This management algorithm has been commissioned and funded by Contura Ltd and developed in partnership with Guidelines. Contura developed the contributor brief and pre-meeting documents, chose and invited the group members, who were paid an honorarium for their participation, and attended the development meeting. Contura carried out full medical approval on all materials to ensure compliance with regulations. The views and opinions of the participants are not necessarily those of Contura, or of Guidelines, its publisher, advisers, or advertisers. 

Anticholinergics and cognitive impairment in the treatment of overactive bladder

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Anticholinergics and OAB algorithm

View Regurin XL (trospium chloride) adverse event reporting and prescribing information

Download a PDF of the algorithm supplement

Group members

  • Professor Linda Cardozo (Chair, Consultant Urogynaecologist)
  • Miss Delia Bishara (Consultant Pharmacist for Mental Health of Older Adults and Dementia)
  • Dr Nikhil Chopra (GP Partner with special interest in Urology)
  • Miss Tamsin Greenwell (Consultant Urological Surgeon with a special interest in Female, Restorative and Functional Urology)
  • Mr Dudley Robinson (Consultant Urogynaecologist)
  • Mr Abdul Sultan (Consultant Obstetrician and Gynaecologist with a special interest in Urogynaecology)

Management algorithm for patients with overactive bladder (OAB) where the risk of cognitive impairment is a concern

Introduction

  • Overactive bladder (OAB) is a common symptom complex affecting both men and women
    • a large population-based survey in five countries reported prevalence of 11.8%4
    • prevalence increases with age,4 and a more recent study found that bothersome OAB affected almost half (46%) of women in the oldest age group (55–64 years)5
  • OAB is defined as: “urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection (UTI) or other obvious pathology”6
  • OAB can be treated with anticholinergics,1 which block the effect of acetylcholine at muscarinic receptors in bladder smooth muscle
    • after lifestyle changes, antimuscarinics are the most common and currently the most widely used treatment for OAB7,8
  • Recently updated guidelines highlight the impact that anticholinergic therapy for OAB may have on cognitive function1,9
  • Conflicting data are present in the literature and it is not clear whether this is a simple association due to the anticholinergics being used in adults with undiagnosed cognitive impairment or prodromal dementia, or if the cognitive impairment or dementia results from the use of these products10–16
  • Some adults will have a high anticholinergic burden due to polypharmacy and may, therefore, experience unintentional anticholinergic adverse effects10,11,14
    • there are many chronic conditions that are often treated with products that have anticholinergic effects, such as psychiatric disorders, depression, insomnia, asthma, and pain10,11
    • over-the-counter preparations may also contribute to the anticholinergic burden17
  • There are also differences in theoretical cognitive risk between the various products with anticholinergic actions available13
    • tools are available to help prescribers understand the differences in putative risk profile for products commonly used for OAB and how to quantify the risk18–20
  • This algorithm aims to complement NICE Guideline 123 (NG123)1 by providing practical guidance on anticholinergics in OAB, particularly if there are concerns about cognitive function.

Anticholinergics and cognitive impairment

  • Products with anticholinergic effects are mainly antimuscarinics that exert their therapeutic effect by binding to the M2 and M3 muscarinic receptors on cells in the bladder to reduce intravesical pressure, increase compliance, raise volume threshold for micturition, and reduce uninhibited contractions8,21
  • Muscarinic receptors are also present on other tissues in the body and this can result in unwanted anticholinergic effects22,23
  • The binding of antimuscarinics to the M1–M5 receptors in the brain can potentially affect cognition
  • To have a detrimental effect on cognition, they must first cross the blood–brain barrier (BBB) and enter the brain by passive diffusion or facilitated transport23
  • The ease and speed of this diffusion may be affected by the characteristics of the antimuscarinic molecule:22
    • molecular size
    • lipophilicity
  • Patient factors are also important in determining the permeability of the BBB
    • age, stress, and trauma are likely to increase permeability22
    • permeability may also be affected by the presence of some comorbidities (for example, Alzheimer’s-type dementia, diabetes, and multiple sclerosis)22
  • Cognitive effects are likely to be reduced if the antimuscarinics can be cleared from the brain quickly22
    • some can only leave the brain by passive diffusion, while others are removed via an active transport mechanism facilitated by permeability-glycoprotein (P-gp), which is present in the cell membrane22,23
  • Antimuscarinics with the following characteristics (see Table 1) are likely to have a reduced effect on cognition:22,23
    • large molecular size
    • hydrophilic
    • can be actively transported across the cell membrane
  • Data on brain to plasma ratios for various antimuscarinics support this assumption, as these are highest for oxybutynin, intermediate for tolterodine and solifenacin, and lowest for darifenacin, fesoterodine, and trospium.22
Table 1: Properties of antimuscarinics that affect ability to cross the blood–brain barrier22–25

