Skip to content

Advertisement

  • Research article
  • Open Access
  • Open Peer Review

An anticholinergic burden score for German prescribers: score development

BMC Geriatrics201818:239

https://doi.org/10.1186/s12877-018-0929-6

  • Received: 13 December 2017
  • Accepted: 26 September 2018
  • Published:
Open Peer Review reports

Abstract

Background

Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level.

Methods

A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well.

Results

The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects.

Conclusions

The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.

Keywords

  • Anticholinergic
  • Geriatrics
  • Anticholinergic scales
  • Anticholinergic burden
  • Germany
  • Expert opinion
  • Potentially inappropriate medicine

Background

Studies show that over 50% of elderly patients take five or more drugs, both prescription and over-the-counter [1]. A cross-sectional study in Germany revealed further that 62% of people aged 65 or older suffer from multimorbidity [2]. This combination of multimorbidity and polypharmacy leads to a higher risk for drug-drug interactions and adverse drug reactions (ADRs) [3, 4]. Hence, the use of drugs should be considered carefully in geriatric patients. Part of this consideration should be to avoid potentially inappropriate medications.

Drugs with anticholinergic properties are part of inappropriate medications for geriatric patients [5, 6]. Anticholinergic activity of multiple drugs add up to the so-called anticholinergic burden (ACB). Older patients are more prone to anticholinergic side effects than younger patients [5, 6]. Due to reduced metabolic capacity and slowed elimination in older patients, drugs are eliminated slower, in addition to age-related reductions in cholinergic transmissions [5, 6]. The permeability of the blood-brain-barrier increases which leads to a higher drug concentration in the central nervous system [7]. Central nervous ADRs may especially increase the risk of falls, e.g. blurred vision, confusion, or tremors [6]. More severe anticholinergic side effects are tachyarrhythmia, hallucinations, delirium, and cognitive impairment [6]. Other ADRs like dry mouth, constipation, and urinary retention might reduce the quality of life [6]. Several reviews indicate a higher risk for falls, cognitive decline and delirium with an increased ACB of older patients [812].

Despite these apparent risks it is estimated that approximately 50% of elderly people take anticholinergic medications [13, 14]. Qualitative studies demonstrated that very few prescribers are aware of the anticholinergic properties of drugs and of the nature of anticholinergic side effects [15]. Even if they know about the negative impact of anticholinergic medications, they hesitate to deprescribe or change those drugs as they do not feel responsible or lack time, knowledge, and resources [16]. In clinical practice there is rarely a registration, documentation and/or conscious reduction of the ACB [15, 17].

Worldwide studies identified over 100 different drugs as having anticholinergic properties [9, 10, 1833]. Depending on study population, method, and setting, there are different drug lists and different scales to calculate the ACB [18, 19]. The variety of scales and systems complicates the implementation in practice.

Therefore, the current study aimed to develop an anticholinergic burden score specifically for the German healthcare system. This, in turn, can help German prescribers identify and reduce drugs with anticholinergic properties in geriatric patients in order to facilitate easy application in the daily clinical setting. To our knowledge a specific ACB score for Germany is not yet available.

Methods

To identify appropriate tools, PubMed was searched for systematic reviews on tools to quantify anticholinergic drug burden. The search terms were “review AND anticholinergic burden AND (scale OR list OR tool)” without a date limitation. The search was conducted on December 1, 2016. The search and identification process is presented in Fig. 1. Articles were excluded if they were not systematic reviews on tools to quantify anticholinergic drug burden or the language was not English. Three systematic reviews [11, 18, 34] were included identifying 12 tools to quantify anticholinergic burden [10, 2026, 32, 33, 35, 36]. Tools were excluded because the scoring system was not comparable to the other tools [33, 36], the tool was outdated, [35] there was an updated version published [32], or the scoring was solely based on serum assays [25]. Literature reviews and meta-analysis failed to show an association of serum anticholinergic activity and anticholinergic effects [37], whereas there is an association shown for anticholinergic drug scores mainly based on expert opinion [812, 27]. To avoid missing relevant tools, the excluded articles were reviewed regarding more tools as they all evaluated the association of anticholinergic drugs and negative outcomes in patients [9, 19, 27, 38, 39]. These reviews identified four further tools, all ineligible for inclusion because (1) it was impossible to access the drug list despite contacting the authors [28, 31], (2) the scoring system was not comparable to other drug lists [29], and (3) the study assessed the overall medication of patients not specific drugs [30]. The included anticholinergic drug lists were summarized and reduced to drugs available in Germany [10, 2024, 26]. For Boustani et al. an updated version was included [10, 40].
Fig. 1
Fig. 1

