Artigos

Introduction
Different transformations in personal, physiological, psychological and social aspects take place in the aging process. However, due to changes in morbidity and mortality profiles, the aged have shown a high prevalence of non-communicable chronic diseases (NCDs), which often leads to high consumption of medication as a way to control these conditions, characterizing the practice of polypharmacy.1-3
In addition to high rates of multimorbidity and polypharmacy, this population also presents a high prevalence of self-medication and non-adherence to medication treatment, resulting in drug interactions and adverse effects such as drowsiness, confusion, falls, renal and hepatic insufficiency, among others.4-8
The use of medication in aged should be carefully monitored since the body’s ability to metabolize and excrete drugs may be reduced in this age group, particularly when they have one or more chronic conditions. However, the use of certain medications in aged deserves special attention, such as those with anticholinergic activity (MAA).9-12 MAA block the action of acetylcholine, an important neurotransmitter in the nervous system that is involved in cognitive and motor functions such as memory, attention, learning, and muscular coordination. Therefore, they can be used to treat various health conditions such as depression, anxiety, insomnia, Parkinson’s disease, urinary incontinence, among others.9, 12-14
Studies have shown that the use of MAA may be associated with a higher number of falls and hospitalizations, delirium, urinary retention, constipation, dry mouth, blurred vision, as well as cognitive and functional impairment in aged; long-term use is associated with an increased risk of dementia and functional disability. The prevalence of MAA use in aged varies widely worldwide, ranging from 14% to 66%.15-20
The adverse events of MAA drugs are not always directly associated with the use of a single medication but may reflect the accumulation of multiple drugs with varying degrees of anticholinergic effects, known as anticholinergic burden. Different scales, such as: Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), Anticholinergic Cognitive Burden Scale (ACB), and the Brazilian Scale of Medications with Anticholinergic Activity (SBMAA), have been proposed to assess this burden in the pharmacotherapy of aged and verify adverse events, as it is considered a simple, quick, and clinically easy method to use.12, 13, 15-17, 21-25
The relationship between anticholinergic burden and cognition and functionality in aged, has been investigated in several studies11, 13, 15, 16, 19, 24, 26, as well as polypharmacy, considered a predictive factor for the use of MAA, as it demonstrates a greater chance of developing anticholinergic adverse events and drug interactions with other medications due to the use of concomitant medications.5,6,10,11,13, 15-19,24 In Brazil, there are few studies on the prevalence of MAA use in aged and the applicability of these scales, however, none of them investigated the relationship with polypharmacy, cognitive and functional impairment, as well as, they did not use the Brazilian scale – SBMAA.20, 27, 28
Therefore, the objective of this article is to investigate, using the ADS, ARS, ACB and BSMAA scales, the prevalence and burden of MAA in aged residents, the agreement between the scales and the implications of use of medications with burden 2 and 3 that appear in all scales in relation to polypharmacy, cognition and functionality.

Methods
For this study, a cross-sectional analysis was conducted with secondary data from the first wave of the Epidoso II project. The Epidoso project is a population cohort study - “Epidemiology of Aging,” which has been investigating the functional capacity of aged 60 years or older, of both sexes, residing in Vila Clementino, a middle-class neighborhood in the district of Vila Mariana, São Paulo/SP, Brazil, since 1991.29-31 In 2006, a new census was conducted in this neighborhood, using a random sample of census sectors, and 4,055 aged were identified via door-to-door survey. Of these, a random sample of 1,500 aged was interviewed at home and subsequently invited to undergo a Comprehensive Geriatric Assessment (CGA) from 2007 to 2008 (first wave) for inclusion in the cohort. Coordinated by a geriatrician, the multidisciplinary team analyzed 1,205 aged. CGA is an extensive individual health assessment of aged that investigates demographic, economic, social, clinical, nutritional, pharmacotherapeutic, psychological, dental, functional, and cognitive data to formulate a therapeutic monitoring plan that directs towards recovery and/or maintenance of functional capacity.29-33
The initial point of the analysis was to verify the aged who used medications based on the following CGA question: “Do you take any medication regularly, prescribed or non-prescribed (self-medication)?” In this question, the aged could self-report, present the boxes of medications or medical prescriptions, and all the medications mentioned were noted. Then, among the aged who were using medications, those using MAA were identified according to at least one of the scales: ADS 21, ARS 22, ACB 23, and SBMAA 25. The anticholinergic burden was then calculated for each aged according to the anticholinergic potential of each medication, in each of the evaluated scales: score “0” refers to “drugs without anticholinergic effects or not listed,” score “1” for “drugs with possible anticholinergic effects based on serum anticholinergic activity or in vitro affinity for muscarinic receptors,” score “2” for “moderate anticholinergic activity,” and “3” for “severe anticholinergic activity.” The total score in each scale is calculated according to the individual sum of the scores of the different drugs used in each aged, in each scale.
