Introduction
Tachyphylaxis is a particular type of tolerance that develops against drugs or other substances.
Therefore, since it is a form of tolerance, the onset of tachyphylaxis involves a reduction in the body 's sensitivity to a specific drug or to a specific toxic substance.
There are basically two different forms of tolerance: chronic tolerance and tachyphylaxis, also known as acute tolerance or short-term tolerance . Unlike chronic tolerance, tachyphylaxis has the characteristic of developing in a very short time (from a few minutes to a few hours). The mechanisms underlying the onset of this form of tolerance are many and can vary depending on the type of drug used and the target on which it must act.
What is that
What is tachyphylaxis?
Tachyphylaxis is a form of tolerance - acute or short-term tolerance - that develops against drugs or other types of substances.
In the pharmacological field that will be taken into consideration in this article, tachyphylaxis is defined as the short-term tolerance that is established shortly after taking a certain drug. More in detail, tachyphylaxis determines the decrease and sometimes the disappearance of the pharmacological effect after administration of a single massive dose of drug, or after administration of equal and repeated doses, very close to each other.
In addition to rapid onset, tachyphylaxis can be resolved just as quickly by stopping the drug.
Did you know that ...
In the presence of tachyphylaxis induced by the administration of drugs, in order to obtain the therapeutic effect again, it might seem obvious to increase the dosage of the drug administered. However, such a practice is not always possible and, on the contrary, is sometimes contraindicated due to the risk of reaching the toxic dose. In fact, although drugs, by definition, are compounds used in therapy for the treatment of disorders and pathologies, taking excessive doses can produce toxic effects that can be very serious and sometimes even fatal.
Causes
What are the causes of tachyphylaxis?
Tachyphylaxis can occur following various mechanisms that depend on various factors, such as the type of drug used, the dose administered, the route and frequency of administration and the biological "target" of the drug.
However, tachyphylaxis occurs following continuous or repeated exposure to equal concentrations of the same drug. The main mechanisms capable of originating this phenomenon are:
- Temporary lack of access to the receptor : the drug fails to bind to its target and, therefore, cannot exercise its action.
- Alterations of receptors representing the drug target (for example, conformational change that hinders the link with the drug).
- Receptor desensitization : following interaction with the drug and activation of an initial response, the target receptor may undergo desensitization. Generally, in such a situation, the receptor is still able to bind to the drug even if with a lower affinity and a reduced ability to respond to the stimulus.
- Loss of receptors or reduced availability of receptors at the cell membrane level: following continuous exposure to the drug, so - called receptor down-regulation can occur, with a consequent reduction in the efficacy of the drug administered.
Deepening: Receptorial Down-regulation
Literally, the down-regulation - also known as negative regulation or down-regulation - is a process implemented by the cell to reduce the quantity of a specific cellular component - such as, for example, proteins and receptors - in response to external variables (in this case, represented by the continuous or repeated administration of the drug).
In simpler terms, due to the continuous or repeated exposure to the drug, the receptors to which the latter should bind - thanks to a series of complex mechanisms implemented by the cell - decrease in number . In doing so, the new drug molecules administered with successive doses - continuous or repeated and close together - are no longer able to bind to their target receptors, since the latter are absent, or present in insufficient quantities to produce a significant effect.
If adequate receptor interaction is lacking or insufficient, the drug administered does not produce the desired therapeutic effect.
- Exhaustion of the endogenous compound that mediates the pharmacological effect : some drugs carry out their therapeutic activity indirectly, through the release or stimulation of the synthesis of endogenous compounds which, in fact, will produce the desired effect. Therefore, if these compounds are absent or present in minimal quantities, the therapeutic effect cannot be achieved.
- Increased metabolic degradation of the administered substance or drug. This phenomenon occurs, for example, after taking repeated doses of ethyl alcohol and barbiturates.
- Physiological adaptation : it is a homeostatic response of the organism that adapts to the administration of a given substance or a given drug. In these cases, the tachyphylaxis - in addition to establishing itself towards the therapeutic effect - can also be established in relation to those that are considered as side effects of the drug (for example, nausea and vomiting that may appear at the beginning of some drug therapies for then decrease and disappear with continued treatment).
Did you know that ...
