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How can repeated drug use cause receptor desensitization?
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Docking of the anticancer drug Gleevec (imatinib) in the abl domain of the bcr-abl tyrosine kinase. Abnormalities in bcr-abl stimulate the continuous proliferation of bone marrow stem cells, causing an increase in myelogenous cells (granulocytes and macrophages) in the body and leading to chronic myelogenous leukemia (CML).
Repeated or continued administration of a drug can lead to desensitization, a phenomenon where the body’s response to the substance progressively diminishes. This adaptive process occurs through complex mechanisms, primarily involving the following:1
- Refractory State: Receptors may be converted into a refractory, or unresponsive, state in the presence of an agonist, preventing further activation.1
- Down-regulation: Following prolonged exposure to an agonist, receptors may be physically removed from the cell membrane.1
While desensitization is a reversible process, the recovery of receptors after down-regulation can take hours or days. These adaptive responses are significant in the therapeutic use of drugs, as they may partially account for the development of tolerance—a condition where an increased dose is required to achieve the same physiological effect.12