Drug tolerance

Physiological tolerance or drug tolerance is commonly encountered in pharmacology, when a subject's reaction to a drug (such as an opiate painkiller, benzodiazepine or other psychotropic drug) is reduced at a later time even though the dose or concentration at the effect site is the same. This means that larger doses are required to achieve the same effect. Drug tolerance can involve both psychological drug tolerance and physiological factors. Characteristics of drug tolerance: it is reversible, the rate depends on the particular drug, dosage and frequency of use, differential development occurs for different effects of the same drug. Physiological tolerance also occurs when an organism builds up a resistance to the effects of a substance after repeated exposure. This can occur with environmental substances, such as salt or pesticides.

Tachyphylaxis is a synonym for drug tolerance.

Mechanisms
There are two major mechanisms for tolerance:

Pharmacokinetic Tolerance- Also known as Dispositional tolerance: occurs because of a decreased quantity of the substance reaching the site it affects. This may be caused by an increase in induction of the enzymes required for degradation of the drug e.g. CYP450 enzymes

Pharmacodynamic Tolerance - Also known as Reduced responsiveness: the response to the substance is decreased by cellular mechanisms. This may be caused by a down regulation of receptor numbers

Morphine as an Example
Tolerance to the analgesic effects of morphine is fairly rapid. There are several hypotheses about how tolerance develops, including opioid receptor phosphorylation (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization), mu-opioid receptor internalization and/or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt. ) CCK might mediate some counter-regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs, specifically proglumide, have been shown to slow the development of tolerance to morphine or any other kind of drug, including alcohol.