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

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1 Basic & Clinical Pharmacology & Toxicology, 2014, 114, Doi: /bcpt MiniReview Anticholinergic Drug Burden in Older People s Brain How well is it Measured? Hege Kersten 1 and Torgeir Bruun Wyller 2,3 1 Old Age Psychiatry Research Network, Telemark Hospital Trust and Vestfold Hospital Trust, Skien, Norway, 2 Institute of Clinical Medicine, University of Oslo, Oslo, Norway and 3 Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway (Received 20 June 2013; Accepted 4 September 2013) Abstract: 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. Anticholinergic drugs entail a high risk of central adverse effects and are denoted as inappropriate in the explicit criteria lists developed to identify high-risk medications for elderly patients [1,2]. Anticholinergic drugs are prescribed for several medical conditions that are common in the older age. Moreover, many drugs not usually denoted as anticholinergic have shown anticholinergic activity towards rat brain receptors and have potential anticholinergic properties in the human brain [3]. Epidemiological studies have reported that approximately 50% of the elderly population uses at least one medication with possible anticholinergic properties [4]. This has given rise to the development of methods for estimating the overall anticholinergic drug burden of a subject. The term drug burden might evoke linguistic pedantry because physicians prescribe medications based on their anticipated benefits rather than on their burden, but because many elderly people use several anticholinergic drugs concurrently [5], cumulative anticholinergic drug exposure could be considered a burden. One in vitro method and several anticholinergic scales have been published that attempt to assess the drug-induced anticholinergic burden and predict the risk of central anticholinergic adverse effects. However, none of these methods have been standardized and there is no consensus on how to define drug exposure [6 9]. Most of the anticholinergic scales rank the anticholinergic Author for correspondence: Hege Kersten, Telemark Hospital Trust, Department of geriatric psychiatry, Ulefossveien, 3711 Skien, Norway (fax: , hege.kersten@sthf.no). activity (AA) of drugs into four levels, ranging from no anticholinergic activity (=0) to definite anticholinergic activity (=3) [6,7,9]. Estimation of the anticholinergic drug burden has been suggested as a way of reducing the risk of secondary negative brain effects of drug therapy and of optimizing polypharmacy in the elderly. The aim of this MiniReview is to describe the methods previously used to assess the anticholinergic drug burden in elderly people and to evaluate the clinical utility of these methods as risk assessment tools in clinical practice. History and Use of Anticholinergic Drugs Anticholinergic agents occur naturally as alkaloids in Atropa belladonna and other plants of the family Solanaceae. Belladonna alkaloids and their synthetic analogues have been used for their cosmetic, therapeutic and toxic effects for centuries. The term belladonna (means beautiful woman in Italian) refers to the Italian women who desired dilated pupils to appear more seductive. In modern times, synthetic anticholinergic drugs have been used for a variety of medical conditions, including Parkinsonism, depression, urinary incontinence, allergy, travel sickness, obstructive lung diseases, sleep disorders, peptic ulcer disease, cardiac arrhythmias and psychoses. As late as the 1950s, atropine-induced coma was used as a treatment for psychosis in Norwegian hospitals [10]. In 1991, approximately 600 of the drugs on the United States market were reported to have anticholinergic activity [11].

