Drugs with anticholinergic properties: a current perspective on use and safety

Introduction: Many commonly used drugs have primary or secondary anticholinergic effects contributing to adverse outcomes ranging from mild-to-severe to potentially lethal. Anticholinergic adverse effects frequently occur with medications prescribed with other intended mechanisms of action, including antihistamines, antidepressants, and antipsychotics. Anticholinergic drugs are also the principal treatments of clinical conditions, such as urinary incontinence, that tend to occur in the elderly. Older patients and those with mental illness are particularly vulnerable to the adverse neuropsychiatric effects of anticholinergics as they may already have cognitive impairment.

Areas covered: Medline and Pubmed literature searches (1966 – the present) were performed using ‘anticholinergic’ and ‘drug safety’. Abstracts were assessed and references scanned for appropriate articles. Here, the authors i) describe the neural pathways of the cholinergic system; ii) outline the main clinical uses and adverse effects of anticholinergic agents with a focus on cognitive impairment; and iii) discuss anticholinergic safety monitoring.

Expert opinion: Prescribers need to be vigilant for adverse anticholinergic effects, particularly in older patients. The symptoms may range from subtle cognitive impairment to delirium and may be due to the cumulative effect of multiple medications of modest antimuscarinic activity. The Anticholinergic Drug Scale and tables listing drugs with known anticholinergic properties may help in guiding clinical decision-making to reduce anticholinergic burden.     

Impact of residential medication management reviews on anticholinergic burden in aged care residents

Objectives:

The primary objective of this study was to investigate the impact of Residential Medication Management Reviews (RMMRs) on anticholinergic burden quantified by seven anticholinergic risk scales.

Design:

Retrospective analysis.

Setting:

Accredited pharmacists conducted RMMRs in aged-care facilities (ACFs) in Sydney, Australia.

Participants:

RMMRs pertained to 814 residents aged 65 years or older.

Measurements:

Anticholinergic burden was quantified using seven scales at baseline, after pharmacists’ recommendations and after the actual GP uptake of pharmacists’ recommendations. Change in the anticholinergic burden was measured using the Wilcoxon sign rank test.

Results:

At baseline, depending on the scale used to estimate the anticholinergic burden, between 36% and 67% of patients were prescribed at least one regular anticholinergic medication (ACM). Anticholinergic burden scores were significantly (p?<?0.001) lower after pharmacists’ recommendations as determined by each of the seven scales. The reduction in anticholinergic burden was also significant (p?<?0.001) after GPs’ acceptance of the pharmacists’ recommendations according to all scales with the exception of one scale which reached borderline significance (p?=?0.052).

Conclusion:

Despite the limitations of the retrospective design and differences in the estimation of anticholinergic burden, this is the first study to demonstrate that RMMRs are effective in reducing ACM prescribing in ACF residents, using a range of measures of anticholinergic burden. Future studies should focus on whether a decrease in anticholinergic burden will translate into improvement in clinical outcomes.     

Anticholinergic burden risk and prevalence of medications carrying anticholinergic properties in elderly cancer patients in Jordan

BackgroundGeriatric cancer patients are susceptible to adverse drug events due to the complexity of their chemotherapy regimens and collateral treatments for their comorbid conditions. Prescribing medications with anticholinergic burden characteristics can complicate their condition, leading to negative impacts on their health outcomes and quality of life, including an increase in adverse drug event frequency, physical and cognitive impairments.ObjectiveThis study aims to examine the prevalence of anticholinergic prescribing and identify the cumulative anticholinergic load risk associated with drugs prescribed to elderly cancer patients. Also, to identify the predictors that might lead to raised anticholinergic burden in these patients.MethodologyThis retrospective cross-sectional study included elderly patients (age ≥ 65) diagnosed with cancer and admitted to the adult oncology unit at King Abdullah University Hospital (KAUH) in Jordan during the period between (January 1st, 2019, and January 1st, 2022). The medication charts of 420 patients were evaluated for study outcomes.ResultsOf the total subjects, females represented 49.3%, and the average age was 72.95 (SD = 7.33). A total of 354 (84.3%) patients were prescribed at least one drug carrying anticholinergic burden properties. Median for anticholinergic medications was 3 (IQR = 4). Our study found that 194 (46.2%) patients were at a high risk of adverse events associated with anticholinergic load (cumulative score ≥ 3). Metoclopramide, furosemide, and tramadol were the most frequently prescribed drugs with anticholinergic properties. Alimentary tract drugs with anticholinergic action were the most commonly encountered items in our study population.ConclusionOur study revealed a significantly high prevalence of anticholinergic prescribing among elderly cancer patients. Nearly half of the patients were at high risk of developing serious effects related to anticholinergic activity from the drugs administered. Polypharmacy was strongly associated with increased anticholinergic burden score. Evidence-based recommendations utilizing prescribing strategies for safer alternatives and deprescribing of inappropriate medications could reduce such inappropriate prescribing.     

