14B15: Exam Report

Define the terms tolerance and tachyphylaxis. (20% of marks) Describe the different mechanisms by which tolerance can develop, and give examples for each. (80% of marks)

15% of candidates passed this question.

Tolerance is the requirement of higher doses of a drug to produce a given response. When this develops rapidly (with only a few administrations of the drug) this is termed tachyphylaxis. Various mechanisms exist by which tolerance occurs and these include cellular tolerance (e.g. neuronal adaptation to opioids or alcohol), enzyme induction and depletion of neurotransmitters.
Few candidates knew a comprehensive list or had a classification system for the different types of tolerance. No candidate had a good definition of tachyphylaxis.

Dvi / 14B15: Define the terms tolerance and tachyphylaxis (20 marks). Describe the different mechanisms by which tolerance can develop and give examples of each (80 marks)


  • A decreased response to a drug which develops over minutes-hrs
  • dose will not ­response
  • Usually due to 2nd msg depletion or receptor internalisation
  • ie depletion of stored NA on repeated Ephedrine doses


  • larger doses are required to produce the same pharmacological effect
  • Occurs over days-weeks


PK Tolerance


  • ­ ↑Metabolism – carbamezapine, alcohol induces liver enzymes
  • ­ ↑Elimination
  • ↓ Uptake

PD Tolerance


  • change or loss of receptors
  • Change in receptors is seen in those coupled to ionic channels
    • ie NMJ, where there is a slow conformational change in the receptor wh results in tight agonist binding without ionic channel opening
    • Mechanism may have something to do with phosphorylation
  • Loss of receptors
    • ie down regulation of b-receptors with b-agonists like isoprenaline, salbutamol
    • Taken into cell by endocytosis
    • Also opiates


  • depletion of intermediate substances
    • ie amphetamine, which causes release of noradrenaline to result in effects
    • tolerance develops as norad stores are depleted


  • increased metabolic degradation leading to lower drug concentration
  • ie thiopentone which induces hepatic enzymes, leading to faster degradation


  • body tries to counteract effect with homeostatic response
  • ie hypotensive action of thiazide diuretics is dampened by activation of RAS

ie Morphine tolerance

  • Opioid receptor phosphorelation → changes receptor conformation
  • Functional Decoupling of Receptors from G Proteins → receptor desensitization
  • Mu Rec internalisation/downregulation → ↓number of receptors
  • Upregulation of cAMP → counter-regulates opioid effects