Thus, with the results obtained on the anticholinergic burden scales, the agreement between the scales was evaluated according to the risk: no risk (zero burden), low risk (burden1), moderate risk (burden 2 or 3) and high risk (burden >3). Then, we checked the medications that the four scales have in common, and which were classified as burden 2 and 3. An analysis to verify the existence of an association between the use of these medications in common in the four scales with burden 2 and 3 and the variables: Gender, Age, Polypharmacy; Cognitive Capacity; and Functional Capacity was then performed.
In accordance with most studies on the use of MAA in relation to polypharmacy, this study adopted the definition of polypharmacy as the consumption of 5 or more medications.3,5,7,8 Cognitive capacity was measured by the Mini-Mental State Examination (MMSE), in which cognitive deficit is defined as a score of less than 24 – aged with cognitive deficits/some psychosis, delirium and/other cognitive disorders, 32, 34 and Functional Capacity was assessed by the BOMFAQ questionnaire, in which functional deficit is characterized by seven or more limitations in Activities of Daily Living (ADLs) – severe dependency.29, 35, 36

Statistical Analysis
For the prevalence analysis, among the aged who used medication, those who used drugs that were included in at least one of the anticholinergic scales were considered. To evaluate the agreement between the scales, the sample was quantified between aged with total anticholinergic burden ? 3 and those with anticholinergic burden > 3, with anticholinergic burden ? 3 classified as aged without anticholinergic risk, low anticholinergic risk or moderate anticholinergic risk, and anticholinergic burden > 3 classified as aged at high anticholinergic risk. The agreement was initially evaluated among the four scales together, and then all two-by-two combinations among the four included scales were evaluated. The Landis and Koch (1977) 37 scale was used to interpret the Kappa concordance coefficient, which classifies the strength of concordance as follows: ?0.20 (poor), >0.20 and ?0.40 (fair), >0.40 and ?0.60 (moderate), >0.60 and ?0.80 (substantial), and >0.80 and ?1.00 (almost perfect).
Statistical analyses were performed using STATA/SE 17.0 (Stata Corp, College Station, TX). The association between the prevalence of aged using medications with a burden of 2 or 3 in the four scales and the variables of sex, age group, polypharmacy, cognitive capacity, and functional capacity was assessed using Fisher’s exact test. Multivariate analysis – logistic regression was performed with the calculation of the odds ratio (OR) and respective 95% confidence interval (95%CI) to evaluate which variables were independently associated with the prevalence of the use of medications with a burden of 2 or 3 in the evaluated scales. For this study, a significance level of 5% was assumed.

Ethical Considerations
The Informed Consent Form was read and signed by all aged participants who agreed to join the cohort, and in case of difficulty in answering the questions with clarity and understanding, a caregiver provided assistance in answering the questions. The Research Ethics Committee of the Federal University of São Paulo approved the project under number 0175/2020.

