2021A12 Define the terms “tolerance” and “tachyphylaxis”.
Discuss the different mechanisms by which tolerance can develop, giving examples where appropriate.

· Tachyphylaxis: definition, cause, examples

· Tolerance: same

· Mechanisms of tolerance

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

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

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 G_i 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