Drug tolerance
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This article is incomplete. (December 2011) |
Physiological tolerance or drug tolerance is commonly encountered in pharmacology, when a subject's reaction to a specific drug and concentration of the drug is progressively reduced, requiring an increase in concentration to achieve the desired effect.[1] 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. A rapid drug tolerance is termed tachyphylaxis.
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Tachyphylaxis [edit]
Tachyphylaxis is a sudden onset drug tolerance which is not dose dependent.
Mechanisms [edit]
Pharmacokinetic Tolerance [edit]
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 [edit]
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.[2]
Tolerance: reduced response to repeated administration of the same dose or increase in the dose are required to produce the same magnitude of response.
Morphine as an Example [edit]
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 or any other kind of drug, including alcohol.
Significant involvement of the intracellular Beta-arrestin-2 protein expression in the agonist-mediated desensitization of G protein-coupled receptors, such as the μ-opioid receptor (MOR), has been elucidated.[5]
See also [edit]
- Desensitization
- Sensitization
- Physical dependence
- Mithridatization
- Reverse tolerance
- Cross-tolerance
- Drug resistance
- Tachyphylaxis
- Multidrug resistance
References [edit]
- ^ Drug Tolerance at the US National Library of Medicine Medical Subject Headings (MeSH)
- ^ Klaassen, Curtis D. (2001-07-27). Casarett & Doull's Toxicology: The Basic Science of Poisons (6th ed.). McGraw-Hill Professional. p. 17. ISBN 0-07-134721-6.
- ^ Roshanpour M, Ghasemi M, Riazi K, Rafiei-Tabatabaei N, Ghahremani MH, Dehpour AR (2009). "Tolerance to the anticonvulsant effect of morphine in mice: blockage by ultra-low dose naltrexone". Epilepsy Res. 83 (2-3): 261–4. doi:10.1016/j.eplepsyres.2008.10.011. PMID 19059761.
- ^ Koch T, Höllt V (2008). "Role of receptor internalization in opioid tolerance and dependence". Pharmacol. Ther. 117 (2): 199–206. doi:10.1016/j.pharmthera.2007.10.003. PMID 18076994.
- ^ Chunfu W et al. (2009), "Improvement of Morphine-Mediated Analgesia by Inhibition of β-Arrestin 2 Expression in Mice Periaqueductal Gray Matter", Int J Mol Sci.10 (3): 954–963. doi:10.3390/ijms10030954 PMID:PMC2672012
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