2012B03 Define the terms “tolerance” and “tachyphylaxis”.
Discuss the different mechanisms by which tolerance can develop, giving examples where appropriate.

 

List:

·      Tachyphylaxis: definition, cause, examples

·      Tolerance: same

·      Mechanisms of tolerance

 

Tachyphylaxis:

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:

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:

Kinetic

·  Absorption/metabolism

o e.g. alcohol -> induce alcohol dehydrogenase, acetaldehyde dehydrogenase

·  Distribution:

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

Dynamic

·  ↓Receptor number

o e.g. salbutamol at β2 adrenoceptor

o Phosphorylate ICF carboxyl terminal -> β-arrestin binds -> internalize & destroy

·  ↓Receptor affinity

o e.g. contributes to insulin resistance

·  ↓ICF signal transduction

o e.g. morphine at mu receptor

o Upregulation of cAMP system -> ↓effect of Gi G protein coupled receptor activation

·  Altered ion conductance

o e.g. suxamethonium phase 2 blockade

o Phosphorylation of tyrosine residues -> conformational change

·  Neuroplasticity:

o e.g. cocaine effect on basal ganglia

o ↓Euphoria

·  Upregulation of antagonistic mechanism

 

 

 

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