Antimuscarinic

Molecular size/ chemical structure (type of amine)

Lipophilicity

P-gp substrate

(passive diffusion across the blood–brain barrier)

(removal from brain by active transport)

5 hydroxymethyl tolterodine

(5-HMT; prodrug for tolterodine)

Tertiary

Low

Yes

Darifenacin

Tertiary

Moderate

Yes

Fesoterodine

Tertiary

Low–moderate

Yes

Oxybutynin

Tertiary

High

No

Solifenacin

Tertiary

Low–moderate

No

Tolterodine

Tertiary

Low–moderate

No

Trospium

Quarternary

Very low/hydrophilic

Yes

Categorising anticholinergic effect on cognition

  • Prior to prescribing antimuscarinics, the anticholinergic burden for the patient should be considered1
  • There are many different tools available to assess this burden, including the anticholinergic cognitive burden scale, anticholinergic risk scale, anticholinergic drug scale, and anticholinergic burden classification18–20
  • There is considerable variation among these tools18,19,26
    • there are differences in the scales used, the tool’s development, and the methods used in evaluating anticholinergic potency
    • factors such as the selectivity of products to specific muscarinic receptor subtypes and the ability of a product to enter the brain have not always been considered
    • many scales are founded on subjective ratings of anticholinergic activity based on the clinical experience and observed cognitive impairment
    • some products are omitted from the tools; it is unclear if this is due to a lack of anticholinergic activity, or if they were not assessed
  • The anticholinergic effect on cognition (AEC) scale, developed by Bishara et al., includes nearly 300 products and is based on robust scientific methodology26,27
    • for each product, a score is provided that considers:
      • the muscarinic binding affinity
      • whether it is selective for the target tissue
      • the extent to which it penetrates the BBB
      • reported cognitive adverse effects
  • This AEC scale can be used in patients presenting with OAB to help quantify the anticholinergic burden and, therefore, cognitive risk26,27
    • the AEC scale is available as a regularly updated web-based app at: www.medichec.com27
  • In older people presenting with symptoms of cognitive impairment, dementia, or delirium, all individual products with an AEC score of 2 or 3 should either be stopped, or the patient switched to an alternative product with a lower AEC score (preferably 0)26
  • If a patient has a total AEC score of 3 or above, a medication review should be performed to see if it is possible to reduce the patient’s anticholinergic burden26
  • Table 2 shows the AEC score27 for the seven antimuscarinic agents reviewed in Evidence Review C of the NICE guideline1
Table 2: Anticholinergic effect on cognition (AEC) scores27 for the seven antimuscarinic agents for the treatment of OAB considered in Evidence Review C of NICE Guideline 1231 and mirabegron

Antimuscarinic

AEC score27

Recommendation27

Darifenacin

0

“Safe to use”

Fesoterodine

0

“Safe to use”

Mirabegron

0

“Safe to use”

Trospium chloride

0

“Safe to use”

Solifenacin

1

“Caution required”

Tolterodine

2

“Review and withdraw or switch”

Oxybutynin

3

“Review and withdraw or switch”

Propiverine

“Limited data – unable to scope”