Anticholinergic Drug Burden in Older People's Brain – How well is it Measured?

Concurrent use of several drugs with potential anticholinergic properties is highly prevalent in the elderly. Methods to determine the overall anticholinergic drug burden have been developed to estimate the risk of central anticholinergic adverse effects. The objective of this MiniReview was to critically appraise the clinical utility of the methods used to assess the anticholinergic drug burden in older people's brain. We evaluated the in vitro method used to measure the anticholinergic activity in a patient's serum and the four anticholinergic drug scales: Anticholinergic Risk Scale, Anticholinergic Cognitive Burden, Drug Burden Index and Anticholinergic Drug Scale. Medline searches of the literature from January 1988 to January 2013 were performed. Studies that related anticholinergic drug burden to central adverse outcomes in elderly people were included, while case reports and studies of single substances were excluded. Despite the consistently reported association between a high anticholinergic drug burden and negative cognitive and psychomotor outcomes in older patients, there are discrepancies in the literature. Furthermore, no significant cognitive improvements after the anticholinergic drug burden was reduced have been shown in randomized controlled trials. It is reasonable to question whether the estimated anticholinergic drug burden can predict the overall brain effects of multiple anticholinergic agents in older people.     

Measuring anticholinergic drug exposure in older community-dwelling Australian men: a comparison of four different measures

Aims

Anticholinergic drug exposure is associated with adverse outcomes in older people. While a number of tools have been developed to measure anticholinergic drug exposure, there is limited information about the agreement and overlap between the various scales. The aim of this study was to investigate the agreement and overlap between different measures of anticholinergic drug exposure in a cohort of community-dwelling older men.

Methods

A cross-sectional study was used to compare anticholinergic drug exposure calculated using the Anticholinergic Risk Scale (ARS), the Anticholinergic Drug Scale (ADS), the Anticholinergic Cognitive Burden (ACB) and the Drug Burden Index anticholinergic subscale (DBI-ACH) in a cohort of community-dwelling men aged 70 years and older (n = 1696). Statistical agreement, expressed as Cohen''s kappa (κ), between these measurements was calculated.

Results

Differences were found between the tools regarding the classification of anticholinergic drug exposure for individual participants. Thirteen percent of the population used a drug listed as anticholinergic on the ARS, 39% used a drug listed on the ADS and the ACB, and 18% of the population used one or more anticholinergic drugs listed on the DBI-ACH. While agreement was good between the ACB and ADS (κ = 0.628, 95% CI 0.593, 0.664), little agreement was found between remaining tools (κ = 0.091–0.264).

Conclusions

With the exception of the ACB and ADS, there was poor agreement regarding anticholinergic drug exposure among the four tools compared in this study. Great care should be taken when interpreting anticholinergic drug exposure using existing scales due to the wide variability between the different scales.     

Safety and tolerability of antipsychotic polypharmacy

Introduction: Antipsychotic polypharmacy (APP), the concomitant use of ≥ 2 antipsychotics, is common in clinical practice. Prior reviews have focused on the efficacy of APP, but no systematic review exists regarding the safety and tolerability of this practice.