Identification of tools

The approach to merge the identified scales was similar to the approach of Duran et al. [18]. For all scales, quantitative grading scores proposed by the authors were extracted. Most lists used scores ranging from 0 to 3, one was modified according to Duran et al. so that its 0–4 scale was comparable to 0–3 scales [18, 24]. Topical, ophthalmic, otic and nasal drugs were excluded, while oral, parenteral, inhalative and transdermal drugs were included as these are more likely to show systemic effects [41]. As these lists have only low to moderate concordance, the algorithm depicted in Fig. 2 was used to get a consistent scoring.
Fig. 2
Fig. 2

Algorithm for consistent scoring

Where further evaluation was needed as existing lists scored them differently or only one of the scores evaluated that specific drug., one researcher (EK) looked at the mechanism of action and the ADRs as reported in the German Summary of Product Characteristics and DRUGDEX® (expert-reviewed database for detailed drug information) to assess the anticholinergic properties of the respective drug. This assessment, the existing scores and the scoring by Duran et al. [18] were discussed in a multidisciplinary team of one geriatrician and two clinical pharmacists. This discussion led to a final score. Each drug was coded according to the Anatomical, Therapeutic and Chemical (ATC) Classification from the World Health Organization. If there were discrepancies in rating within the same drug class, we reconsidered some ratings as well.

In order to tailor the ACB list to the clinical setting a retrospective evaluation of admission and discharge medication on an acute geriatric ward identified a range of further drugs. Consecutive patients for two 6-week-periods were included, which meant the admission and discharge medication of 34 patients was evaluated. The patients were prescribed a total of 235 drugs at admission and 276 drugs at discharge. All drugs thus identified that were not mentioned in the reviewed scales were evaluated for their anticholinergic properties as described above. Based on our final anticholinergic drug list, we designed a pocket-sized guideline for prescribers with information on anticholinergic drugs, anticholinergic side effects and recommendations how to assess and handle the ACB of patients on ward. The recommendation was based on the approach of Boustani et al. and is presented in Fig. 3 [10].
Fig. 3
Fig. 3

Recommendation for prescribers on pocket-card based on Boustani et al. [10]

The anticholinergic scores of all drugs used by a patient were calculated in total. If one drug scored 3 or the patient had a summated score of 3 or higher, it was recommended to switch to alternative drugs with a lesser ACB score in order to reduce the summated score to < 3 [10]. If discontinuation or switching was not possible, a dose reduction and/or monitoring for ADRs were advised. Through the upper limit of score 3, the suggested ceiling effect of the ACB is included [19]. This means that at a high ACB, drug effects are assumed to reach a plateau even when the number of anticholinergic drugs further increases [19].

Results

The summary of existing anticholinergic drug lists [2024, 26, 40] resulted in a list of 692 different drugs with 548 available in Germany (for excluded, international drugs see Additional file 1: Table S1). In total, 67 drugs were excluded because they were rated for topical, nasal, ophthalmic, or otic application only, or were drug combinations (Additional file 1: Table S2).

In terms of effect, 334 of the drugs were categorised as having no anticholinergic effects (ACB score = 0), 77 of the drugs were scored as displaying weak anticholinergic effects (ACB score = 1), 10 as moderate anticholinergic effects (ACB score = 2) and 27 as strong anticholinergic effects (ACB score = 3). These anticholinergic drugs are displayed in Table 1. Drugs rated as having no anticholinergic effects are available in the supplementary material.
Table 1

Anticholinergic drugs with concordant ratings of sores

Drug

ATC-Code

Carnahan 2006 USA [20]

Ancelin 2006 France [21]

Rudolph 2008 USA [22]

Han 2008 USA [23]

Ehrt 2010 Norway modified [24]

Sittironnarit 2011 Australia [26]

Boustani 2012 USA [40]

Duran 2013 [18]

Weak anticholinergic effects ACB score 1

 Ampicillin

J01CA01

1

      

0 or 1

 Aripiprazole

N05AX12

     

0

1

 

 Atenolol

C07AB03

0

  

1

0

0

1

0

 Azathioprine

L04AX01

1

      

0 or 1

 Benazepril

C09AA07

0

  

1

   

0 or 1

 Betaxolol

C07AB05

   

1

 

0

 

