Attenuation of Response to Repeated Drug Administration: A Proposal for Differentiating Tachyphylaxis and Tolerance

Attenuation of drug response with repeated administration is referred to as tachyphylaxis or tolerance, though the distinction between these two is obscured through both their usage in the literature and imprecise definitions in common pharmacology texts. In this perspective, I propose that these terms be distinguished by the mechanisms underlying the attenuation of drug response. Specifically, tachyphylaxis should be reserved for attenuation that occurs in response to cellular depletion, whereas tolerance should be used to describe attenuation that arises from cellular adaptations. A framework for understanding behavioral tolerance, physiologic tolerance, and dispositional tolerance as distinct phenomena is also discussed. Using this framework, a classification of drugs exhibiting attenuation of drug response with repeated administration is presented. SIGNIFICANCE STATEMENT: Distinction between tachyphylaxis and tolerance is unclear in the literature. Nonetheless, a mechanistic basis for distinguishing these important terms has practical implications for managing or preventing attenuation of drug response with repeated administration.