Areas covered: A systematic review of adverse effects associated with APP was conducted to prepare this review; case series with ≥ 2 patients, chart reviews, naturalistic, database, cohort and randomized studies that reported on the association between APP in general or specific APP combinations and global or specific adverse effect were included. Methodological limitations of available studies are discussed and recommendations for clinicians and future research are provided.

Expert opinion: Across mostly small and uncontrolled studies, APP has been associated with increased global side effect burden, rates of Parkinsonian side effects, anticholinergic use, hyperprolactinemia, sexual dysfunction, hypersalivation, sedation/somnolence, cognitive impairment and diabetes. Effects on akathisia and mortality were inconclusive. Although some combinations, particularly aripiprazole augmentation of an agent with greater side effect burden, may reduce weight gain, dyslipidemia, hyperprolactinemia and sexual dysfunction, APP should remain a last-resort treatment option after monotherapy, switching and non-antipsychotic combinations have failed. More data are needed to further inform the individualized risk–benefit evaluation of APP.     

Drugs with anticholinergic properties: a current perspective on use and safety

INTRODUCTION: Many commonly used drugs have primary or secondary anticholinergic effects contributing to adverse outcomes ranging from mild-to-severe to potentially lethal. Anticholinergic adverse effects frequently occur with medications prescribed with other intended mechanisms of action, including antihistamines, antidepressants, and antipsychotics. Anticholinergic drugs are also the principal treatments of clinical conditions, such as urinary incontinence, that tend to occur in the elderly. Older patients and those with mental illness are particularly vulnerable to the adverse neuropsychiatric effects of anticholinergics as they may already have cognitive impairment. AREAS COVERED: Medline and Pubmed literature searches (1966 - the present) were performed using 'anticholinergic' and 'drug safety'. Abstracts were assessed and references scanned for appropriate articles. Here, the authors i) describe the neural pathways of the cholinergic system; ii) outline the main clinical uses and adverse effects of anticholinergic agents with a focus on cognitive impairment; and iii) discuss anticholinergic safety monitoring. EXPERT OPINION: Prescribers need to be vigilant for adverse anticholinergic effects, particularly in older patients. The symptoms may range from subtle cognitive impairment to delirium and may be due to the cumulative effect of multiple medications of modest antimuscarinic activity. The Anticholinergic Drug Scale and tables listing drugs with known anticholinergic properties may help in guiding clinical decision-making to reduce anticholinergic burden.     

Measuring drug burden in older adults with intellectual disabilities: Critical issues for consideration in finding the optimal measure to improve safety of medicines use

ABSTRACT

Older adults with Intellectual Disability have been described as among the most medicated groups in society, with rates of polypharmacy significantly exceeding that of the general population. They are at heightened risk of medication-related harm and have high exposure to high-risk medications, for example, anticholinergic ad sedative medicines. There has been significant controversy internationally relating to the inappropriate use of antipsychotics for challenging behavior, often in the absence of a psychiatric diagnosis. Despite this, the evidence base of the safety of use of medicines in this population is lacking, the provision of healthcare is often suboptimal and this population is often excluded from Randomized Controlled Trials. In this editorial, we describe the unique challenges in ensuring safe and appropriate medicines in this population. We describe tools to date that has been used in this population to measure the burden of medicines that increase the risk of adverse outcomes. We outline current and future developments required to improve the quality and safety of medicines use in this population, for example, longitudinal cohort studies.     

Choosing oral drug therapy for overactive bladder in older people

Introduction: Overactive bladder (OAB) and urgency incontinence are common in older people. Nevertheless, there remains a paucity of prospectively collected data on the efficacy of commonly used drug treatments for the condition. Many trials have included older people, but have seldom reported results stratified by age or reported adverse events of particular relevance to older people in clinical practice. This has partially been rectified with the introduction of more recently introduced antimuscarinic agents, particularly fesoterodine, and the beta-3-agonist, mirabegron.

