• 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:
  • Nitrates
  • Hydralazine
  • Indirect sympathomimetic drugs (e.g., ephedrine)
  • 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