• The underlying mechanism responsible for the decreased effect of a drug involves depletion of the body’s stores of an endogenous mediator and downregulation of receptors.
  • Cannot be overcome by increasing the drug dose.
  • Develops quickly (within a few hours of dosing)
  • Examples include:
    • Adrenergic agonists
      • Receptor inactivation & internalization by arrestins
    • Indirect sympathomimetics
      • Depletion of catecholamines from nerve terminals
    • Nitrates
      • Depletion of reduced thiols decreases mtALDH activity & NO production
    • Desmopressin (vWD)
      • Depletion of vWF from endothelial storage sites
    • Barbiturates
    • Direct sympathomimetic drugs (e.g., phenylephrine, niacin, LSD, MDMA ): the response to the repeated use of nasal decongestants (e.g., oxymetazoline) reduces the response over a short period of time and may cause rebound congestion (Rhinitis medicamentosa)
      • Treatment: Discontinuation of intranasal sympathomimetics