0 or 1

 Bisacodyl

A06AB02

0

    

1

 

0 or 1

 Bromocriptine

N04 BC01

1

   

0

  

weak(1–2)

 Bupropion

N06AX12

0

  

1

  

1

0 or 1

 Captopril

C09AA01

1

   

0

0

1

0 or 1

 Celecoxib

M01AH01

0

    

1

 

0 or 1

 Chlordiazepoxide

N05BA02

1

  

1

   

weak(1–2)

 Chlorthalidone

C03BA04

1

    

0

1

0 or 1

 Ciclosporin

L04 AD01

1

      

0 or 1

 Citalopram

N06AB04

0

   

1

1

 

weak(1–2)

 Clindamycin

J01FF01

1

      

0 or 1

 Clonazepam

N03AE01

1

    

1

 

weak(1–2)

 Dexamethasone

H02AB02

1

    

0

 

0 or 1

 Dextromethorphan

R05DA09

0

  

1

   

0 or 1

 Diazepam

N05BA01

1

  

1

1

1

1

weak(1–2)

 Digitoxin

C01AA04

1

   

1

  

weak(1–2)

 Diltiazem

C08DB01

1

    

0

 

0 or 1

 Dipyridamole

B01AC07

1

   

0

 

1

0 or 1

 Domperidone

A03FA03

     

1

 

weak(1–2)

 Entacapone

N04BX02

0

 

1

    

weak(1–2)

 Escitalopram

N06AB10

0

    

1

 

0 or 1

 Famotidine

A02BA03

1

    

0

 

0 or 1

 Fentanyl

N02AB03

1

     

1

weak(1–2)

 Flunitrazepam

N05CD03

    

1

  

0 or 1

 Fluoxetine

N06AB03

1

  

1

1

1

 

weak(1–2)

 Flurazepam

N05CD01

1

      

0 or 1

 Fluvoxamine

N06AB08

1

   

1

1

1

weak(1–2)

 Gentamicin

J01GB03

1

      

0 or 1

 Guaifenesin

R05CA03

0

  

1

   

0 or 1

 Hydralazine

C02DB02

1

    

0

1

0 or 1

 Hydrocortisone

H02AB09

1

     

1

0 or 1

 Isosorbide dinitrate

C01DA08

1

   

0

0

 

0 or 1

 Isosorbide mononitrate

C01DA14

1

    

0

 

0 or 1

 Ketorolac

M01AB15

   

1

   

weak(1–2)

 Lansoprazole

A02BC03

0

   

1

0

 

0 or 1

 Levodopa

N04BA01

0

 

1

1

0

0 or 1

 

0 or 1

 Lithium

N05AN01

0

    

1

 

weak(1–2)

 Lorazepam

N05BA06

1

      

0 or 1

 Metformin

A10BA02

0

    

1

 

0 or 1

 Methotrexate

L04AX03

0

    

1

 

0 or 1

 Methylprednisolone

H02AB04

1

    

0

 

0 or 1

 Metoprolol

C07AB02

0

  

1

0

0

1

0

 Midazolam

N05CD08

1

      

0 or 1

 Mirtazapine

N06AX11

0

 

1

    

weak(1–2)

 Morphine

N02AA01

1

  

1

  

1

weak(1–2)

 Naratriptan

N02CC02

     

1

 

0 or 1

 Nifedipine

C08CA05

1

   

0

0

1

0

 Oxazepam

N05BA04

1

   

0

1

 

0 or 1

 Oxycodone

N02AA05

1

  

1

 

1

 

weak(1–2)

 Pancuronium

M03 AC01

1

      

0 or 1

 Phenobarbital

N03AA02

0

  

1

1

  

0 or 1

 Piperacillin

J01CA12

1

      

0 or 1

 Pramipexole

N04 BC05

0

 

1

 

0

  

0 or 1

 Prednisolone

A07EA01

1

   

0

0

 

0 or 1

 Prednisone

A07EA03

1

     

1

 

 Quinidine

C01BA01

0

     

1

 

 Risperidone

N05AX08

0

 

1

1

 

1

1

weak(1–2)

 Selegiline

N04BD01

0

 

1

 

0

  

0 or 1

 Sertraline

N06AB06

1

  

1

0

0

 

0

 Sumatriptan

N02CC01

     

1

 

0 or 1

 Temazepam

N05CD07

1

    

1

 

weak(1–2)

 Trandolapril

C09AA10

0

  

1

 

0

 

