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
Structure:
- Tachyphylaxis: Definition, cause, examples
- Tolerance: Same
- Mechanisms of tolerance
Tachyphylaxis
| Property | Detail |
|---|---|
| Definition | - 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 |
| Examples | - Ephedrine: Depletion of NAd at post-ganglionic SNS nerve endings - GTN: Depletion of intracellular sulfhydryl groups → ↓ Nitric oxide release |
Tolerance
| Property | Detail |
|---|---|
| Definition | - 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 |
| Representation | Right shift log(dose) – response curve
|
Mechanisms of Tolerance
| Factor | Mechanism |
|---|---|
| Kinetic | - Absorption/metabolism - e.g. Alcohol → Induce alcohol dehydrogenase, acetaldehyde dehydrogenase - Distribution: - e.g. ↑ P-glycoprotein-mediated efflux of opioids |
| Dynamic | - ↓ 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 |