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]

## Contents

* 1 List of peripherally selective drugs
* 2 See also
* 3 References
* 4 External links

## List of peripherally selective drugs

* 4-HO-TMT – a non-selective serotonin receptor agonist
* 5-Methoxytryptamine – a non-selective serotonin receptor agonist
* Aeruginascin – a non-selective serotonin receptor agonist
* α-Methylserotonin – a non-selective serotonin receptor agonist
* AL-34662 – a serotonin 5-HT2A 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 (β-adrenergic receptor antagonist)
* Baeocystin – a non-selective serotonin receptor agonist
* 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 (β-adrenergic receptor antagonist)
* Bufotenidine (5-HTQ) – a serotonin 5-HT3 receptor antagonist
* Bufotenin – a non-selective serotonin receptor agonist and serotonergic psychedelic
* BW-501C67 – a serotonin 5-HT2A and 5-HT2C receptor antagonist
* 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
* Carmoxirole – a dopamine D2 receptor agonist
* Carteolol – a beta blocker (β-adrenergic receptor antagonist)
* 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
* Docarpamine – a dopamine prodrug and non-selective dopamine receptor agonist
* Domperidone – a dopamine D2 receptor antagonist used as an antiemetic, gastroprokinetic agent, and galactogogue
* Dopamine – a non-selective dopamine and adrenergic 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
* Entacapone – a catechol-O-methyltransferase inhibitor used in combination with levodopa in the treatment of Parkinson's disease[9]
* Epinephrine (adrenaline) – a non-selective adrenergic receptor agonist used as a cardiac stimulant and in the treatment of anaphylaxis
* Ergotamine – non-selective serotonin, adrenergic, and dopamine receptor modulator used as a vasoconstrictor to treat migraines[10][11]
* Esmolol – a beta blocker (β-adrenergic receptor antagonist)
* Etamicastat – a dopamine β-hydroxylase inhibitor developed as an antihypertensive agent
* Etilefrine – a non-selective adrenergic receptor agonist used as an antihypotensive agent
* Fenoldopam – a dopamine 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 GABA receptor agonist and dietary supplement
* Glycopyrronium bromide – an anticholinergic (acetylcholine receptor antagonist)
* Guvacine – a GABA reuptake inhibitor
* Hyoscine butylbromide – an anticholinergic (acetylcholine receptor antagonist)
* Isoprenaline – a β-adrenergic receptor agonist used as a sympathomimetic
* Itopride – a dopamine D2 receptor antagonist and acetylcholinesterase inhibitor used as a gastroprokinetic agent
* Ivermectin – an antiparasitic
* Labetalol – a beta blocker (β-adrenergic receptor antagonist)
* 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 (acetylcholine receptor antagonist)
* Methylnaltrexone – a μ-opioid receptor antagonist used in the treatment of opioid-induced constipation
* Metopimazine – a dopamine 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
* Monlunabant – a cannabinoid CB1 receptor antagonist
* Muscarine – a muscarinic acetylcholine receptor agonist[12]
* Nadolol – a beta blocker (β-adrenergic receptor antagonist)
* Naloxegol – a μ-opioid receptor antagonist used in the treatment of opioid-induced constipation
* Nebicapone – a catechol-O-methyltransferase inhibitor for Parkinson's disease that was never marketed
* Nipecotic acid – a GABA reuptake inhibitor
* Norepinephrine (noradrenaline) – a non-selective adrenergic receptor agonist
* Norpsilocin – a non-selective serotonin receptor agonist
* Ondansetron – a serotonin 5-HT3 receptor antagonist with some peripheral selectivity
* Opicapone – a catechol-O-methyltransferase inhibitor used in combination with levodopa in the treatment of Parkinson's disease[13]
* Oxidopamine (6-hydroxydopamine; 6-OHDA) – a dopaminergic neurotoxin
* Peptides and proteins (e.g., insulin, oxytocin, vasopressin, opioid peptides, growth factors, many others)
* Phenylephrine – an α1-adrenergic receptor agonist used as a decongestant, to treat hypotension, and for other uses
* Phenylpropanolamine – a norepinephrine releasing agent and indirectly acting sympathomimetic with some peripheral selectivity
* Pirenzepine – an anticholinergic (acetylcholine receptor antagonist)
* Pseudoephedrine – a norepinephrine releasing agent and indirectly acting sympathomimetic with some peripheral selectivity
* Pyridostigmine – an acetylcholinesterase inhibitor and parasympathomimetic
* Sarpogrelate a serotonin 5-HT2 receptor antagonist
* Serotonin – a non-selective serotonin receptor agonist
* Sotalol – a beta blocker (β-adrenergic receptor antagonist)
* Sumatriptan – a triptan antimigraine agent and serotonin 5-HT1B and 5-HT1D receptor agonist
* Terfenadine – a non-sedating antihistamine
* THPO – a GABA reuptake inhibitor
* Timepidium bromide – an anticholinergic (acetylcholine receptor antagonist)
* Tolcapone – a catechol-O-methyltransferase inhibitor used in combination with levodopa in the treatment of Parkinson's disease[14]
* Trepipam – a dopamine D1 receptor agonist that was never marketed
* Trimetaphan camsilate – a nicotinic acetylcholine receptor antagonist
* Trospium chloride – an anticholinergic (acetylcholine receptor antagonist)
* Tyramine – a norepinephrine–dopamine releasing agent and sympathomimetic agent[15][16]
* Vinblastine – a Vinca alkaloid and antineoplastic agent
* VU0530244 – a selective serotonin 5-HT2B receptor antagonist[17]
* Xamoterol – a β1-adrenergic receptor partial agonist
* Xanomeline/trospium chloride – a combination of a centrally active M1 and M4 receptor muscarinic acetylcholine receptor agonist (xanomeline) and a peripherally selective non-selective muscarinic acetylcholine receptor antagonist (trospium chloride) used to treat schizophrenia
* Xylamidine – a serotonin 5-HT2A and 5-HT2C receptor antagonist
* Zamicastat – a dopamine β-hydroxylase inhibitor developed as an antihypertensive agent
* Zevaquenabant – a cannabinoid CB1 receptor antagonist