Areas covered: This article discusses evidence from recent trials relevant to robust and medically complex older people including synthesis of evidence on the association of anticholinergic medications and impaired cognition with relevance to OAB medications

Expert opinion: There are increasing data concerning pharmacological therapy in both robust and medically complex older adults. There is a need to explore the efficacy and tolerability of pharmacological treatment of OAB and UUI (urgency urinary incontinence) in specific subgroups and to produce confirmatory real-world data on efficacy and tolerability. Guidelines which address treatment of older people is currently sparse but, as time progresses and data improve, more specific guidance should become available.     

Oral pharmacotherapy for overactive bladder in older patients: mirabegron as a potential alternative to antimuscarinics

Objective Overactive bladder (OAB) is a particular challenge to treat in older adults with co-morbid conditions taking multiple medications. Antimuscarinics (e.g., solifenacin, fesoterodine) and β₃-adrenergic receptor agonists (mirabegron) are similarly efficacious; however, antimuscarinics may be associated with side effects that result in poor persistence and contribute to anticholinergic burden, particularly in those taking other medications with anticholinergic properties. With a mechanism of action distinct from antimuscarinics, mirabegron has a different tolerability profile and does not contribute to anticholinergic burden. The objective of this review was to compare and contrast the tolerability profiles of antimuscarinics and mirabegron in older patients to inform practice.

Methods Prospective trials or retrospective subgroup analyses of antimuscarinics for the treatment of OAB in older patients were identified through a search of PubMed. Tolerability data and results of subgroup analyses of mirabegron in patients aged ≥65 and ≥75 years from a pooled analysis of three trials each of 12 weeks and a 1 year trial are described.

Results Anticholinergic adverse events (AEs) including dry mouth and constipation were more frequent with antimuscarinics versus mirabegron. In patients aged ≥65 years, dry mouth occurred with a six-fold higher incidence with tolterodine extended-release (ER) 4?mg than with mirabegron 25?mg or 50?mg over 12 weeks, and a three-fold higher incidence with tolterodine ER than mirabegron 50?mg over 1 year. Mirabegron had a low incidence of central nervous system effects. A systematic review of the cardiovascular safety profile of mirabegron has not identified any clinically significant effects on blood pressure or pulse rate at therapeutic doses amongst patients aged ≥65 years.

Conclusions Mirabegron has a more favorable tolerability profile than antimuscarinics amongst older patients and may provide an improved benefit-to-risk ratio and therefore be considered as an alternative to antimuscarinics for older patients.     

Drugs with anticholinergic effects and cognitive impairment,falls and all-cause mortality in older adults: A systematic review and meta-analysis

AimThe aim was to investigate associations between drugs with anticholinergic effects (DACEs) and cognitive impairment, falls and all-cause mortality in older adults.MethodsA literature search using CINAHL, Cochrane Library, Embase and PubMed databases was conducted for randomized controlled trials, prospective and retrospective cohort and case-control studies examining the use of DACEs in subjects ≥65 years with outcomes on falls, cognitive impairment and all-cause mortality. Retrieved articles were published on or before June 2013. Anticholinergic exposure was investigated using drug class, DACE scoring systems (anticholinergic cognitive burden scale, ACB; anticholinergic drug scale, ADS; anticholinergic risk scale, ARS; anticholinergic component of the drug burden index, DBI_AC) or assessment of individual DACEs. Meta-analyses were performed to pool the results from individual studies.ResultsEighteen studies fulfilled the inclusion criteria (total 124 286 participants). Exposure to DACEs as a class was associated with increased odds of cognitive impairment (OR 1.45, 95% CI 1.16, 1.73). Olanzapine and trazodone were associated with increased odds and risk of falls (OR 2.16, 95% CI 1.05, 4.44; RR 1.79, 95% CI 1.60, 1.97, respectively), but amitriptyline, paroxetine and risperidone were not (RR 1.73, 95% CI 0.81, 2.65; RR 1.80, 95% CI 0.81, 2.79; RR 1.39, 95% CI 0.59, 3.26, respectively). A unit increase in the ACB scale was associated with a doubling in odds of all-cause mortality (OR 2.06, 95% CI 1.82, 2.33) but there were no associations with the DBI_AC (OR 0.88, 95% CI 0.55, 1.42) or the ARS (OR 3.56, 95% CI 0.29, 43.27).ConclusionsCertain individual DACEs or increased overall DACE exposure may increase the risks of cognitive impairment, falls and all-cause mortality in older adults.     

