Anticholinergic scales and their relation to polypharmacy, cognition, and functional losses in aged in BrazilAbstract
Aged have a high consumption of medications with anticholinergic activity (MAA), being more vulnerable to adverse events. Using the anticholinergic risk scales, we investigated the prevalence and burden of MAA in the aged, the agreement between the scales and the implications of using MAA with a burden of 2 and 3 on the scales in relation to polypharmacy, cognition and functionality. Cross-sectional study with aged, of both sexes, aged ≥ 60 years old. The prevalence and burden of MAA were investigated by scales: anticholinergic drug scale (ADS), anticholinergic risk scale (ARS), anticholinergic cognitive burden scale (ACB), Brazilian scale of medications with anticholinergic activity (BSMAA). We analyzed the agreement of the scales with Kappa coefficient and investigated by logistic regression the association of MAA with: gender, age, polypharmacy; cognitive capacity (MMSE) and functional capacity (BOMFAQ questionnaire). Of those interviewed, 1,143 aged used medication and 53.5% used MAA. A good agreement was found between: ADS/ACB (0.642), ADS/SBMAA (0.669), ACB/SBMAA (0.656). In the multivariate analysis: gender and polypharmacy were statistically significant.
Key words:
Aged; Cholinergic antagonists; Polypharmacy; Cognition; Functional status
Resumo
Idosos têm alto consumo de medicamentos com atividade anticolinérgica (MAA), sendo mais vulneráveis a eventos adversos. Investigou-se, pelas escalas de risco anticolinérgico, a prevalência e carga de MAA nos idosos, a concordância entre as escalas e as implicações do uso de MAA com carga 2 e 3 nas escalas em relação à polifarmácia, à cognição e à funcionalidade. Estudo transversal com idosos de ambos os sexos ≥ 60 anos. A prevalência e a carga de MAA foram investigadas pelas escalas: anticholinergic drug scale (ADS), anticholinergic risk scale (ARS), anticholinergic cognitive burden scale (ACB), Brazilian scale of medications with anticholinergic activity (BSMAA). Analisamos a concordância das escalas com coeficiente Kappa e investigamos por regressão logística a associação de MAA com: gênero, idade, polifarmácia; capacidade cognitiva (MEEM) e capacidade funcional (questionário BOMFAQ). Dos entrevistados, 1.143 idosos utilizavam medicamentos e 53,5% faziam uso de MAA. Foi encontrada uma boa concordância entre as ADS/ACB (0,642), ADS/SBMAA (0,669), ACB/SBMAA (0,656). Na análise multivariada: sexo e polifarmácia foram estatisticamente significativos.
Palavras-chave:
Idosos; Antagonistas colinérgicos; Polifarmácia; Cognição; Estado funcional
Resumen
Las personas mayores tienen un alto consumo de medicamentos con actividad anticolinérgica (MAA), siendo más vulnerables a eventos adversos. Utilizando las escalas de riesgo anticolinérgico, investigamos la prevalencia y la carga de MAA en los ancianos, la concordancia entre las escalas y las implicaciones del uso de MAA con una carga de 2 y 3 en las escalas en relación con la polifarmacia, la cognición y la funcionalidad. Estudio transversal con adultos mayores de ambos sexos con edad ≥ 60 años. La prevalencia y la carga de MAA se investigaron utilizando las siguientes escalas: escala de fármacos anticolinérgicos (ADS), escala de riesgo anticolinérgico (ARS), escala de carga cognitiva anticolinérgica (ACB) y la escala brasileña de medicamentos con actividad anticolinérgica (BSMAA). Analizamos la concordancia de las escalas con el coeficiente Kappa e investigamos por regresión logística la asociación de MAA con género, edad, polifarmacia; capacidad cognitiva (MEEM) y capacidad funcional (cuestionario BOMFAQ). De los entrevistados, 1.143 ancianos utilizaban medicación y el 53,5% utilizaba MAA. Se encontró una buena concordancia entre ADS/ACB (0,642), ADS/BSMAA (0,669), ACB/BSMAA (0,656). El sexo y la polifarmacia fueron estadísticamente significativos en el análisis multivariado.
