Generality
Tolerance and resistance to drugs are different phenomena but they share the decrease of the therapeutic effect of a given drug.
While tolerance develops in the patient who takes the drug, drug resistance normally refers to an insensitivity that develops in pathogenic microorganisms (such as, for example, bacteria and viruses) and in cancer cells, respectively, of anti-infective drugs (antibiotics)., antiviral) and anticancer drugs. Despite this difference, in both cases - to obtain the desired therapeutic effect - doses of drug higher than those normally administered and / or tolerated would be necessary. Of course, increasing the dose of medication is not always possible; on the contrary, in some cases it is even contraindicated due to the risk of reaching the toxic dose.
In the course of the article, the main characteristics and causes of tolerance and drug resistance phenomena will be described, with some hints about the stratagems that can be put into practice to try to prevent their occurrence.
Drug tolerance
Drug tolerance: What is it?
Drug tolerance can be defined as the reduction of the therapeutic efficacy of a given drug following repeated or continuous administration of the same.
In this regard, it is necessary to specify that there are basically two types of tolerance: chronic or long-term tolerance and acute or short-term tolerance . In this article we will deal mainly with long-term tolerance; while for what concerns the short-term tolerance, see the reading of the dedicated article: Tachyphylaxis.
Characteristics of long-term drug tolerance
Long-term tolerance has the following main features:
- It can be caused by many drugs, but not by everyone. In this regard, among the drugs capable of giving rise to long-term tolerance we mention benzodiazepines, barbiturates and opioid drugs (such as, for example, morphine).
- It can only develop for some of the actions a drug takes. For example, morphine is a substance capable of giving rise to long-term tolerance; however, this phenomenon develops only due to the analgesic effect of morphine, but not due to other effects (also collateral) induced by the drug, such as respiratory depression and miosis.
- It can also occur in isolated organs, tissues or cells.
- Generally, it disappears after drug withdrawal .
Causes of Drug Tolerance Development
Long-term drug tolerance is a form of tolerance that manifests after a continued use of a given drug over time. In other words, it is the tolerance that can develop towards a certain active ingredient following the chronic administration of drugs that contain it.
The causes underlying the onset of this type of tolerance are not always known, however, among the mechanisms that can give rise to this phenomenon, we recall:
- Adaptation processes that occur in the body following continuous exposure to the drug.
- Decreased affinity of the link between drug and biological target (receptor).
- Decrease in the number of receptors to which the drug should bind to obtain the therapeutic effect.
- Increased drug metabolism (for example, through the induction of liver enzymes - such as cytochrome P450 - implicated precisely in the metabolism of drugs and substances).
Classification of the different forms of tolerance
Depending on the mechanisms that lead to the development of tolerance, it is possible to distinguish:
Pharmacodynamic tolerance
The appearance of pharmacodynamic tolerance is considered as the result of a series of adaptive processes that occur following a chronic exposure to the drug . To achieve the desired therapeutic effect in patients who develop pharmacodynamic tolerance, it would be necessary to increase the dose of drug administered periodically. In other words, in the presence of this type of tolerance, the minimum effective concentration (MEC) of a drug is excessively high compared to normal values.
The typical example of a drug capable of giving rise to pharmacodynamic tolerance is morphine .
Pharmacokinetic tolerance
The onset of pharmacokinetic tolerance is usually determined by changes in the distribution of the drug or by the increase in its metabolism (for example, through the induction of liver enzymes responsible for metabolizing the active ingredient used). Also in this case, to obtain the desired therapeutic effect it would be necessary to increase the dosage of the drug administered. However, contrary to what happens in pharmacodynamic tolerance, the pharmacokinetic one does not lead to an abnormal increase in the minimum effective concentration (MEC) of the drug.
Examples of drugs capable of giving rise to pharmacokinetic tolerance are benzodiazepines and barbiturates .
Crusade tolerance
Pharmacokinetic tolerance can be crossed and be induced by drugs able to influence the pharmacokinetics of other drugs .
