Blood-brain barrier permeation and efflux exclusion of anticholinergics used in the treatment of overactive bladder.

Michael B. Chancellor, David R. Staskin, Gary G. Kay, Bobby W. Sandage, Michael G. Oefelein, Jack W. Tsao

Research output: Contribution to journalReview article

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 (M(1)) 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.

Original languageEnglish (US)
Pages (from-to)259-273
Number of pages15
JournalDrugs and Aging
Volume29
Issue number4
DOIs
StatePublished - Apr 1 2012
Externally publishedYes

Fingerprint

Overactive Urinary Bladder
Cholinergic Antagonists
Blood-Brain Barrier
Permeability
Central Nervous System
Active Biological Transport
Glycoproteins
Therapeutics
Pharmaceutical Preparations
Brain
Genetic Polymorphisms
Cholinergic Agents
Cerebrospinal Fluid
Urinary Bladder
Pharmacology
Food

All Science Journal Classification (ASJC) codes

  • Pharmacology (medical)
  • Geriatrics and Gerontology

Cite this

Blood-brain barrier permeation and efflux exclusion of anticholinergics used in the treatment of overactive bladder. / Chancellor, Michael B.; Staskin, David R.; Kay, Gary G.; Sandage, Bobby W.; Oefelein, Michael G.; Tsao, Jack W.

In: Drugs and Aging, Vol. 29, No. 4, 01.04.2012, p. 259-273.

Research output: Contribution to journalReview article

Chancellor, Michael B. ; Staskin, David R. ; Kay, Gary G. ; Sandage, Bobby W. ; Oefelein, Michael G. ; Tsao, Jack W. / Blood-brain barrier permeation and efflux exclusion of anticholinergics used in the treatment of overactive bladder. In: Drugs and Aging. 2012 ; Vol. 29, No. 4. pp. 259-273.
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