Viva C(iv)a

This viva is relevant to the objectives of Section C(iv)  of the 2017 CICM Primary Syllabus, which asks the exam candidate to "to explain receptor activity".

What is receptor regulation?
  • Receptor regulation  is the homeostatic increase or decrease in receptor activity or number, in response to activation or blockade.
How are drug receptors regulated?
  • Regulation can occur by modifying drug receptor numbers, or their function, or both.
  • Drugs (or endogenous ligands) binding to receptors produce a downstream effect
  • In most circumstances, this downstream effect triggers regulatory mechanisms
  • Regulatory mechanisms are designed to homeostatically respond to receptor activation, i.e. to dampen the response where it is exaggerated, or to amplify it where it is deficient.
What cellular mechanisms exist to regulate drug receptors?
  • There are several mechanisms of such regulation:
    • Increase or decrease of the number of receptor molecules expressed on the cell surface (or wherever the drug finds its targets)
    • Increase or decrease of the concentration of downstream secondary messenger molecules (eg. cAMP)
    • Alteration of substrate availability, eg. metaraminol and noradrenaline
Give some examples of drug receptor regulation which can be seen in clinical practice

(Numerous possible responses exist)

  • acetylcholine-associated sodium channels at the neuromuscular junction, upregulated following a stroke or paralysis
  • Opioid receptors, regulated by opioid administration
  • etc...

References

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Huganir, Richard L., and Paul Greengard. "Regulation of receptor function by protein phosphorylation." Trends in Pharmacological Sciences 8.12 (1987): 472-477.

Harrison, Laura M., Abba J. Kastin, and James E. Zadina. "Opiate tolerance and dependence: receptors, G-proteins, and antiopiates." Peptides 19.9 (1998): 1603-1630.

Zaliauskiene, Lolita, et al. "Down-regulation of cell surface receptors is modulated by polar residues within the transmembrane domain." Molecular Biology of the Cell 11.8 (2000): 2643-2655.

Blakely, Randy D., et al. "Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin transporter proteins." Biological psychiatry 44.3 (1998): 169-178.

JA, Jeevendra Martyn. "Basic and clinical pharmacology of the acetylcholine receptor: implications for the use of neuromuscular relaxants." The Keio journal of medicine 44.1 (1995): 1-8.

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Zuo, Yantao, et al. "Acute nicotine-induced tachyphylaxis is differentially manifest in the limbic system." Neuropsychopharmacology 36.12 (2011): 2498.

Münzel, T., et al. "Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance." The Journal of clinical investigation 95.1 (1995): 187-194.

Andén, Nils‐Erik. "On the mechanism of noradrenaline depletion by α‐methyl metatyrosine and metaraminol." Acta pharmacologica et toxicologica 21.3 (1964): 260-271.

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