Palabras clave:
Adulto mayor; Antagonistas colinérgicos; Polifarmacia; Cognición; Estado funcional
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 polypharmacy1-3.
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 others4-8.
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 others9,12-14.
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 use12,13,15-17,21-25.
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 medications5,6,10,11,13,15-19,24. 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 - SBMAA20,27,28.
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 199129-31. 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 capacity29-33.
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: ADS21, ARS22, ACB23, and SBMAA25. 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 medications3,5,7,8. 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 disorders32,34, 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 dependency29,35,36.
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 scales21-23, 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 four 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 aged20. 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 participants28.
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 aged15-19. 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 doses14-16,26.
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 scoring17,21-23,25.
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, respectively39, 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, respectively40.
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 (κ = 0.628), study by Naples et al. (2015)41 - ACB and ADS (κ ≤ 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 interchangeable17,21,23,40,41,43.
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 aging15,16,19,24,44,45.
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 impairment10,13,19,24,46.
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 cascade3,5,8,10,13,19,24,46.
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 aged15,16,19,44,45. However, the systematic review by Welsh et al. (2018)47 showed that 16 studies found a significant association between CAC and cognitive impairment, however, eight 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 losses11,16,17,19,24,38.
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 aged11,12.
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.
References
- 1 Ramos LR. Fatores determinantes do envelhecimento saudável em idosos residentes em centro urbano: Projeto Epidoso, São Paulo. Cad Saude Publica 2003; 19(3):793-798.
- 2 Malta DC, Bernal RT, Lima MG, Araujo SS, Silva MM, Freitas MI, Barros MB. Noncommunicable diseases and the use of health services: analysis of the National Health Survey in Brazil. Rev Saude Publica 2017; 51(Supl. 1):4s.
- 3 Mercadante ACC, Conti MSB, Wagner GA, Andreoni S, Ramos LR. Fatores determinantes da polifarmácia entre idosos residentes em um grande centro urbano da região sudeste do Brasil. Rev Valore 2021; 6:167-182.
- 4 Baldoni AO, Chequer FM, Ferraz ER, Oliveira DP, Pereira LRL, Dorta DJ. Elderly and drugs: risks and necessity of rational use. Braz J Pharm Sci 2010; 46(4):617-631.
- 5 Secoli SR. Polifarmácia: interações e reações adversas no uso de medicamentos por idosos. Rev Bras Enferm 2010; 63(1):136-140.
- 6 Jyrkkä J, Enlund H, Lavikainen P, Sulkava R, Hartikainen S. Association of polypharmacy with nutritional status, functional ability, and cognitive capacity over a three-year period in an elderly population. Pharmacoepidemiol Drug Saf 2011; 20(5):514-522.
- 7 Ramos LR, Tavares NU, Bertoldi AD, Farias MR, Oliveira MA, Luiza VL, Dal Pizzol TS, Arrais OS, Mengue SS. Polypharmacy and polymorbidity in older adults in Brazil: a public health challenge. Rev Saude Publica 2016; 50(Supl. 2):9.
- 8 Rochon, PA, Petrovic M, Cherubini A, Onder G, O'Mahony D, Sternberg SA, Stall NM, Gurwitz JH. Polypharmacy, inappropriate prescribing, and deprescribing in older people: through a sex and gender lens. Lancet Healthy Longev 2021; 2(5):e290-e300.
- 9 Gerretsen P, Pollock BG. Drugs with anticholinergic properties: a current perspective on use and safety. Expert Opin Drug Saf 2011; 10(5):751-765.
- 10 Lu WH, Wen YW, Chen LK, Hsiao FY. Effect of polypharmacy, potentially inappropriate medications and anticholinergic burden on clinical outcomes: a retrospective cohort study. CMAJ 2015; 187(4):E130-E137.
- 11 Cardwell K, Hughes CM, Ryan C. The Association Between Anticholinergic Medication Burden and Health Related Outcomes in the 'Oldest Old': A Systematic Review of the Literature. Drugs Aging 2015; 32(10):835-848.
- 12 Conti MSB, Sañudo A, Ramos LR. Prescrição de medicamentos para idosos: indicadores de qualidade, seus instrumentos e medidas como estratégias indispensáveis no sistema de saúde. RSD 2022; 11(2):e55311225942.
