Drug tolerance
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. The following are 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.[citation needed] A rapid drug tolerance is termed tachyphylaxis.
Tachyphylaxis
Tachyphylaxis is a sudden onset drug tolerance which is not dose dependent.
Mechanisms
Pharmacokinetic tolerance
Pharmacokinetic tolerance (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. This is most commonly seen with substances such as ethanol, barbiturates, benzodiazapines and opiates.
Pharmacodynamic tolerance
Pharmacodynamic tolerance (reduced responsiveness) is when the response to the substance is decreased by cellular mechanisms. This may be caused by a down regulation of receptor numbers[2] (or up regulation in the case of a receptor antagonist).
Tolerance is a 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
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]
It was reported that VTA dopamine neurons in rats remain increased for at least 3 days after a single morphine exposure. Within this limited window of time, the VTA dopamine neurons failed to respond to additional morphine challenge. Indicating a transient morphine tolerance in VTA DA neuron activity in rats was developed with a single dose of morphine treatment. It further demonstrated that this acute morphine tolerance was associated with impairment of opiate receptor-G protein coupling, indicating that down regulation of G-protein activation may contribute to acute morphine tolerance.[6]
See also
- Desensitization
- Sensitization
- Physical dependence
- Mithridatization
- Reverse tolerance
- Cross-tolerance
- Drug resistance
- Tachyphylaxis
- Multidrug resistance
References
- ↑ 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.
- ↑ Li, Y; Liu, X; Liu, C; Kang, J; Yang, J; Pei, G; Wu, C (2009). "Improvement of Morphine-Mediated Analgesia by Inhibition of β-Arrestin 2 Expression in Mice Periaqueductal Gray Matter". International Journal of Molecular Sciences 10 (3): 954–963. doi:10.3390/ijms10030954. PMC 2672012. PMID 19399231.
- ↑ Zhang, Die; Zhang, Hai; Jin, Guo-Zhang; Zhang, Kehong; Zhen, Xuechu (2008). "Single dose of morphine produced a prolonged effect on dopamine neuron activities". Molecular Pain 4: 57. doi:10.1186/1744-8069-4-57. PMC 2603002. PMID 19014677.
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