## See also

* Brain-to-blood ratio

## References

1. ↑ Stein, C; Zöllner, C (2009). "Opioids and Sensory Nerves". Sensory Nerves. Handbook of Experimental Pharmacology. 194. pp. 495–518. doi:10.1007/978-3-540-79090-7_14. ISBN 978-3-540-79089-1.
2. ↑ 2.0 2.1 2.2 "P-Glycoprotein, a gatekeeper in the blood-brain barrier". Adv Drug Deliv Rev 36 (2–3): 179–194. April 1999. doi:10.1016/s0169-409x(98)00085-4. PMID 10837715.
3. ↑ "The blood-brain barrier". J Neuroimmune Pharmacol 8 (4): 763–73. September 2013. doi:10.1007/s11481-013-9473-5. PMID 23740386.
4. ↑ "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. January 2005. doi:10.1602/neurorx.2.1.63. PMID 15717058.
5. ↑ "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. June 1996. doi:10.1172/JCI118699. PMID 8647944.
6. ↑ "Why Dexamethasone Poorly Penetrates in Brain". Stress 2 (1): 13–20. October 1997. 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. ISBN 978-3-030-84573-5.
8. ↑ "Why are second-generation H1-antihistamines minimally sedating?". Eur J Pharmacol 765: 100–6. October 2015. doi:10.1016/j.ejphar.2015.08.016. PMID 26291661.
9. ↑ "Clinical Pharmacology of Entacapone (Comtan) From the FDA Reviewer". Int J Neuropsychopharmacol 25 (7): 567–575. August 2022. doi:10.1093/ijnp/pyac021. PMID 35302623. "Entacapone is a potent and specific peripheral catechol-O-methyltransferase inhibitor. [...] Entacapone has no antiparkinsonian activity as a sole agent. Therefore, it must be given as an adjunct to LD and a peripherally acting DDC inhibitor, such as carbidopa. Entacapone acts peripherally and does not penetrate the blood-brain barrier (BBB). [...] It is poorly lipophilic and does not penetrate the BBB to any significant extent. Its clinical effects are thus due to peripheral COMT inhibition only (Nutt, 1998; Fahn et al, 2004). [...] Entacapone is poorly lipophilic. Therefore, its clinical effects are due to peripheral COMT inhibition alone. [...] Entacapone is a potent, specific, and reversible COMT inhibitor. The drug has been shown to act peripherally, but not centrally, when given at clinically effective doses.".
10. ↑ "Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action". Handb Exp Pharmacol. Handbook of Experimental Pharmacology 252: 227–260. 2018. doi:10.1007/164_2018_107. ISBN 978-3-030-10560-0. PMID 29532180.
11. ↑ "Dopamine D2-receptor imaging with 123I-iodobenzamide SPECT in migraine patients abusing ergotamine: does ergotamine cross the blood brain barrier?". Cephalalgia 13 (5): 325–329. October 1993. doi:10.1046/j.1468-2982.1993.1305325.x. PMID 8242725.
12. ↑ Ordak, Michal (26 May 2026). "Amanita muscaria in the evolving novel psychoactive substances landscape - toxicological risks and clinical implications: a narrative review". Frontiers in Pharmacology 17. doi:10.3389/fphar.2026.1838212. ISSN 1663-9812.
13. ↑ "Clinical pharmacology review of opicapone for the treatment of Parkinson's disease". Neurodegener Dis Manag 6 (5): 349–62. October 2016. doi:10.2217/nmt-2016-0022. PMID 27599671. "Opicapone (OPC) is a novel, long-acting, peripherally selective, once daily, third-generation catechol-O-methyl transferase inhibitor.".
14. ↑ "Tolcapone: a review of its use in the management of Parkinson's disease". CNS Drugs 19 (2): 165–184. 2005. doi:10.2165/00023210-200519020-00006. PMID 15697329. "The efficacy of tolcapone as an adjunct to levodopa in patients with Parkinson's disease has primarily been attributed to its ability to inhibit peripheral it is thought that tolcapone enters the CNS to a minimal extent only.[16] However, results [17] of a study in patients with Parkinson's disease, as well as results of animal studies,[18-21] suggest that tolcapone also has central activity.".
15. ↑ "A reassessment of the safety profile of monoamine oxidase inhibitors: elucidating tired old tyramine myths". J Neural Transm (Vienna) 125 (11): 1707–1717. November 2018. doi:10.1007/s00702-018-1932-y. PMID 30255284.
16. ↑ "Monoamine transporters and psychostimulant drugs". Eur J Pharmacol 479 (1–3): 23–40. October 2003. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135.
17. ↑ "Identification of Potent, Selective, and Peripherally Restricted Serotonin Receptor 2B Antagonists from a High-Throughput Screen". Assay Drug Dev Technol 21 (3): 89–96. April 2023. doi:10.1089/adt.2022.116. PMID 36930852.

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