0 or 1

 Trazodone

N06AX05

0

 

1

1

  

1

weak(1–2)

 Triamcinolone

H02AB08

1

    

0

 

0 or 1

 Triamterene

C03DB02

1

    

0

1

0 or 1

 Triazolam

N05CD05

1

  

1

   

weak(1–2)

 Valproic acid

N03AG01

1

    

0

 

0 or 1

 Vancomycin

J01XA01

1

      

0 or 1

 Venlafaxine

N06AX16

0

  

1

0

1

1

0

 Warfarin

B01AA03

1

   

0

0

1

0

 Ziprasidone

N05AE04

  

1

    

0 or 1

 Zolmitriptan

N02CC03

     

1

 

0 or 1

Moderate anticholinergic effects ACB score 2

 Amantadine

N04BB01

1

 

2

   

2

weak(1–2)

 Cimetidine

A02BA01

2

 

2

   

1

weak(1–2)

 Loperamide

A07DA03

1

 

2

1

 

1

1

weak(1–2)

 Loxapine

N05AH01

2

     

2

weak(1–2)

 Methadone

N07 BC02

   

2

   

weak(1–2)

 Oxcarbazepine

N03AF02

2

     

2

weak(1–2)

 Pimozide

N05AG02

2

     

2

weak(1–2)

 Ranitidine

A02BA02

2

 

1

2

1

1

1

weak(1–2)

 Theophylline

R03DA04

1

2

  

1

2

1

weak(1–2)

 Tramadol

N02AX02

1

  

2

 

2

 

weak(1–2)

Strong anticholinergic effects ACB score 3

 Amitriptyline

N06AA09

3

3

3

3

3

3

3

Strong(3)

 Atropine

A03BA01

3

 

3

3

 

3

3

Strong(3)

 Chlorpheniramine

R06AB04

3

3

3

3

 

3

3

Strong(3)

 Clemastine

R06AA04

3

     

3

Strong(3)

 Clomipramine

N06AA04

3

3

    

3

Strong(3)

 Clozapine

N05AH02

3

 

2

 

3

 

3

Strong(3)

 Cyproheptadine

R06AX02

2

 

3

  

3

2

Strong(3)

 Darifenacin

G04BD10

3

     

3

Strong(3)

 Dimenhydrinate

A04AB02

3

     

3

Strong(3)

 Diphenhydramine

A04AB05

3

 

3

3

  

3

Strong(3)

 Doxepin

N06AA12

3

  

3

3

3

3

Strong(3)

 Flavoxate

G04BD02

3

     

3

Strong(3)

 Hydroxyzine

N05BB01

3

3

3

   

3

Strong(3)

 Imipramine

N06AA02

3

3

3

3

 

3

3

Strong(3)

 Levomepromazine

N05AA02

2

3

    

2

Strong(3)

 Nortriptyline

N06AA10

3

 

2

3

2

 

3

Strong(3)

 Orphenadrine

N04AB02

3

3

  

3

 

3

Strong(3)

 Oxybutynin

G04BD04

3

3

3

 

3

2

3

Strong(3)

 Procyclidine

N04AA04

3

      

Strong(3)

 Scopolamine

A04AD01

3

  

3

  

3

Strong(3)

 Thioridazine

N05 AC02

3

 

3

3

3

 

3

Strong(3)

 Tizanidine

M03BX02

  

3

    

Strong(3)

 Tolterodine

G04BD07

3

 

2

3

 

3

3

Strong(3)

 Trihexyphenidyl

N04AA01

3

3

 

3

3

 

3

Strong(3)

 Trimipramine

N06AA06

3

3

  

3

 

3

Strong(3)

Drugs are sorted by their assigned score and then alphabetical

Further evaluation was required for 35 drugs. After consideration of adverse drug reactions and mechanism of action, we scored one drug with no anticholinergic effects (ACB score = 0), 22 drugs with weak anticholinergic effects (ACB score = 1), eight as moderate anticholinergic effects (ACB score = 2), and four as having strong anticholinergic effects (ACB score = 3). See Table 2 for specific drugs.
Table 2

Scoring of drugs with discrepant ratings (=ratings differed more than 1 score) or only one previous scoring

Drug

ATC-Code

Carnahan 2006 USA [20]

Ancelin 2006 France [21]

Rudolph 2008 USA [22]

Han 2008 USA [23]

Ehrt 2010 Norway modified [24]

Sittironnarit 2011 Australia [26]

