Drug tolerance

1. Acquired Pharmacokinetic Tolerance

• Mechanism:
  • ADME: ↓ Absorption, ↑ Distribution, or ↑ Metabolism & Excretion (e.g., enzyme induction)
  • ↓ Plasma drug concentration relative to naïve state
• Example:
  • Rifampin (CYP3A4 inducer) accelerates the metabolism of warfarin.
  • Carbamazepine induces its own metabolism after repeated dosing.

2. Acquired Pharmacodynamic Tolerance

• Mechanism:
  • ↓ Cellular response to drug (e.g., receptor downregulation)
  • Unchanged plasma drug concentration relative to naïve state
• Example:
  • Chronic opioid use: ↓ expression & responsivity of μ receptor systems.
  • Frequent albuterol rescue inhaler: ↓ expression of airway β2 receptors.

3. Innate Tolerance

• Mechanism:
  • Genetic (e.g., polymorphisms) & epigenetic (e.g., DNA methylation) differences
  • Leads to pharmacokinetic or pharmacodynamic tolerance
  • Tolerance apparent from first dose
• Example:
  • Slow metabolizer CYP2C19 allele: ↓ clopidogrel activation (↓ antiplatelet effect)
  • Slow metabolizer CYP2D6 allele: ↓ codeine conversion to morphine (↓ analgesic effect)

4. Behavioral (Functional) Tolerance

• Mechanism:
  • Ability to compensate for drug-induced impairment through learning & practice
• Example:
  • Maintaining appearance & mannerisms to appear non-intoxicated at work

Tachyphylaxis

• 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
    • Induction of CYP450 enzymes
  • 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