Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
International Urogynecology Journal
Published in: International Urogynecology Journal 8/2011

01-08-2011 | Review Article

Antimuscarinics for the treatment of overactive bladder: understanding the role of muscarinic subtype selectivity

Authors: Karin Glavind, Michael Chancellor

Published in: International Urogynecology Journal | Issue 8/2011

Login to get access

Abstract

Introduction and hypothesis

Antimuscarinic agents appear to exert their therapeutic activity in overactive bladder (OAB) via blockade of the M3 muscarinic receptor subtype. Antimuscarinics are broadly similar in efficacy, but their safety and tolerability profiles vary, which may reflect differences in muscarinic receptor selectivity profiles.

Methods

This review of available literature aims to determine whether antimuscarinic agents with greater M3 selectivity have clinical advantages over less selective drugs.

Results

Antimuscarinic agents differ widely in their propensity to cause cognitive and cardiovascular (CV) effects, which appear mainly to be related to differences in their relative selectivity for binding to non-M3 receptors, including M1 receptors in the brain and cardiac M2 receptors.

Conclusions

Cognitive and CV effects are especially pertinent for the OAB patient who tends to be older with various comorbidities and is often taking multiple medications. Hence, it is important to consider the risk/benefit balance of antimuscarinic agents when selecting OAB treatment.
Literature
1.
Andersson KE (2002) Potential benefits of muscarinic M3 receptor selectivity. Eur Urol 1:23–28
2.
Caulfield MP, Birdsall NJM (1998) International Union of Pharmacology XVII Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50:279–290PubMed
3.
Abrams P, Andersson KE, Buccafusco JJ et al (2006) Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol 148:565–578PubMedCrossRef
4.
Collison DJ, Coleman RA, James RS, Carey J, Duncan G (2000) Characterization of muscarinic receptors in human lens cells by pharmacologic and molecular techniques. Invest Ophthalmol Vis Sci 41:2633–2641PubMed
5.
Jeon J, Dencker D, Wortwein G et al (2010) A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors. J Neurosci 30:2396–2405PubMedCrossRef
6.
Raffa RB (2009) The M5 muscarinic receptor as possible target for treatment of drug abuse. J Clin Pharm Ther 34:623–629PubMedCrossRef
7.
Ragozzino ME, Mohler EG, Prior M, Palencia CA, Rozman S (2009) Acetylcholine activity in selective striatal regions supports behavioral flexibility. Neurobiol Learn Mem 91:13–22PubMedCrossRef
8.
Tobin G, Ryberg AT, Gentle S, Edwards AV (2006) Distribution and function of muscarinic receptor subtypes in the ovine submandibular gland. J Appl Physiol 100:1215–1223PubMedCrossRef
9.
Chess-Williams R (2002) Muscarinic receptors of the urinary bladder: detrusor, urothelial and prejunctional. Auton Autacoid Pharmacol 22:133–145PubMedCrossRef
10.
Haylen BT, De Ridder D, Freeman RM et al (2010) An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int Urogynecol J Pelvic Floor Dysfunct 21:5–26CrossRef
11.
Fetscher C, Fleichman M, Schmidt M, Krege S, Michel MC (2002) M3 muscarinic receptors mediate contraction of human urinary bladder. Br J Pharmacol 136:641–643PubMedCrossRef
12.
Chapple CR, Khullar V, Gabriel Z, Muston D, Bitoun CE, Weinstein DA (2008) The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol 54:543–562PubMedCrossRef
13.
Novara G, Galfano A, Secco S et al (2008) A systematic review and meta-analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder. Eur Urol 54:740–763PubMedCrossRef
14.
