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
- α-Methylserotonin – a serotonin receptor agonist
- Alvimopan – a μ-opioid receptor antagonist used in the treatment of postoperative ileus
- Anastrozole – an aromatase inhibitor used in the treatment of breast cancer
- Atenolol – a beta blocker
- Benserazide – an aromatic L-amino acid decarboxylase inhibitor used in combination with levodopa in the treatment of Parkinson's disease
- Bethanechol – a muscarinic acetylcholine receptor agonist used in the treatment of dry mouth and urinary retention
- Bicalutamide – an antiandrogen with peripheral selectivity in animals but seemingly not in humans
- Bilastine – a non-sedating antihistamine
- Bisoprolol – a beta blocker
- Carbachol – a non-selective acetylcholine receptor agonist used in the treatment of glaucoma
- Carbidopa – an aromatic L-amino acid decarboxylase inhibitor used in combination with levodopa in the treatment of Parkinson's disease
- Cetirizine – a non-sedating antihistamine
- Colchicine – an alkaloid and tubulin polymerization inhibitor used to treat gout
- Darolutamide – an antiandrogen used in the treatment of prostate cancer
- Desloratadine – a non-sedating antihistamine
- Dexamethasone – a glucocorticoid with some peripheral selectivity
- Digoxin – a cardiac glycoside and sodium–potassium pump inhibitor
- Domperidone – a D2 receptor antagonist used as an antiemetic, gastroprokinetic agent, and galactogogue
- Dopamine – a dopamine receptor agonist used as a cardiac stimulant and positive inotropic agent
- Eluxadoline – a μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist used in the treatment of diarrhea-predominant irritable bowel syndrome
- Epinephrine (adrenaline) – an adrenergic receptor agonist used as a cardiac stimulant and in the treatment of anaphylaxis
- Fenoldopam – a D1 receptor agonist used as an antihypertensive agent
- Fexofenadine – a non-sedating antihistamine
- Fulvestrant – an antiestrogen used in the treatment of breast cancer
- GABA – a dietary supplement
- Glycopyrronium bromide – an anticholinergic
- Hyoscine butylbromide – an anticholinergic
- Itopride – a D2 receptor antagonist and acetylcholinesterase inhibitor used as a gastroprokinetic agent
- Ivermectin – an antiparasitic
- Labetalol – a beta blocker
- Levocetirizine – a non-sedating antihistamine
- Loperamide – a μ-opioid receptor agonist used as an antidiarrheal
- Loratadine – a non-sedating antihistamine
- Methacholine – a choline ester and muscarinic acetylcholine receptor agonist
- Methylhomatropine – an anticholinergic
- Methylnaltrexone – a μ-opioid receptor antagonist used in the treatment of opioid-induced constipation
- Metopimazine – a D2 receptor antagonist used in the treatment of nausea, vomiting, and gastroparesis
- Midodrine – an α1-adrenergic receptor agonist used in the treatment of orthostatic hypotension
- Nadolol – a beta blocker
- Naloxegol – a μ-opioid receptor antagonist used in the treatment of opioid-induced constipation
- Norepinephrine (noradrenaline) – an adrenergic receptor agonist
- Ondansetron – a 5-HT3 receptor antagonist with some peripheral selectivity
- Peptides and proteins (e.g., insulin, oxytocin, vasopressin, opioid peptides, growth factors, many others)
- Pirenzepine – an anticholinergic
- Pyridostigmine – an acetylcholinesterase inhibitor and parasympathomimetic
- Serotonin – a serotonin receptor agonist
- Sotalol – a beta blocker
- Terfenadine – a non-sedating antihistamine
- Timepidium bromide – an anticholinergic
- Trimetaphan camsilate – a nicotinic acetylcholine receptor antagonist
- Trospium chloride – an anticholinergic
- Vinblastine – a Vinca alkaloid and antineoplastic agent
References
- 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.
- 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.
- 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.
- 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.
- 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.
- De Kloet ER (October 1997). "Why Dexamethasone Poorly Penetrates in Brain". Stress. 2 (1): 13–20. doi:10.3109/10253899709014734. PMID 9787252.
- Church, Martin K. (2021). "Antihistamines". Urticaria and Angioedema. Springer International Publishing. pp. 153–165. doi:10.1007/978-3-030-84574-2_11.
- 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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