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Tolerance and Resistance

By Daniel A. Hussar, PhD

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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 (see Drug Metabolism). 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.

Tolerance differs from dependence. Dependence is characterized by a desire to use a drug (psychologic dependence—see Overview of Substance-Related Disorders : Classification of substance-related disorders) and/or unpleasant physical symptoms, known as a withdrawal syndrome, when use of the drug is stopped (physical dependence—see Substance-Induced Disorders : Withdrawal).

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 preferentially eliminates nonresistant organisms, the resistant organisms become the predominant species (see Overview of Antibacterial Drugs : Antibiotic Resistance). Similarly, 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.

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