Management algorithm

  • The algorithm summarises the treatment pathway for patients who present with OAB where concerns exist over the risk of cognitive impairment
  • Primary treatment of OAB, especially in the elderly, should follow a non‑surgical approach and incorporate non‑pharmaceutical measures1,8
  • If anticholinergics are needed, a review of the patient’s medication is warranted prior to prescribing treatment1
    • the review should consider the patient’s comorbidities, the potential effect on cognition, anticholinergic load, and the level of polypharmacy
  • If there are no cognitive concerns, treatment can be prescribed according to cost and patient need1
    • treatment choice (including product formulation and whether topical application is needed) should be individualised according to each patient’s needs
  • Where a cognitive concern exists, anticholinergics of choice are likely to be darifenacin, fesoterodine, or trospium (Table 3), due to their lower risk of an effect on cognition27
  • Solifenacin can be used where cognitive impairment is not a significant concern or where one of the other anticholinergics has not been effective, but an anticholinergic is not contraindicated; the patient should be monitored closely for any change in cognitive function
    • while it is somewhat selective, it can readily penetrate the BBB and, as it is not a substrate for P-gp, it is not cleared rapidly from the brain25
  • If treatment failure is seen, an alternative anticholinergic, a different drug class (for example, mirabegron), or a transdermal patch should be trialled1
    • NICE recommends mirabegron as an option only for people in whom antimuscarinics are contraindicated or clinically ineffective, or have unacceptable side-effects3
  • In cases of refractory OAB, a referral to secondary care should be made.1
Table 3: Once-daily antimuscarinic preparations with AEC score of zero2,27–30

Generic name

Available preparations

Cost per 30 days2

Undesirable effects: very common (≥1/10)

Trospium chloride 60 mg OD28

Regurin XL

£23.05

Dry mouth

Darifenacin hydrobromide
7.5 mg/15 mg OD29

Emselex

£25.48

Constipation, dry mouth

Fesoterodine fumarate 4 mg/8 mg OD30

Toviaz

£25.78

Dry mouth

Refer to the summary of product characteristics for the full list of undesirable effects, indications, precautions for use, drug interactions, etc.28–30

Conflicts of interest

The group members received an honorarium from Contura Ltd to develop this management algorithm. Professor Cardozo has, during the last year, received funding for research, lecturing and/or advice/consultancies from the following organisations: Boston Scientific, Contura Ltd, ConvaTech DEKA, Merck, and Shionogi. Dudley Robinson has received funding for research from Astellas, Allergan, and Ixaltis, and for consultancy/speaker fees from Astellas, Allergan, Ferring, and Ixaltis.