- 13 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 Ageing 2014; 43(5):604-615.
- 14 Brunton LL, Chabner BA, Knollmann BC. As bases farmacológicas da terapêutica de Goodman e Gilman. Porto Alegre: AMGH; 2018.
- 15 Ruxton K, Woodman R, Mangoni A. Drugs with anticholinergic effects and cognitive impairment, falls and all-cause mortality in older adults: a systematic review and meta-analysis. Br J Clin Pharmacol 2015; 80(2):209-220.
- 16 Salahudeen MS, Duffull SB, Nishtala PS. Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review. BMC Geriatrics 2015; 15(31):1-14.
- 17 Mayer T, Meid AD, Saum KU, Brenner H, Schottker B, Seidling HM, Haefeli WE. Comparison of Nine Instruments to Calculate Anticholinergic Load in a Large Cohort of Older Outpatients: Association with Cognitive and Functional Decline, Falls, and Use of Laxatives. Am J Geriatr Psychiatry 2017; 25(5):531-540.
- 18 Byrne CJA, Walsh C, Cahir C, Ryan C, Williams DJ, Bennett K. Anticholinergic and sedative drug burden in community-dwelling older people: a national database study. BMJ Open 2018; 8(7):e022500.
- 19 Soysal T, Akin S, Durmus NS, Gökçekuyu BM, Özer FF, Zararsiz GE. Comparison of Anticholinergic Burden Measured with Three Different Anticholinergic Risk Scales and Association with Cognitive and Physical Functions in Older Adults. Arch Gerontol Geriatr 2021; 96:104451.
- 20 Miranda VIA, Silveira MPT, Lutz BH, Pirolli F, Zambiasi L, Bielemann RM, Gonzalez MC, Bertoldi AD. Uso de medicamentos com ação anticolinérgica em idosos e comparação entre escalas de risco: estudo de base populacional. Cien Saude Colet. 2022; 27(3):1087-1095.
- 21 Carnahan RM, Lund BC, Perry PJ, Pollock BG, Culp KR. The Anticholinergic Drug Scale as a Measure of Drug-Related Anticholinergic Burden: Associations with Serum Anticholinergic Activity. J Clin Pharmacol 2006; 46(12):1481-1486.
- 22 Rudolph JL, Salow MJ, Angelini MC, McGlinchey RE. The anticholinergic risk scale and anticholinergic adverse effects in older persons. Arch Intern Med. 2008; 168(5):508-513.
- 23 Boustani M, Campbell N, Munger S, Maidment I, Fox C. Impact of anticholinergics on the aging brain: a review and practical application. Aging Health 2008; 4(3):311-320.
- 24 Hsu WH, Wen YW, Chen LK, Hsiao FY. Comparative Associations Between Measures of Anti-cholinergic Burden and Adverse Clinical Outcomes. Ann Fam Med 2017; 15(6):561-569.
- 25 Nery RT, Reis, AMM. Desenvolvimento de uma escala brasileira de medicamentos com atividade anticolinérgica. Einstein 2019; 17(2):1-8.
- 26 Gerretsen P, Pollock BG. Cognitive risks of anticholinergics in the elderly. Aging Health 2013; 9(2):159-166.
- 27 Gorzoni ML, Fabri RM. Applicability of Anticholinergic Risk Scale in hospitalized elderly persons. Thematic Section - Drug Use and Associated Risks Among the Elderly. Rev Bras Geriatr Gerontol 2017; 20(1):123-128.
- 28 Pinto ECP, Silva AMR, Cabrera MAS, Baldoni A de O, Alfieri DF, Andrade GF, Girotto E. O uso de fármacos anticolinérgicos e fatores associados em adultos de meia-idade e idosos. Cien Saude Colet 2022; 27(6):2279-2290.
- 29 Ramos LR, Goihman S. Geographic stratification by socio-economic status: methodology from a household survey with elderly people in S. Paulo, Brazil. Rev Saude Publica 1989; 23(6):478-492.
- 30 Ramos LR, Toniolo J, Cendoroglo MS, Garcia JT, Najas MS, Perracini M, Paola CR, Santos FC, Bilton T, Ebel SJ, Macedo MB, Almada CM, Nasri F, Miranda RD, Gonçalves M, Santos AL, Fraietta R, Vivacqua I, Alves ML, Tudisco ES. Two-year follow-up study of elderly residents in S. Paulo, Brazil: methodology and preliminary results. Rev Saude Publica. 1998; 32(5):397-407.
- 31 Ramos LR, Andreoni S, Coelho-Filho JM, Lima-Costa MF, Matos DL, Rebouças M, Veras R. Screening for dependence in activities of daily living in the elderly: minimum set of questions. Rev Saude Publica 2013; 47(3):506-513.
- 32 Ramos LR, Simoes EJ, Albert MS. Dependence in activities of daily living and cognitive impairment strongly predicted mortality in older urban residents in Brazil: a 2-year follow-up. J Am Geriatr Soc 2001; 49(9):1168-1175.
- 33 Rebouças M, Coelho-Filho JM, Veras RP, Lima-Costa MF, Ramos LR. Validity 63 of questions about activities of daily living to screen for dependency in older. Rev Saude Publica 2017; 51:84.
- 34 Bertolucci PHF, Brucki SMD, Campacci SR, Juliano Y. O mini-exame do estado mental em uma população geral: impacto da escolaridade. Arq Neuro-Psiquiatr 1994; 52(1):1-7.
- 35 Ramos LR, Perracini M, Rosa TEC, Kalache A. Significance and management of disability among urban elderly residents in Brazil. J Cross Cult Gerontol 1993; 8(4):313-323.
- 36 Rosa TEC, Benicio MHD, Latorre MR, Ramos LR. Determinant factors of functional status among the elderly. Rev Saude Publica 2003; 37(1):40-48.
- 37 Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977; 33(1):159-174.
- 38 Jun K, Ah YM, Hwang S, Chung JE, Lee JY. Prevalence of anticholinergic burden and risk factors amongst the older population: analysis of insurance claims data of Korean patients. Int J Clin Pharm 2020; 42(2):453-461.
- 39 Sumukadas D, McMurdo ME, Mangoni AA, Guthrie B. Temporal trends in anticholinergic medication prescription in older people: repeated cross-sectional analysis of population prescribing data. Age Ageing 2014; 43(4):515-521.
- 40 Pont LG, Nielen JT, McLachlan AJ, Gnjidic D, Chan L, Cumming RG, Taxis K. Measuring anticholinergic drug exposure in older community-dwelling Australian men: a comparison of four different measures. Br J Clin Pharmacol 2015; 80(5):1169-1175.
- 41 Naples JG, Marcum ZA, Perera S, Gray SL, Newman AB, Simonsick EM, Yaffe K, Shorr RI, Hanlon JT. Health, Aging and Body Composition Study: Concordance Between Anticholinergic Burden Scales. J Am Geriatr Soc 2015; 63(10):2120-2124.
- 42 Lertxundi U, Domingo-Echaburu S, Hernandez R, Peral J, Medrano J. Expert-based drug lists to measure anticholinergic burden: similar names, different results. Psychogeriatrics 2013; 13(1):17-24.
- 43 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. Arch Gerontol Geriatr 2020; 87:103885.
- 44 Borja-Oliveira CR. Effect of anticholinergic cognitive burden in the elderly - an integrative review. Estud Interdiscipl Envelhec 2017; 22(2):57-74.
- 45 Grossi CM, Richardson K, Savva GM, Fox C, Arthur A, Loke YK, Steel N, Brayne C, Matthews FE, Robinson L, Myint PK, Maidment ID. Increasing prevalence of anticholinergic medication use in older people in England over 20 years: cognitive function and ageing study I and II. BMC Geriatr 2020; 20(1):267.
- 46 Joung KI, Shin JY, Cho SI. Features of anticholinergic prescriptions and predictors of high use in the elderly: Population-based study. Pharmacoepidemiol Drug Saf 2019; 28(12):1591-1600.
- 47 Welsh TJ, van der Wardt V, Ojo G, Gordon AL, Gladman JRF. Anticholinergic Drug Burden Tools/Scales and adverse outcomes in different clinical settings: a systematic review of reviews. Drugs Aging 2018; 35(6):523-538.