Ikeda K, Kobayashi S, Suzuki M et al (2002) M3 receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland. Naunyn Schmiedebergs Arch Pharmacol 366:97–103PubMedCrossRef
15.
16.
Ohtake A, Saitoh C, Yuyama H et al (2007) Pharmacological characterization of a new antimuscarinic agent, solifenacin succinate, in comparison with other antimuscarinic agents. Biol Pharm Bull 30:54–58PubMedCrossRef
17.
Ney P, Pandita RK, Newgreen DT, Breidenbach A, Stohr T, Andersson KE (2008) Pharmacological characterization of a novel investigational antimuscarinic drug, fesoterodine, in vitro and in vivo. BJU Int 101:1036–1042PubMedCrossRef
18.
Wiedemann A, Schwantes PA (2007) Antimuscarinic drugs for the tretment of overactive bladder: are they really the same?—A comparative review of data pertaining to pharmacological and physiological aspects. Euro J Geriatr 9(Suppl 1):29–42
19.
Irwin DE, Milsom I, Hunskaar S et al (2006) Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC Study. Eur Urol 50:1306–1314PubMedCrossRef
20.
Stewart W, Herzog R, Wein A et al (2001) Prevalence and impact of overactive bladder in the US: results from the NOBLE program. Neurourol Urodyn 20:406–408
21.
Garnett S, Swithinbank L, Ellis-Jones J, Abrams P (2009) The long-term natural history of overactive bladder symptoms due to idiopathic detrusor overactivity in women. BJU Int 104:948–953PubMedCrossRef
22.
Crook TH, Lebowitz BD, Pirozzolo FJ et al (1993) Recalling names after introduction: changes across the adult life span in two cultures. Dev Neuropsychol 9:103–113CrossRef
23.
Shi S, Morike K, Klotz U (2008) The clinical implications of ageing for rational drug therapy. Eur J Clin Pharmacol 64:183–199PubMedCrossRef
24.
Andersson KE, Sarawate C, Kahler KH, Stanley EL, Kulkarni AS (2009) Cardiovascular morbidity, heart rates and use of antimuscarinics in patients with overactive bladder. BJU Int 106:268–274PubMedCrossRef
25.
Kay G, Granville LJ (2005) Antimuscarinic agents: implications and concerns in the management of overactive bladder in the elderly. Clin Ther 27:127–138PubMedCrossRef
26.
Milsom I, Abrams P, Cardozo L, Roberts RG, Thuroff JW, Wein AJ (2001) How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 87:760–766PubMedCrossRef
27.
Meek PD, Evang SD, Tadrous M, Roux-Lirange D, Triller DM, Gumustop B (2011) Overactive bladder drugs and constipation: a meta-analysis of randomized, placebo-controlled trials. Dig Dis Sci 56:7–18PubMedCrossRef
28.
Zinner N, Tuttle J, Marks L (2005) 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 23:248–252PubMedCrossRef
29.
Abrams P, Andersson KE (2007) Muscarinic receptor antagonists for overactive bladder. BJU Int 100:987–1006PubMedCrossRef
30.
Kay GG, Ebinger U (2008) Preserving cognitive function for patients with overactive bladder: evidence for a differential effect with darifenacin. Int J Clin Pract 62:1792–1800PubMedCrossRef
31.
Olshansky B, Spierings E, Brum J, Mongay L, Egermark M, Seifu Y (2009) Validation of the differential cardiovascular effects of the antimuscarinic agents, darifenacin and tolterodine, in a randomized, placebo-controlled, 3-way crossover study. UroToday Int J 2
32.
Olshansky B, Ebinger U, Brum J, Egermark M, Viegas A, Rekeda L (2008) Differential pharmacological effects of antimuscarinic drugs on heart rate: a randomized, placebo-controlled, double-blind, cross-over study with tolterodine and darifenacin in healthy participants > or =50 years old. J Cardiovasc Pharmacol Ther 13:241–251PubMedCrossRef
33.
Schabert VF, Bavendam T, Goldberg EL, Trocio JN, Brubaker L (2009) Challenges for managing overactive bladder and guidance for patient support. Am J Manag Care 15:S118–S122PubMed