Prevalence of anticholinergic burden and risk factors amongst the older population: analysis of insurance claims data of Korean patients

Background Despite growing interest in the negative clinical outcomes of multiple anticholinergic use, limited studies have evaluated anticholinergic burden in the geriatric population nationally. Objective To evaluate the prevalence of high anticholinergic burden using the newly developed Korean Anticholinergic Burden Scale in comparison with previous tools and to identify associated factors. Setting National insurance data from a cross section (20%) of older Koreans (2016). Methods Anticholinergic burden was measured using the Korean scale in comparison to the Anticholinergic Drug Scale, Anticholinergic Cognitive Burden, and Anticholinergic Risk Scale. High anticholinergic burden was defined as a summed score of ≥?3 for concurrent medications or a dose-standardized average daily score of ≥?3, using each anticholinergic scale. Main outcomes measured Prevalence and predictors of high anticholinergic burden. Results Data of 1,292,323 patients were analyzed. According to the Korean scale, the prevalence of high anticholinergic burden was 25.5%. This result was similar to that from the Anticholinergic Drug Scale (24.9%) and Anticholinergic Cognitive Burden (22.2%). Factors associated with an increased likelihood of anticholinergic burden include: age, gender (female), high Charlson comorbidity index score, polypharmacy, medical aid beneficiary, co-morbidities (such as schizophrenia, depression, urinary incontinence, and Parkinson’s disease), frequent healthcare visits, various healthcare facilities utilized, and predominantly visiting hospital-level facilities. According to the Korean Anticholinergic Burden Scale, the major drugs contributing to the anticholinergic burden were ranitidine, chlorpheniramine, tramadol, and dimenhydrinate. Conclusion This study showed that 1 in 4 older Koreans are exposed to high anticholinergic burden. The predictors identified in this research might assist pharmacists in early interventions for their patients.

     

Patients’ lived experiences with antineoplastic medicines for the management of malignant solid tumours: A systematic review

BackgroundAntineoplastic medicines affect the patients' physical and psychosocial well-being posing challenges for patients, caregivers and healthcare professionals. However, little is known about the patients' lived experience with medicines (PLEM) for antineoplastic treatment. It is the lived experience that gives meaning to each individual's perception of a particular phenomenon which is influenced by internal and external factors relevant to the individual.ObjectivesTo critically appraise, synthesise and present the available evidence of patients’ lived experience with antineoplastic medicines prescribed for the management of malignant solid tumours.MethodA systematic literature search was conducted in six electronic databases for articles published in English with no date restrictions. The search terms were related to beliefs, practice and burden in relation to patient, antineoplastic medicines, tumours and lived experience. Study selection, quality assessment and data extraction were performed independently by 2 reviewers. Research findings were analysed using narrative and meta-synthesis approaches.ResultsThe search retrieved 31,004 articles with only 10 studies satisfying the inclusion and exclusion criteria. These studies were published between 2005 and 2016 in Europe (n = 6), America (n = 3) and Asia (n = 1). Nine themes were identified to contribute to the patients’ lived experience with antineoplastic medicines. These were (a) influence from family members, healthcare professionals, media and culture, (b) general attitude towards medicine, (c) accepting medicine, (d) modifying or altering medicine regimen or dose, (e) medicine characteristics, (f) medicine routine, (g) medicine adverse events, (h) medicine and social burden and (i) healthcare associated medicine burden. Patients tend to undergo a continuous process of reinterpretations of their experience with medicines throughout their treatment journey.ConclusionThe use of antineoplastic medicines has a profound effect on the patients’ lives. Further longitudinal in-depth studies are required to provide deeper insight into PLEM and support patients in their treatment journey.     

