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Tolerance and Resistance to Drugs


Shalini S. Lynch

, PharmD, University of California San Francisco School of Pharmacy

Reviewed/Revised Jul 2022 | Modified Sep 2022

Tolerance is a person's diminished response to a drug, which occurs when the drug is used repeatedly and the body adapts to the continued presence of the drug. Resistance refers to the ability of microorganisms or cancer cells to withstand the effects of a drug usually effective against them.


A person may develop tolerance to a drug when the drug is used repeatedly. For instance, when morphine or alcohol is used for a long time, larger and larger doses must be taken to produce the same effect. Usually, tolerance develops because metabolism of the drug speeds up (often because the liver enzymes involved in metabolizing drugs become more active) and because the number of sites (cell receptors) that the drug attaches to or the strength of the bond (affinity) between the receptor and drug decreases (see Receptors on Cells Receptors on Cells After being swallowed, injected, inhaled, or absorbed through the skin, mucosa under the tongue, or mucosa inside the cheek, most drugs enter the bloodstream and circulate throughout the body... read more ).


Strains of microorganisms (bacteria or viruses) are said to develop resistance when they are no longer killed or inhibited by the antibiotics and antiviral drugs that are usually effective against them (or, in practice, when significantly higher than normal doses are required to have an effect). Similarly, cancer cells may develop resistance to chemotherapy drugs.

Resistance appears because of the mutations that take place spontaneously in any group of growing microorganisms or cells, whether exposed to drugs or not. Most such mutations change the microorganism's or cell's structure or biochemical pathways in a way that is harmful to the microorganism or cell. But some mutations change the parts of the microorganism or cell that are affected by drugs, decreasing the drug's ability to work (that is, causing resistance). Because such mutations are very rare, there are normally only a few such resistant microorganisms or cells in any group. However, if all or many of the “normal” microorganisms or cells are killed by a drug, a much higher proportion of the survivors are likely to be resistant. If the resistant survivors are not killed by the body's natural defenses, which is more likely when drugs are stopped too soon or not taken in the proper manner, they may reproduce and pass on the resistant trait to their descendants.

Prevention and Treatment

To prevent the development of resistance, doctors try to use antibiotics only when necessary (not for viral infections such as a cold) and have people take them for a full course of treatment. In the treatment of certain serious infections, such as HIV, doctors usually give two or more different drugs at the same time because it is very unlikely that a cell would spontaneously be resistant to two drugs at the same time. However, giving one drug for a short time followed by another can produce resistance to multiple drugs. Multi-drug resistance has become a problem with tuberculosis in particular.

Once tolerance or resistance has developed to a drug, doctors may increase the dose or use a different drug.

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