Tolerance is a gradual decrease in drug response following prolonged exposure \(\to\) reduced drug potency. Mechanisms of tolerance include
- Pharmacokinetic
- Self-enzyme induction (carbemazepine)
- Pharmacodynamic:
- Cellular
- Receptor downregulation (e.g. \(\beta_2\) receptors with chronic salbutamol use)
- Receptor uncoupling (e.g. \(\mu\) opioid receptors \(\to \ \beta\)-arrestins block g-protein
- Accumulation of second messengers
- Homeostatic
- e.g. RAAS activation with antihypertensive use
- Behavioural
- I.e. learned adjustments to compensate for drug effect
Tachyphylaxis is a rapid decrease in drug efficacy due to receptor desensitization or mediator depletion (e.g. sulfhydryl groups in GTN, presynaptic norad in metaraminol). Rapidly reversible if drug is withheld.