34.
Benner JS, Nichol MB, Rovner ES et al (2010) Patient-reported reasons for discontinuing overactive bladder medication. BJU Int 105:1276–1282PubMedCrossRef
35.
DuBeau CE (2007) Treatment of OAB in geriatric patients. Clin Geriatr 15(Suppl 2):4–6
36.
Katz G, Lazcano-Ponce E (2008) Intellectual disability: definition, etiological factors, classification, diagnosis, treatment and prognosis. Salud Pública Méx 50(Suppl 2):s132–s141PubMed
37.
McGrother CW, Donaldson MM, Hayward T, Matthews R, Dallosso HM, Hyde C (2006) Urinary storage symptoms and comorbidities: a prospective population cohort study in middle-aged and older women. Age Ageing 35:16–24PubMedCrossRef
38.
Fowler CJ, Panicker JN, Drake M et al (2009) A UK consensus on the management of the bladder in multiple sclerosis. Postgrad Med J 85:552–559PubMedCrossRef
39.
de Seze M, Ruffion A, Denys P, Joseph PA, Perrouin-Verbe B (2007) The neurogenic bladder in multiple sclerosis: review of the literature and proposal of management guidelines. Mult Scler 13:915–928PubMedCrossRef
40.
Rudolph JL, Salow MJ, Angelini MC, McGlinchey RE (2008) The anticholinergic risk scale and anticholinergic adverse effects in older persons. Arch Intern Med 168:508–513PubMedCrossRef
41.
Kay G (2007) Anticholinergic therapy for OAB: Cognitive implications for an at-risk geriatric population. Clin Geriatr 15(Suppl 2):10–13
42.
Merchant RA, Li B, Yap KB, Ng TP (2009) Use of drugs with anticholinergic effects and cognitive impairment in community-living older persons. Age Ageing 38:105–108PubMedCrossRef
43.
Isik AT, Celik T, Bozoglu E, Doruk H (2009) Trospium and cognition in patients with late onset Alzheimer disease. J Nutr Health Aging 13:672–676PubMedCrossRef
44.
Geyer J, Gavrilova O, Petzinger E (2009) The role of p-glycoprotein in limiting brain penetration of the peripherally acting anticholinergic overactive bladder drug trospium chloride. Drug Metab Dispos 37:1371–1374PubMedCrossRef
45.
Malhotra B, Wood N, Sachse R, Gandelman K (2008) Lipophilicity of 5-hydroxymethyl tolterodine, the active metabolite of fesoterodine. UroToday Int J 1
46.
Malhotra B, Gandelman K, Sachse R, Wood N, Michel MC (2009) The design and development of fesoterodine as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of tolterodine. Curr Med Chem 16:4481–4489PubMedCrossRef
47.
Maniscalco M, Singh-Franco D, Wolowich WR, Torres-Colon R (2006) Solifenacin succinate for the treatment of symptoms of overactive bladder. Clin Ther 28:1247–1272PubMedCrossRef
48.
Michel MC (2008) Fesoterodine: a novel muscarinic receptor antagonist for the treatment of overactive bladder syndrome. Expert Opin Pharmacother 9:1787–1796PubMedCrossRef
49.
Devineni D, Skerjanec A, Woodworth TG (2005) Low central nervous system (CNS) penetration by darifenacin in rats. AAPS J 7:T2277 (abstract)
50.
Påhlman I, d’Argy R, Nilvebrant L (2001) Tissue distribution of tolterodine, a muscarinic receptor antagonist, and transfer into fetus and milk in mice. Arzneimittelforschung 51:125–133PubMed
51.
Yoshida A, Maruyama S, Fukumoto D, Tsukada H, Ito Y, Yamada S (2010) Noninvasive evaluation of brain muscarinic receptor occupancy of oxybutynin, darifenacin and imidafenacin in rats by positron emission tomography. Life Sci 87:175–180PubMedCrossRef
52.
Maruyama S, Tsukada H, Nishiyama S et al (2008) In vivo quantitative autoradiographic analysis of brain muscarinic receptor occupancy by antimuscarinic agents for overactive bladder treatment. J Pharmacol Exp Ther 325:774–781PubMedCrossRef
53.