2 152 HEGE KERSTEN AND TORGEIR BRUUN WYLLER MiniReview Currently, many of these drugs have been withdrawn, but a large number of drugs with anticholinergic properties are still commonly used. Advanced age is a risk factor for the use of anticholinergic drugs because these drugs are prescribed for the symptomatic management of medical conditions that often occur in later life, such as urinary incontinence and sleep disorders [3]. Other risk factors for anticholinergic prescriptions are polypharmacy and institutionalization. Elderly people in nursing home care use significantly more anticholinergic drugs than the home-dwelling elderly [12,13]. Despite the anticholinergic hypersensitivity of patients with dementia, elderly patients with dementia are more frequently exposed to definite anticholinergic drugs than are those without dementia [14]. Furthermore, epidemiological studies have reported that people using acetylcholinesterase inhibitors have an increased risk of receiving an anticholinergic drug with the potential to antagonize the effects of the cholinesterase inhibitor [15,16], possibly because the adverse effects of the cholinesterase inhibitor are misinterpreted [15]. It has also been reported that among hospitalized people aged above 65 years, the prevalence of anticholinergic prescriptions increases significantly during their hospital stay, although it seems like Geriatric Units are more vigilant than others to the use of anticholinergic drugs [17]. Finally, it has been shown that in palliative care, the use of anticholinergic drugs increases as death approaches [18]. Mechanism of Action Anticholinergic drugs act on the muscarinic receptors in the central and peripheral nervous systems and inhibit acetylcholine-mediated responses by competitively binding to these receptors. Hence, muscarinic receptor antagonists would be a more pharmacologically precise term, but in accordance with the terminology used in the literature, we use anticholinergic drugs throughout this MiniReview. There are five subtypes of muscarinic receptors, M1, M2, M3, M4 and M5, which have been characterized by molecular cloning [19]. The G-proteincoupled muscarinic receptors have seven transmembrane regions, and there are probably three classes of muscarinic antagonist binding sites [20]. Muscarinic receptors are widely distributed throughout the human body and mediate distinct physiological responses according to their location and receptor subtype [21]. All five receptor subtypes are expressed in the brain, and there is a potential interplay between the excitatory (M1, M3, M5) and the inhibitory (M2, M4) receptor subtypes responsible for the diversity of central acetylcholinemediated responses. The M1 receptor outnumbers the other receptor subtypes in the brain and constitutes 40 50% of the total number of muscarinic receptors in the human body [21]. Activation of M1 and M2 receptor is important for higher cognitive processes, and antagonism of central M1 and M2 receptors impairs memory and learning processes [21]. Moreover, M2 receptor is important for the acetylcholine homeostasis by pre-synaptic regulation of acetylcholine release [22]. Antagonism of the M4 and M5 receptors alters the regulation of other neurotransmitters such as dopamine, while M3 receptors are found in lower concentration in the brain and M3 antagonism does not affect behaviour or cognition [21,22]. Almost every anticholinergic drug on the market is a non-selective antimuscarinic agent which means that the drug does not discriminate among the five muscarinic receptor subtypes. Thereby, the drugs inhibit all the central acetylcholine-mediated muscarinic responses that are involved in a widespread of different mechanisms such as controlling autonomic responses, regulation of the release of other neurotransmitters, synaptic plasticity and cognitive functions. Central Anticholinergic Adverse Effects The symptoms of central adverse effect of anticholinergic drugs may be dramatic such as delirium, but are more often subtle and easily discounted as the natural consequences of ageing, such as mild alterations in memory skills. The symptoms are linked to the inhibition of acetylcholine transmission in certain brain areas, including the forebrain, cerebral cortex, hippocampus and corpus striatum. Acetylcholine transmission is involved especially in memory processes, particularly in short-term memory and attention [23], but cholinergic blockade in the brain has been related to widespread undesired adverse effects, including delirium, behavioural disturbances, reduced executive functions, altered emotions and reduced motor functions [24 27]. The risk of central anticholinergic adverse effects is determined by the drugs distribution to the brain and their competitive binding affinities for the cerebral muscarinic receptors. The concentrations of the drugs within the brain are regulated by the balance between their passive influx and active efflux across the blood brain barrier (BBB). Factors that influence the permeability of the BBB are factors that contribute to the risk assessment of adverse central effects. Certain drug characteristics, such as small molecular size, apolarity and high lipophilicity, allow their passive influx through the BBB. In general, tertiary amines such as the natural alkaloid atropine cross the BBB, while positively charged quaternary amines such as ipatropium bromide have little CNS penetrance. It has also been observed in mice that quaternary