Tolerance development
In pharmacology , tolerance means getting used to an active ingredient, whereby its effect decreases with repeated or chronic ingestion over a certain period of time. If there is a tolerance towards whole substance groups, one speaks of a cross tolerance . In many, but not all cases, the dose can be increased to achieve the same effect size. There are various neurochemical mechanisms that underlie the development of tolerance.
Pharmacodynamic tolerance
Under Pharmacodynamics refers to the effect that produces a drug in the body. Pharmacodynamic tolerance mechanisms are therefore:
Regulation of the receptor density
The body influences the sensitivity of a cell to a certain active substance by regulating the receptor density on the cell surface. If the density is downregulated by internalization of receptors (and less new synthesis), the cell is less sensitive to a receptor agonist . This down-regulation occurs through phosphorylation of the receptor and the binding of arrestin , a signaling molecule that induces endocytosis of the receptor. An increase in the receptor density is also possible after prolonged use of an antagonist (such as caffeine ).
Attenuation of signal transduction
In many cases a cell has a reserve of receptors . In order to bring about a significant decrease in the receptor density, it may be necessary to remove a large number of receptors (up to 99% are not uncommon) from the surface. To avoid this effort, the body makes the signal transduction cascade more inefficient. It synthesizes fewer G proteins , adenylate cyclases or protein kinases . The activation of the G-protein coupled receptors (GPCR) is therefore less efficient.
Another important dynamic development of tolerance is towards the drug glycerol trinitrate or nitroglycerin (which the inventor himself used). Today it is used in the long-term therapy of angina pectoris as a vasodilator of the coronary arteries in the form of tablets or plasters that evenly release the active ingredient through the skin. Since the body develops tolerance to this drug within 24 hours, it is advisable to take a nitrate break of 12 hours overnight . Failure to observe the nitrate break to sensitize the body has already resulted in deaths.
Change in receptors
The GPCRs mentioned above have multiple places where they can interact with other molecules. For example, the beta- adrenoceptor is phosphorylated by an enzyme, the β- adrenoceptor kinase (general GPCR kinases = GRK). This prevents activation of a G protein. Protein kinases also have a similar effect . The interaction with the beta-gamma subunit of the G protein also leads to a change in conformation and to inactivation of the receptor.
The thrombin receptor , which is located on platelets and endothelial cells, is a special case here . The protease thrombin cleaves off a 41 amino acid long N-terminal end of the receptor, thus exposing a domain that can activate the receptor. One speaks of an auto-activation. Once activated, the receptor is changed so much that it is internalized by endocytosis and is only available for activation again through new synthesis. A newly discovered receptor of this class is located on nociceptors and is called PAR-2 (for protease-activated receptor , now known as PAR 1-3). PAR-2 plays a role in neurogenic inflammation and pain .
Influencing the body's own antagonistic systems
DBI is the abbreviation for the diazepam binding inhibitor molecule. When the benzodiazepine diazepam is given, it is increasingly synthesized and causes the drug to be weakened. DBI also binds to the benzodiazepine binding site of the GABA receptor A and thus acts as a competitive antagonist against diazepam.
Pharmacokinetic tolerance
The pharmacokinetics describes how rapidly and to what extent after the administration of a substance that then occurs in the blood plasma and in the various tissues of the body and where and in what way it is excreted. The body has the option of reducing the effectiveness of a drug by accelerating its elimination or by downregulating its own, similarly acting systems.
Accelerated elimination
Above all, this includes the increased expression of enzymes that are part of the biotransformation . In smokers, for example, certain cytochrome P450 enzymes are increasingly expressed and z. B. the methylxanthine theophylline is broken down more quickly. The antibiotic rifampicin and St. John's wort preparations also induce enzyme induction and accelerate the breakdown of some drugs. The birth control pill, for example, can become ineffective.
Downregulating the body's own systems
The strong habituation to opioids (dose increase up to 20 times) cannot be explained by the pharmacodynamic tolerance development alone. The exact mechanism of this development of tolerance has not yet been fully clarified, but a decrease in endogenous opioids is also observed. The same can be observed with the administration of glucocorticoids such as cortisol , dexamethasone , and prednisolone . If you give these substances continuously over a longer period of time, the body's own production of glucocorticoids goes down. Organically, this manifests itself in an atrophy (decrease in tissue) of the adrenal cortex , where the glucocorticoids are formed.
A transport protein called P-glycoprotein is located in the blood-brain barrier as well as in the kidneys and intestines . This transports exogenous substances that should not get into the brain from the cells back into the blood. Fexofenadine is a histamine receptor antagonist that does not enter the brain through this mechanism and only acts peripherally. If fexofenadine is administered for a longer period of time, the P-glycoprotein is more strongly expressed and thus increases the tolerance of the blood-brain barrier to this drug.
Another example is the activation of the renin-angiotensin-aldosterone system when diuretics are administered.
Tachyphylaxis
As tachyphylaxis (from ancient Greek ταχύς Tachys , fast 'and φύλαξις phylaxis , guard', 'protection') refers to a form of quick-impact reduction repeated dose of a drug.
For example, if substances such as amphetamine , methamphetamine or methylphenidate are taken repeatedly at short intervals, a considerable weakening of the effect achieved in each case can be observed. This increasing loss of effectiveness as a result of the developing tachyphylaxis can soon no longer be compensated by increasing the dose. In the case of the active ingredients mentioned, this can be attributed to a similar principle of action. Amphetamines develop their drive-increasing effect by inhibiting the re-uptake of neurotransmitters in the presynapse of various nerve cells and thus causing a short-term excess of transmitters such as noradrenaline and dopamine in the synaptic gap . However, due to the lack of reuptake, there is also a lack of these in intracellular stores of the presynaptic cell, so that less noradrenaline and dopamine are available for release. Therefore, the concentration of these substances in the synaptic cleft subsequently also drops, and the intended effect is weakened or canceled out. The storage vesicles of the presynapse fill up again and signal transduction normalizes only after the drug exposure has subsided . Amphetamine, methamphetamine and methylphenidate are counted among the indirect sympathomimetics , as they do not act directly on adrenoceptors , but indirectly and the resumption and the like. a. inhibit norepinephrine.
Allergological tolerance
Induced by treatment ( desensitization ), but also spontaneously, the patient can tolerate contact with allergens without reacting excessively. This occurs through modification of the formation of antibodies , mast cells and granulocytes or as a result of other changes in the immune system .
literature
- Heinz Lüllmann, Klaus Mohr, Lutz Hein: Pharmacology and Toxicology . 16th edition. Thieme, Stuttgart 2006, ISBN 3-13-368516-3 . , Chapter 10: Vegetative System, Box 10.5 " Tachyphylaxis and Desensitization "
- Charles Janeway , Paul Travers, Mark Walport, Mark Shlomchik: Immunology. 5th edition, Spektrum Akademischer Verlag, Heidelberg 2002, ISBN 3-8274-1079-7 ; Online version in English , 5th edition, 2001.