Yoshida A, Fujino T, Maruyama S, Ito Y, Taki Y, Yamada S (2010) The forefront for novel therapeutic agents based on the pathophysiology of lower urinary tract dysfunction: bladder selectivity based on in vivo drug–receptor binding characteristics of antimuscarinic agents for treatment of overactive bladder. J Pharmacol Sci 112:142–150PubMedCrossRef
54.
Callegari E, Webster R, Fenner K, LaPerle J, Malhotra BK, Bungay P (2010) Focused Conference Group: P08—Developments in the treatment of sexual dysfunction and diseases of the lower urinary tract. Comparison of central nervous system penetration of antimuscarinic drugs for overactive bladder. Basic Clin Pharmacol Toxicol 107(Suppl. 1):162–192
55.
Klausner AP, Steers WD (2007) Antimuscarinics for the treatment of overactive bladder: a review of central nervous system effects. Curr Urol Rep 8:441–447PubMedCrossRef
56.
Anagnostaras SG, Murphy GG, Hamilton SE et al (2003) Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nat Neurosci 6:51–58PubMedCrossRef
57.
Messer WS Jr, Bohnett M, Stibbe J (1990) Evidence for a preferential involvement of M1 muscarinic receptors in representational memory. Neurosci Lett 116:184–189PubMedCrossRef
58.
Kay G, Crook T, Rekeda L et al (2006) Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol 50:317–326PubMedCrossRef
59.
Kay G, Wesnes K (2005) Pharmacodynamic effects of darifenacin, a muscarinic M3 selective receptor antagonist for the treatment of overactive bladder, in healthy volunteers. BJU Int 96:1055–1062PubMedCrossRef
60.
Lipton RB, kolodner K, Wesnes K (2005) Assessment of cognitive function of the elderly population: effects of darifenacin. J Urol 173:493–498PubMedCrossRef
61.
62.
Wesnes KA, Edgar C, Tretter RN, Bolodeoku J (2009) Exploratory pilot study assessing the risk of cognitive impairment or sedation in the elderly following single doses of solifenacin 10 mg. Expert Opin Drug Saf 8:615–626PubMedCrossRef
63.
Staskin D, Kay G, Tannenbaum C et al (2010) Trospium chloride has no effect on memory testing and is assay undetectable in the central nervous system of older patients with overactive bladder. Int J Clin Pract 64:1294–1300PubMedCrossRef
64.
Giramonti KM, Kogan BA, Halpern LF (2008) The effects of anticholinergic drugs on attention span and short-term memory skills in children. Neurourol Urodyn 27:315–318PubMedCrossRef
65.
66.
Diefenbach K, Arold G, Wollny A, Schwantes U, Haselmann J, Roots I (2005) Effects on sleep of anticholinergics used for overactive bladder treatment in healthy volunteers aged >=50 years. BJU Int 95:346–349PubMedCrossRef
67.
Tsao JW, Heilman KM (2003) Transient memory impairment and hallucinations associated with tolterodine use. N Engl J Med 349:2274–2275PubMedCrossRef
68.
Salvatore S, Serati M, Cardozo L, Uccella S, Bolis P (2007) Cognitive dysfunction with tolterodine use. Am J Obstet Gynecol 197:e8PubMedCrossRef
69.
70.
Diefenbach K, Donath F, Maurer A et al (2003) Randomised double-blind study of the effects of oxybutynin tolterodine trospium chloride and placebo on sleep in healthy young volunteers. Clin Drug Investig 23:395–404PubMedCrossRef
71.
Nye AM, Clinard VB, Barnes CL (2010) Medication nonadherence secondary to drug-induced memory loss. Consult Pharm 25:117–121PubMedCrossRef
72.
Gulsun M, Pinar M, Sabanci U (2006) Psychotic disorder induced by oxybutynin: presentation of two cases. Clin Drug Investig 26:603–606PubMedCrossRef
73.
Ohtake A, Sato S, Sasamata M, Miyata K (2010) The forefront for novel therapeutic agents based on the pathophysiology of lower urinary tract dysfunction: ameliorative effect of solifenacin succinate (Vesicare), a bladder-selective antimuscarinic agent, on overactive bladder symptoms, especially urgency episodes. J Pharmacol Sci 112:135–141PubMedCrossRef