Results
A total of 1205 aged participated in the cohort, of which approximately 95% (n=1,143) used medications; of these, 612 aged used MAA scored on at least one of the scales that were considered for the study. Thus, the prevalence of MAA observed in this study was 53.5% (95%CI: 50,6%; 56,5%).
Of the aged who used MAA, 55 (9%) had an anticholinergic burden greater than 3 by the ADS scale; 15 (2.4%) by the ARS; 52 (8.5%) by the ACB; and 95 (15.5%) by the SBMAA (Table 1). The agreement between the four scales evaluated was moderate (kappa=0.469). By restricting the comparison of the anticholinergic burden from four scales (ARS, ACB, ADS, and SBMAA) to two-by-two combinations, there was a good agreement confirmed by the kappa value for the scales – ADS with ACB: 0.642 (95%CI: 0,532 – 0,751); ADS with SBMAA: 0.669 (95%CI: 0.580 – 0.758); and ACB with SBMAA: 0.656 (95%CI: 0.565 – 0.747) (Table 2).
Of the medications that compose the four scales, 117 in ADS; 49 in ARS; 88 in ACB; and 125 in SBMAA, it was observed that 26 of them were classified as MAA. However, 19 of them (73%) were classified as “burden 2 or 3” in the four scales (Table 3). Of the 1,143 aged who used medications, 48 (4.2%) aged used MAA classified as burden 2 or 3 in the four scales (95%CI: 3,1%; 5,5%). We found an association between the use of MAA classified as burden 2 or 3 in the four scales with the variables sex (p <0.001); polypharmacy (p = 0.000); and functional disability (? 7 limitations) (p = 0.011) (Table 4). However, in the multivariate analysis, only sex (p = 0.003) and polypharmacy (p = 0.000) remained independently associated with the prevalence of the use of medications with burden 2 or 3 in the scales (Table 5).

Discussion
So far, this is the first Brazilian study that aimed to compare the use of MAA in four anticholinergic risk scales 21-23, including the Brazilian scale – SBMAA, which was developed by Nery and Reis (2019) 25, but was not evaluated in aged residents. The relationship between MAA using the 4 scales (ADS, ARS, ACB SBMAA) with functional losses assessed by the BOMFAQ questionnaire and cognitive deficits using the MMSE instrument has not been investigated by any Brazilian study.
The study showed a 53.5% prevalence of aged who used MAA, that is, for every ten aged, five use MAA that were included in at least one of the risk scales. The prevalence found was close to that of the Brazilian population-based study in southern Brazil – in which 60.7% of aged used at least one MAA present in one of the three scales: ADS, ARS, and ACB; the sample of this study was composed of 1,304 aged.20 However, the prevalence in our study is considered high when compared to another Brazilian study, in which the prevalence found was 31% in middle age and aged who used at least one MAA according to the ADS scale in a sample of 885 participants.28
The prevalence found in this study is within the range of values found in international studies, which vary from 14% to 60%. These studies also present results on the association of the use and anticholinergic burden with negative outcomes in aged.15-19 The exposure of aged to these medications can compromise several domains, impacting the overall safety and well-being of the aged, as the use of these medications can block muscarinic receptors, decrease cholinergic neurotransmission, cause adverse effects that can be mild or severe, emerging at both toxic and therapeutic doses.14-16, 26
The difference in prevalence values found in various studies can be explained by the different methods used in developing these scales and their evaluation, as there is no consensus among the scales and their scoring.17, 21-23, 25
When evaluating the anticholinergic burden for each aged, the study showed that few individuals had an anticholinergic burden > 3 on the four scales – 55 (9%) on ADS; 15 (2.4%) on ARS; 52 (8.5%) on ACB; and 95 (15.5%) on SBMAA. However, these results, compared to the study by Soysal et al. (2021) 19, were similar in the ADS scale (5.3%), but lower compared to the ACB scale (18.6%); whereas the study by Jun et al. (2020) 38 showed higher results when compared to our study: ADS (24.7%), ACB (22%), ARS (12.2%). We also mention two other studies with similar results: the study conducted in Scotland which showed that 7.3% and 9.9% of aged were exposed to high anticholinergic burden ? 3 as measured by the ARS in 1995 and 2010, respectively 39, and the study from Australia that compared anticholinergic burden showing that 5%, 11%, and 8% of aged were exposed to an anticholinergic burden of ? 3 when measured with ARS, ADS, and ACB, respectively.40
The values found by this study differ from the findings of Brazilian studies, such as the study by Gorzoni and Fabri (2017) 27 that analyzed the anticholinergic burden by the ARS scale in 109 institutionalized aged and found 4.1% of aged with a burden ? 3. The values also differ from the study by Pinto et al. (2022) 28 with a sample of 312 aged living in Brazil aged ? 60 years, which demonstrated that 53 aged (16.9%) had anticholinergic burden ? 3.
