A role of fesoterodine in treatment of overactive bladder

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access


The muscarinic receptors have been used as target in treatment of overactive bladder (OAB) for a long time. ^ese patients have complaints of urgency, increased urinary frequency and nocturia, sometimes with urinary incontinence (involuntary urine leakage which is associated with abrupt and strong desire to void). Fesoterodine is a prodrug that is structurally and functionally associated with tolterodine and it is the novel drug for OAB treatment. As a result of fesoterodine cleavage by non-specific esterase, the active metabolite 5-hydroxymethyl tolterodine (5-НМТ) is formed. Like other antimuscarinic drugs, fesoterodine allows to improve bladder storage function (reducing the frequency of urination) and urgency. For assessing an improvement of the quality of life after treatment by fesoterodine the KHQ questionnaire was used.

Full Text

Restricted Access

About the authors

Yu. A Kupriyanov

Federal State Budgetary Educational Institution of Higher Education «A.I. Evdokimov Moscow State University of Medicine and Dentistry» of the Ministry of Healthcare of the Russian Federation; hospital n.a. S.I. Spasokukockogo

Email: Dr.kupriyanov@gmail.com
PhD in МєФієзі Sciences, assistent at department of urology; Urologist

G. R Kasyan

Federal State Budgetary Educational Institution of Higher Education «A.I. Evdokimov Moscow State University of Medicine and Dentistry» of the Ministry of Healthcare of the Russian Federation; hospital n.a. S.I. Spasokukockogo

Urologist; PhD in medical Sciences, professor at department of urology

D. Yu Pushkar

Federal State Budgetary Educational Institution of Higher Education «A.I. Evdokimov Moscow State University of Medicine and Dentistry» of the Ministry of Healthcare of the Russian Federation

PhD in medical Scieces, FEBU, professor, Corr. МєшЬєг of the RAS, Urologist General of Russia and Moscow, General scientific secretary Russian Society of Urology, Chairman department


