Harvey's Garden

Drug tolerance and tachyphylaxis

3 min read

Tip

  • Pharmacokinetics (PK): What the body does to the drug.
    • Focus: Movement of drug into, through, and out of the body.
    • Determines the concentration of the drug at its site of action over time.
  • Pharmacodynamics (PD): What the drug does to the body.
    • Focus: Mechanism of action and physiological effects.
    • Determines the intensity and duration of the clinical effect.

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

  • Definition
    • Acute, sudden decrease in response to a drug after its administration.
      • Tachy- (tachys) = Rapid or Fast (e.g., Tachycardia).
      • -phylaxis (phylax) = Protection or Guarding (e.g., Prophylaxis, Anaphylaxis).
      • Literal translation: “Rapid protection.”
    • Distinguish from tolerance, which is a more gradual loss of response over time (days/weeks).
  • Pathophysiology / Mechanism
    • Receptor Desensitization/Internalization: Receptors become unresponsive to the ligand or are removed from the cell surface.
    • Depletion of Intracellular Mediators: Drugs that act indirectly (e.g., by releasing stored neurotransmitters) fail when the stored supply is exhausted.
  • Classic USMLE Examples
    • Nitrates (Nitroglycerin, Isosorbide dinitrate)
      • Mechanism: Often attributed to depletion of intracellular sulfhydryl (-SH) groups or generation of free radicals inhibiting NO signaling.
      • Management: Requires a “Nitrate-free interval” of 8–12 hours daily (usually at night) to restore sensitivity.
      • “Monday Disease”: Industrial workers exposed to nitrates develop headaches (vasodilation) on Mondays due to loss of tolerance over the weekend; symptoms disappear later in the week due to tachyphylaxis.
    • Nasal Decongestants (Oxymetazoline, Phenylephrine)
      • Condition: Rhinitis Medicamentosa (Rebound Congestion).
      • Mechanism: Alpha-adrenergic receptor downregulation and desensitization.
      • Clinical: Severe congestion returns after stopping the drug if used for >3 days.
    • Indirect Sympathomimetics (Ephedrine, Tyramine, Amphetamines)
      • Mechanism: These drugs displace norepinephrine (NE) from presynaptic vesicles into the synapse.
      • Effect: Tachyphylaxis occurs when the presynaptic stored pool of NE is depleted; additional drug doses cannot release more NE.
    • Local Anesthetics
      • Can occur with repeated injections into the same site, leading to ↓ duration or intensity of analgesia.

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