More precisely, with the name of cross-tolerance we want to indicate a phenomenon of tolerance that develops in relation to drugs other than that of chronic use, but having a similar chemical structure and similar mechanism of action . A typical example of cross-drug tolerance is given by benzodiazepines and barbiturates. Indeed, it is not uncommon for the chronic intake of these latter ports - in addition to a reduction in their therapeutic effect over time - to the development of cross-tolerance with benzodiazepines, even if the patient has never come into contact with this class of drugs.
The spaevi that ...
There is also a sort of reverse phenomenon to tolerance due to which a given drug, following prolonged use over time, produces a greater effect than that produced after its first administration. This phenomenon is known as awareness raising .
Drug resistance
Drug resistance or drug resistance: What is it?
When we talk about drug resistance we want to indicate a reduction in the therapeutic efficacy of a given drug, generally, with particular reference to anti-infective and anticancer treatments .
In fact, pathogenic microorganisms - such as, for example, bacteria and viruses - and cancer cells can develop resistance, in fact, towards the drugs normally used to fight and kill them (antibiotics, antivirals and anti-cancer chemotherapy).
Drug resistance - also known as drug resistance - is therefore a sort of "opposition" that bacteria, viruses, other microorganisms and cancer cells are able to exercise against the drugs normally used to eliminate them.
Did you know that ...
We often hear talk of resistance to antibiotics and antivirals, but not resistance to antifungals (or antifungals, if you prefer). This is because the appearance of resistance to antifungal drugs is usually considered to be a relatively rare phenomenon, although still possible.
Furthermore, it is also reported that parasites are able to develop resistance against anti-parasitic drugs .
Nevertheless, this article will focus mainly on the drug resistance developed by pathogenic microorganisms (such as viruses and especially bacteria) and on drug resistance developed by cancer cells.
The drug resistance can be divided into:
- Intrinsic drug resistance, when the pathogenic microorganisms taken into consideration or the tumor cells are insensitive to the action of the drug administered immediately.
- Acquired (or induced) drug resistance, when pathogenic microorganisms and tumor cells become insensitive to the drug after a certain period of treatment.
Please note
Sometimes the term drug resistance is also used in other situations in which a patient does not respond to the pharmacological treatment given to him. An example of this type is given by the resistance to antidepressant therapy. However, in such situations, it would probably be better to talk about a resistance to treatment than a phenomenon of drug resistance. The latter term, in fact - as already stated several times - is mainly used to indicate resistance to one or more drugs that develops in pathogenic microorganisms and cancer cells.
Multi-drug resistance
When we speak of multi-drug resistance we are referring to a form of resistance developed towards different drugs normally used in therapy (antivirals, antibiotics, anticancer drugs, etc.), even belonging to different classes and having different chemical structures and mechanisms of action .
The multi-drug resistance can be developed both by pathogenic microorganisms of different types and by tumor cells.
Drug resistance: Causes and Mechanisms
The phenomenon of drug resistance sees its main cause in the onset of particular genetic mutations or in the acquisition of new genetic material (the latter is a rather widespread phenomenon especially, but not exclusively, in bacterial cells) that lead to a reduced or totally absent sensitivity to a drug, an effective time.
The mutations responsible for the emergence of drug resistance can involve different types of genes, such as genes that code for drug target proteins; or genes that code for proteins capable of interfering / hindering the activity of the drug itself.
Going into more detail, the various mutations responsible for drug resistance can lead to:
- Modifications of drug target cellular structures . Because of these modifications, the drug is no longer able to bind, or bind effectively, to its targets. In this way, its therapeutic action is insufficient or null.
- Modifications of cellular permeability to the drug due to which the latter is no longer able to enter the cell where it should have exerted its action.
- Drug elimination / inactivation . An example of this type is given by the production of enzymes capable of inactivating the active ingredient contained in the drug used, as happens in the case of bacterial strains that produce β-lactamases (enzymes responsible for the degradation of beta-lactam rings contained within antibiotic drugs such as penicillins, cephalosporins, carbapenems and monobactams).
- Increased elimination or efflux of the drug from the cell or micro-organism (the drug, even if it succeeds in entering the cell or micro-organism, is transported quickly outside).