  1. Milsom I., Abrams P., Cardozo L., et al. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int. 2001;87(9):760-766.
  2. Stewart W.F., Van Rooyen J.B., Cundiff G.W., et al. Prevalence and burden of overactive bladder in the United States. World J. Urol. 2003;20(6): 327-336.
  3. Abrams P., Cardozo L., Fall M., et al. Standardisation Sub-committee of the International Continence Society The standardisation of terminology of lower urinary tract function: report from the Standardisation Subcommittee of the International Continence Society. Neurourol Urodyn. 2002;21(2):167-178.
  4. Tubaro A. Defining overactive bladder: epidemiology and burden of disease. Urology. 2004;64(6 Suppl 1):2-6.
  5. Hu T.W., Wagner T.H., Bentkover J.D., et al. Estimated economic costs of overactive bladder in the United States. Urology. 2003;61(6):1123-1128.
  6. Brubaker L. Urgency: the cornerstone symptom of overactive bladder. Urology. 2004;64(6 Suppl 1):12-16.
  7. Abrams P., Andersson K.E. Muscarinic receptor antagonists for overactive bladder. BJU Int. 2007;100(5):987-1006.
  8. Andersson K.E., Yoshida M. Antimuscarinics and the overactive detrusor-which is the main mechanism of action? Eur Urol. 2003;43(1):1-5.
  9. Hegde S.S. Muscarinic receptors in the bladder: from basic research to therapeutics. Br J. Pharmacol. 2006;147(Suppl 2):S80-S87.
  10. Ferguson D.R., Kennedy I., Burton T.J. ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes - a possible sensory mechanism? J. Physiol. 1997;505(2):503-511.
  11. Downie J.W., Dean D.M. The contribution of cholinergic postganglionic neurotransmission to contractions of rabbit detrusor. J. Pharmacol Exp Ther. 1977;203(2):417-425.
  12. Caulfield M.P., Birdsall N.J. International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev. 1998;50(2):279-290.
  13. Eglen R.M., Hegde S., Watson N. Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev. 1996;48(4):531-565.
  14. Nilvebrant L., Andersson K.E., Mattiasson A. Characterization of the muscarinic cholinoceptors in the human detrusor. J. Urol. 1985;134(2): 418-423.
  15. Wang P., Luthin G.R., Ruggieri M.R. Muscarinic acetylcholine receptor subtypes mediating urinary bladder contractility and coupling to GTP binding proteins. J. Pharmacol Exp Ther. 1995;273(2):959-966.
  16. Goepel M., Gronewald A., Krege S., et al. Muscarinic receptor subtypes in porcine detrusor: comparison with humans and regulation by bladder augmentation. Urol Res. 1998;26(2):149-154.
  17. Mansfield K.J., Liu L., Mitchelson F.J., et al. Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radioligand binding and quantitative competitive RT-PCR: changes in ageing. Br J. Pharmacol. 2005;144(8):1089-1099.
  18. Matsui M., Motomura D., Karasawa H., et al. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Nat Acad Sci U. S. A. 2000;97(17):9579-9584.
  19. Chess-Williams R., Chapple C.R., Yamanishi T., et al. The minor population of M3-receptors mediate contraction of human detrusor muscle in vitro. J. Auton Pharmacol. 2001;21(5-6):243-248.
  20. Fetscher C., Fleichman M., Schmidt M., et al. M(3) muscarinic receptors mediate contraction of human urinary bladder. Br J. Pharmacol. 2002;136(5):641-643.
  21. Matsui M., Motomura D., Fujikawa.T., et al. Mice lacking M2 and M3 muscarinic acetylcholine receptors are devoid of cholinergic smooth muscle contractions but still viable. J. Neurosci. 2002;22(24):10627-10632.
  22. Ehlert F.J. Contractile role of M2 and M3 muscarinic receptors in gastrointestinal, airway and urinary bladder smooth muscle. Life Sci. 2003;74(2-3):355-266.
  23. Fredericks C.M., Green R.L., Anderson G.F. Comparative in vitro effects of imipramine, oxybutynin, and flavoxate on rabbit detrusor. Urology. 1978;12(4):487-491.
  24. Paulson D.F. Oxybutynin chloride in control of post-trasurethral vesical pain and spasm. Urology. 1978;11(3):237-238.
  25. Moisey C.U., Stephenson T.P., Brendler C.B. The urodynamic and subjective results of treatment of detrusor instability with oxybutynin chloride. Br J. Urology. 1980;52(6):472-475.
