How are the side effects of drugs detected
And because of what the drug may be withdrawn from the market
Back in the XVI century, Paracelsus said that the difference between a medicine and a poison is in the dose. And now we know for sure that in different circumstances, the same drug can save a patient, and can greatly harm his health. Pharmacologist Yuri Kiselyov tells about how human genes affect the formation of side effects, why some drugs cannot be taken by pregnant women and how to cure epilepsy, but get a blue skin color at the same time.
Three factors are important in the formation and development of side effects from taking medications: the dose of the drug, exposure (that is, the total duration of time during which the drug acts on the body) and individual predisposition, including genetic. So, we know that some antiviral drugs used in the treatment of HIV infection can cause rare, but very severe skin lesions. Among Europeans, this severe side effect is extremely rare, but among East Asians, due to genetic characteristics, it is observed quite often. Therefore, for example, in the USA, before prescribing this medication, a patient is checked for the presence of a certain genetic marker to check individual predisposition and exclude the risk of developing this side effect.
Scientists receive information about possible side effects already at the stage of drug development: in silico, that is, as a result of computer modeling, and in vitro, that is, when studying on cell cultures. For example, it is very important to assess whether the drug will lead to hemolysis, that is, to the breakdown of red blood cells. Of course, we also learn a lot about possible negative effects in vivo, when testing on laboratory animals. Among other things, in vivo tests are conducted for teratogenicity, that is, for the risk of developing birth defects in the fetus, and carcinogenicity — the risk of developing malignant tumors.
The next very important source of information about the safety of the drug is clinical trials. The most severe and frequent side effects can be noticed already in the first phase, but, unfortunately, if the side effect is rare, it can be skipped. If it is very rare, it is not enough to even look at several thousand tested patients: such information must be collected after the drug has entered clinical use. An example of such a situation is retigabine, which was developed to treat certain forms of epilepsy. When the drug was already approved for widespread use, separate signals began to arrive that it caused an unexpected thing — persistent blue staining of the sclera and skin. Because of this side effect, albeit infrequent, the drug was withdrawn from the market.
Unpredictable side effects
Side effects can be divided into two main groups: group A and group B. Group A are predictable, usually dose—dependent side effects. For example, warfarin (a blood-thinning drug, anticoagulant) is used to prevent blood clots, and if we give it in a large dose, the risk of bleeding will increase.
However, the side effect can also be unpredictable, for example, a change in color perception to the blue side of the spectrum in patients receiving sildenafil, a drug for the treatment of erectile dysfunction. Another example of unexpected side effects is the antibiotic chloramphenicol: it can lead to the development of aplastic anemia — a very powerful, persistent suppression of hematopoiesis in the bone marrow. Therefore, today this drug is not used systematically, but, for example, for the treatment of eye or skin infections.
The mechanisms of side effects may be understandable and predictable, or they may be unknown to this day. The first include, say, side effects of cytostatics — drugs used in the treatment of cancer. Many good chemotherapeutic drugs act on all fast-growing cells, for example, disrupting the spindle of division or damaging DNA, and not only tumor cells suffer from this, but also other fast-growing cells of the body, such as skin cells, hair follicle or mucosal cells.
But there are also unexpected, paradoxical phenomena, for example, in the case of paracetamol. In a patient taking paracetamol in normal doses not exceeding 3-4 grams per day, not abusing alcohol and not having severe liver diseases, paracetamol is perfectly processed in the liver and removed from the body. However, if a patient abuses alcohol, uses ultra-high doses or has a severe liver disease, the metabolism of paracetamol can follow the paradoxical path of the so-called toxic synthesis, when a metabolic product dangerous to the body is formed from paracetamol, which, in particular, can cause a very severe blow to the liver, up to acute liver failure.
Rofecoxib and the thalidomide disaster
In the late 1950s, a drug called Thalidomide was introduced to the market in Europe, as well as in Australia and several other countries. It was prescribed and promoted for the treatment of sleep disorders and anxiety in pregnant women — precisely because it was considered safer than the then popular phenobarbital. Since there was no system of supervision and systematic observation at that time, it took about two years before reports began to arrive from the field that women receiving thalidomide had children with severe malformations — for example, with the absence or gross underdevelopment of the upper or lower extremities.
Interestingly, the manufacturing company wanted to register thalidomide and start selling it not only in Europe, but also in the USA. The registration documents were submitted to the FDA (FDA) and were submitted to the clinical pharmacologist Frances Kelsey. It was a unique phenomenon at that time: there were very few women in the agency. Frances Kelsey was a good, responsible specialist, she was very attentive to the documents and demanded some additional studies on rats for the toxicity of the drug in relation to embryos.
The manufacturer refused additional tests. There are even documents proving that he pressured Frances Kelsey and the agency's management. But at that time, reports of fetal damage began to arrive from Germany and Australia, and the drug never entered the American market. Thus, Frances Kelsey prevented the birth of a huge number of children with severe disabilities.
The thalidomide catastrophe, which affected thousands of children, became an incentive for the emergence of a modern pharmacovigilance system. It is curious that, although thalidomide is categorically not allowed to be used in pregnant women, now we use it in the treatment of, for example, myeloma — a malignant disease of the blood system.
In most countries, there is a system of voluntary reports on side effects of drugs. In different countries, this system works a little differently: in some places, only health care workers can send such messages, but in some places, patients too. For example, in Norway, anyone can go to the website of the Ministry of Health and, if he believes that he has experienced a side effect of a drug, he can fill out a notice and send it to the Ministry. Then these arrays of information are analyzed, and if a certain trend is detected, commissions are created, a signal is sent to the European Medicines Agency, and this issue is thoroughly investigated.
Another example of a drug withdrawn from the market is Rofecoxib, which was prescribed for the treatment of various forms of pain, for example, osteoarthritis. It seemed that this drug should be an ideal analgesic: it does not have a negative effect on the gastrointestinal tract and does not lead to the formation of addiction. At some point, about 60 million people managed to take this medicine, but as a result of the accumulation of information, it became clear that it increases the risks of heart attacks and strokes. It is believed that this drug influenced the development of these conditions in about 50-100 thousand people. Because of this, it was withdrawn from the market, and the company received multibillion-dollar fines because it was suspected of withholding this information from the state.
Interestingly, after the withdrawal of the drug from the market, with a closer study of the data, it became clear that the negative effects are more pronounced when using high doses, and small and medium doses are relatively safe. Therefore, now there is a conversation that maybe the drug will return to the market, but in different dosages.
Portal "Eternal youth" http://vechnayamolodost.ru