When comparing, via two-by-two combinations, the agreement of the four scales (ADS, ACB, ARS, and SBMAA) in a population of aged, we found a good agreement confirmed by the kappa value between the scales – ADS with ACB. 0.642 (0.532 – 0.751); ADS with SBMAA: 0.669 (0.580 – 0.758); and ACB with SBMAA: 0.656 (0.565 – 0.747), similar to the study by Pont et al. (2015) – ACB and ADS (? = 0.628), study by Naples et al. (2015)41 – ACB and ADS (? ? 0.70), and the Brazilian study by Miranda et al. (2022)20, in which they found a good agreement between the ADS and ACB scales (0.63), however, the findings differ from the study by Lertxundi et al. (2013) 42 conducted with hospitalized older psychiatric patients, in which the kappa statistics between each pairing were ACB-ARS: 0.25; ADS-ARS: 0.19 and ADS-ACB: 0.21. This discrepancy can be explained by differences in the population of patients sampled, and drugs not available in the study region.
The good agreement found between the ADS and ACB scales can be explained by the method in which both were developed, as both the ADS and ACB attribute anticholinergic activity based on receptor binding studies and reports of clinically relevant anticholinergic adverse reactions. However, the lack of agreement between the scales may be explained by the inability to update scales to include new anticholinergic medications and by the large differences in the classification of the anticholinergic burden of different drugs, thus demonstrating that the scales are not interchangeable.17, 21, 23, 40, 41, 43
Studies suggest that evaluating the use and burden of MAA medications measured by the scales can be useful in identifying aged at risk of adverse effects, as the results have shown an association with some outcomes such as falls, hospitalizations, mortality, and cognitive and functional impairments. Thus, the evaluation of use and burden by these scales helps not to confuse these events as symptoms of aging.15, 16, 19, 24, 44, 45
Therefore, the results of this study suggest that, in clinical practice, before prescribing or deprescribing a drug to an aged, only one of these three risk scales ADS, ACB, or SBMAA should be used to check the anticholinergic action of the drug. However, the SBMAA scale analyzes a greater number of drugs for the Brazilian context compared to the others, in addition to greater agreement with the results of the other scales. However, so far there are no Brazilian studies that we can use to compare with the results presented by the evaluation and comparison of SBMAA in our study.