  26. Bary P.R., Moisey C.U., Stephenson T.P., et al. The urodynamic and subjective results of treatment of detrusor instability with oxybutynin chloride. Prog Clin Biol Res. 1981;78:313-319.
  27. Nilvebrant L., Gillberg P.G., Sparf B. Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine. Pharmacol Toxicol. 1997;81(4):169-172.
  28. Van Kerrebroeck P., Kreder K., Jonas U., et al. Tolterodine Study Group Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57(3):414-421.
  29. Sussman D., Garely A. Treatment of overactive bladder with once-daily extended-release tolterodine or oxybutynin: the antimuscarinic clinical effectiveness trial (ACET) Cur Med Res Opin. 2002;18(4):177-184.
  30. Diokno A.C., Appell R.A., Sand P.K., et al. OPERA Study Group Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc. 2003;78(6):687-695.
  31. Kaplan S.A., Roehrborn C.G., Dmochowski R., et al. Tolterodine extended release improves overactive bladder symptoms in men with overactive bladder and nocturia. Urology. 2006;68(2):328-332.
  32. Dmochowski R., Abrams P., Marschall-Kehrel D., et al. Efficacy and tolerability of tolterodine extended release in male and female patients with overactive bladder. Eur Urol. 2007;51(4):1054-1064.
  33. Andersson S.H., Lindgren A., Postlind H. Biotransformation of tolterodine, a new muscarinic receptor antagonist, in mice, rats, and dogs. Drug Met Disp. 1998;26(6):528-535.
  34. Postlind H.D., Lindgren A., Andersson S.H. Tolterodine, a new muscarinic receptor antagonist, is metabolized by cytochromes P450 2D6 and 3A in human liver microsomes. Drug Met Disp. 1998;26(4):289-293.
  35. Palmér L., Andersson L., Andersson T., et al. Determination of tolterodine and the 5-hydroxymethyl metabolite in plasma, serum and urine using gas chromatography-mass spectrometry. J. Pharm Biomed Anal. 1997;16(1):155-165.
  36. Ney P., Pandita R.K., Newgreen D.T., et al. Pharmacological characterization of a novel investigational antimuscarinic drug, fesoterodine, in vitro and in vivo. BJU Int. 2008;101(8):1036-1042.
  37. Khullar V., Rovner E.S., Dmochowski R., et al. Fesoterodine dose response in subjects with overactive bladder syndrome. Urology. 2008;71:839-843.
  38. Michel M.C., Hedge S. Treatment of the overactive bladder syndrome with muscarinic receptor antagonists: a matter of metabolites? Naunyn Schmiedebergs Arch Pharmacol. 2006;374(2):79-85.
  39. Brynne N., Dalén P., Alvân G., et al. Influence of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamic of tolterodine. Clin Pharmacol Ther. 1998;63(5):529-539.
  40. Xie H.G., Kim R.B., Wood A.J., et al. Molecular basis of ethnic differences in drug disposition and response. Ann Rev Pharmacol Toxicol. 2001;41: 851-850.
  41. Simon H.U., Malhotra B. The pharmacokinetic profile of fesoterodine: similarities and differences to tolterodine. Swiss Med Weekly. 2009;139(9-10):146-151.
  42. Malhotra B., Gandelman K., Sachse R., et al. Assessment of the effects of renal impairment on the pharmacokinetic profile of fesoterodine. J. Clin Pharmacol. 2009;49(4):477-482.
  43. Sachse R., Cawello W., Haag C., et al. Pharmacodynamics and pharmacokinetics of ascending multiple doses of the novel bladder-selective antimuscarinic fesoterodine. Eur Urol. 2003;2(1):30.
  44. Cawello W., Auer S., Hammes W., et al. Multiple dose pharmacokinetics of fesoterodine in human subjects. Naunyn-Schmiedeberg’s Arch Pharmacol. 2002;365(Suppl 1):R110.
  45. Malhotra B., Sachse R., Wood N. Evaluation of drug-drug interactions with fesoterodine. Eur J. Clin Pharmacol. 2009;65(6):551-560.
  46. Malhotra B., Guan Z., Wood N., et al. Pharmacokinetic profile of fesoterodine. Int J. Clin Pharmacol Ther. 2008;46(11):556-563.
  47. Chapple C., VKerrebroeck P., Tubaro., et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol. 2007;52(4):1204-1212.
  48. Nitti V.W., Dmochowski R., Sand P.K., et al. Efficacy, safety and tolerability of Fesoterodine for overactive bladder syndromes. J. Urol. 2007;178:2488- 2494.
  49. Sand P.K., Morrow J., Bavendam T., et al. Efficacy and tolerability of fesoterodine in women with overactive bladder.Int Urogynaecol J. 2009;20:827-835.
