Peripherally selective drug explained

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.^{[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.^{[5] [6] [7] [8]}

Examples

• α-Methylserotonin – a non-selective 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 (β-adrenergic receptor antagonist)
• 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)
• 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
• 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
• 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
• Esmolol – a beta blocker (β-adrenergic receptor antagonist)
• 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)
• 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
• Nadolol – a beta blocker (β-adrenergic receptor antagonist)
• Naloxegol – a μ-opioid receptor antagonist used in the treatment of opioid-induced constipation
• Norepinephrine (noradrenaline) – a non-selective adrenergic 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^[10]
• 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
• Serotonin – a non-selective serotonin receptor agonist
• Sotalol – a beta blocker (β-adrenergic receptor antagonist)
• Terfenadine – a non-sedating antihistamine
• 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^[11]
• Trimetaphan camsilate – a nicotinic acetylcholine receptor antagonist
• Trospium chloride – an anticholinergic (acetylcholine receptor antagonist)
• Tyramine – a norepinephrine–dopamine releasing agent and sympathomimetic agent^{[12] [13]}
• Vinblastine – a Vinca alkaloid and antineoplastic agent
• Xamoterol – a β₁-adrenergic receptor partial agonist

Notes and References

1. Book: Stein. C. Zöllner. C. Sensory Nerves. Opioids and Sensory Nerves. Handbook of Experimental Pharmacology. 2009. 194. 194. 495–518. 19655116. 10.1007/978-3-540-79090-7_14. 978-3-540-79089-1.
2. Schinkel AH . P-Glycoprotein, a gatekeeper in the blood-brain barrier . Adv Drug Deliv Rev . 36 . 2–3 . 179–194 . April 1999 . 10837715 . 10.1016/s0169-409x(98)00085-4 .
3. Dyrna F, Hanske S, Krueger M, Bechmann I . The blood-brain barrier . J Neuroimmune Pharmacol . 8 . 4 . 763–73 . September 2013 . 23740386 . 10.1007/s11481-013-9473-5 . 255272031 .
4. Terasaki T, Ohtsuki S . 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 . 15717058 . 539321 . 10.1602/neurorx.2.1.63 .
5. Schinkel AH, Wagenaar E, Mol CA, van Deemter L . 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 . 8647944 . 507337 . 10.1172/JCI118699 .
6. De Kloet ER . Why Dexamethasone Poorly Penetrates in Brain . Stress . 2 . 1 . 13–20 . October 1997 . 9787252 . 10.3109/10253899709014734 .
7. Book: Urticaria and Angioedema . Church . Martin K. . Antihistamines . 2021 . 153–165 . Springer International Publishing . 10.1007/978-3-030-84574-2_11 . 978-3-030-84573-5 . 239944965 .
8. Hu Y, Sieck DE, Hsu WH . Why are second-generation H1-antihistamines minimally sedating? . Eur J Pharmacol . 765 . 100–6 . October 2015 . 26291661 . 10.1016/j.ejphar.2015.08.016 .
9. Habet S . Clinical Pharmacology of Entacapone (Comtan) From the FDA Reviewer . Int J Neuropsychopharmacol . 25 . 7 . 567–575 . August 2022 . 35302623 . 9352175 . 10.1093/ijnp/pyac021 . 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. Fabbri M, Rosa MM, Ferreira JJ . Clinical pharmacology review of opicapone for the treatment of Parkinson's disease . Neurodegener Dis Manag . 6 . 5 . 349–62 . October 2016 . 27599671 . 10.2217/nmt-2016-0022 . Opicapone (OPC) is a novel, long-acting, peripherally selective, once daily, third-generation catechol-O-methyl transferase inhibitor..
11. Keating GM, Lyseng-Williamson KA . Tolcapone: a review of its use in the management of Parkinson's disease . CNS Drugs . 19 . 2 . 165–184 . 2005 . 15697329 . 10.2165/00023210-200519020-00006 . 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..
12. Gillman PK . 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 . 30255284 . 10.1007/s00702-018-1932-y .
13. Rothman RB, Baumann MH . Monoamine transporters and psychostimulant drugs . Eur J Pharmacol . 479 . 1-3 . 23–40 . October 2003 . 14612135 . 10.1016/j.ejphar.2003.08.054 .