Tachyphylaxis

Definition

Tachyphylaxis is the rapid development of tolerance to a compound's effects, occurring over a short time period (minutes to hours) with repeated exposure. The term comes from Greek words meaning 'rapid' and 'protection' (from the drug). Tachyphylaxis is distinct from other forms of tolerance that develop more slowly over days or weeks. Tachyphylaxis is often caused by receptor desensitization (rapid loss of receptor responsiveness) or depletion of a limited intracellular resource (such as depletion of neurotransmitter stores). For example, with ephedrine (a sympathomimetic drug), repeated doses produce progressively smaller blood-pressure increases due to rapid depletion of intracellular noradrenaline stores that the drug releases. With peptide agonists, tachyphylaxis can occur if the peptide activates desensitization pathways. Understanding whether a peptide compound exhibits tachyphylaxis is important for designing dosing schedules; if tachyphylaxis occurs, intermittent dosing (with time between doses for recovery) may be more effective than continuous exposure.

Tachyphylaxis is particularly important for peptide-based treatments because peptides often act through G-protein-coupled receptors, which are prone to rapid desensitization. For example, exenatide (a GLP-1 receptor agonist) produces desensitization of the GLP-1 receptor when exposed to continuous high concentrations, reducing its effectiveness. This is one reason why some GLP-1 agonists are dosed intermittently (once weekly) rather than continuously.

To avoid or minimize tachyphylaxis, several strategies can be employed: intermittent dosing (giving doses with time intervals between them, allowing receptor resensitization), using compounds that are weak agonists (partial agonists) rather than full agonists (producing less desensitization), rotating between different compounds that act through different pathways, and modifying the dosing schedule based on patient response. In research, understanding whether a peptide exhibits tachyphylaxis is important for interpreting time-course studies and for designing optimal dosing schedules.