Boustani 2012 USA [40]

Duran 2013 [18]

No anticholinergic effects ACB score 0

 Colchicine

M04 AC01

0

3

   

0

1

discrepant

Weak anticholinergic effects ACB score 1

 Alprazolam

N05BA12

1

3

 

1

 

1

1

discrepant

 Asenapine

N05AH05

      

1

 

 Baclofen

M03BX01

0

 

2

2

   

1 or 2

 Cetirizine

R06AE07

0

 

2

2

 

2

1

1 or 2

 Clorazepate

N05BA05

1

3

    

1

discrepant

 Codeine

R05DA04

1

2

 

1

0

1

1

1 or 2

 Desloratadine

R06AX27

      

1

 

 Digoxin

C01AA05

1

3

  

1

1

1

discrepant

 Doxylamine

R06AA09

     

0

3

 

 Fexofenadine

R06AX26

0

  

2

 

2

0

1 or 2

 Fluphenazine

N05AB02

1

 

3

  

3

 

3

 Furosemide

C03CA01

1

3

  

1

0

1

discrepant

 Ipratropium inhalative

R03BB01

0

   

3

  

3

 Levocetirizine

R06AE09

      

1

 

 Loratadine

R06AX13

0

 

2

1

 

1

1

1 or 2

 Methocarbamol

M03BA03

  

1

1

  

3

1 or 2

 Metoclopramide

A03FA01

0

 

1

3

0

1

 

discrepant

 Paliperidone

N05AX13

      

1

 

 Perphenazine

N05AB03

1

 

3

2

0

 

3

discrepant

 Promethazine

R06AD02

3

 

3

  

0

3

3

 Pseudoephedrine

R01BA02

0

    

2

 

0 oder 1

 Tiotropium inhalative

R03BB04

     

0

  

Moderate anticholinergic effects ACB score 2

 Carbamazepine

N03AF01

2

  

1

0

0

2

1 or 2

 Haloperidol

N05 AD01

0

 

1

 

0

2

1

1 or 2

 Maprotiline

N06AA21

 

3

     

discrepant

 Pethidine

N02AB02

2

   

0

 

2

1 or 2

 Olanzapine

N05AH03

1

 

2

1

2

 

3

1 or 2

 Opipramol

N06AA05

 

3

     

discrepant

 Paroxetine

N06AB05

1

 

1

2

2

2

3

1 or 2

 Quetiapine

N05AH04

0

 

1

2

1

 

3

1 or 2

Strong anticholinergic effects ACB score 3

 Fesoterodine

G04BD11

      

3

 

 Propiverine

G04BD06

      

3

 

 Solifenacin

G04BD08

     

0

3

 

 Trospium

G04BD09

      

3

 

Drugs are sorted first by their assigned score and then alphabetical

During the retrospective evaluation, 26 drugs were identified that were not yet scored by these already existing scores. Parallel to drugs with inconsistent scores, the adverse drug reactions and the mechanism of action were reviewed and the drugs discussed by three researchers to score the drugs. Five drugs were scored as weak anticholinergic effects (ACB score = 1) and 21 drugs were categorised as having no anticholinergic effects (ACB score = 0). See Table 3 for specific drugs.
Table 3

Drugs added during retrospective evaluation

Drug

ATC-Code

No anticholinergic effects ACB score 0

 Agomelatine

N06AX22

 Apixaban

B01FAF02

 Colecalciferol

A11CC05

 Dabigatran

B01AE07

 Dulaglutide

A10BJ05

 Edoxaban

B01AF03

 Empagliflozin

A10BK03

 Fenoterol inhalative

R03AC04

 Formoterol inhalative

R03AC13

 Metamizole

N02BB02

 Saccharomyces boulardii

A07FA02

 Phenprocoumon

B01AA04

 Pipamperone

N05 AD05

 Piritramide

N02 AC03

 Rivaroxaban

B01AF01

 Sevelamer

V03AE02

 Sitagliptin

A10BH01

 Teriparatide

H05AA02

 Thiamazole

H03BB02

 Tilidine/Naloxone

N02AX51

 Vemurafenib

L01XE15

Weak anticholinergic effects ACB score 1

 Aclidinium inhalative

R03BB05

 Dimetindene

R06AB03

 Etoricoxib

M01AH05

 Glycopyrronium inhalative

R03BB06

 Rotigotine patch

N04 BC09

Drugs are sorted by their assigned score and then alphabetical

Table 4 shows all drugs scored sorted by their score. Additional file 1: Table S3 shows all drugs scored 0.
Table 4