Consequences of Pharmacoresistance
In the case of development of resistance to a certain drug (anti-infective, antitumor, etc.), it is able to eliminate only the micro-organisms and "normal" tumor cells that have not undergone the genetic mutations mentioned above.
Microorganisms and tumor cells that present the mutation, on the other hand, remain alive despite drug therapy. If they are not destroyed by the body's immune defenses, they can therefore replicate by transmitting the mutation responsible for drug resistance, thus giving rise to a population of tumor cells or microorganisms resistant to the drug used.
Other mechanisms that can cause drug resistance
Drug resistance can also occur thanks to other mechanisms implemented by pathogenic microorganisms and cancer cells.
For example, cancer cells can "defend themselves" from the activity of the drug by increasing the synthesis of its biological target through a mechanism known as " gene amplification ". In other words, if a drug inhibits a certain enzyme, the cancer cell - through gene amplification - increases the production of that same enzyme. In doing so, the drug, administered at the "traditional" dose, fails to bind and inactivate all target enzymes - the number of which has increased due to increased synthesis - with a consequent reduction in therapeutic efficacy .
Another example is the ability of bacteria to use metabolic pathways different from those inhibited by the drug. Many antibiotic drugs, in fact, act on key proteins involved in metabolic processes fundamental to the survival of the microorganism. In some cases, the bacteria are able to use an alternative metabolic pathway, different from that on which the drug acts, thus causing the onset of resistance.
Prevention
How to prevent drug tolerance and resistance?
The most effective way to combat the onset of tolerance and drug resistance is prevention . Fortunately, in many cases, we are aware of which drugs can give rise to tolerance and in which populations of microorganisms or cancer cells resistance can develop.
To try to prevent the development of tolerance, therapies with drugs capable of causing it are processed - in terms of the dose administered, type of active ingredient used, frequency and time of intake, etc. - in such a way as to try to limit this phenomenon as much as possible (for example, by reducing the duration of the treatment to the strictly necessary time).
A similar argument regarding the drug resistance developed by pathogenic microorganisms and tumor cells: drug therapy must be adapted and implemented in such a way as to try to minimize the probability that the pathogen or tumor cells develop insensitivity or reduced drug sensitivity. In detail:
- To try to prevent antibiotic resistance it is necessary:
- On the part of the doctor, prescribe their use only when strictly necessary and when the infection is actually supported by bacterial microorganisms.
- On the patient's part, avoid self-diagnosis and avoid taking antibiotics in the absence of a doctor 's prescription . In the event that the therapy has been prescribed by the doctor, instead, the patient must complete the treatment strictly respecting the posology indicated by the aforementioned health figure (dose and duration of therapy).
- To try to prevent antiviral resistance, the indications are very similar to those above for antibiotics. However, in the case of particularly serious infections - such as, for example, that sustained by HIV - the doctor may resort to the use of combinations of different antiviral drugs.
- To try to prevent resistance to anticancer drugs, when possible, the doctor may resort to polychemotherapy, that is, the administration of more than one anticancer drug at a time. This approach - in addition to trying to prevent the formation of cell clones resistant to anticancer drugs - could be useful to enhance the antineoplastic action ( synergistic effect ) of the treatment. However, this therapeutic strategy also presents limitations and disadvantages, including the possibility of increasing the toxicity of the overall treatment compared to the drugs used individually.
In the event that prevention does not prove effective and the patient still develops tolerance and resistance to drugs, where possible, the doctor can proceed in two ways: increase the dose of the drug administered, or stop taking it and resort to use of a different drug .
However, it is important to point out that the possibility of prevention, as well as the possibility of intervening on tolerance and resistance to drugs that have already arisen, is correlated to the type of drug used, the disease that afflicts the patient and also the way in which the patient responds to the therapy administration. For this reason, if you notice a decrease in the effectiveness of a drug you are taking, it is of fundamental importance to immediately contact your doctor and in any case avoid the self-diagnosis and / or self-prescription of more dosages high levels of medication or different drugs.
