Receptor downregulation, enzyme induction and physiological adaptation
Expansion
Tolerance: reduced effect with repeated use, requiring a higher dose. Mechanisms:
- Receptor downregulation or desensitisation: opioids, beta agonists
- Enzyme induction (pharmacokinetic tolerance): alcohol, barbiturates
- Physiological adaptation: nitrate tolerance from depleted sulphydryl groups
- Behavioural adaptation
Tachyphylaxis: rapid tolerance over minutes to hours, typically from depletion of a mediator. The classic example is ephedrine, which depletes noradrenaline stores.
Dependence
- Physical: withdrawal syndrome on stopping. Opioids, benzodiazepines, alcohol
- Psychological: craving and compulsive use
Withdrawal syndromes are generally the opposite of the drug’s effects: opioid withdrawal causes diarrhoea, mydriasis, agitation and lacrimation; benzodiazepine and alcohol withdrawal cause seizures and delirium, and are potentially fatal.
Two clinically important points: tolerance to opioid respiratory depression develops but tolerance to constipation does not; and tolerance is lost rapidly during abstinence, which is why overdose deaths cluster after release from prison or discharge from detoxification.