Overview of all drugs scored. Caution: This list does not contain necessarily all drugs with anticholinergic properties

ACB score = 1

ACB score = 2

ACB score = 3

Aclidiniuminh

Alprazolam

Ampicillin

Aripiprazole

Asenapine

Atenolol

Azathioprine

Baclofen

Benazepril

Betaxolol

Bisacodyl

Bromocriptine

Bupropion

Captopril

Celecoxib

Cetirizine

Chlordiazepoxide

Chlorthalidone

Ciclosporin

Citalopram

Clindamycin

Clonazepam

Clorazepate

Codeine

Desloratadine

Dexamethasone

Dextromethorphan

Diazepam

Digitoxin

Digoxin

Diltiazem

Dimetindene

Dipyridamole

Domperidone

Doxylamine

Entacapone

Escitalopram

Etoricoxib

Famotidine

Fentanyl

Fexofenadine

Flunitrazepam

Fluoxetine

Fluphenazine

Flurazepam

Fluvoxamine

Furosemide

Gentamicin

Glycopyrroniuminh

Guaifenesin

Hydralazine

Hydrocortisone

Ipratropiuminh

Isosorbide dinitrate

Isosorbide mononitrate

Ketorolac

Lansoprazole

Levocetirizine

Levodopa

Lithium

Loratadine

Lorazepam

Metformin

Methocarbamol

Methotrexate

Methylprednisolone

Metoclopramide

Metoprolol

Midazolam

Mirtazapine

Morphine

Naratriptan

Nifedipine

Oxazepam

Oxycodone

Paliperidone

Pancuronium

Perphenazine

Phenobarbital

Piperacillin

Pramipexole

Prednisolone

Prednisone

Promethazine

Pseudoephedrine

Quinidine

Risperidone

Rotigotine patch

Selegiline

Sertraline

Sumatriptan

Temazepam

Tiotropiuminh

Trandolapril

Trazodone

Triamcinolone

Triamterene

Triazolam

Valproic acid

Vancomycin

Venlafaxine

Warfarin

Ziprasidone

Zolmitriptan

Amantadine

Carbamazepine

Cimetidine

Haloperidol

Loperamide

Loxapine

Maprotiline

Methadone

Olanzapine

Opipramol

Oxcarbazepine

Paroxetine

Pethidine

Pimozide

Quetiapine

Ranitidine

Theophylline

Tramadol

Amitriptyline

Atropine

Chlorpheniramine

Clemastine

Clomipramine

Clozapine

Cyproheptadine

Darifenacin

Dimenhydrinate

Diphenhydramine

Doxepin

Fesoterodine

Flavoxate

Hydroxyzine

Imipramine

Levomepromazine

Nortriptyline

Orphenadrine

Oxybutynin

Procyclidine

Propiverine

Scopolamine

Solifenacin

Thioridazine

Tizanidine

Tolterodine

Trihexyphenidyl

Trimipramine

Trospium

inhinhalative

Discussion

To our knowledge, this is the first ACB score developed especially for prescribers in Germany. There have been similar international publications [18, 27]. The drugs most commonly used in Germany differ from other countries especially England, USA, and Australia, where many published studies on anticholinergic drugs were conducted. Our ACB score did not only summarize existing scores but re-evaluated the drugs, especially those with discrepancies, and reduced the list to those authorized in Germany. This saves valuable time and effort for clinicians trying to evaluate anticholinergic burden in patients.

The scores used were identified via a systematic literature search in pubmed. This systematic approach should ensure a replicable and complete choice of peer-reviewed and published ACB scores, although it was not a systematic literature review conducted in different databases. All included scores were previously validated. Drug evaluation was based on expert opinion which was previously preferred to measuring serum assays [18, 27]. This expert review of the drugs by three different people (one geriatrician and two clinical pharmacists) based on clinical experience and literature data on method of action and ADRs strengthens the development of this score. Scoring was confirmed by the expert committee not only for drugs with discrepancies, but also for drugs that were only scored by one of the existing scores. Being rated by only one score is not necessarily a limitation as the individual selection of drugs is always depending on the country, the setting, and other specifics of the score development.