74.
Maruyama S, Tsukada H, Yamada S (2007) In vivo analysis of brain muscarinic receptor occupancy after oral oxybutynin in conscious rhesus monkey by using positron emission tomography (PET). Neurourol Urodyn 26:703–704
75.
US Department of Health and Human Services (2007) Summary Health Statistics for US Adults: National Health Interview Survey, 2007. Centers for Disease Control and Prevention and National Center for Health Statistics, 10
76.
Andersson KE, Olshansky B (2007) Treating patients with overactive bladder syndrome with antimuscarinics: heart rate considerations. BJU Int 100:1007–1014PubMed
77.
Jouven X, Empana JP, Escolano S et al (2009) Relation of heart rate at rest and long-term (>20 years) death rate in initially healthy middle-aged men. Am J Cardiol 103:279–283PubMedCrossRef
78.
Fox K, Borer JS, Camm AJ et al (2007) Resting heart rate in cardiovascular disease. J Am Coll Cardiol 50:823–830PubMedCrossRef
79.
Hsia J, Larson JC, Ockene JK et al (2009) Resting heart rate as a low tech predictor of coronary events in women: prospective cohort study. BMJ 338:b219PubMedCrossRef
80.
Tsuji H, Venditti FJ Jr, Manders ES et al (1994) Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation 90:878–883PubMed
81.
Tsuji H, Larson MG, Venditti FJ Jr et al (1996) Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation 94:2850–2855PubMed
82.
Colhoun HM, Francis DP, Rubens MB, Underwood SR, Fuller JH (2001) The association of heart-rate variability with cardiovascular risk factors and coronary artery calcification: a study in type 1 diabetic patients and the general population. Diabetes Care 24:1108–1114PubMedCrossRef
83.
Schiffers M, Sauermann P, Schurch B, Mehnert U (2010) The effect of tolterodine 4 and 8 mg on the heart rate variability in healthy subjects. World J Urol 28:651–656PubMedCrossRef
84.
Chapple C, Van KP, Tubaro A et al (2007) Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol 52:1204–1212PubMedCrossRef
85.
Hozawa A, Ohkubo T, Kikuya M et al (2004) Prognostic value of home heart rate for cardiovascular mortality in the general population: the Ohasama Study. Am J Hypertens 17:1005–1010PubMed
86.
Dwyer P, Kelleher C, Young J et al (2008) Long-term benefits of darifenacin treatment for patient quality of life: results from a 2-year extension study. Neurourol Urodyn 27:540–547PubMedCrossRef
87.
Abrams P, Cardozo L, Fall M et al (2002) The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 21:167–178PubMedCrossRef
Metadata
Title
Antimuscarinics for the treatment of overactive bladder: understanding the role of muscarinic subtype selectivity
Authors
Karin Glavind
Michael Chancellor
Publication date
01-08-2011
Publisher
Springer-Verlag
Published in
International Urogynecology Journal / Issue 8/2011
Print ISSN: 0937-3462
Electronic ISSN: 1433-3023
DOI
https://doi.org/10.1007/s00192-011-1411-6

Other articles of this Issue 8/2011

International Urogynecology Journal 8/2011 Go to the issue

Original Article

The effect of solifenacin on urethral sphincter morphology

Original Article

An anatomic comparison of the original versus a modified inside-out transobturator procedure

Original Article

The relationship between anthropometric measurements and the bony pelvis in African American and European American women

Original Article

“J” cut of sling for postoperative voiding dysfunction following synthetic midurethral slings

Erratum

Erratum to: Differential profile analysis of urinary cytokines in patients with overactive bladder

Case Report

Rectal obstruction after a vaginal posterior compartment polypropylene mesh fixed to the sacrospinous ligaments