section, and the patient and his doctor will be responsible for them (if he prescribes more than necessary).
And all the other "normal" adverse reactions are recorded in the instructions as a "side effect" of the drug, and in everyday life they are often called "side effects" or simply "side effects".
The doctor prescribed a medicine with a bunch of side effects. Will I feel bad?
Probably not.
It is quite difficult to predict exactly what effect, in addition to the target, the drug will have on a person. But you can, looking at the instructions, make an approximate forecast.
WHO identifies five groups of side effects depending on the frequency of their occurrence:
- very frequent (once for 10 doses of this medicine),
- frequent (once per 100),
- infrequent (once per 1000),
- rare (once per 10,000),
- very rare (less than once per 10,000).
The instructions for some drugs indicate the frequency for each side effect, but, as a rule, they are simply listed in a list and divided only by body systems. However, according to the rules The undesirable reactions of the Customs Union should be listed in a certain order: first frequent, then more rare. Therefore, looking at any list of "side effects", you can roughly imagine what to expect in the first place, and what to expect in extreme cases.
Can everything happen at once?
It's almost impossible.
Any undesirable reaction can occur with a certain probability (which is indicated in the instructions). To calculate whether several reactions can occur simultaneously, you need to multiply these individual probabilities. Here's what happens if we take, for example, a regular solution of paracetamol for intravenous administration.
The instructions list ten side effects: increased activity of liver enzymes, decreased blood pressure, tachycardia, a decrease in the number of platelets, leukocytes and neutrophils, redness of the skin, itching, rash and general malaise. Three of them have a frequency of 0.0001, and seven have less than 0.0001 (there are also 16 side reactions with an unspecified frequency in the instructions, we will not take them into account). For simplicity, we assume that each of the effects can occur with a probability of 0.0001. Multiply these probabilities:
(10–4)10 = 10–40.
Thus, the probability that a person who is injected with paracetamol will have ten adverse reactions at the same time is almost one case out of a tredecillion.
However, there is one subtlety here. To get this number, we assumed that all ten side effects of paracetamol are independent of each other. But not with all the effects and not for all drugs this is the case. For example, in the instructions for nitroglycerin, there is a drop in blood pressure and dizziness — these are almost certainly related events. And some drugs have undesirable reactions that even exclude each other: the anxiolytic diazepam has "dry mouth or hypersalivation (excess saliva)" indicated in the instructions. In such cases, it is necessary to calculate the probability of the occurrence of all side effects using more complex formulas. If the effects are interrelated, it will be higher, if mutually exclusive, it will be lower. But over time, the outcome of these calculations will change — as doctors get to know human physiology better and find non-obvious connections between individual symptoms.
In the case of paracetamol, there are only four really independent side effects — an increase in the activity of liver enzymes, a decrease in blood pressure (tachycardia and general malaise will be considered its consequence), a decrease in the number of neutrophils and platelets (and the number of leukocytes, apparently, decreases due to the number of neutrophils) and a rash (where you can turn on redness and itching). But even these four reactions can occur simultaneously with a probability of (10-4)4 = 10-16, or once per ten quadrillion injections. So many people have not yet been born on Earth for the entire time of its existence (and certainly have not taken paracetamol).
What if I have a side effect that is not in the instructions?
See your doctor as soon as possible.
In 1988, German scientists described a case of severe liver failure in a fifty-year-old man who had drunk the painkiller metamizole (we know it as "Analgin") five hours before. Previously, metamizole did not cause such effects in anyone. Doctors found out that the cause of liver problems was an allergic reaction to the medicine. After that, it was included in the instructions — even though since then the same severe allergy after taking metamizole was described only twice.
In order to track such cases, each country has a pharmacovigilance system. In Russia, such monitoring is carried out by the Federal Service for Supervision of Healthcare (Roszdravnadzor). If the doctor considers that the patient's complaints and symptoms are related to taking the medication (even if they are not in the instructions), he is obliged to send a message to Roszdravnadzor describing the reaction that occurred. Each such case is investigated by a special commission: she studies a person's state of health and discusses whether his symptoms are related to treatment. Further, Roszdravnadzor may amend the instructions, suspend the use of the drug or withdraw it from circulation altogether.