Herbal Medicines Induced Anticholinergic Poisoning in Hong Kong

In the present review, the main objective was to report the incidence and causes of herbal medicines induced anticholinergic poisoning in Hong Kong during 1989–2012 and to emphasize the importance of pharmacovigilance, investigations and preventive measures. Relevant papers, official figures and unpublished data were obtained from Medline search, the Department of Health and the Drug and Poisons Information Bureau. In the New Territories East (where ~20% of the Hong Kong population lived), the incidence of herbal medicines induced anticholinergic poisoning during 1989–1993 was 0.09 per 100,000 population. There were no confirmed cases during 1994–1996. In the whole of Hong Kong, the incidence during 2000–June 2005 was 0.03 per 100,000 population. Contamination of Rhizoma Atractylodis (50%) and erroneous substitution (42%) were the main causes. The incidence during 2008–2012 was 0.06 per 100,000 population. Contamination of non-toxic herbs (50%) and erroneous substitution (41%) were the main causes. In Hong Kong, contamination of non-toxic herbs by tropane alkaloids and substitution of Flos Campsis by toxic Flos Daturae Metelis were the predominant causes of herbal medicines induced anticholinergic poisoning. Systematic studies along the supply chain are necessary to identify the likely sources of contamination. If erroneous substitution of Flos Campsis by Flos Daturae Metelis could be prevented, 40% of herbal medicines induced anticholinergic poisoning would not have occurred. Regular inspection of the retailer, continuing education for the staff in the herbal trade and repeated publicity measures will also be required. Pharmacovigilance of herbal medicines should help determine the incidence and causes of adverse reactions and monitor the effectiveness of preventive measures.     

Higher anticholinergic drug scale (ADS) scores are associated with peripheral but not cognitive markers of cholinergic blockade. Cross sectional data from 21 Norwegian nursing homes

AimThis study evaluated a presumed gradual decline in cognitive function in nursing home residents when the anticholinergic drug scale (ADS) score increased above 3.MethodThe study population was recruited from 21 nursing homes in Norway. Criteria for inclusion were ADS score ≥ 3 and no severe dementia, defined as Clinical Dementia Rating (CDR) score < 3. Primary cognitive end points were CERAD 10‐word lists for recall and Mini Mental State Examination (MMSE). Secondary end points were activity of daily living (ADL), mouth dryness and serum anticholinergic activity (SAA). The patients were stratified into subgroups according to ADS score, i.e. a reference group with score 3 and test groups with scores 4, 5 or ≥6. End points were compared by analyses of covariance (ancova).ResultsOverall, 230 of the 1101 screened nursing home residents (21%) had an ADS score ≥3. After exclusion 101 residents were recruited and among these, 87 managed to participate in the study. No significant differences were detected in cognitive function or ADL when ADS increased above 3 (P > 0.10), but in vivo (mouth dryness) and in vitro (SAA) measures of peripheral anticholinergic activity were significantly higher in patients with an ADS score ≥6 (P < 0.01).ConclusionThe present study does not support a progressive decline in cognitive function with ADS score above 3. This might indicate that the ADS score model has limited potential to predict the clinical risk of central anticholinergic side effects in frail elderly patients receiving multiple anticholinergic drugs.     

Adverse neuropsychiatric effects of antimalarial drugs

ABSTRACT

Introduction: Antimalarial drugs are the primary weapon to treat parasite infection, save lives, and curtail further transmission. Accumulating data have indicated that at least some antimalarial drugs may contribute to severe neurological and/or psychiatric side effects which further complicates their use and limits the pool of available medications.

Areas covered: In this review article, we summarize published scientific studies in search of evidence of the neuropsychiatric effects that may be attributed to the commonly used antimalarial drugs administered alone or in combination. Each individual drug was used as a search term in addition to keywords such as neuropsychiatric, adverse events, and neurotoxicity.

Expert opinion: Accumulating data based on published reports over several decades have suggested that among the major commonly used antimalarial drugs, only mefloquine exhibited clear indications of serious neurological and/or psychiatric side effects. A more systematic approach to assess the neuropsychiatric adverse effects of new or repurposed antimalarial drugs on their safety, tolerability and efficacy phases of clinical studies and in post-marketing surveillance, is needed to ensure that these life-saving tools remain available and can be prescribed with appropriate caution and medical judgment.