compounds have much weaker central anticholinergic effects than their corresponding tertiary analogoues [28]. The drugs efflux across the BBB is facilitated by the drugs specificity for the active transporter molecule permeability glycoprotein (PgP). Moreover, PgP-mediated efflux can be affected by genetic polymorphisms and/or drug-induced inhibition of the transporter protein [21]. As an example, anticholinergic drugs used to treat urinary incontinence show different propensities to cause central anticholinergic effects because their different molecular characteristics differentially affect their penetration of the BBB [29]. Anticholinergic Hypersensitivity Normal ageing is accompanied by increased pharmacodynamic sensitivity to the blockade of the muscarinic receptors in the central nervous system. Different changes in the cholinergic nervous system can lead to reduced cholinergic reserves

3 MiniReview CENTRAL ANTICHOLINERGIC DRUG BURDEN IN THE ELDERLY 153 in the ageing brain. A structural change in the muscarinic binding sites that leads to lower binding affinity for acetylcholine has been identified in rat models [30]. A reduction in the activity of the pre-synaptic enzyme choline acetyltransferase that reduces the amount of acetylcholine in the central nervous system has been described, and a lower muscarinic receptor density in the aged brain is also reported [31,32]. Age-related pharmacokinetic changes also contribute to a further increase in an individual s susceptibility to central adverse effects, particularly the increased permeability of the BBB. The mechanisms involved in increased BBB permeability include epithelial shrinkage, the opening of tight junctions and the dilation of blood vessels, resulting in increased blood flow and the leakage of larger molecules, as has been demonstrated in a rat model [21]. Auxiliary leakage through the BBB is reported in certain conditions that are common in the elderly, including neurodegenerative diseases and diabetes [21]. Vulnerability to central muscarinic antagonism is further increased in patients with Alzheimer s disease. These patients have severely impaired cholinergic neurotransmission, secondary to the degeneration of neurons, and it has been shown that older people with dementia are more sensitive to central anticholinergic adverse effects than their age-matched controls [33]. Monitoring the Anticholinergic Drug Burden in the Brain Determination of the anticholinergic drug burden has been suggested as an approach to reduce the risk of central anticholinergic adverse effects in the elderly [34,35]. The serum anticholinergic activity (SAA) is an estimate of the overall anticholinergic activity towards rat brain muscarinic receptors in an individual s serum. The SAA could be caused by medications, endogenous substances and stress responses, whereas the various anticholinergic drug scales identify the drugs that might cause adverse effects. The SAA can potentially be used to identify those individuals with a high anticholinergic load and hence an increased risk of anticholinergic adverse effects, whereas the anticholinergic scales might provide guidance for which drugs to prescribe and which to withdraw to optimize pharmacotherapy for the elderly. Interindividual Variability in the Sensitivity for Central Anticholinergic Effects A major drawback of all the anticholinergic risk assessment tools is the absence or limited consideration of the variability of a drug s distribution to the brain. This limitation is of particular importance in geriatric risk assessment because certain neurodegenerative diseases, polypharmacy and the differential ageing process increase the diversity of brain distribution. Moreover, the anticholinergic sensitivity within the brain is increasingly varied in older people. For example, the interindividual variability is caused by genetic polymorphism at the muscarinic receptor level, cholinergic degeneration caused by ageing per se or by the presence of dementia, or finally, by the extent of tolerance that could be developed for cumulative anticholinergic drug exposure. Methods used to Measure the Anticholinergic Drug Burden A radio receptor bioassay to measure the Serum Anticholinergcio Activity (SAA). The anticholinergic activity of many drugs has been determined by the in vitro measurement of their competitive binding inhibition of a specific radiolabelled ligand, tritiated quinuclidinyl benzilate ( 3 H-QNB), to the muscarinic receptors in the rat forebrain [36]. Many drugs not generally considered to be anticholinergic have been shown to displace 3 H-QNB from the muscarinic receptors in this bioassay [3]. In 2008, Chew et al. [3] assessed the dose AA relationships of 107 medications at doses typically administered to older adults. The radio receptor bioassay might be useful for quantifying and comparing the AA of different drugs within the same therapeutic group. For instance, the dose AA relationship for atypical antipsychotic medications showed that clozapine, olanzapine and quetiapine increased AA within their therapeutic ranges, whereas aripiprazole, risperidone and ziprasidone did not [37]. Clinicians might use these results when choosing between equally efficacious medications. Limitations of SAA. For several reasons, the in vitro method used to measure SAA is not suitable for estimating the overall anticholinergic drug burden in the human brain. Firstly, SAA is a measure of the peripheral circulating anticholinergic