- 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