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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.{{cite book|last1=Stein|first1=C|last2=Zöllner|first2=C|title=Sensory Nerves|chapter=Opioids and Sensory Nerves|series=Handbook of Experimental Pharmacology|date=2009|volume=194|issue=194|pages=495–518|pmid=19655116|doi=10.1007/978-3-540-79090-7_14|isbn=978-3-540-79089-1}} These peripherally selective opioids can be used as antidiarrheals, for instance loperamide (Imodium).{{cite journal | vauthors = Schinkel AH | title = P-Glycoprotein, a gatekeeper in the blood-brain barrier | journal = Adv Drug Deliv Rev | volume = 36 | issue = 2–3 | pages = 179–194 | date = April 1999 | pmid = 10837715 | doi = 10.1016/s0169-409x(98)00085-4 | url = }}

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.{{cite journal | vauthors = Dyrna F, Hanske S, Krueger M, Bechmann I | title = The blood-brain barrier | journal = J Neuroimmune Pharmacol | volume = 8 | issue = 4 | pages = 763–73 | date = September 2013 | pmid = 23740386 | doi = 10.1007/s11481-013-9473-5 | s2cid = 255272031 | url = }}{{cite journal | vauthors = Terasaki T, Ohtsuki S | title = Brain-to-blood transporters for endogenous substrates and xenobiotics at the blood-brain barrier: an overview of biology and methodology | journal = NeuroRx | volume = 2 | issue = 1 | pages = 63–72 | date = January 2005 | pmid = 15717058 | pmc = 539321 | doi = 10.1602/neurorx.2.1.63 | url = }} 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.{{cite journal | vauthors = Schinkel AH, Wagenaar E, Mol CA, van Deemter L | title = P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs | journal = J Clin Invest | volume = 97 | issue = 11 | pages = 2517–24 | date = June 1996 | pmid = 8647944 | pmc = 507337 | doi = 10.1172/JCI118699 | url = }}{{cite journal | vauthors = De Kloet ER | title = Why Dexamethasone Poorly Penetrates in Brain | journal = Stress | volume = 2 | issue = 1 | pages = 13–20 | date = October 1997 | pmid = 9787252 | doi = 10.3109/10253899709014734 | url = }}{{cite book | title = Urticaria and Angioedema | last1 = Church | first1 = Martin K. | chapter = Antihistamines | date = 2021 | pages = 153–165 | publisher = Springer International Publishing | doi = 10.1007/978-3-030-84574-2_11 | isbn = 978-3-030-84573-5 | s2cid = 239944965 | url = }}{{cite journal | vauthors = Hu Y, Sieck DE, Hsu WH | title = Why are second-generation H1-antihistamines minimally sedating? | journal = Eur J Pharmacol | volume = 765 | issue = | pages = 100–6 | date = October 2015 | pmid = 26291661 | doi = 10.1016/j.ejphar.2015.08.016 | url = }}

List of peripherally selective drugs

References

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External links

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