2021A Question 12

Define the terms “tolerance” and “tachyphylaxis”. Discuss the different mechanisms by which tolerance can develop, giving examples where appropriate.

Examiner Report

48.2% of candidates achieved a pass in this question.

The domains which attracted marks for this question were:

  • Correct definition of both tachyphylaxis and tolerance
  • Mechanisms for tachyphylaxis with examples
  • Mechanisms for tolerance with examples

Common problems with the answers included:

  • Not stating time course for these effects
  • Confounding tolerance with ceiling effect/zero order kinetics/drug interactions
  • Using phenylephrine as an example of an indirectly acting drug
  • Confusing transmitter depletion with re-uptake inhibition

Model Answer


  • Tachyphylaxis: Definition, cause, examples
  • Tolerance: Same
  • Mechanisms of tolerance


Property Detail

- Decreased response to a drug with repeated short-term use

- Usually over minutes to hours

- Cannot be easily overcome with increased dose

Cause Usually mediator depletion

- Ephedrine: Depletion of NAd at post-ganglionic SNS nerve endings

- GTN: Depletion of intracellular sulfhydryl groups → ↓ Nitric oxide release


Property Detail

- Decreased duration then decreased magnitude of effect of a given drug dose with long term use

- Usually over days to weeks

- Can be overcome with increased dose

Cause Chronic use of drug resulting in adaptation
Examples e.g. Chronic opioid use

Right shift log(dose) – response curve

Mechanisms of Tolerance

Factor Mechanism

- Absorption/metabolism

 - e.g. Alcohol → Induce alcohol dehydrogenase, acetaldehyde dehydrogenase

- Distribution:

 - e.g. ↑ P-glycoprotein-mediated efflux of opioids


- ↓ Receptor number

 - e.g. Salbutamol at β2 adrenoceptor

 - Phosphorylate ICF carboxyl terminal → Β-arrestin binds → Internalize & destroy

- ↓ Receptor affinity

 - e.g. Contributes to insulin resistance

- ↓ ICF signal transduction

 - e.g. Morphine at mu receptor

 - Upregulation of cAMP system → ↓ Effect of Gi G protein coupled receptor activation

- Altered ion conductance

 - e.g. Suxamethonium phase 2 blockade

 - Phosphorylation of tyrosine residues → Conformational change

- Neuroplasticity:

 - e.g. Cocaine effect on basal ganglia

 - ↓ Euphoria

- Upregulation of antagonistic mechanism

Last updated 2021-08-23

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