In addition, this information will be transferred to the next instance — the WHO Pharmacovigilance service, which will already conduct its own investigation. If the specialists there are convinced that there is a connection between the side effect and taking the medicine, then changes will appear in the instructions for all countries.
Why can't we take into account all the side effects from the very beginning?
It would take too many test subjects.
To find out how the medicine works on health, it is not enough just to give a pill to several people and monitor their condition. Since a person's condition is affected not only by the drug, but also by many external and internal events, doctors need to figure out where each specific symptom came from.
Therefore, a control group is always needed in trials. Its participants may be given classical therapy (another drug, about which it is already known for sure that it works) or a placebo, and sometimes not prescribe any drugs at all. The gold standard in such studies is considered to be a double-blind placebo-controlled study, when neither the patients nor the researcher himself know who was in which group, and only the external coordinator of the study has information about this.
Next, the researchers compare which health disorders occurred in different groups. If the participants of the experimental group had similar symptoms, but they did not appear in the placebo group, then they may well be mistaken for undesirable drug reactions. For example, in trials of a coronavirus vaccine from Pfizer, pain at the injection site a week after the injection was observed in 83.7 percent of participants in the experimental group, and only 14.2 percent of participants in the control group. Therefore, it was considered an undesirable reaction to the vaccine and entered into the instructions.
It also happens that an undesirable reaction occurs literally in one or two participants from the entire group. For example, during the trials of the Sputnik V vaccine, doctors recorded a variety of health disorders in the experimental group, including jaw abscess and prostatitis. In these cases, they decided that the problems appeared regardless of the vaccination.
But sometimes a very rare adverse reaction is really associated with treatment. For example, if a person is a carrier of a rare variant of a gene that is responsible for one of the biotransformation proteins — usually from the cytochrome P450 group. The metabolism of drugs will directly depend on the individual activity of these proteins.
For example, in 2007, American psychiatrists observed a woman with bipolar disorder who, with standard doses of normotimics and neuroleptics, had the same intensity of adverse reactions that are usually observed with overdoses of these drugs. Reducing the dose did not help. Geneticists found a variant of CYP2D6 in the patient *3/*5 , which manifests itself as a slow-acting CYP2D6 enzyme. And he is just responsible for the metabolism of those drugs that the patient took. The liver did not break down the drugs as quickly as the doctors expected, which is why their concentration in the blood was always higher than necessary.
Similar effects also fall into the instructions: either as very rare side effects, or with a direct indication of a connection with a non-working enzyme (there is a separate item in the instructions for aripiprazole about how to prescribe it to people with low activity of the CYP2D6 enzyme). You can, of course, be safe and try to check all of them in advance before releasing the drug on the shelves. But to do this, you either need to recruit a very large experimental group, in which there will be carriers of different gene variants, or you need to have a very good idea of which variants and how they can affect a person's metabolism. This is studied by a special section of pharmacology — pharmacogenetics, but there are still many unexplored areas in it.
Can the side effect manifest itself in the next generation?
This is tested on animals even before the start of clinical trials with humans.
Clinical research of the drug is not a cheap pleasure, and pharmaceutical companies do not conduct special long—term studies to search for delayed adverse reactions. They are usually detected during post-registration studies. That is, doctors are already using the new drug with might and main, but at the same time they note and investigate all cases of new side effects, reporting them to pharmacovigilance. For example, ibuprofen synthesized in 1962 is still being tested: now in the context of use in covid.
But not all side effects can be treated this way. In some cases, doctors cannot afford to fix them after the fact — because the harm done to a person will be irreparable. This primarily concerns the effect of drugs on fertility and the health of offspring. It is very difficult to notice this in clinical trials. In trials of the infamous drug thalidomide doctors did not notice anything suspicious, but they found out that it causes developmental abnormalities in the fetus much later, when children with damaged limbs began to be born in Europe.