As our score is based on previously published ACB scores and drugs within our hospital during a retrospective evaluation, we do not claim this list to be comprehensive. There are over 2000 drugs approved in Germany, so there are potentially more anticholinergic drugs not yet considered in this list. There were few drugs found in our retrospective evaluation that had not been rated by previously published ACB scores. Potential reasons for those drugs missing could be that the drugs were mainly used in Germany and not internationally, e.g. Metamizol sodium, or that the drugs were new on the market and not previously analysed, e.g. Apixaban. To address missing and potentially new anticholinergic drugs, updates are planned in follow-up projects.

The validity of selection of drugs with anticholinergic activity and the grading can be questioned. Among the selected scores there is a great variety in study design and setting. Different methods to assess and rate anticholinergic activity were used: product information, specialised literature on ADRs, review of literature, expert opinion as well as serum radio receptor assay, dissociation constant for cholinergic receptor and other laboratory data [10, 1824, 26, 40]. We worked with that variety by comparing different scores. As final decision on inclusion and rating of anticholinergic drugs was mainly a subjective decision of experts and not based on clinical outcomes, the ratings may be discussed further. Nevertheless, there is no approved methodology to measure the ACB and expert rating is preferred to measuring serum assays [27]. The list did not include topical, ophthalmic, otic or nasal drugs. It cannot be excluded that there might be systemic or local anticholinergic effects with these application routes.

The distinction of anticholinergic potency from 0 to 3 might not be the best method to quantify anticholinergic burden, but as most existing scores used this or a similar rating it was the only way to work with the existing lists [18, 19]. Through the upper limit of score 3, the suggested ceiling effect of the ACB was included [19]. This means that at a high ACB, drug effects are assumed to reach a plateau even when the number of anticholinergic drugs further increases [19]. For a more accurate evaluation of anticholinergic burden a finer distinction in some drug classes would be useful. Drug classes like tricyclic antidepressants or anticholinergics for urinary incontinence were all scored with a strong ACB (ACB = 3). Although those drugs all have a strong anticholinergic burden, some are more problematic than others. For example, Trospium should have less central reactions than other anticholinergics for urinary incontinence because of its quaternary chemical structure, but it still shows anticholinergic adverse effects and was rated having strong anticholinergic properties by Boustani et al. [40]. Another method to further refine the evaluation of ACB would be to consider the dosages of anticholinergic drugs via the Drug Burden Index [33]. A recently published cohort study of German older outpatients found a significant association of the drug Burden Index with Mini-Mental State Examination Score, Barthel index, Falls and use of laxatives [42]. We did not use this approach as it is more complicated and time-consuming to use in daily routine and it is not compatible with the scores used [11]. Our decision to apply the higher score (Fig. 2 step 3) might be questioned due to the automatic application of a higher anticholinergic rating. We decided to take this approach in order to avoid missing any drugs with anticholinergic properties.

Although a high anticholinergic burden should be avoided if possible, the deprescribing of anticholinergic drugs is not always possible. Some indications like for example urinary incontinence or some psychiatric indications require anticholinergic medications that cannot be easily subsidised by other non-anticholinergic drugs due to clinical reasons. While urinary incontinence can be handled well with non-pharmacological options, if pharmacological treatment is required anticholinergic drugs are the best options. Thus, this list should be considered as decision support for the prescriber rather than as a strict deprescribing directive.

Conclusion

Although anticholinergic burden is only one factor of many to consider in multimorbid geriatric patients, it is important to discuss anticholinergic burden and its effects. This list can be used in Germany and countries with similar drugs approved to assess the anticholinergic burden of geriatric patients. It is valuable for prescribers to use in the daily clinical setting as only drugs available in Germany are listed and data from different studies is merged into one table so that a quick overview is possible. Further cluster-randomised studies investigating whether the implementation of the list reduces anticholinergic side effects, falls or delirium are necessary for its validation.

Abbreviations

ACB: 

Anticholinergic burden

ADR: 

Adverse drug reaction

ATC: 

Anatomical, Therapeutic and Chemical

Declarations

Acknowledgements

We thank Carla Widman for language editing of the manuscript and all original authors for providing us with their drug lists. This research was supported within the interprofessional PhD-program Clinical Pharmacy, LMU Munich.

Funding

This research was co-funded by the Friedrich-Baur-Stiftung and the Stiftung Patient und Klinische Pharmazie, Munich, Germany.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Authors’ contributions

All authors (EKK, YMH, MD) conceived the idea for conducting the study. EKK conducted the database searches, extracted and summarized existing scores. All authors (EKK, YMH, MD) were involved in the evaluation process as outlined in the methods section. The final manuscript was written, checked, and approved by all authors (EKK, YMH, MD).

