3.3 · Acute effects, adaptation and tolerance

Learning objective

Separate receptor adaptation from metabolic tolerance and distinguish tolerance from dependence.

Immediate effects and repeated exposure

Acute receptor effects occur during a particular exposure. Repeated exposure can change receptor availability, sensitivity and downstream signaling. The book illustrates downregulation with persistent agonist stimulation and upregulation during prolonged antagonism. Treat these as possible adaptive patterns, not guaranteed outcomes for every drug, tissue and exposure schedule.

Two different routes to a smaller response

Pharmacokinetic or metabolic tolerance can arise when exposure falls, such as increased metabolism. Pharmacodynamic tolerance can arise when the target responds less strongly at the same concentration. Behavioral learning and context can also affect an observed response. A smaller effect after the same administered dose does not alone identify which process changed.

Tolerance, dependence and withdrawal

Tolerance means a reduced response to repeated exposure under a specified comparison. Physical dependence is an adapted state in which reducing or stopping exposure can produce withdrawal. These are related but distinct; neither alone defines addiction. Adaptation can outlast the immediate presence of drug, which helps explain why disappearance from plasma does not guarantee immediate return to the prior functional state.

Check your understanding

Explain it without notes

What measurement helps separate PK and PD tolerance?

Why can withdrawal persist after most drug has been eliminated?

Revisit the connected course lessons and visuals

Tolerance, dependence and discontinuation

Enzyme induction, inhibition and variation

Julien’s Primer of Drug Action, supplied consolidated PDF pages 20, 21, 35, 36 (Chapter 3). Locators refer to PDF captures, not printed pages. Original paraphrase and practice; source conformance reviewed, not independently clinically certified.