Drug tolerance

In physiology, 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) decreases^[1] so 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 medical term referring to the rapid decrease in response to a drug after repeated doses over a short period of time.

Contents 1 Mechanisms 1.1 Morphine as an Example 2 See also 3 References

Mechanisms

There are two major mechanisms for tolerance:

• Dispositional tolerance: occurs because of a decreased quantity of the substance reaching the site it affects.
• Reduced responsiveness: the response to the substance is decreased by cellular mechanisms.^[2]

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),^[3] 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.^[4]) 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.

See also

• Desensitization
• Sensitization
• Physical dependence
• Mithridatization
• Reverse tolerance
• Cross-tolerance
• Drug resistance
• Tachyphylaxis
• Multidrug resistance

References

v • d • e Medication > Pharmacology Pharmacokinetics ADME: Absorption • Distribution • Metabolism • Excretion (Clearance) Loading dose • Volume of distribution (Initial) • Rate of infusion Compartment • Bioequivalence • Bioavailability Onset of action • Biological half-life • Plasma protein binding Phase 1 reaction • Phase 2 reaction Therapeutic index (LD50/ED50) Pharmacodynamics Toxicity (Neurotoxicology) • Dose-response relationship (Efficacy, Potency) Antimicrobial pharmacodynamics: Minimum inhibitory concentration/Bacteriostatic • Minimum bactericidal concentration/Bactericide Agonism and antagonism Agonist: Inverse agonist • Irreversible agonist • Partial agonist • Superagonist • Physiological agonist Antagonist: Competitive antagonist • Irreversible antagonist • Physiological antagonist Other: Binding • Affinity • Binding selectivity • Functional selectivity Other Drug tolerance: Tachyphylaxis Drug resistance: Antibiotic resistance • Multiple drug resistance Related fields/subfields Pharmacogenetics • Pharmacogenomics • Neuropsychopharmacology (Neuropharmacology, Psychopharmacology)