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Impact of on the aging brain: A review and practical application

Article in Aging Health · June 2008 DOI: 10.2217/1745509X.4.3.311

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Malaz Boustani Noll Campbell Indiana University School of Medicine Purdue University

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Impact of anticholinergics on the aging brain: a review and practical application

Malaz Boustani1†, Objective: in an effort to enhance prescribing for older adults and reduce the Noll Campbell2, burden of cognitive impairment, this paper reviews the literature regarding the negative Stephanie Munger1,3, Ian Maidment4 & impact of anticholinergics on cognitive function and provides clinicians with a practical Chris Fox5 guidance for use in older adults. Methods: a Medline search identified studies evaluating the use of anticholinergics and the relationship between †Author for correspondence 1Regenstrief Institute, Inc., anticholinergics and cognitive impairment. Results: prescribing anticholinergics for older 410 West 10th Street, adults leads to acute cognitive impairment and, possibly, chronic cognitive deficits. Suite 2000, IN 46202, USA Assessing anticholinergic burden with a simple scale may represent a useful noninvasive and, Indiana University Center for tool to optimize geriatric pharmacotherapy. Conclusion: more studies are needed to Aging Research, 410 West validate the Anticholinergic Cognitive Burden scale and establish therapeutic guidelines in 10th Street, Suite the presence of cognitive anticholinergic adverse effects. 2000IN 46202-3012, USA Tel.: +1 317 423 5633; Fax: +1 317 423 5695; Background & significance What is the burden of cognitive E-mail: mboustani@ with anticholinergic activity (anti- impairment among older adults? regenstrief.org 2Wishard Health Services, ) are commonly prescribed to the The aging of the US population has been accom- 1001 West 10th Street, 36 million older Americans for treating condi- panied by a dramatic rise in the prevalence of cog- IN 46202, USA tions such as , depression, hypertension, nitive impairment [101]. Cognitive impairment in Tel.: +1 317 630 2214; Parkinson’s disease, vertigo, asthma, cardio- older adults includes a variety of disorders ranging E-mail: noll.campbell@ wishard.edu vascular disease, incontinence, psychotic symp- from mild cognitive impairment (MCI) and 3Indiana University Center toms and behavioral problems [1,2]. Older adults to overt dementia. Dementia is an for Aging Research, 410 West are particularly vulnerable to anticholinergic- acquired syndrome of progressive decline in 10th Street, Suite 2000 IN 46202-3012, USA related cognitive effects for two main reasons. memory and at least one other cognitive domain, Tel.: +1 317 423 5606; First, older adults have a high probability of such as language, visuospatial or executive func- Fax: +1 317 423 5695; being exposed to anticholinergics owing to their tion, to an extent that is sufficient to interfere E-mail: smunger@ high medical comorbidity and their use of with social or occupational functioning in an alert regenstrief.org 4Eastern & Area Coastal multiple prescribed and over-the-counter medi- person [8]. Delirium is an acute disturbance of Office, St Martin’s Hospital, cations [3–5]. Second, older adults are more sensi- consciousness with reduced ability to focus, sus- Littlebourne Road, tive to develop serious anticholinergics-related tain or shift attention that occurs over a short Canterbury, Kent, cognitive adverse effects owing to their age [6]. period of time and tends to fluctuate over the CT1 1AZ, UK Tel.: +44 1227 812 115; Aging is accompanied by a decline in hepatic course of the day [9]. MCI with no dementia is E-mail: ian.maidment@ and renal , an increase in defined as the presence of cognitive deficit with nhs.net blood–brain barrier permeability and a the absence of delirium that is not affecting the 5Shepway Caste Department reduction in central activities [6,7]. individual’s functional performance [10]. Delirium of Old Age Psychiatry, Fokestone Health Centre, Our article provides first a review of the litera- and dementia are the underlying causes of cogni- 15–25 Dover Road, ture regarding the prevalence of anticholinergics tive impairment among the majority of hospital- Folkestone, Kent, and the relationship between anticholinergic ized older adults [11], whereas MCI and dementia CT2 1JY, UK exposure and cognitive impairment; and second, are the main causes of cognitive impairment Tel.: +44 1303 228 836; Fax: +44 1303 228 837; the article offers real-world clinicians practicing at outside hospital [12]. E-mail: [email protected] hospital, ambulatory and long-term healthcare Depending on the method used to define settings a practical guide for the use of antichol- cognitive impairment (delirium, MCI or

Keywords: anticholinergic inergics, which aims to enhance the safety and dementia) and the clinical setting (hospital, activity, cognitive quality of prescribing of these medications for nursing home or primary care), its prevalence impairment, delirium, older adults. This contribution to existing knowl- among older adults ranges from 6 to 66% dementia, elderly, prescribing edge hopes to assist with identification of the bur- [9,11–13]. Cognitive impairment causes a high den of anticholinergics and, thus, reduce the risk burden of suffering for patients and their part of for developing adverse cognitive outcomes such as families [9,101]. For patients, in addition to cog- dementia and delirium. nitive and functional deterioration, cognitive

10.2217/1745509X.4.3.311 © 2008 Future Medicine Ltd ISSN 1745-509X Aging Health (2008) 4(3), 311–320 311 REVIEW – Boustani, Campbell, Munger, Maidment & Fox

impairment leads to behavioral and psycho- The above cholinergic-loss hypothesis has been logical complications, increased use of health the underlying justification for the current cholin- and social services, complicated clinical man- ergic enhancement therapy for patients with agement of other comorbid conditions and dementia, including the four US FDA-approved increased risk for medical complications such as inhibitors for the treatment of falls, motor vehicle accidents, incontinence, Alzheimer’s disease and Parkinson’s disease fractures and infections. For family caregivers, dementia [10,17,18,101]. The use of cholinesterase cognitive impairment can lead to higher levels inhibitors improves the cognitive symptoms of of anxiety, depression, use of psychotropic patients and might slow the progression of Alzhe- medications and chronic fatigue [12,101]. Accord- imer’s disease. Furthermore, concomitant use of ing to the Global Burden of Disease estimates cholinesterase inhibitors and anticholinergics may for the 2003 World Health Report, dementia in result in pharmacological antagonism [7,24]. In particular contributed to 11% of years lived fact, the use of anticholinergics such as with disability in people aged 60 years and has been successful as an antidote for older; more than cardiovascular disease [14]. By cholinesterase-inhibitor overdose [25]. 2050, Medicare will be spending over More recently, a new hypothesis has been US$1 trillion on beneficiaries suffering from emerging that connects the effect of antichol- dementia [15]. inergics to the pathogenesis of Alzheimer’s dis- ease. This hypothesis states that long-term What is the role of the exposure to anticholinergics may be associated central cholinergic system in with increased Alzheimer-type pathology. Perry cognitive impairment? et al. found that amyloid plaque densities were The role of the central cholinergic system in cog- more than 2.5-fold higher in Parkinson’s disease nitive impairment was discovered more than patients treated with anticholinergics and that three decades ago [16–18]. Multiple human and neurofibrillary tangle densities were also highest animal studies consistently demonstrated that among the chronic users by comparison with the numerous problems in the central nervous untreated or acutely-treated groups [26]. The cholinergic system lead to both cognitive and above data suggest that blockade of cholinergic noncognitive symptoms [9,16–19]. Some of these transmission might lead to the development of cholinergic system abnormalities include both acute and chronic cognitive impairment. changes and modifications in transport, release, nicotinic- and muscarinic- How can we determine the central receptor expression, neurotrophin support and anticholinergic effect of medications? axonal transport [16–18]. The dysfunction of the Although the use of anticholinergics has been cholinergic neurons throughout the basal and part of the routine treatment of common medi- rostral forebrain pathways leads to a low level of cal conditions in the elderly, the adverse effects the neurotransmitter acetylcholine, which con- of these anticholinergics, as represented by atro- tributes substantially to the cognitive impair- pine and , have been known for cen- ment and behavioral symptoms of patients with turies. This includes peripheral effects such as Alzheimer’s disease, Lewy body dementia, dry mouth, , and vascular dementia and even delirium [6,9,10,16–18]. , and CNS effects such as cognitive Early work on developing animal and impairment, behavioral excitation, attention def- human models for delirium and dementia was icits and [6]. Although therapeutic based on the use of agents blocking the central anticholinergics are well recognized by clinicians, nervous muscarinic and nicotinic receptors, such as oxybutinin for and such as scopolamine, atropine, and ipratropium for chronic obstructive pulmonary mecamylamine [9,17,18,20–23]. In addition, disease, other medications have anticholinergic administration of scopolamine has been shown effects as secondary, unintentional effects. Many to reduce hippocampal activation on func- of these medications are not well recognized by tional MRI during cognitive tasks [20]. Further- clinicians, such as , antidepres- more, lesions in animals and humans that sants and neuroleptics. Furthermore, some med- damage cholinergic input to the neocortex or ications have very limited anticholinergic effects hippocampus from the basal forebrain lead to but might lead to clinically significant anti- the same cognitive impairment induced by cholinergic effects if used in combination with anticholinergics [6,9,10,16–18]. other anticholinergics [6,7].

312 Aging Health (2008) 4(3) futurefuture sciencescience groupgroup Impact of anticholinergics on the aging brain – REVIEW

Determining the anticholinergic properties of prescribed for elderly patients, ten of them had various medications may be quantified by three recognizable anticholinergic effects [29]. Despite methods: the development of criteria aimed at identifying • Serum radioreceptor anticholinergic activity drugs with anticholinergic activity as inappropri- assay (SAA) [5,28,29] ate for use by older adults [37], the utilization of such agents range from 14 to 50%, depending • In vitro measurement of drug affinity to on the definition of anticholinergic, the muscarinic receptors [27] prevalence method and the settings [4,5,30,31,37,38]. • Expert-based list of medications with In the primary care urban setting, we estimated anticholinergic activity [5,30–32] that 60% of approximately 4000 older adults The first method of SAA quantifies a person’s received at least one anticholinergic [11,30]. In overall anticholinergic burden caused by all drugs another study that randomly recruited 372 elderly and their metabolites. SAA uses tritiated people from general practices in France, 14% were quinuclidinyl benzilate as a high and specific taking at least one anticholinergic and 2% were affinity agent that competes with other anti- taking more than two anticholinergics. At a 1-year cholinergics for the muscarinic receptors [33]. SAA follow-up, 59% of these study subjects were still measures the cumulative anticholinergic effect of taking anticholinergic drugs regularly and 41% all prescribed or over-the-counter medications had stopped taking anticholinergic drugs during taken by the patient but reflects a transitional state the year, while 1% of the cohort had started tak- outside the brain. Cognitive impairment has been ing them [31]. In nursing homes, more than 30% reported with several drugs despite normal SAA of elderly residents take more than two antichol- concentrations [34] and several epidemiological inergics, and 5% take more than five [4,38]. In a studies reported no association between SAA and longitudinal follow-up study of 1627 older, rural number of anticholinergic drugs taken by patients community-residing patients, [5,35,36]. The second method to measure anti- as a sleeping aid with a strong central anticholiner- cholinergic activity of medications uses the same gic effect was reported by 8% of participants and radioreceptor assay as in SAA but is performed in its use has increased from 0.4 to 8% as the cohort an in vitro sample. It measures the binding of a aged from a mean of 73.4 to 80.5 years [39]. Fur- specific medication into a specific muscarinic thermore, in randomly selected community- receptor, and quantifies the antagonistic proper- dwelling elders, serum anticholinergic activity was ties with a comparative cholinergic agonist, lead- detectable in 90% of the sample; 51% received at ing to a measurement of the direct anticholinergic least one anticholinergic [5]. effect [27]. Translating the result of this method into the clinical world might be limited to drugs Is there association between cognitive with clear peripheral anticholinergic properties impairment and the exposure to with limited estimation of the drug’s central or anticholinergic medications? cognitive anticholinergic properties [27]. The third A review of 80 studies found a significant asso- method is based on the opinions of clinicians, ciation between the use of anticholinergics and pharmacists and pharmacology researchers who postoperative delirium [7]. Furthermore, Tune combine their expertise with drug information et al. also found delirium occurred in demented available in the literature to determine the anti- patients as a result of anticholinergic activities cholinergic properties of certain medications. This [40]. They noticed that this adverse effect does method is the most clinically relevant method but not arise from exposure to individual medica- it is the least standardized method [27]. At the tions with strong anticholinergic properties, but current stage of research, Rudd et al. believe that as an accumulation of anticholinergic effects the only method clinically useful for measuring from multiple medications [32]. the cognitive or central anticholinergic effects of In a systematic evidence review of the literature, drugs is the expert-based drug list [27]. we found 13 published longitudinal cohort and case–control studies that evaluated the relation- What is the prevalence of ship between the use of anticholinergic and cogni- anticholinergics use in older adults? tive impairment, including dementia, delirium Older adults are prone to suffer from multiple and MCI [41]. Cognitive performance was evalu- acute and chronic conditions and, therefore, may ated using the Mini-Mental State Examination be prescribed several anticholinergics [30]. (MMSE) in most studies. Delirium was clinically Among the top 25 medications most commonly diagnosed using the Diagnostic and Statistical futurefuture sciencescience groupgroup www.futuremedicine.com 313 REVIEW – Boustani, Campbell, Munger, Maidment & Fox

Manual of Mental Disorders, 4th Edition groups over a 3- to 12-month follow-up period. (DSM-IV) criteria or using their derivatives, such This study found that older adults with probable as the Confusion Assessment Method (CAM). dementia were more likely to use anticholinergics Anticholinergic activities were evaluated using the than matched comparison group patients (33 vs SAA or the expert-based drug list. All of the 13 23%, respectively) [2]. studies found an association between the anti- cholinergic activity of a drug and either cognitive How can we translate the finding from impairment or delirium. However, we found only the literature to the clinical setting? one longitudinal study that evaluated the long- Development of the Anticholinergic term exposure to anticholinergics and the risk of Cognitive Burden scale developing dementia or MCI [31]. In this study, Reviewing the literature strongly supports that the among the 297 consistent nonusers of anticholin- use of anticholinergics leads to acute and possibly ergic drugs, MCI was diagnosed in 105 (35%). chronic cognitive impairment among older adults. Among the 30 consistent users of anticholinergic While physicians are aware of the side effects of drugs, 24 (80%) met the MCI criteria [31]. drugs from the anticholinergic family, a countless Although the consistent users of anticholinergic number of new drugs are launched in the market drugs were significantly more likely to have a diag- every day with ‘possible’ or ‘definite’ antichol- nosis of MCI at 1-year follow-up than consistent inergic activities that remain unrecognized by nonusers, there were no differences in overall many prescribers. Furthermore, the risk of adverse dementia rates at 8-year follow-up between the effects is increased by polypharmacy, not only from drug users (16%) and nonusers (14%) [31]. In prescription drugs but also from over-the-counter another longitudinal study that did not specifically medications in the context of comorbid chronic evaluate the association between anticholinergics diseases. Most drugs with possible anticholinergic and dementia but focused on cognitive decline, activities are likely to be ignored among the medi- Bottiggi et al. used retrospective data from a longi- cal community [30,32]. It was reported that even tudinal elderly cohort at one of the Alzheimer’s some drugs regularly prescribed for delirium, such Disease Research Center [42]. The study partici- as , or , had some pants received annual mental status evaluations anticholinergic activities [43,44]. and physical examinations. This study divided the As a first step in reducing the cognitive burden participants into two groups: those taking one or of anticholinergic use in older adults, our inter- more anticholinergics and those not taking any. disciplinary team developed the Anticholinergic Cognitive data were collected from a total of five Cognitive Burden (ACB) scale as a practical tool consecutive annual visits after the baseline visit. A that identifies the severity of anticholinergic nega- thorough literature search was conducted to derive tive effects on cognition of prescribed and over- a list of commonly prescribed anticholinergics. the-counter medications, and provides the clini- The study found that anticholinergic use did not cian with a simple score that captures the accumu- lead to an accelerated rate of decline in global cog- lative anticholinergic cognitive burden resulting nitive status, but it did lead to an accelerated rate from the total medications taking by older adults. of decline in scanning and visuomotor tracking We searched the Medline database from 1966 to and components of executive functioning, such as 2007 for any study that measured the antichol- attention, sequencing, concentration and cogni- inergic activities of a drug and evaluated the asso- tive flexibility [42]. Finally, Roe et al. conducted a ciation between such activities and the cognitive retrospective cohort study of 836 community- function in older adults. We extracted from each dwelling older adults to compare the prevalence of study the method used to determine such activi- anticholinergic use in older adults with probable ties and the list of medications with anticholin- dementia with that of a matched comparison ergic activities that were associated with negative group of older adults who were unlikely to have cognitive effects, including delirium, MCI, dementia. They used the pharmacy claim data as dementia or cognitive decline. This list was pre- the source for determining both the presence of sented to an expert interdisciplinary team that dementia and measure exposure to anticholiner- included geriatricians, geriatric pharmacists, geri- gics. Patients taking (n = 418) consti- atric psychiatrists, general physicians, geriatric tuted the dementia group. Patients not taking nurses and aging brain researchers. Subsequently, donepezil (n = 418) constituted the comparison the team categorized the above medications into group. The prevalence of anticholinergic use was three classes of mild, moderate and severe compared in the treatment and comparison cognitive anticholinergic negative effects (Table 1).

314 Aging Health (2008) 4(3) futurefuture sciencescience groupgroup Impact of anticholinergics on the aging brain – REVIEW

Table 1. Anticholinergic Cognitive Burden scoring of drugs. Score 1 Score 2 Score 3 * *‡ Alverine Belladone alkaloids Alprazolam‡ ‡ Atropine*‡ *‡ Benztropine*‡ maleate ‡ Brompheniramine‡ hydrochloride Empracet ‡ Captopril‡ ‡ Chlorpheniramine*‡ Chlorthalidone‡ Meperidine‡ *‡ hydrochloride Methotrimeprazine‡ ‡ * ‡ ‡ Clorazepate‡ ‡ ‡ Codeine‡ hydrochloride ‡ Colchicine ‡ ‡ Coumadin Dicyclomine*‡ Diazepam‡ ‡ Digoxin‡ Diphenhydramine*‡ Dipyridamole‡ ‡ Disopyramide phosphate ‡ Fentanyl‡ *‡ Furosemide‡ *‡ ‡ *‡ Haloperidol* *‡ Hydralazine‡ ‡ ‡ Olanzapine Isosorbide‡ ‡ Loperamide‡ *‡ Metoprolol ‡ * ‡ ‡ Prednisone‡ *‡ * Propentheline‡ Theophylline‡ Pyrilamine‡ Trazodone* ‡ Scopolamine‡ *‡ ‡ * Trihexyphenidy*‡ ‡ A total Anticholinergic Cognitive Burden scale score of ≥3 is considered clinically relevant. *The same score given by Anticholinergic Risk Scale. ‡The same score given by Anticholinergic Drug Scale. futurefuture sciencescience groupgroup www.futuremedicine.com 315 REVIEW – Boustani, Campbell, Munger, Maidment & Fox

Furthermore, the interdisciplinary team the ACB scale in measuring the peripheral anti- established a scoring system: drugs with cholinergic effects of medications. As expected, possible anticholinergic effects (as demon- the Carnahan team found that ADS total scores strated by the SAA or the in vitro affinity to were significantly associated with SAA among muscarinic receptors but with no clinically long-term care residents [32]. relevant negative cognitive effects) were given a More recently, Rudolph et al. developed the score of 1. Drugs with established and clinically Anticholinergic Risk Scale (ARS) [45]. The ARS relevant cognitive anticholinergic effects were attempts to measures both the peripheral and given a score of either 2 or 3, based on the drug central anticholinergic effects of medications. blood–brain barrier permeability and its The ARS developers reviewed the medical liter- association with the development of delirium. ature, the National Institute of Mental Health All other drugs with no anticholinergic effects Screening Program and the can be considered as having a score of zero. The Micromedex databases to determine the anti- total added score of different drugs taken by cholinergic effects of the 500 most prescribed the patient determines the accumulative drugs within one veteran healthcare system in anticholinergic cognitive burden. Boston, MA, USA. Similar to the ACB scale, Using the ACB scale, we assessed the anti- ARS ranked medications on a scale of 0 to 3 cholinergic burden of medication among a according to the level of anticholinergic effects. cohort of older adults attending primary care Using data from 249 patients aged 65 years and clinics in Indianapolis (Table 2) [13]. Similar to older attending geriatric or primary care ambu- other studies, we found a high level of anti- latory clinics, the authors assessed the associa- cholinergic burden with a mean ACB score of tion between the total anticholinergic burden 1.9, and more than 23% of older adults were of medications as measured by the ARS and the receiving at least one medication that might overall anticholinergic adverse effects as deter- lead to the development of delirium. mined by a review of the medical records. The Over the past 2 years, two similar tools have mean ARS score ranged from 0.7 points in the been published to help physicians recognize the primary care clinic to 1.4 points in the geriatric adverse effects of anticholinergics among older clinic, and higher ARS scores were associated adults [32,45]. Carnahan and colleagues have with increased risk of both peripheral and cen- established the anticholinergic drug scale tral anticholinergic effects, with a relative risk (ADS), which determined the anticholinergic ratio ranging from 1.3 to 1.9 [45]. By compari- property of medications based on their effects son with the ACB, the ARS was not based on a on the serum anticholinergic activity, and systematic evidence review of the literature, accordingly categorized medications from 0 to focused on medications used in one healthcare 3, with 0 signifying no known anticholinergic system that serves a predominantly male popu- activity and 3 signifying marked anticholinergic lation and aimed to capture both the peripheral activity [32]. The ADS did not use the clinical and central anticholinergic effects of medica- input of expert clinicians and did not focus on tion. Furthermore, the ARS developers include the cognitive effects of anticholinergics. Thus, fall, dizziness and confusion in the definition of the ADS is most likely to be a better tool than central anticholinergic adverse effects and did

Table 2. The burden of anticholinergic use among 3013 older adults attending urban primary care clinics, as determined by the Anticholinergic Cognitive Burden scale. Variable Overall Mean age 73.4 Female (%) 66.6 African–American (%) 64.5 Mean total ACB score (SD) 1.9 (2.4) Percentage with at least one medication with ACB score ≤1 61 Percentage with at least one medication with ACB score = 2 4 Percentage with at least one medication with ACB score = 3 20 Percentage with at least one medication with ACB score = 2 or 3 23 ACB: Anticholinergic Cognitive Burden.

316 Aging Health (2008) 4(3) futurefuture sciencescience groupgroup Impact of anticholinergics on the aging brain – REVIEW

not use a standardized cognitive assessment taken by the patient. Using the ACB scale, a such as the confusion assessment scale or the physician might consider first identifying med- MMSE in their definition of confusion. Thus, ications with an ACB score of 2 or 3 and, sec- we believe that the ACB categorization is more ond, calculate the total ACB score. In the case accurate to measure the cognitive anticholiner- of an older adult prescribed a drug with an gic negative effects of medications than the ACB score of 2 or 3, a prescriber needs to dis- ARS or the ADS. However, the ACB, the ADS cuss with the patient the benefits and harms of and the ARS are easily applied to drug lists in a continuous use of this specific drug. Together clinical or research setting in order to determine they could make an informed decision whether the overall drug-related anticholinergic burden to switch to an alternative medication with less and do not require specialized laboratory testing. anticholinergic cognitive effects, hold the med- Table 1 provides the reader with a list of anti- ication during hospitalization or acute illness, cholinergics with negative cognitive effects as completely discontinue the drug if there is no determined by the ACB, the ADS and the ARS. absolute need or monitor the patient’s cognitive performance regularly while receiving the anti- Using the ACB scale in the real cholinergic drug. This review should include clinical world both prescribed and over-the-counter medica- The ratings of anticholinergic potency of differ- tions, particularly as some of the latter group ent drugs have the potential to decrease the with anticholinergic activity have been asso- burden of the two most devastating cognitive ciated with cognitive impairment [11]. A similar disorders facing older adults; dementia and patient–clinician informed-decision process delirium. Outlining the process of using any of might take place in cases where the patient is the three anticholinergic burden scales within not receiving any medication with an ACB the real clinical world might be very helpful. score of 2 or 3 but his/her total ACB score is However, any utility of these scales needs to be above 3. Furthermore, when the withdrawal of investigated in experimental studies using suspected agents is appropriate, we suggest the randomized clinical trial methodology. withdrawal to occur with an appropriate, gradual During a primary care or specialty care schedule to avoid rebound anticholinergic or ambulatory visit for older people who have a psychiatric adverse effects (Figure 1). past medical history of MCI, dementia or delir- ium, or those patients presenting with cognitive The case of Marie Doe complaints, we recommend that the treating Mrs Doe is an 80 year old African–American clinicians review the anticholinergic effects of all female with past medical history of chronic prescribed or over-the-counter medications being heart failure (CHF), osteoarthritis, hyperten- sion, gastroesophagus reflex disorder and mixed Figure 1. Practical guide to assess urine incontinence who presented to her geria- anticholinergic burden in older adults. trician at the Healthy Aging Brain Center in Indianapolis, IN, USA, with a chief complaint of memory loss for the past 4 months observed Older adults with cognitive symptoms or by her husband. This problem started during PMH of dementia, MCI or delirium her recent hospitalization for CHF exacerba- tion. In the hospital, the patient suffered from and displayed 48 h of agitated behav- ior such as pulling her Foley catheter. Her CHF Taking one medication with ACB score >2 was treated with diuretic and antihypertensive or having a total ACB score 3 or more medications and her insomnia and agitation were treated with a combination of olanzepine and diphenhydramine. After the hospitaliza- tion, the patient’s confusion continued to a Consider alternative medication with ACB score <3 or reduce the total ACB score to <3 lesser degree. Currently, the patient has short- term memory loss and psychomotor retardation

but she has no language problems, attention ACB: Anticholinergic Cognitive Burden; problems or fluctuation. Her mood is stable MCI: Mild cognitive impairment; PMH: Past and her insomnia is resolved. She is still inde- medical history. pendent with her basic activities of daily living, futurefuture sciencescience groupgroup www.futuremedicine.com 317 REVIEW – Boustani, Campbell, Munger, Maidment & Fox

but requires some assistance in taking her med- on the aging brain. It is conceivable and valuable ications. Her current drug list includes olan- to create a process within the new drug approval zepine, furesomide, cardizam, , system of the US FDA that provides data on the acetoaminophen, digoxin, oxybutynin, multi- anticholinergic cognitive effects of every medica- vitamin, and calcium with vitamin D. Her tion targeting older adults. These important data physical examination revealed symmetrical can then be translated into feasible and useful neurological examination, normal gait and no decision-support tools that enhance geriatric evidence of acute infection process. Her MMSE pharmacotherapy. More studies are needed, score was 20, her confusion assessment method however, to validate all of the three ACB scales as was negative for delirium. Her geriatrician cal- well as establish therapeutic guidelines in the culated her total ACB score to be 8 points and presence of suspected or established cognitive identified oxybutynin and olanzepine as drugs anticholinergic adverse effects. with an ACB score of 3. He discussed the nega- In a world of increasing pharmacological tive anticholinergic effects of the above two complexity, the integration of the ACB scale into medications with Mrs Doe and her husband, decision-support systems may have the potential who selected to stop olanzepine and oxybu- to improve patients’ outcomes by improving tynin. The geriatricians suggested alternative cognitive functioning. nonpharmacological intervention for her urine incontinence and a follow-up visit. By Financial & competing interests disclosure 3 months later, Mrs Doe’s MMSE score The authors have no relevant affiliations or financial increased to 23 and her ACB score was 2. involvement with any organization or entity with a finan- cial interest in or financial conflict with the subject matter or Conclusion & future perspective materials discussed in the manuscript. This includes employ- As the number of older adults suffering from ment, consultancies, honoraria, stock ownership or options, both cognitive impairment and multiple chronic expert testimony, grants or patents received or pending, or conditions that require management with royalties. numerous medication increases, it is important No writing assistance was utilized in the production of to recognize the negative impact of medication this manuscript.

Executive summary Background & significance • Medications with anticholinergic activity are commonly prescribed to older adults. • Older adults are vulnerable to anticholinergic-related cognitive effects. What is the burden of cognitive impairment among older adults? • Depending on the method used to define cognitive impairment and the clinical setting, approximately 6–66% of older adults suffer from cognitive deficits. • Cognitive impairment causes a high burden of suffering for patients and their families. What is the role of the central cholinergic system in cognitive impairment? • Blockade of cholinergic transmission might lead to the development of both acute and chronic cognitive impairment. How can we determine the central anticholinergic effect of medications? • The most clinically useful method to determine the anticholinergic cognitive effects of drugs is the expert-based drug list. What is the prevalence of anticholinergics use in older adults? • In the primary care urban setting, approximately 60% of older adults receive at least one anticholinergic. Is there an association between cognitive impairment & exposure to anticholinergic medications? • Anticholinergics for older adults lead to acute cognitive impairment and possibly chronic cognitive deficits. How can we translate the finding from the literature to the clinical setting? • Assessing anticholinergic burden with the Anticholinergic Cognitive Burden scale may represent a useful noninvasive tool to optimize geriatric pharmacotherapy. Future perspective • We need to build a process within the new drug approval system of the US FDA that provides data on the anticholinergic cognitive effects of every medication used by older adults.

318 Aging Health (2008) 4(3) futurefuture sciencescience groupgroup Impact of anticholinergics on the aging brain – REVIEW

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futurefuture sciencescience groupgroup www.futuremedicine.com 319 REVIEW – Boustani, Campbell, Munger, Maidment & Fox

34. Moore AR, O’Keeffe ST: Drug-induced 39. Basu R, Dodge H, Stoehr GP, Ganguli M: 44. deLion J: Letter to the editor. Benztropine cognitive impairment in the elderly. Drugs –hypnotic use of diphenhydramine equivalents for antimuscarinic Aging 15, 15–28 (1999). in a rural, older adult, community-based medication. Am. J. Psychiatry 162, 627 35. Francis J: A half-century of delirium cohort: effects on cognition. Am. J. Geriatr. (2005). research: time to close the gap. J. Am. Psychiatry 11, 205–213 (2003). 45. Rudolph JL, Sallow MJ, Angelini MC, Geriatr. Soc. 43, 585–586 (1995). 40. Tune L, Coyle JT: Acute extrapyramidal side McGlinchey RE: The anticholinergic risk 36. Han L, McCusker J, Cole M, effects: serum levels of neuroleptics and scale and anticholinergic adverse effects in Abrahamowicz M, Primeau F, Elie M: anticholinergics. Psychopharmacology 75, older adults. Arch. Intern. Med. 168, Use of medications with anticholinergic 9–15 (1981). 508–513 (2008). effect predicts clinical severity of delirium 41. Boustani MA, Limbil T, Campbell N, • A good reference for the anticholinergic symptoms in older medical inpatients. Fox C, Maidment I: Anticholinergic risk scale,which is a good alternative Arch. Intern. Med. 161, 1099–1105 (2001). burden: measurement and impact. J. Am. to the Anticholinergic Cognitive 37. Fick DM, Cooper JW, Wade WE, Waller JL, Geriatr. Soc. 55, S52 (2007). Burden scale. Maclean JR, Beers MH: Updating the Beers 42. Bottigi KA, Salazar JC, Yu L et al.: criteria for potentially inappropriate Long-term cognitive impact of Website medication use in older adults: results of a anticholinergic medications in older 101. Boustani M, Peterson B, Hanson L, US consensus panel of experts. Arch. Intern. adults. Am. J. Geriatr. Psychiatry 14(11), Harris R, Krasnov C: Screening for Med. 163, 2716–2724 (2003). 980–984 (2006). dementia. Systematic evidence review. 38. Feinberg M: The problems of 43. Lim CJ, Trevino C, Tampi RR: Can Agency for Healthcare Research and anticholinergic adverse effects in olanzapine cause delirium in the Quality, Rockville, MD, USA (2003). older patients. Drugs Aging 3, 335–348 elderly? Ann. Pharmacother. 40, 135–138 www.ahrq.gov/clinic/uspstfix.htm (1993). (2006).

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