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