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Physiologic tolerance, or desensitization, is well described in clinical pharmacology. It is defined by progressively diminished response to drug at a certain dose following repeated exposure, and requiring increasing dosages to achieve the desired effect on subsequent administrations. Drug tolerance refers to changes in the potency (higher effective dose required), the effectiveness (decreased maximal effect), or both aspects of the drug.

There are four key characteristics of drug tolerance:

  1. Reversible, once exposure to the drug is discontinued.

  2. Dependent on the dose and frequency of drug exposure.

  3. Variable time course and extent of tolerance development between different drugs.

  4. Not all drug effects develop the same amount of tolerance.

Physiologic tolerance may also occur in the form of drug resistance, whereby an organism develops resistance to the effects of a substance following exposure. Pathogens are said to be drug resistant when drugs meant to neutralize them have reduced effects.

On a dose–response curve, drug tolerance causes a right shift of the curve, thereby increasing median effective dose (ED50) and requiring greater dosages to achieve similar effects. ED50 does not necessarily increase with tolerance and may have serious implications.


Drug tolerance is not equal to drug dependence, although they often coexist and have similar cellular mechanisms. Whereas tolerance requires increasing dosages of a drug to achieve similar effects, dependence is defined as the compulsive need of an individual to use a drug to function normally. Dependence develops in an individual when the brain adapts to continuous, high drug levels and appears to function “normally” at those levels due to functional tolerance. If drug administration is halted, an abrupt decrease in drug levels results in abstinence syndrome or withdrawal reactions that are opposite to the drug’s initial effects (ie, hyperactivity for depressants or hypoactivity for stimulants).


There are multiple mechanisms that explain tolerance to a drug following repeated exposure. It is possible for a single drug to develop more than one type of tolerance. The three major mechanisms responsible for tolerance are:

  • Dispositional (metabolic) tolerance occurs when repeated use of a drug reduces the amount of that drug available at the target tissue. The underlying pharmacokinetic mechanism involves accelerated drug clearance due to induction of metabolic enzymes from repeated or continuous use of the drug. While this usually takes weeks to develop, the net effect is a shortened half-life and a decreased quantity of drug at the target site. Examples of this phenomenon are seen with alcohol, opiates, and barbiturates.

  • Reduced responsiveness (pharmacodynamic) tolerance occurs when repeated use of a drug alters nerve cell function (ie, receptor density, intracellular cascade). This type of tolerance takes days or weeks to develop. Chronically increased receptor activation by agonistic drugs results in receptor ...

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