Anticholinergic load and the management of overactive bladder

Anticholinergic load and the management of overactive bladder.

PRINTABLE VERSION

Anticholinergic medications for overactive bladder (OAB) block muscarinic receptors not only in the detrusor muscle but also all over the body. Muscarinic receptors are present in the brain and are important for higher cognitive processes. Therefore these medications have a risk of cognitive side effects, relating to learning, memory, somnolence and confusion. The elderly are more susceptible to these adverse events due to increased permeability of the blood brain barrier and polypharmacy.Darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin and tolterodine, are tertiary amines. Their molecular properties allow the drug to pass into the central nervous system. Trospium chloride is a quaternary amine, which theoretically is less likely to cross the blood brain barrier and lead to cognitive side effects.Anticholinergic load is the cumulative effect of taking medication with anticholinergic properties. Drug scales exist to determine the anticholinergic load. They are a list of medication with a score allocated to each drug. The higher the score, the higher the load and potentially greater risk to the patient.1 Subspecialty Fellow in Urogynaecology, King’s College Hospital, London, UK
2 Consultant Urogynaecologist, Norfolk and Norwich University Hospital, Norwich, UK
A recent review article of published anticholinergic scales identified 16 in the literature (1). The Anticholinergic Cognitive Burden scale is the most common and well suited to be used in studies.A systematic review investigating the effects of anticholinergic load found that 23 out of 33 studies reported a significant decline in cognitive function (2). Three out of nine studies showed a significant increased risk of death. A UK case controlled study of 40,770 patients from GP data, of adults aged over 65 years, investigated the association between anticholinergics and dementia (3). Drugs used for OAB significantly increased the risk of dementia. When the drug was used 4-10years, 10-15 years and 15-20 years prior to dementia diagnosis, there were odds ratios of 1.23, 1.22 and 1.27 (p<0.01) respectively. The drugs predominantly used were oxybutynin and tolterodine. Former users of the drugs appear to have similar risks compared to current users. Using oxybutynin for over three years carries the greatest risk of dementia.
When treating patients at risk, management should include lifestyle modification, fluid management, urgency suppression and bladder retraining. When medical treatment is needed, trospium chloride should be considered as its least likely to cross the blood brain barrier. A study found undetectable levels of the drug in the cerebral spinal fluid, despite being present in plasma (4). Trospium chloride did not affect memory testing in that study. Fesoterodine also has a low risk of crossing the blood brain barrier and can
be actively transported out of the central nervous system. A pooled analysis of 10 studies with 4040 patients, found a very low chance of development of central nervous system side effects (5). Alternatively, mirabegron could be used as treatment as it does not add to the anticholinergic load. A phase IV study found that mirabegron improved symptoms of OAB in the elderly, with safety and tolerability consistent with known mirabegron safety profile (6). A sub-analysis found no significant cognitive decline at 12 weeks of treatment and there was no difference in cognition compared with placebo.

References
1. Lozano-Ortega G, Johnston KM, Cheung A, Wagg A, Campbell NL, Dmochowski RR, Ng DB. A review of published anticholinergic scales and measures and their applicability in database analyses. Archives of Gerontology and Geriatrics. 2020 Mar 1;87:103885.
2. Fox C, Smith T, Maidment I, Chan WY, Bua N, Myint PK, Boustani M, Kwok CS, Glover M, Koopmans I, Campbell N. Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality: a systematic review. Age and ageing. 2014 Sep 1;43(5):604-15.
3. Richardson K, Fox C, Maidment I, Steel N, Loke YK, Arthur A, Myint PK, Grossi CM, Mattishent K, Bennett K, Campbell NL. Anticholinergic drugs and risk of dementia: case-control study. bmj. 2018 Apr 25;361:k1315.
4. Staskin D, Kay G, Tannenbaum C, Goldman HB, Bhashi K, Ling J,
Oefelein MG. Trospium chloride has no effect on memory testing and is assay undetectable in the central nervous system of older patients with overactive bladder. International journal of clinical practice. 2010 Aug;64(9):1294-300.
5. Wagg A, Arumi D, Herschorn S, Angulo Cuesta J, Haab F, Ntanios F, Carlsson M, Oelke M. A pooled analysis of the efficacy of fesoterodine for the treatment of overactive bladder, and the relationship between safety, co-morbidity and polypharmacy in patients aged 65 years or older. Age and ageing. 2017 Jul 1;46(4):620-6.
6. Wagg A, Staskin D, Engel E, Herschorn S, Kristy RM, Schermer CR. Efficacy, safety, and tolerability of mirabegron in patients aged≥ 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). European Urology. 2020 Feb 1;77(2):211-20.