  50. Larsson G., Hallén B., Nilvebrant L. Tolterodine in the treatment of overactive bladder: analysis of the pooled phase II efficacy and safety data. Urology. 1999;53(5):990-998.
  51. Millard R., Tuttle J., Moore K.H., et al. Clinical efficacy and safety of tolterodine compared to placebo in detrusor overactivity. J. Urol. 1999;161(5):1551-1555.
  52. Van Kerrebroeck P.E., Amarenco G., Thüroff J.W., et al. Dose-ranging study of tolterodine in patients with detrusor hyperreflexia. Neurourol Urodyn. 1998;17(5):499-512.
  53. Hill S., Khullar V., Wyndaele J.J., et al. Darifenacin Study Group Dose response with darifenacin, a novel once-daily M3 selective receptor antagonist for the treatment of overactive bladder: results of a fixed dose study. Int Urogynecol J. Pelvic Floor Dysfunct. 2006;17:239-247.
  54. Cardozo L., Lisec M., Millard R., et al. Randomized, double-blind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J. Urol. 2004;172:1919-1924.
  55. Kelleher C.J., Cardozo L.D., Khullar V., et al. A new questionnaire to assess the quality of life of urinary incontinent women. Br J. Obstet Gynaecol. 1997;104(12):1374-1279.
  56. Chapple C.R., Van Kerrebroeck P., Jünemann K.P., et al. Comparison of fesoterodine and tolterodine in patients with overactive bladder. BJU Int. 2008;102(9):1128-1132.
  57. Kelleher C.J., Tubaro A., Wang J.T., et al. Impact of fesoterodine on quality of life: pooled data from two randomized trials. BJU Int. 2008;102(1):56-61.
  58. Kelleher C.J., Pleil A., Reese P.R., et al. How much is enough and who says so? BJOG. 2004;111(6):605-612.
  59. Morris A.R., Westbrook J., Moore K.H. A longitudinal study over 5 to 10 years of clinical outcomes in women with idiopathic detrusor overactivity. BJOG. 2008;115(2):239-246.
  60. Colli E., Digesu G., Olivieri L. Overactive bladder treatments in early phase clinical trials. Exp Opin Invest Drugs. 2007;16(7):999-1007.
  61. Martos F., Bermudez R., Gomez A., et al. Characterization of muscarinic receptors in human submandibular salivary glands. Eur J. Pharmacol. 1985;116(3):319-321.
  62. Mansfield K.J., Mitchelson F., Moore K.H., et al. Muscarinic receptor subtypes in the human colon: lack of evidence for atypical subtypes. Eur J. Pharmacol. 2004;482(1-3):101-109.
  63. Wyndaele J.J., Goldfischer E.R., Morrow J.D., et al. Effects of flexible-dose fesoterodine on overactive bladder symptoms and treatment satisfaction: an open-label study. Int J. Clin Pract. 2009;63(4):560-567.
  64. Chapple C.R., Fianu-Jonsson A., Indig M., et al. STAR study group Treatment outcomes in the STAR study: a subanalysis of solifenacin 5 mg and tolterodine ER 4 mg. Eur Urol. 2007;52(4):1195-1203.
  65. Zinner N., Tuttle J., Marks L. Efficacy and tolerability of darifenacin, a muscarinic M3 selective receptor antagonist (M3 SRA), compared with oxybutynin in the treatment of patients with overactive bladder. World J. Urol. 2005;23(4):248-252.
  66. Nilvebrant L., Andersson K.E., Gillberg P.G., et al. Tolterodine - a new bladder-selective antimuscarinic agent. Eur J. Pharmacol. 1997;327(2-3):195-207.
  67. Freeman R., Hill S., Millard R., et al. Tolterodine Study Group Reduced perception of urgency in treatment of overactive bladder with extended-release tolterodine. Obstet Gynaecol. 2003;102(3):605-611.
  68. Chapple C.R., Arano P., Bosch J.L., et al. Solifenacin appears effective and well tolerated in patients with symptomatic idiopathic detrusor overactivity in a placebo- and tolterodine-controlled phase 2 dose-finding study. BJU Int. 2004;93(1):71-77.
  69. Millard R.J., Halaska M. Efficacy of solifenacin in patients with severe symptoms of overactive bladder: a pooled analysis. Curr Med Res Opin. 2006;22(1):41-48.
  70. Wagg A., Wyndaele J.J., Sieber P. Efficacy and tolerability of solifenacin in elderly subjects with overactive bladder syndrome: a pooled analysis. Am J. Geriatr Pharmacother. 2006;4(1):14-24.
  71. Zinner N., Gittelman M., Harris R., et al. Trospium Study Group Trospium chloride improves overactive bladder symptoms: a multicenter phase III trial. J. Urol. 2004;171(6 pt 1):2311-2315.