References

  1. NICE. Urinary incontinence and pelvic organ prolapse in women: management. NICE Guideline 123. NICE, 2019 (last updated June 2019). Available at: www.nice.org.uk/ng123
  2. NHS. August 2020 Drug Tariff. www.nhsbsa.nhs.uk/pharmacies-gp-practices-and-appliance-contractors/drug-tariff (Accessed 3 August 2020)
  3. NICE. Mirabegron for treating symptoms of overactive bladder. Technology appraisal guidance 290. NICE, 2013. Available at: www.nice.org.uk/ta290
  4. Irwin DE, Milsom I, Hunskaar S et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. European Urology 2006; 50 (6): 1306–1315.
  5. Robinson D, Åkervall S, Wagg A et al. Prevalence and predictors of overactive bladder in nonpregnant nulliparous women below 65 years of age. International Urogynecology Journal 2018; 29 (4): 531–537.
  6. Haylen BT, de Ridder D, Freeman RM et al. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourology and Urodynamics 2010; 29 (1): 4–20.
  7. Andersson KE, Wein AJ. Pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence. Pharmacological Reviews 2004; 56 (4): 581–631.
  8. Cardozo L. Systematic review of overactive bladder therapy in females.Canadian Urological Association Journal 2011; 5 (5 Suppl2): S139–S142.
  9. European Association of Urology (EAU). EAU Guidelines on Urinary Incontinence in Adults. EAU, 2018. Available at: uroweb.org/guideline/urinary-incontinence.
  10. Green AR, Reifler LM, Boyd CM et al. Medication profiles of patients with cognitive impairment and high anticholinergic burden. Drugs & Aging 2018; 35 (3): 223–232.
  11. Campbell N, Boustani M, Limbil T et al. The cognitive impact of anticholinergics: a clinical review. Clinical Interventions in Aging 2009; 4: 225–233.
  12. Geller EJ, Crane AK, Wells EC et al. Effect of anticholinergic use for the treatment of overactive bladder on cognitive function in post-menopausal women. Clinical Drug Investigation 2012; 32 (10): 697–705.
  13. Richardson K, Fox C, Maidment I et al. Anticholinergic drugs and risk of dementia: case-control study. BMJ 2018; 361: k1315.
  14. Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Internal Medicine 2015; 175 (3): 401–407.
  15. Fox C, Richardson K, Maidment ID et al. Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study. Journal of the American Geriatrics Society 2011; 59 (8): 1477–1483.
  16. Fox C, Smith T, Maidment I et al. Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality: a systematic review. Age and Ageing 2014; 43 (5): 604–615.
  17. Mintzer J, Burns A. Anticholinergic side-effects of drugs in elderly people. Journal of the Royal Society of Medicine 2000; 93 (9): 457–462.
  18. Welsh TJ, van der Wardt V, Ojo G et al. Anticholinergic drug burden tools/scales and adverse outcomes in different clinical settings: a systematic review of reviews. Drugs & Aging 2018; 35 (6): 523–538.
  19. Durán CE, Azermai M, Vander Stichele RH. Systematic review of anticholinergic risk scales in older adults. European Journal of Clinical Pharmacology 2013; 69 (7): 1485–1496.
  20. Regenstrief Institute, Inc. Anticholinergic cognitive burden scale. 2012 update. Available at: http://www.uea.ac.uk/documents/3306616/10940915/Anticholinergics/088bb9e6-3ee2-4b75-b8ce-b2d59dc538c2 (Accessed 3 August 2020)
  21. Abrams P, Andersson KE. Muscarinic receptor antagonists for overactive bladder. BJU International 2007; 100 (5): 987–1006.
  22. Chancellor MB, Staskin DR, Kay GG et al. Blood-brain barrier permeation and efflux exclusion of anticholinergics used in the treatment of overactive bladder. Drugs & Aging 2012; 29 (4): 259–273.
  23. Staskin DR, Zoltan E. Anticholinergics and central nervous system effects: are we confused? Reviews in Urology 2007; 9 (4): 191–196.
  24. Wagg A, Verdejo C, Molander U. Review of cognitive impairment with antimuscarinic agents in elderly patients with overactive bladder. International Journal of Clinicial Prac tice 2010; 64 (9): 1279–1286.
  25. Callegari E, Malhotra B, Bungay PJ et al. A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder. British Journal of Clinical Pharmacology 2011;72 (2): 235–246.
  26. Bishara D, Harwood D, Sauer J, Taylor DM. Anticholinergic effect on cognition (AEC) of drugs commonly used in older people. International Journal of Geriatric Psychiatry 2017; 32 (6): 650–656.
  27. South London and Maudsley NHS Foundation Trust. MediChec: The anticholinergic effect on cognition tool.www.medichec.com (Accessed 3 August 2020)
  28. Mylan Products Ltd. Regurin XL 60 mg Prolonged-release Hard Capsules—summary of product characteristics. November 2018. www.medicines.org.uk/emc/product/6644
  29. Merus Labs Luxco II S.à R.L. Emselex 7.5mg prolonged release tablets and Emselex 15mg prolonged release tablets—summary of product characteristics. February 2019. www.medicines.org.uk/emc/product/5129 and www.medicines.org.uk/emc/product/7019
  30. Pfizer Limited. TOVIAZ 4 mg prolonged-release tablets and TOVIAZ 8 mg prolonged-release tablets—summary of product characteristics. July 2019. www.medicines.org.uk/emc/product/6291 and www.medicines.org.uk/emc/product/7970

This management algorithm has been commissioned and funded by Contura Ltd and developed in partnership with Guidelines. Contura developed the contributor brief and pre-meeting documents, chose and invited the group members, who were paid an honorarium for their participation, and attended the development meeting. Contura carried out full medical approval on all materials to ensure compliance with regulations. The views and opinions of the participants are not necessarily those of Contura, or of Guidelines, its publisher, advisers, or advertisers. No part of this publication may be reproduced in any form without the permission of the publisher.

REG/2020/224

Date of preparation: September 2020