Overactive bladder (OAB) is a clinical diagnosis characterized by urgency, with or without urgency incontinence, usually with frequency and nocturia. In contrast, detrusor overactivity (DO) is a urodynamic diagnosis defined by involuntary detrusor contraction during filling cystometrogram.
There is substantial overlap between OAB and DO, and DO is generally regarded as the major underlying pathophysiology of OAB. The overall prevalence of OAB in the general population may be as high as 12% to 17%, and it significantly impacts the daily activities and quality of life of affected individuals.
In patients desiring treatment for symptoms of overactive bladder/detrusor overactivity (OAB/DO), behavioral therapies should be instituted first. If behavioral therapies do not control symptoms, then the American Urological Association and the Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction Guideline on OAB recommends antimuscarinic or beta-3 agonists as pharmacologic treatment.
Trials of different medications in these classes in varying doses are acceptable, and extended release formulations are preferred because of lower rates of dry mouth. The guideline does note that clinicians should use caution in prescribing antimuscarinic or beta-3 agonists for OAB in frail patients or those with cognitive deficits.
Antimuscarinic medications are a type of anticholinergic medication that block the activity of acetylcholine at muscarinic receptors. Muscarinic receptors are distributed throughout the body and give rise to the potential for a broad range of anticholinergic adverse effects such as dry mouth, blurred vision, constipation, and impaired cognition.
Oxybutynin and tolterodine, the most studied medications, were compared in a Cochrane review.
Although these medications did not statistically differ in quality of life and subjective or objective outcomes, there were significantly fewer study withdrawals due to adverse events and less risk of dry mouth with tolterodine. In older patients, mirabegron, a beta-3 agonist, has been shown to have a more favorable tolerability profile in comparison with antimuscarinics.
Over time, the properties of anticholinergic medications have been modified in an attempt to mitigate undesirable cognitive adverse effects by improving muscarinic receptor selectivity and decreasing its ability to cross the blood-brain barrier. In a nonclinical study, 5-hydroxymethyl tolterodine, darifenacin, and trospium displayed low brain penetration, whereas oxybutynin, solifenacin, and tolterodine showed significant brain penetration.
Several publications have raised concerns about anticholinergic medications in general and the associated risk of cognitive impairment, dementia, and Alzheimer disease.
A population-based prospective cohort study of 3434 participants sampled from an integrated health care delivery system was performed to examine the association between cumulative anticholinergic use and the risk for dementia.
Bladder antimuscarinics accounted for 10.5% of anticholinergic medication use. In comparison, antidepressant medications comprised 63.1%, and antihistamines comprised 17.2%. Participants in the highest exposure category (corresponding to oxybutynin chloride 5 mg taken daily for more than 3 years) had a statistically significant increased risk for dementia (adjusted hazard ratio [HR], 1.54; 95% confidence interval, 1.21–1.96) or Alzheimer disease (adjusted HR, 1.63; 95% confidence interval, 1.24–2.14) compared with those with no use. Although these results support an association between anticholinergic medication use and dementia and Alzheimer disease, causation cannot be concluded from this study. A notable strength of the study was that the authors took measures to correct for bias due to the use of other anticholinergic medications to treat the prodromal symptoms of dementia (eg, antidepressant medications used to treat depression-like symptoms secondary to undiagnosed early dementia).
A second recent study examined a cohort of participants from 2 longitudinal studies to investigate the association between anticholinergic medication use and neuroimaging biomarkers of brain metabolism and atrophy, giving a biologic basis to the findings in previous studies.
Significant differences were noted in measures of cognitive performance when comparing anticholinergic users and nonusers. In addition, anticholinergic users showed significantly reduced brain glucose metabolism and significant evidence of temporal lobe and whole-brain atrophy when compared with nonusers. Anticholinergic medication use was also associated with progression to mild cognitive impairment and/or Alzheimer disease (
= 0.01; HR, 2.47). This risk was greatest in patients taking drugs with the most anticholinergic activity.
When considering these studies, several limitations are important to mention. First, there is no single criterion standard method used to estimate anticholinergic burden and the total load of anticholinergic medications from all sources including antidepressants, antihistamines, bladder antimuscarinics, and other medications, and therefore, overall anticholinergic exposure and results cannot be easily compared. Multiple risk scales are available for estimating anticholinergic burden of medications.
In addition, the methods of collecting medication use, although more reliable with the use of electronic pharmacy dispensing data, may not accurately reflect actual use. Furthermore, there may be unobserved confounding or bias inherent to these observational-type studies. Despite these limitations, the literature presents considerable data for the association between anticholinergic medication use and cognitive impairment, dementia, and Alzheimer disease.
Female Pelvic Medicine & Reconstructive Surgery.