Tolerance from the Pharmacokinetic and Pharmacodynamic Viewpoints
One of the most interesting properties of many biologically active xenobiotica is that these substances not only have the capacity to stimulate a target organ but also produce desensitization or tolerance. This means that after the drug has been used for a certain time the response of the target organ disappears despite the maintained presence of the drug. This phenomenon is referred to in the literature as “desensitization”, “tolerance”, “tachyphylaxis”, or “refractoriness”. The nature of a particular receptor can be the reason why the complete spectrum of effects or a component of the drug’s action is limited with respect to time on development of tolerance. If it were possible to understand the molecular basis of desensitization, then it would be possible to develop corresponding therapeutic measures. As far as can be established, only agonists have the capacity to stimulate or to desensitize a target organ; antagonists are not able to do this. For this reason it is probable that stimulation and desensitization properties of agonists are very closely correlated with one another. I should like to present the general problem of tolerance and its development and to point out the complexities of the phenomenon and its inherent molecular mechanisms — so far as these are known — using a few chosen examples. The development of tolerance can be interpreted as an adaptive protection mechanism against the effects of flooding the body with exogenous compounds or endogenous substances. Tolerance can be regarded as a very general phenomenon observable in the case of numerous substances and in conjunction with a variety of mechanisms.
KeywordsAdenylate Cyclase Organic Nitrate Nitrate Tolerance Frog Erythrocyte Tritiated Digoxin
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