Now such side effects are being sought even at the stage of preclinical trials, testing on non-pregnant and pregnant animals, for example, rats, rabbits and lower primates. Researchers select some individuals from the experimental group, open them and look for tissue damage. Fertility is calculated in some animals. And then their offspring are also opened — and they look for malformations.
But even if an animal study finds that the drug affects the reproductive health and development of the fetus, this does not mean that it cannot be used. It's just that the instructions will indicate that it is dangerous to take it during pregnancy, its planning and breastfeeding (just such instructions are in the instructions for favipiravir).
If preclinical tests have shown that the drug does not affect fertility and is safe for animal embryos and fetuses, then doctors can initiate a clinical trial of the drug with pregnant women. At the same time, it is necessary to ensure that the clinical trial potentially brings direct benefits to a pregnant woman or fetus (embryo or child after birth), and this benefit would exceed the risks associated with the study. Therefore, the thalidomide catastrophe is unlikely to happen again in our time.
Are there any drugs without side effects?
Alas, no.
For the human body, any medicine is a foreign agent, from which it will protect itself in any case. Enzymes in the stomach and intestines will attack him, then — in the blood, then — a whole arsenal of enzymes in the liver. But in rare cases, the immune system enters into battle, and then the drug can cause immunopathological reactions up to anaphylactic shock. Allergy can occur in absolutely anyone, and it is often impossible to predict it. Therefore, in the instructions for almost every drug, you can find some form of allergic reactions — even if it's just a rash or runny nose.
Many might object that they have been using the same drugs for years, but they do not observe any side effects and health disorders. This may well be the case if the drug has just a small number of adverse reactions, such as, for example, the skin antiseptic chlorhexidine. His instructions indicate only dermatitis, itching, stickiness of the skin of the hands, photosensitization and anaphylaxis. Since the frequency of reactions is not specified in the instructions, it is difficult to say with what probability they will develop in a particular patient. However, it is known, for example, that dermatitis from chlorhexidine develops in about 2-5 percent of people. If we recall that the most frequent side effect is in the first place in the instructions, then we can assume that other undesirable reactions develop even less often — that is, almost 90 out of 100 people do not experience them. Such a low probability of developing adverse reactions, together with their small number, is called by many doctors in everyday life "the absence of side effects".
Are there "good" side effects?
Yes, but then the medicine begins to be used in a different way.
The most famous story about the "good" side effect is the story of sildenafil. At first, it was tested as a cure for high blood pressure and chest pain. In the first tests, it turned out that the drug has little effect on angina, but causes a pronounced erection. Pfizer, which was engaged in the development and research of the drug, quickly got its bearings and decided to use this effect as the main one. In 1998, the American FDA approved sildenafil as the first oral treatment for erectile dysfunction — today we know it under the name "Viagra" — of course, with its side effects, such as headache and flushes of blood to the face.
Another example of repurposing a drug is nitrous oxide, which is also laughing gas. Once it was wanted to be used in a mixture with other gases as a cure for tuberculosis. But they quickly noticed that the decrease in sensitivity and intoxication that it causes when inhaled are useful in dentistry and surgery.
And yet: if I feel bad from the medicine, is the medicine bad?
No, but you need to tell the doctor about it.
Sometimes medications can really have severe side effects that affect health and quality of life. With chemotherapy of malignant tumors, hair falls out, simple aspirin can cause bleeding, and taking psychotropic drugs threatens addiction. However, when prescribing any drug (or other method of treatment) in medicine, it is customary to be guided by a simple principle: there should be more benefit than harm. That is, if a (conscious and competent) doctor prescribes medicine, then he assumes that its side effects are not as terrible as the disease threatening the patient.
This, of course, does not mean that, having received the recipe, you can relax. The patient who has been prescribed the medicine is still responsible for reading the instructions and not going beyond the prescribed dosages (even if we are talking about the most harmless medicine). And also for carefully monitoring the side effects and responding in time if some unexpected ones arise among them - maybe this is an occasion to adjust the treatment together with the doctor. Or maybe this is the beginning of another study — because human physiology is diverse, and the list of side effects is almost never complete.
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