compounds and does not reflect the concentrations of anticholinergic drugs in the brain. One study has even shown that SAA did not correlate with the cerebral cholinergic function measured with electroencephalography [38]. Using the bioassay to measure the AA in cerebrospinal fluid would probably give a better estimate of the anticholinergic burden in the brain, but still not predict the interindividual sensitivity of being cognitively affected by the drugs. Although, there are numerous reasons why the correlation between SAA and the cognitive abilities of older people might be difficult to show; high SAA has been related to low cognitive abilities in several studies [26,39,40]. However, the prediction of central adverse effects of drugs should obviously be adjusted to the degree of brain distribution of the drug. For example, one study reported that the in vitro AA of oxybutynin was relatively low compared with those of other urinary spasmolytic drugs, but clinical studies have shown that oxybutynin can cause cognitive impairment, which might be explained by its relatively higher brain distribution [41]. Secondly, SAA only indicates that a patient s serum contains compounds that affect binding to one or more of the five muscarinic receptor subtypes, but whether elevated SAA is caused by medication, endogenous compounds or stress responses to acute illness is unclear [42]. It has been shown that the level of SAA increases during acute illness, regardless of any drug changes. The SAA increment was reversed after recovery from illness, and it was suggested that SAA is increased by a nonspecific stress response to illness in older people [43]. It has also been shown that naturally occurring substances, such as cortisol, have binding affinity for muscarinic receptors in vitro

4 154 HEGE KERSTEN AND TORGEIR BRUUN WYLLER MiniReview [42]. Furthermore, plasma proteins have inhibited the binding of 3 H-QNB in the bioassay and interfered with the resulting SAA levels [44]. For these reasons, it is uncertain to what extent the level of SAA is associated with anticholinergic drugs. Thirdly, the binding assay does not distinguish between antagonistic and agonistic activity towards the muscarinic receptors nor between the specific binding to each muscarinic subtype. Finally, the bioassay is not standardized and the levels of SAA vary considerably between different reports [42]. This might be caused by the differences among the populations studied, but could also partly attribute to intralaboratory heterogeneity in the assay methodology. For instance, different curve models might have been used to calculate the atropine standard curves used as the references for AA. Anticholinergic drug scales. The anticholinergic drug scales are expert-based score models developed to determine the anticholinergic drug burden of an individual. The Anticholinergic Drug Scale (ADS) was the first scale developed and is based on a three-level anticholinergic classification system of 62 medications that was published in 1978 [45]. In 2001, Han et al. rated the AA of 340 medications as ranging from 0 (none) to 3 (high), based on the list from 1978, their clinical experiences and the available ratings for the in vitro AAs of the drugs [46]. In 2006, Carnahan et al. [6] validated and renamed this clinician-rated anticholinergic scale as the ADS. They showed that ADS was significantly associated with SAA, although ADS explained less than 10% of the variability in SAA [6]. The amount of variance explained did not improve with a dose-adjusted ADS score model. The 0:1:2:3 weighting strategy appeared to be reasonable, although 0:1:2:5 weighting was thought to be a more precise three-point ratio of the relative AAs of different drugs [6]. Nevertheless, the simple four-point 0:1:2:3 model of anticholinergic ratings was established and the model is userfriendly in clinical practice. More recently, two other anticholinergic scales have been published. The Anticholinergic Burden Scale (ACB) assesses the cognitive impact of any anticholinergic drug, whereas the Anticholinergic Risk Scale (ARS) assesses the risk of both peripheral and central anticholinergic adverse effects [7,9]. The two more recent scales rate the AAs of drugs in an ordinal fashion from 0 to 3 based on clinical experiences similar to those underpinning the original ADS [6,7,9]. The ratings of drug AAs on the ACB scale and the ARS are based on literature reviews of the drugs anticholinergic potential [7,9]. Furthermore, the anticholinergic ranking on the ARS also take into account the dissociation constants for the muscarinic receptors [7]. Only the Drug Burden Index (DBI), which includes both sedative and anticholinergic drugs, is adjusted for dose [8], which is a major advantage compared with the other scales. The DBI was developed in Australia based on specific drug characteristics. Drugs that are reported to be both sedative and anticholinergic are registered as anticholinergic. A separate anticholinergic burden index can be calculated from the DBI. Drug burden index incorporates a classic dose response relationship for each drug involved in the anticholinergic burden [8]. However, in all the anticholinergic scale models, the total anticholinergic burden of an individual is determined by the summation of each drug s anticholinergic score. Therefore, the calculation of the anticholinergic drug burden is based on the assumption that the anticholinergic effects of different drugs are additive in a linear fashion. Limitations of anticholinergic drug scales. As the anticholinergic drug scales are expert-based score models partly based upon the in vitro detection of SAA, the limitations of SAA and the drug scales overlap. However, the scales have some additional drawbacks related to the categorization and summation of each drugs potential AA. It seems unlikely that the cumulative exposure to anticholinergic drugs can be simplified into linear additive models. The models do not consider the drugs different actions on the muscarinic receptor subtypes, the possible synergistic or deleterious effects of different drugs, or individuals possible development of tolerance for anticholinergic drug effects. Furthermore, anticholinergic effects are dose-dependent and the relative AAs of different drugs are unlikely to be proportional to a 0:1:2:3 ratio. The current anticholinergic drug scales simplify complex pharmacological mechanisms, which is particularly problematic in geriatric risk assessment because of the increased biological variation in the aged population. Differential ageing, the degree of drug drug interactions and the variable impacts of different diseases are continuously dispersed variables that are inimical to categorization [47]. Finally, there is no consensus on how to define anticholinergic drug exposure on the different scales, and both the number and ranking of the anticholinergic drugs listed vary considerably between the scales [6 9]. Furthermore, some scales have considered the impact of different routes of administration when ranking the anticholinergic activity of drugs, while others have excluded topical, ophthalmic, otologic and inhaled medication preparations. However, a recent review has developed a new list of 100 anticholinergic drugs based on previously published lists in a first attempt to standardize an anticholinergic scale [48]. Relationship between Anticholinergic Drug Burden and Central Adverse Effects in Older Adults In previous reviews, a high anticholinergic drug burden has been associated with negative cognitive outcomes in elderly patients [49], but contradictory findings have been reported. Table 1 gives an overview of the observational studies of the anticholinergic burden performed from January 1988 to January 2013 and found with searches of Medline using the key word term and title term anticholinergic burden, anticholinergic load, anticholinergic drugs and adverse effects. We also retrieved related publications in the search results and relevant papers from the reference lists of the selected articles. We included studies that measured the anticholinergic burden using SAA, ADS, ACB, ARS or DBI in relation to central adverse outcomes in people 65 years old. Case reports and

5 MiniReview CENTRAL ANTICHOLINERGIC DRUG BURDEN IN THE ELDERLY 155 Table 1. Association between the methods used to determine the anticholinergic burden (AB) and central clinical outcomes in older adults. Findings of observational studies over the last 25 years. Method Estimation of AB Study population Clinical outcomes Serum anticholinergic activity (SAA): measures a drug s displacement of 3 H-QNB from muscarinic receptors, expressed in atropine equivalents [36] Anticholinergic Drug Scale (ADS): Four-rank scale of AAs of drugs: 0 = no known AA, 1 = potential AA according to in vitro studies, 2 = AA observed at high doses, 3 = marked anticholinergic effects [6] An objective measure of the ΣAA in vitro of serum compounds Expert-based ΣAA of drugs based on drug characteristics, clinical experience and SAA N = 61, >65 years, hospitalized patients N = 61, >80 years, hospitalized patients with and without dementia N = 67, 75 years, medically ill inpatients N = 90, 65 years, cognitively intact, community dwelling N = 201, 65 years, cognitively intact, community dwelling N = 26, geriatric patients with dementia and behavioural disturbance N = 61, >80 years, hospitalized patients with and without dementia N = 152, 65 years, cognitive intact, community dwelling N = 22, demented nursing home patients N = 278, 65 years, medical inpatients with and without dementia N = 364, >65 years, hip fracture inpatients N = 544, men 65 years, community dwelling* N = 461, elderly patients in palliative care N = 461, elderly patients in palliative care N = 544, men 65 years, community dwelling* Delirium Confusion Assessment Method (CAM) [40] CAM [38] Delirium Symptom Interview [61] Psychomotor function Gait speed, simple response time [62] Cognitive impairment Mini mental state examination (MMSE) [39] MMSE Severe Impairment Battery (SIB) [63] Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) [38] Working memory [64] Self-care capacity Psychogeriatric Dependency Rating Scale [26] Delirium Evaluation of the severity of delirium symptoms based on CAM [46] CAM [65] Cognitive function Verbal recall test [25] Quality of life McGill s Quality of life Index [18] Functional status Australian Karnofsky Performance Scale [18] ADL [25] Anticholinergic Cognitive Burden (ACB): Four-rank scale of drug AAs 0 = no AA, 1 = possible in vitro AA, 2 = definite anticholinergic effect shown by association with clinically significant cognitive anticholinergic adverse effects 3 = BBB-permeable drugs shown association with delirium [66] Expert-based ΣAAs of drugs based on drugs BBB permeability, risk assessments of drugs cognitive adverse effects and SAA N = 147, 65 years, cognitively impaired inpatients N = 13,004, 65 years, community dwelling with and without cognitive impairment N = 224, elderly patients with Alzheimer s dementia [67] N = 13,004, 65 years, community dwelling with and without cognitive impairment N = 87, 65 years, nursing home patients with dementia Cognitive function CAM [68] Only those using definite anticholinergic drugs had lower MMSE [4] MMSE Severity of cognitive decline Mortality After 2 years (covariate correlated with outcome measures) [4] Quality of life Multiple engagement observations [69] / (continued)

6 156 HEGE KERSTEN AND TORGEIR BRUUN WYLLER MiniReview Table 1. (continued) Method Estimation of AB Study population Clinical outcomes Anticholinergic Risk Scale (ARS): Four-rank scale of drugs AAs: 0 = limited or no risk, 1 = moderate risk, 2 = strong risk, 3 = very strong risk [7] Expert-based ΣAA-based risk assessments of drugs peripheral and central adverse effects N = 132, 65 years, in geriatric evaluation management and N = 117, males 65 years, in primary care clinics Central effects Falls, dizziness, and confusion [7] N = 1004, elderly in long-term care Mortality [53] Drug Burden Index: Anticholinergic and sedative effects of drugs ranked 0 1 with a hyperbolic dose response function [8] Expert-based ΣAA based on risk of adverse drug events N = 1705, males 70 years, community dwelling with no, mild or severe dementia N = 3075, 70 years, functioning well, community dwelling N = 932, women 65 years, community dwelling N = 3075, 70 years, functioning well, community dwelling N = 1705, males 70 years, community dwelling with no, mild or severe dementia N = 602, 70 years, community dwelling N = 932, women 65 years, community dwelling** Cognitive function Addenbrooke s Cognitive Examination and Trail Making Test [70] Digit Symbol Substitution test [8] MMSE [27] Physical function Health ABC performance score [8] Physical function ADL [71] Falls [72] Physical function ADL [27] refers to association, refers to no association between the anticholinergic burden and the outcome measures. AA, anticholinergic activity; SAA, serum anticholinergic activity; 3 HQNB, tritiated quinuclidinyl benzilate; ADL, activity of daily living; BBB, blood brain barrier. *ADS adjusted for exposure time. **Anticholinergic drug burden index. studies that monitored the anticholinergic activity of single substances were excluded. Because there is no consensus on how to quantify the anticholinergic burden and different methods are used, it is difficult to compare the results. It is also difficult to compare studies that have used the same method because different cutoff values for a high anticholinergic burden have been used. It is noteworthy that a recent study found no association between any of the four anticholinergic drug scales and the objective measure of SAA [50]. A recent comparison of the ARS and ACB scales highlighted the poor overlap between the two and suggested that the ARS is more specific but less selective than the ACB in identifying medications that are associated with poorer cognitive outcomes [35]. Despite the poor correlation between the two scales, the overall conclusion was that a high anticholinergic burden is associated with cognitive decline and impairment of the activities of daily living [35]. There is certainly considerable evidence that the use of anticholinergic drugs entails a high risk of central adverse effects in elderly patients, but more studies are required to determine how to estimate the total anticholinergic burden in older people s brain. One study did not support the additive properties of the anticholinergic risk scale scores as no progressive decline in cognitive function was observed when the ADS scores increased above 3 in a nursing home population [5]. Nine of the studies summarized in table 1 found no significant relationship between a high anticholinergic burden and poorer cognitive outcomes whereas 10 reported statistically significant relationships. The major reason why the relationship between cognitive abilities and anticholinergic burden is hard to show in elderly populations, is probably because of the heterogeneity in cholinergic brain reserves, which causes great differences in the sensitivity to central anticholinergic effects. However, the findings related to functional status are more consistent: nine studies reported that a high anticholinergic drug burden had a significantly negative impact on physical functions and functional status, whereas only one study failed to show such a relationship. In particular, the association between the DBI and physical function has been strongly supported in different elderly populations. In the only study that distinguished between the anticholinergic DBI and sedative DBI, the anticholinergic DBI had a stronger negative association with physical function than the sedative DBI [27]. These findings are important because a poorer outcome in, for instance, gait speed or hand grip strength might predict cognitive decline, frailty and disability, which are of major importance in geriatric risk management [51,52]. The impact of the anticholinergic burden on quality of life and mortality has also been studied, although without consistent findings. One study reported that a high ACB score was related to increased mortality, but this result has been criticized because the covariates correlated with the outcome measure [47]. Moreover, a Finnish study did not support that higher ARS scores were associated with mortality in long-term care patients [53].

7 MiniReview CENTRAL ANTICHOLINERGIC DRUG BURDEN IN THE ELDERLY 157 All the outcomes used to measure the risks of central adverse effects related to anticholinergic drug burden could be affected by the use of other centrally acting drugs. For example, the use of benzodiazepines is correlated with both poorer cognitive and physical function [54]. Additionally, drugs might interact and potentiate the central effect of anticholinergic drugs. For example, it has been shown that opioid agonists reduce the release of acetylcholine and might potentiate the effects of anticholinergic drugs [55]. It is also difficult to adjust for all the different intercurrent diseases and conditions that might affect the CNS function of the older study population. In general, all the observational studies summarized in table 1 are limited by their cross-sectional design and longitudinal studies, and randomized controlled trials are required to provide evidence for the presumed relationship between the anticholinergic drug burden and the risk stratification of elderly populations. Cumulative anticholinergic drug exposure has been related to deficits in cognitive functioning in longitudinal studies, but its relationship to the risks of dementia and mortality is unclear [4,25,56,57]. However, one longitudinal study found no long-term cognitive impact of chronic anticholinergic drug use in older adults [58]. All the longitudinal studies have to be interpreted with awareness of the epidemiological pitfall that those who undergo long-time treatment of anticholinergic drugs might be a selected group of elderly people that are less sensitive for anticholinergic adverse effect. The cognitive effects of a reduced ADS score have been studied in two randomized, controlled trials conducted in nursing home patients [11,59]. The first study was conducted in 34 elderly residents without dementia. When the ADS score was significantly reduced from 3.7 to 1.3, improvements in two of the 12 psychometric scales measured were observed. Unfortunately, this study carried a very high risk of type I error because many outcomes were assessed in a very small study sample [11]. The second study was conducted in very old residents with no, mild or moderate dementia. When the average ADS score was reduced significantly, from 4 to 2, the reduction did not translate into cognitive improvement, reduced SAA or reduced mouth dryness. No significant differences were observed between the control group and the interventional group 8 weeks after the drug changes [59]. Furthermore, a pilot randomized trial that utilized the DBI failed to reduce the anticholinergic drug prescriptions made by general practitioners [60]. This result might indicate that the DBI is not easily integrated in clinical practice. Summary Evidence-based knowledge of drug safety in geriatric patients treated with polypharmacy is still sparse, but the use of risk assessment tools has been increasingly focused. The concurrent use of several drugs with potential anticholinergic properties is common in elderly people, and methods have been developed to monitor the overall anticholinergic drug burden. A high anticholinergic drug burden has been associated with secondary negative brain effects and poorer outcomes in elderly people in observational studies, but the findings are in part contradictory. Little is known about the additive pharmacodynamic properties of potential and definite anticholinergic drugs and larger randomized, controlled trials are encouraged. However, we believe that the simplifications inherent in the current anticholinergic risk assessment tools might be inappropriate when the tools are applied to complex pharmacological mechanisms in older people s brain. Although, prescribers must be vigilant in identifying the adverse effects of anticholinergic drugs, the anticipated benefits of some of these drugs should not be overlooked in therapeutic risk/benefit management. Reference 1 American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc 2012;60: Lam MP, Cheung BM. The use of STOPP/START criteria as a screening tool for assessing the appropriateness of medications in the elderly population. Expert Rev Clin Pharmacol 2012;5: Chew ML, Mulsant BH, Pollock BG, Lehman ME, Greenspan A, Mahmoud RA et al. Anticholinergic activity of 107 medications commonly used by older adults. 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