Drug tolerance

Did You Know?

• Drug tolerance should not be confused with drug tolerability, which refers to the degree to which overt adverse effects of a drug can be tolerated by a patient.
• Tachyphylaxis is a subcategory of drug tolerance referring to cases of sudden, short-term onset of tolerance following the administration of a drug.

Pharmacodynamic tolerance

Pharmacodynamic tolerance begins when the cellular response to a substance is reduced with repeated use. A common cause is high concentrations of a substance constantly binding with a receptor, desensitizing it. Other mechanisms include a reduction in receptor density, changes in action potential firing rate, or alterations in protein transcription. For receptor antagonists, the reverse occurs, such as increased receptor firing rate or density. Acute or instant tolerance, known as tachyphylaxis, can also occur.

Pharmacokinetic (metabolic) tolerance

Pharmacokinetic tolerance, or dispositional tolerance, happens when less of a drug reaches the place where it works. This can result from increased activity of enzymes like CYP450 that break the drug down, which is often seen with alcohol. It is most noticeable when a drug is taken by mouth, since other methods avoid the liver's first-pass effect. While enzyme induction contributes to tolerance, it is just one of several processes that reduce a drug's effect with repeated use.

Behavioral tolerance

Behavioral tolerance occurs with certain psychoactive drugs, where tolerance to a behavioral effect, such as increased motor activity from methamphetamine, develops with repeated use. It may arise through drug-independent learning or as a form of pharmacodynamic tolerance in the brain. The former mechanism involves learning to actively overcome drug-induced impairment through practice. Behavioral tolerance is often context-dependent, meaning it depends on the environment rather than the drug itself.