  72. Finney S.M., Andersson K.E., Gillespie J.I., et al. Antimuscarinic drugs in detrusor overactivity and the overactive bladder syndrome: motor or sensory actions? BJU Int. 2006;98(3):503-507.
  73. Hawthorn M.H., Chapple C.R., Cock M., et al. Urothelium-derived inhibitory factor(s) influences on detrusor muscle contractility in vitro. Br J. Pharmacol. 2000;129(3):416-419.
  74. Bschleipfer T., Schukowski K., Weidner W., et al. Expression and distribution of cholinergic receptors in the human urothelium. Life Sci. 2007;80(24-25):2303-2307.
  75. Tyagi S., Tyagi P., Van-le S., et al. Qualitative and quantitative expression profile of muscarinic receptors in human urothelium and detrusor. J. Urol. 2006;176(4 pt 1):1673-1678.
  76. Mukerji G., Yiangou Y., Grogono J., et al. Localization of M2 and M3 muscarinic receptors in human bladder disorders and their clinical correlations. J. Urol. 2006;176(1):367-373.
  77. Grol S., Essers P., van Koeveringe G.A., et al. M(3) muscarinic receptor expression on suburothelial interstitial cells. BJU Int. 2009;104(3):398-405.
  78. Kim Y., Yoshimura N., Masuda H., et al. Antimuscarinic agents exhibit local inhibitory effects on muscarinic receptors in bladder-afferent pathways. Urology. 2005;65(2):238-242.
  79. de Wachter S., Wyndaele J.J. Intravesical oxybutynin: A local anaesthetic effect on bladder C. afferents. J. Urol. 2003;169:1892-1895.
  80. Yokoyama O., Yusup A., Miwa Y., et al. Effects of tolterodine on an overactive bladder depend on suppression of C-fiber bladder afferent activity in rats. J. Urol. 2005;174(5):2032-2036.
  81. Iijima K., de Wachter S., Wyndaele J.J. Effects of the M3 receptor selective muscarinic antagonist darifenacin on bladder afferent activity of the rat pelvic nerve. Eur Urol. 2007;52(3):842-847.
  82. de Laet K., de Wachter S., Wyndaele J.J. Systemic oxybutynin decreases afferent activity of the pelvic nerve of the rat: new insights into the working mechanism of antimuscarinics. Neurourol Urodyn. 2006; 25(2):156-161.
  83. Madersbacher H., Jilg G. Control of detrusor hyperreflexia by the intravesical instillation of oxybutynine hydrochloride. Paraplegia. 1991;29(2):84-90.
  84. Lose G., Nargaard J.P. Intravesical oxybutynin for treating incontinence resulting from an overactive detrusor. BJU Int. 2001;87(9):767-773.
  85. Ikeda K., Kobayashi S., Suzuki M., et al. M(3) receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland. Naunyn-Schmiedeberg’s Arch Pharmacol. 2002;366(2):97-103.
  86. Moriya H., Takagi Y., Nakanishi T., et al. Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular gland. Life Sci. 1999; 64(25):2351-2358.
  87. Watson N., Daniels D.V., Ford A.P., et al. Comparative pharmacology of recombinant human М3 and М5 muscarinic receptors expressed in CHO-K1 cells. Br J. Pharmacol. 1999;127(2):590-596.
  88. McNamara A., Pulido-Rios M.T., Sweazey S., et al. Pharmacological properties of TD-6301, a novel bladder selective muscarinic receptor antagonist. Eur J. Pharmacol. 2009; 605(1-3):145-153.
  89. Ohtake A., Saitoh C., Yuyama H., et al. Pharmacological characterization of a new antimuscarinic agent, solifenacin succinate, in comparison with other antimuscarinic agents. Biol Pharm Bull. 2007;30(1):54- 58.
  90. Nilvebrant L., Sundquist S., Gillberg P.G. Tolterodine is not subtype (m1- m5) selective but exhibits functional bladder selectivity in vivo. Neurourol Urodyn. 1996;15:310-311.
  91. Gillberg P.G., Sundquist S., Nilvebrant L. Comparison of the in vitro and in vivo profiles of tolterodine with those of subtype-selective muscarinic receptor antagonists. Eur J. Pharmacol. 1998; 349(2-3):285-292.
  92. Mansfield K.J., Chandran J., Vaux K.J., et al. Comparison of receptor binding characteristics of commonly used muscarinic antagonists in human bladder detrusor and mucosa. J. Pharmacol Exp ТИєт. 2009;328(3):893-899.
  93. Ito Y., Oyunzul L., Yoshida A., et al. Comparison of muscarinic receptor selectivity of solifenacin and oxybutynin in the bladder and submandibular gland of muscarinic receptor knockout mice. Eur J. Pharmacol. 2009;615(1- 3):201-206.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies