Older adults are vulnerable to adverse drug reactions and drug-drug interactions because they frequently experience multiple systemic diseases, leading to multiple drug use. Hence, polypharmacy is a significant concern in the management of older patients, and several tools have been developed to review medications, such as Beers Criteria (1), STOPP (Screening Tool of Older Persons' Prescriptions) and START (Screening Tool to Alert to Right Treatment) criteria (2). Basically, anticholinergic effect determines the safety of the drugs. Anticholinergics inhibit acetylcholine action, which has a crucial role in the regulation of several central and peripheral nervous system functions. Significant anticholinergic effects include dry mouth, constipation, tachycardia, urinary retention, drowsiness, and confusion (3).

Mainly, immobilization, urinary incontinence, neurologic and psychiatric comorbidities (dementia, depression, Parkinson's disease, epilepsy) were reported as the most significant risk factors for the anticholinergic prescription (4). This group is also at risk of malnutrition. Due to the effects on gastrointestinal motility and secretions, as well as sedative potency, anticholinergics were reported to be related to gait imbalance, dysphagia, delirium (5, 6). A dry mouth may cause difficulty in swallowing, and decreased gastric motility and constipation may contribute to satiety and anorexia. Drowsiness and confusion may cause dehydration, swallowing problems, and aspiration (5), each of which poses a severe risk for malnutrition.

Moreover, older adults are more susceptible to anticholinergic agents because of physiological and pathological changes with aging, including decreased physiological reserve, pharmacodynamic and pharmacokinetic alterations. The anticholinergic burden is termed the cumulative effect of anticholinergic agents and reported as a predictor of cognitive decline, poorer physical performance, falls, and even mortality (7–11). Currently, the optimal scale has not been determined to qualify total anticholinergic drug burden (12). The Drug Burden Index (DBI) is one of the most commonly used validated risk assessment scales to estimate cumulative exposure to anticholinergic medications (13). Additionally, the DBI enables dose-related measurement of each drug and offers an extensive evaluation of several drug classes. Accumulating evidence indicates DBI is a useful indicator of adverse health outcomes and functionality in older adults (14, 15).

Many studies have investigated the relationship between anticholinergic drug burden and cognitive, physical functions. However, the information about the impact of anticholinergics on the nutritional status is limited. We aimed to show the association between DBI score and malnutrition in older adults.

A total of 423 patients were included in the study. Participants' mean age was 79.40 ± 7.50, and 68.6% were female. When the patients were divided into three according to DBI risk score in the baseline, 225 patients had DBI 0 score, 135 had low risk, and 33 had high risk. Age, sex, and educational status were similar between the groups. Patients diagnosed with diabetes mellitus and depression were common in the low and high-risk groups (p < 0.05). Compared with patients with a DBI score 0, those in the risk groups had a higher rate of polypharmacy, falls and malnutrition, and higher Charlson Comorbidity Score, whereas lower baseline albumin, and hemoglobin levels. Moreover, the DBI 0 score group has the best values in regards to CGA parameters. Table 1 summarizes the baseline characteristics of the patients.

According to the MNA-SF scores, normal nutritional status was statistically higher in the patients with DBI 0 score (p < 0.01) compared to both low and high DBI risk groups in the baseline. The total rate of malnutrition and malnutrition risk was similar in the DBI low and high risk groups. Figure 2 shows the nutritional status of the groups in the baseline.

When the relationship between nutritional status and DBI score and number of drugs routinely used was evaluated, it was found that both parameters were associated with increased malnutrition and malnutrition risk. However, the DBI score was found to have a more substantial contribution to the risk. The odds of having malnutrition or risk of malnutrition is 2.21 times greater for every one-unit increase in DBI score. The anticholinergic characteristics of drugs is more substantial impact on the nutritional status instead of total number of drugs used. Table 2 shows the relationship between nutritional status and drug number, and DBI scores.

Accordingly, the follow-up data of 414 patients whose DBI score of 0 from the beginning or DBI score changed was analyzed. According to the change in DBI score, three groups were obtained: no DBI exposure from the beginning, decreased DBI scores, and increased DBI scores. Delta scores did not differ between the three groups (Table 3).

When the change in CGA parameters was analyzed, it was shown that every one-unit increase in the DBI score decreases the positive change in nutrition score by 37%. Similarly, the MMSE score decreases by almost 40%. Moreover, a one-unit increase in DBI score also associated with the decrease in albumin level (Table 4).

The study shows that increased DBI scores are related to geriatric syndromes such as falls, malnutrition, and polypharmacy. Additionally, an increase in the DBI score during the sixth-month follow-up duration is associated with the lower cognitive and nutritional status in cognitively intact older patients. Notably, the DBI score seems more influential on nutritional status than the total drug number.

Parkinson's disease, cognitive impairment, genitourinary conditions, depression, and institutionalization are major predictors of the higher use of anticholinergic drugs. Although older patients are more vulnerable to the side effects of these drugs, anticholinergic drugs are frequently prescribed to older adults. Anticholinergic use prevalence is reported from 22.8 to 55.9% in community-dwelling older adults (12) and more than 79% of inpatients (25). Several tools and guidelines designed to review drugs accept anticholinergic drugs as potentially inappropriate drugs (26). Higher anticholinergic burden is blamed for adverse health outcomes, such as cognitive decline, poorer physical performance, falls, longer length of stay and mortality (11, 12, 27–29). The present study results also support the negative effect of the anticholinergic burden on cognitive functions. The anticholinergic effects on the central nervous system (CNS) areas responsible for movement control, balance, learning, and memory were blamed for the worse outcomes. On the other hand, it is a debate whether increased anticholinergic burden leads to worse outcomes or whether the diseases being treated by the anticholinergic drugs, including neurodegenerative diseases, are responsible for the decline in cognition and physical performance. Therefore, we excluded patients diagnosed with dementia to mitigate the confounding effect of the underlying condition on the course of patients.

Moreover, malnutrition and risk of malnutrition are significant conditions that are reported between 10 and 40% in community dwelling older adults (30). Malnutrition also causes serious health consequences such as falls, osteoporosis, orthostatic hypotension, and mortality (31). Many risk factors, including increased age, dementia, decreased social support, dysphagia, depression, polypharmacy, anorexia were specified to develop inadequate nutrition (32). However, to our knowledge, the relationship between malnutrition and anticholinergic drug burden is not elaborated in literature so far. In this longitudinal study, it was observed that increased anticholinergic load was associated with worsening nutritional status and decreased albumin level which is also an indirect marker for malnutrition (33). The impact of the anticholinergic burden on nutrition may be explained by the gastrointestinal system and cognitive effects of anticholinergic agents (5). One of the well-known peripheral side effects, dry mouth (xerostomia), leads to poor dentition, altered taste, difficulty in deglutition, and digestion (34). Dysphagia makes the development of aspiration more likely and causes serious complications such as aspiration pneumonia. Reduced gastrointestinal motility and secretion contribute to constipation, anorexia, and early satiety. Additionally, central side effects including cognitive impairment, drowsiness, confusion, poor attention, restlessness may lead to swallowing difficulties, dehydration, and aspiration. Sedative effects of the drugs contribute to anorexia (3).

Although the best scale evaluates the cholinergic load is not determined, DBI is a feasible and validated scale (29, 35). Using the DBI offers an assessment of anticholinergic activity with a dose-response model. Thus, the exposure of drugs being administered to a patient could precisely be estimated. Previous studies support that DBI is related to worse cognitive and physical function (6, 36–39). Accordingly, DBI is selected in the present study to evaluate the anticholinergic burden. High and low exposure risk groups were identified to show the impact of cholinergic burden change on nutrition, cognition, and functionality in the longitudinal analysis. Increased DBI scores negatively influence cognitive and nutritional scores.

The study has many strength aspects. First, the anticholinergic burden was evaluated based on medications at the baseline, and changes take into consideration during the 6-month follow-up. Second, all patients were examined in a detailed manner with CGA, including functionality, global cognition, nutritional status, and most of the geriatric syndromes. Third, the study has a large sample size, and a validated scale was used to quantify the anticholinergic burden objectively. Fourth, to the best of our knowledge, the study is the first longitudinal study investigating the relationship between DBI rated anticholinergic burden and nutritional status in older adults. On the contrary, there are limited features of the study. Although patients with major neurocognitive disorders were excluded from the study, we could not adjust all confounding factors such as depression, increasing the risk of exposure to drugs with anticholinergic properties. In addition, the follow-up duration may be shorter to assess long-term effects of anticholinergic drugs. Thus, larger size, long term follow-up studies are needed to clarify the complex relationship between anticholinergic burden and nutritional status in older adults.

The serious adverse effects may be prevented because the anticholinergic activity is a potentially reversible factor. Therefore, reducing exposure to drugs with anticholinergic activity has particular importance in geriatric practice. Withdrawal of unnecessary drugs (to avoid potential drug interactions) or decrease anticholinergic agents are the main strategies that should be implemented in clinical settings to improve nutritional and cognitive outcomes in older adults. Such tiny interventions provide essential contributions in the management of geriatric cases. Further evidence is warranted to explain the mechanisms that effects of anticholinergic medications on nutrition.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

The studies involving human participants were reviewed and approved by Non-interventional Studies Ethics Committee of Dokuz Eylül University. The patients/participants provided their written informed consent to participate in this study.

AI and EA made the study concept and design. NE and FD helped acquisition of data. EA and DK performed analysis, interpretation of data, and draft the manuscript. AI established critical revision of the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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