Peripherally selective drug

Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest of the body without producing side-effects related to their effects on the brain or spinal cord. For example, most opioids cause sedation when given at a sufficiently high dose, but peripherally selective opioids can act on the rest of the body without entering the brain and are less likely to cause sedation.[1] These peripherally selective opioids can be used as antidiarrheals, for instance loperamide (Imodium).[2]

Mechanisms of peripheral selectivity include physicochemical hydrophilicity and large molecular size, which prevent drug permeation through the lipid bilayer cell membranes of the blood–brain barrier, and efflux out of the brain by blood–brain barrier transporters such as P-glycoprotein among many others.[2][3][4] Transport out of the brain by P-glycoprotein is thought to be responsible for the peripheral selectivity of many drugs, including loperamide, domperidone, fexofenadine, bilastine, cetirizine, ivermectin, and dexamethasone, among others.[2][5][6][7][8]

Examples

References

  1. Stein, C; Zöllner, C (2009). "Opioids and sensory nerves". Handbook of Experimental Pharmacology. 194 (194): 495–518. doi:10.1007/978-3-540-79090-7_14. ISBN 978-3-540-79089-1. PMID 19655116.
  2. Schinkel AH (April 1999). "P-Glycoprotein, a gatekeeper in the blood-brain barrier". Adv Drug Deliv Rev. 36 (2–3): 179–194. doi:10.1016/s0169-409x(98)00085-4. PMID 10837715.
  3. Dyrna F, Hanske S, Krueger M, Bechmann I (September 2013). "The blood-brain barrier". J Neuroimmune Pharmacol. 8 (4): 763–73. doi:10.1007/s11481-013-9473-5. PMID 23740386.
  4. Terasaki T, Ohtsuki S (January 2005). "Brain-to-blood transporters for endogenous substrates and xenobiotics at the blood-brain barrier: an overview of biology and methodology". NeuroRx. 2 (1): 63–72. doi:10.1602/neurorx.2.1.63. PMC 539321. PMID 15717058.
  5. Schinkel AH, Wagenaar E, Mol CA, van Deemter L (June 1996). "P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs". J Clin Invest. 97 (11): 2517–24. doi:10.1172/JCI118699. PMC 507337. PMID 8647944.
  6. De Kloet ER (October 1997). "Why Dexamethasone Poorly Penetrates in Brain". Stress. 2 (1): 13–20. doi:10.3109/10253899709014734. PMID 9787252.
  7. Church, Martin K. (2021). "Antihistamines". Urticaria and Angioedema. Springer International Publishing. pp. 153–165. doi:10.1007/978-3-030-84574-2_11.
  8. Hu Y, Sieck DE, Hsu WH (October 2015). "Why are second-generation H1-antihistamines minimally sedating?". Eur J Pharmacol. 765: 100–6. doi:10.1016/j.ejphar.2015.08.016. PMID 26291661.


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