Tolerance development pathways

Pharmocodynamic tolerance develops in response to continued application of drugs, by mechanisms that include reversible cellular adaptation processes, such as receptor desensitization, internalization and downregu-lation as well as changes in the activity and levels of other components of the receptor s signal transduction pathways. 

Constriction of the pupils is seen with virtually all opioid agonists. Miosis is a pharmacologic action to which little or no tolerance develops (Table 31-3) thus, it is valuable in the diagnosis of opioid overdose. Even in highly tolerant addicts, miosis is seen. This action, which can be blocked by opioid antagonists, is mediated by parasympathetic pathways, which, in turn, can be blocked by atropine. 

Chlorpromazine produces a tranquihty characterized by a detached serenity without depression of mental faculties or clouding of consciousness. It depresses the CNS selectively by reducing input directed to the reticular formation through collaterals arriving from the sensory pathways. Chlorpromazine-induced sedation differs from that caused by barbiturates in that the patient can be easily aroused. In practice, the more sedative neuroleptics are often prescribed for agitated, overactive patients, and the less sedative agents are used for apathetic, withdrawn patients. However, sedation is not necessary for its antipsychotic property for two reasons (1) tolerance develops to the sedative effects, and (2) fluphenazine, prochlorperazine, and trifluoperazine are excellent neuroleptics that lack pronounced sedative effects. 

Desensitization describes the rapid signal attenuation in response to stimulation of cells by receptor agonists. Changes in the coupling efficiency of receptors to signal transduction pathways and receptor internalization can account for desensitization and the development of pharmacodynamic tolerance. 

Further work at EniTecnologies was conducted with Rhodococcus strains. Rhodococ-cus was selected for its metabolical versatility, easy availability in soils and water, and remarkable solvent tolerance. Its capabilities for catalyzing diverse transformation reactions of crude oils, such as sulfur removal, alkanes and aromatics oxidation and catabolism caught their attention. Hence, genetic tools for the engineering of Rhodococcus strains have been applied to improve its biotransformation performance and its tolerance to certain common contaminants of the crude oil, such as cadmium. The development of active biomolecules led to the isolation and characterization of plasmid vectors and promoters. Strains have been constructed in which the careful over-expression of selected components of the desulfurization pathway leads to the enhancement of the sulfur removal activity in model systems. Rhodococcus, Gordona, and Nocardia were transformed in this way trying to improve their catalytic performance in BDS. In a... 

Electrodeposition of metal onto structured objects, such as circuits, is controlled in part by a template. At the same time, the deposit must fill all the recesses uniformly and seamlessly, the texture and crystal structure must fall within tolerances, and the quality of the features must be sustained over a large workpiece. The distribution of material within recesses or onto widely separated portions of the workpiece is subject to a limited number of macroscopic control-parameters such as applied potential and plating bath composition. Success therefore depends on exploitation of the natural pathways of the process. The spontaneous and unconstrained development of structure must be taken into consideration in the production of highly organized and functional patterns. 

Upregulation of the cAMP pathway may be a common mechanism by which a number of neuronal cell types respond to chronic opiates and develop tolerance and dependence (see Ch. 56). There is also evidence that similar mechanisms involving alterations in the cAMP second-messenger and protein phosphorylation pathway may mediate aspects of addiction to other types of drugs of abuse, for example, cocaine and alcohol [66],... 

Martin BR, Sim-Selley LJ, Selley DE. Signaling pathways involved in the development of cannabinoid tolerance. Trends Pharmacol Sci 2004 25 325-30. 

However, in individuals with increased intracranial pressure, asthma, chronic obstructive pulmonary disease, or cor pulmonale, this decrease in respiratory function may not be tolerated. Opioid-induced respiratory depression remains one of the most difficult clinical challenges in the treatment of severe pain. Research is ongoing to understand and develop analgesic agents and adjuncts that avoid this effect. Research to overcome this problem is focused on 5 receptor pharmacology and serotonin signaling pathways in the brainstem respiratory control centers. 

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