Only 26 medications were common in the four scales, and the value was similar to that found in the study by Naples et al. (2015) 41 and Pont et al. (2015) 40 by the ADS, ARS, and ACB scales, respectively 20 and 27 drugs. However, of these 26 common medications in the four scales, 19 of them are classified with a burden of 2 and 3, and although few aged in our study used medication with burden 2 and 3 in the four scales, an association was found between the use of these medications and the variables female sex (p-value 0.001), polypharmacy (p-value 0.000), and functional impairment (? 7 limitations) (p-value 0.011), confirming international studies that describe that use and anticholinergic burden are related to higher chances in aged females who practice polypharmacy and have functional impairment.10, 13, 19, 24, 46
However, when the multivariate analysis was carried out, the variables sex and polypharmacy remained. The significant association of MAA use by women can be attributed to the fact that women have longer life expectancy than men, suffer from chronic conditions more frequently, receive greater medical attention, seek medical care more frequently, and have worse functional status, present more depressive symptoms and receive more assistance from health policies, resulting in more frequent prescriptions. Furthermore, the use of MAA was associated with a higher chance of polypharmacy, since the use of these medications can lead to adverse events, which are then treated with additional medications, often in large numbers and even concurrently, resulting in polypharmacy and an iatrogenic cascade.3, 5, 8, 10, 13, 19, 24, 46
However, we did not find an association between cognitive impairment and the use of these medications, which differs from international studies that show an association between anticholinergic burden and cognitive impairment, being considered a coherent cause of the decline in cognitive functions among the aged 15, 16, 19, 44, 45. However, the systematic review by Welsh et al. (2018)47 showed that 16 studies found a significant association between CAC and cognitive impairment, however, 8 studies did not show any significant relationship. Perhaps we did not find a significant association between the use of MAA and cognitive capacity due to the fact that the Epidoso project is carried out in São Paulo and the majority of aged who participate in this project have a high socioeconomic profile and high level of education - factors considered as protective of cognitive capacity1,19,26,29,30,32.
The functional capacity measured by the BOMFAQ instrument, in the multivariate analysis, did not remain significantly associated with the use of MAA with burden 2 and 3, diverging from international studies that, despite measuring functional capacity using other instruments, demonstrated a relationship between the use of MAA with functional losses. 11,16,17,19,24,38
The list of MAA medications in Table 2 will serve as support in clinical practice for prescribing medications to aged, as our study demonstrated that the use of at least these 19 medications may be associated with polypharmacy and functional impairment. Thus, it is essential to manage pharmacotherapy in aged during prescription and deprescription to establish a balance between therapeutic effects and adverse events, to avoid a high number of hospitalizations, institutionalizations, healthcare costs, and mortality in aged.11, 12
However, among the limitations of the study, we highlight the fact that this is a cross-sectional study, in which associations are subject to reverse causality; therefore, caution is needed when establishing cause-effect relationships since the data on dependent and independent variables were collected at the same time. Moreover, there is a possibility of memory bias in medication use, which may lead to an underestimation or overestimation of the collected data. However, to minimize this bias, interviewers requested the prescription and packaging of medications, and some usage-oriented questions were asked, so that the aged could remember the medications used. We also emphasize that the results cannot be generalized to other aged populations, such as, for example, to institutionalized aged.
The study has strengths such as the sample size with population representativeness and rigor in data collection and analysis. It is also innovative since it is the first Brazilian study that investigates the use of anticholinergics in aged via four risk scales, bringing a focus on the relationship between the use of 19 drugs with anticholinergic activity that appear in the four anticholinergic scales, with functional loss and polypharmacy in aged. In the context of the reality of Brazilian aged, this knowledge can help healthcare professionals identify aged who use MAA via the scales and determine the best therapeutic strategy that will assist in appropriate pharmacotherapy and better quality of life.

Conclusion
Our study showed a high prevalence of MAA use across the four studied risk scales, as well as good agreement between the ADS, ACB, and SBMAA scales, suggesting the use of these risk scales in clinical practice to assess the anticholinergic action of drugs. Our study also showed an association of the use of MAA with a anticholinergic burden of 2 and 3 in all four risk scales with polypharmacy and functional impairment, indicating that the use of these medications should be carefully analyzed at the time of prescription and deprescription. Thus, anticholinergic risk scales are indispensable in the identification, prevention, and reduction of adverse events.
The information generated by this study should assist in the prescription of medications for aged, by reviewing and optimizing pharmacotherapy to be adequate and of quality, in order to ensure the safe and rational use of medications.

Funding support
001 - CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Conflict of Interest
Authors report none.
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