Tachyphylaxis is a well-known phenomenon, as are the active ingredients used in therapy that are able to cause it. For this reason, the administered dose and frequency of administration are normally determined taking into account the occurrence of this phenomenon, in order to ensure maximum therapeutic efficacy and maximum safety of use.
drugs
Which drugs can give rise to Tachyphylaxis?
The drugs capable of giving rise to tachyphylaxis are truly many and belong to rather heterogeneous classes and categories. Among these, we mention a few:
- Anti- asthmatic drugs and, in particular, β2-agrenergic agonists;
- Opioid analgesics ;
- Corticosteroid drugs, in particular, when used for topical use;
- Barbiturates ;
- Nasal decongestants (such as, for example, ephedrine);
- Antidepressant drugs ;
- Nitroderivative drugs with vasodilating action (such as sodium nitroprussiate and nitroglycerin);
- Nicotine ;
- Local anesthetic drugs (eg, lidocaine, procaine, etc.).
Examples of Tachyphylaxis
Below, some examples of tachyphylaxis caused by different drugs and substances will be reported, highlighting which mechanisms lead to the development of this acute form of tolerance.
Ephedrine-induced tachyphylaxis
Ephedrine - an active ingredient with a vasoconstrictor action widely used as a nasal decongestant - is perhaps the most classic example of a drug capable of causing tachyphylaxis. To understand why, however, it is necessary to be aware of its mechanism of action.
The vasoconstrictor effect of ephedrine is due to two mechanisms, one direct and one indirect:
- Direct action : ephedrine directly stimulates the alpha and beta adrenergic receptors present at the level of the nasal mucosa.
- Indirect action : ephedrine has a prevalent indirect action thanks to which it stimulates the release of noradrenaline from the deposits present in the nerve endings.
Since the vasoconstrictor action depends largely on the indirect action of ephedrine, it is easy to understand how the administration of repeated and close doses of the active principle lead to the appearance of tolerance in the short term. In fact, when ephedrine is administered for the first time, it induces the depletion of noradrenaline deposits from the nerve endings. If the second dose of ephedrine is administered at an excessively close interval of time, the active ingredient may also stimulate the release of noradrenaline, but the deposits of the nerve endings are empty or at least almost completely emptied; for this reason, noradrenaline is not released because it is not available or is released in small quantities, the vasoconstrictor effect does not occur or is insufficient. Therefore, the mechanism underlying the tachyphylaxis induced by ephedrine lies in the exhaustion of the endogenous compound that mediates the pharmacological effect .
Nitroglycerin-induced tachyphylaxis
Nitroglycerin administered through the application of transdermal patches - then administered transdermally to the patient - is another example of tachyphylaxis.
The transdermal patches containing nitroglycerin must be applied to the skin once a day, but should be kept for a maximum of 12-16 hours and then removed in such a way as to have a time interval of 8-12 hours in which the drug is not taken . After 24 hours (including both time intervals with and without the patch), a new transdermal patch can be applied. However, you must follow the instructions given by your doctor.
If, on the other hand, the patch remains applied to the skin for 24 consecutive hours, the effect of nitroglycerin should gradually decrease until it disappears due to the appearance of tachyphylaxis. Furthermore, the therapeutic effect would not be achieved even with the application of a new patch, since by now the phenomenon of acute tolerance has been established.
Although the exact mechanism underlying tachyphylaxis caused by the transdermal administration of nitroglycerin is still not completely clear, it is believed that it lies in the depletion of a cofactor necessary for the action of nitroglycerin . To overcome this problem, it is necessary to resort to the so-called intermittent administration (12-16 hours with patch alternating with 8-12 hours without patch).
Please note
Some of the sources consulted do not agree with the above reported description of nitroglycerin-induced tachyphylaxis, since they believe that the reduction of the effect of the drug is not due to the appearance of a short-term tolerance phenomenon.
Nicotine-induced tachyphylaxis
Finally, we briefly recall that nicotine is also a substance capable of giving rise to tachyphylaxis. Nicotine binds to nicotinic receptors present in the central and peripheral nervous system, activating them (it is, therefore, an agonist ) and producing a series of effects throughout the body. The continued intake of nicotine, however, causes a desensitization of these same receptors which leads to the appearance of tachyphylaxis.
