Tolerance (Pharmacology)
A gradual decrease in the body's response to a drug with repeated use over time, requiring higher doses to achieve the same effect. Tolerance develops more slowly than tachyphylaxis and involves adaptive changes in receptor number, sensitivity, or downstream signalling pathways.
Technical Context
Tolerance develops through multiple mechanisms: receptor downregulation (reduced receptor number), receptor desensitisation (reduced receptor sensitivity), enhanced drug metabolism (metabolic/pharmacokinetic tolerance), and physiological counter-regulation (homeostatic mechanisms opposing the drug's effect). For peptide drugs, some degree of tolerance to gastrointestinal side effects of GLP-1 RAs is observed (nausea typically diminishes over weeks), which is beneficial. However, significant tolerance to the primary therapeutic effect (glycaemic control, weight loss) has not been a major issue for GLP-1 RAs at currently approved doses. Cross-tolerance (tolerance to related drugs that share the same mechanism) is an important consideration when switching between agents in the same class.