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Tolerance and Resistance

By Shalini S. Lynch, PharmD, Associate Professor, Department of Clinical Pharmacy, University of California San Francisco School of Pharmacy

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Tolerance is a decrease in response to a drug that is used repeatedly. Resistance is development of the ability to withstand the previously destructive effect of a drug by microorganisms or tumor cells.

Examples of drugs that result in tolerance include alcohol and opioids. One mechanism responsible for tolerance is accelerated metabolism, for example, by induction of hepatic enzymes such as the cytochrome P-450 system enzymes. Generally, tolerance leads to increasing doses of a drug being required to produce the same effect. Other possible mechanisms are a decrease in binding affinity between a drug and receptor and a decrease in the number of receptors. The mechanisms responsible for drug tolerance are not always known.

Examples of resistance include the following:

  • Strains of microorganisms are resistant when they are no longer killed or inhibited by previously effective antimicrobial drugs. The mechanism begins with a genetic change resulting from a mutation or gene acquisition. Because the previously effective antimicrobial drug preferentially eliminates nonresistant organisms, the resistant organisms become the predominant species (see Overview of Antibacterial Drugs : Antibiotic Resistance).

  • Tumors can become resistant if a mutation develops that confers resistance to an anticancer drug and that anticancer drug is used repeatedly, preferentially eliminating nonresistant tumor cells. For example, many patients with chronic myeloid leukemia have become resistant to the tyrosine kinase inhibitor imatinib because of the presence of the T315I mutation.

  • Corticosteroid resistance can affect the treatment of a number of disorders such as asthma or inflammatory bowel disease. The mechanism of this type of resistance is not fully understood but may involve a number of different factors (eg, infection, oxidative stress, allergen exposure, inflammation, deficient vitamin D3, genetic mutations or variations).