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Blood-Brain Barrier Permeation and Efflux Exclusion of Anticholinergics Used in the Treatment of Overactive Bladder

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Abstract

Overactive bladder (OAB) is a common condition, particularly in the elderly. Anticholinergic agents are the mainstay of pharmacological treatment of OAB; however, many anticholinergics can cross the blood-brain barrier (BBB) and may cause central nervous system (CNS) effects, including cognitive deficits, which can be especially detrimental in older patients. Many anticholinergics have the potential to cause adverse CNS effects due to muscarinic (M1) receptor binding in the brain. Of note, permeability of the BBB increases with age and can also be affected by trauma, stress, and some diseases and medications. Passive crossing of a molecule across the BBB into the brain is dependent upon its physicochemical properties. Molecular characteristics that hinder passive BBB penetration include a large molecular size, positive or negative ionic charge at physiological pH, and a hydrophilic structure. Active transport across the BBB is dependent upon protein-mediated transporter systems, such as that of permeability-glycoprotein (P-gp), which occurs only for P-gp substrates, such as trospium chloride, darifenacin and fesoterodine. Reliance on active transport can be problematic since genetic polymorphisms of P-gp exist, and many commonly used drugs and even some foods are P-gp inhibitors or are substrates themselves and, due to competition, can reduce the amount of the drug that is actively transported out of the CNS. Therefore, for drugs that are preferred not to cross into the CNS, such as potent anticholinergics intended for the bladder, it is optimal to have minimal passive crossing of the BBB, although it may also be beneficial for the drug to be a substrate for an active efflux transport system. Anticholinergics demonstrate different propensities to cross the BBB. Darifenacin, fesoterodine and trospium chloride are substrates for P-gp and, therefore, are actively transported away from the brain. In addition, trospium chloride has not been detected in cerebrospinal fluid assays and does not appear to have significant CNS penetration. This article reviews the properties of anticholinergics that affect BBB penetration and active transport out of the CNS, discusses issues of increased BBB permeability in patients with OAB, and examines the clinical implications of BBB penetration on adverse events associated with anticholinergics.

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Acknowledgements

Mary Hines, Ray Hill and Alan J. Klopp, PhD, of inScience Communications, provided editorial support, which was funded by Allergan, Inc.

Dr Michael B. Chancellor is a consultant and investigator for and has received honoraria from Allergan, Inc., Astellas Pharma US, Inc., Pfizer and Ono Pharmaceuticals and has received grants from Pfizer and Medtronic. Dr David R. Staskin is a consultant for Allergan, Inc., Astellas Pharma US, Inc., GlaxoSmithKline and Pfizer and a speaker for and/or has received honoraria from Allergan, Inc., Astellas Pharma US, Inc., GlaxoSmithKline, Pfizer and Watson Pharmaceuticals. Dr Gary G. Kay is a consultant and speaker for and has received grants and honoraria from Allergan, Inc., Novartis, Pfizer and Watson Pharmaceuticals. Dr Bobby W. Sandage, Jr, was formerly an employee of Covidien Pharmaceuticals and Indevus. Dr Michael G. Oefelein was an employee of Allergan, Inc. at the time this manuscript was written. Dr Jack W. Tsao has no potential conflicts of interest to declare. In the US, Allergan, Inc. manufactures and distributes trospium chloride (Sanctura®), Astellas Pharma US, Inc. manufactures and distributes solifenacin (VESIcare®), Novartis manufactures and distributes darifenacin (Enablex®), Pfizer Inc. distributes fesoterodine (Toviaz®) and tolterodine (Detrol®), and Ortho-McNeil-Janssen Pharmaceuticals Inc. manufactures and distributes oxybutynin chloride (Ditropan®).

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the United States Department of the Navy or the Department of Defense.

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Authors and Affiliations

  1. Oakland University William Beaumont School of Medicine, and Department of Urology, William Beaumont Hospital, Royal Oak, MI, USA

    Michael B. Chancellor

  2. Division of Urology, Caritas St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA, USA

    David R. Staskin

  3. Neurophysiology Division, Department of Neurology, Georgetown University School of Medicine, Washington, DC, USA

    Gary G. Kay

  4. Coronado Biosciences, Inc., Burlington, MA, USA

    Bobby W. Sandage Jr

  5. Allergan, Inc., Irvine, CA, USA

    Michael G. Oefelein

  6. Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Jack W. Tsao

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Correspondence to Michael B. Chancellor.

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Chancellor, M.B., Staskin, D.R., Kay, G.G. et al. Blood-Brain Barrier Permeation and Efflux Exclusion of Anticholinergics Used in the Treatment of Overactive Bladder. Drugs Aging 29, 259–273 (2012). https://doi.org/10.2165/11597530-000000000-00000

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