Ethics approval and consent to participate

The study was conducted according to ethical standards at university hospital of Munich. Formal ethical approval was obtained form the research ethics committee of the university hospital of Munich (534-16).

Consent to participate is not applicable.

Consent for publication

Not applicable.

Competing interests

EKK and MD declare that they have no competing interests. YMH received a research grant from the Friedrich-Baur-Stiftung.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Pharmacy, University Hospital, LMU Munich, Munich, Germany
(2)
Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany

References

  1. Kaufman D, Kelly J, Rosenberg L, Anderson T, Mitchell A. Recent patterns of medication use in the amulatory adult population of the United States. JAMA. 2002;287:337–44.View ArticleGoogle Scholar
  2. van den Bussche H, Schaefer I, Koller D, Hansen H, von Leitner E-C, Scherer M, Wegscheider K, Glaeske G, Schoen G. Multimorbidity in the German elderly population - part 1: prevalence in ambulatory medical care. ZFA (Stuttgart). 2012;88(9):365–71.Google Scholar
  3. Field TS, Gurwitz JH, Harrold LR, Rothschild J, DeBellis KR, Seger AC, Auger JC, Garber LA, Cadoret C, Fish LS, et al. Risk factors for adverse drug events among older adults in the ambulatory setting. J Am Geriatr Soc. 2004;52(8):1349–54.View ArticleGoogle Scholar
  4. Maher RL, Hanlon J, Hajjar ER. Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf. 2014;13(1):57–65.View ArticleGoogle Scholar
  5. Feinberg M. The problems of anticholinergic adverse effects in older patients. Drugs Aging. 1993;3(4):335–48.View ArticleGoogle Scholar
  6. Mintzer J, Burns A. Anticholinergic side-effects of drugs in elderly people. J R Soc Med. 2000;93:457–62.View ArticleGoogle Scholar
  7. Schliebs R, Arendt T. The cholinergic system in aging and neuronal degeneration. Behav Brain Res. 2011;221(2):555–63.View ArticleGoogle Scholar
  8. Fox C, Smith T, Maidment I, Chan WY, Bua N, Myint PK, Boustani M, Kwok CS, Glover M, Koopmans I, et al. Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality: a systematic review. Age Ageing. 2014;43(5):604–15.View ArticleGoogle Scholar
  9. Ruxton K, Woodman RJ, Mangoni AA. Drugs with anticholinergic effects and cognitive impairment, falls and all-cause mortality in older adults: a systematic review and meta-analysis. Br J Clin Pharmacol. 2015;80(2):209–20.View ArticleGoogle Scholar
  10. Boustani M, Campbell N, Munger S, Maidment I, Fox C. Impact of anticholinergics on the aging brain: a review and practical application. Aging Health. 2008;4(3):311–20.View ArticleGoogle Scholar
  11. Cardwell K, Hughes CM, Ryan C. The association between anticholinergic medication burden and health related outcomes in the ‘oldest old’: a systematic review of the literature. Drugs Aging. 2015;32(10):835–48.View ArticleGoogle Scholar
  12. Marcum ZA, Wirtz HS, Pettinger M, LaCroix AZ, Carnahan R, Cauley JA, Bea JW, Gray SL. Anticholinergic medication use and falls in postmenopausal women: findings from the women's health initiative cohort study. BMC Geriatr. 2016;16:76.View ArticleGoogle Scholar
  13. Best O, Gnjidic D, Hilmer SN, Naganathan V, McLachlan AJ. Investigating polypharmacy and drug burden index in hospitalised older people. Intern Med J. 2013;43(8):912–8.View ArticleGoogle Scholar
  14. Fox C, Richardson K, Maidment ID, Savva GM, Matthews FE, Smithard D, Coulton S, Katona C, Boustani MA, Brayne C. Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study. J Am Geriatr Soc. 2011;59(8):1477–83.View ArticleGoogle Scholar
  15. Mayer T, Haefeli WE, Seidling HM. Vorgehen bei der Erkennung, Bewertung und Vermeidung anticholinerger Nebenwirkungen - eine Querschnittsbefragung unter Ärzten. Krankenhauspharmazie. 2017;38(2):111.Google Scholar
  16. Kouladjian L, Gnjidic D, Reeve E, Chen TF, Hilmer SN. Health care Practitioners’ perspectives on Deprescribing anticholinergic and sedative medications in older adults. Ann Pharmacother. 2016;50(8):625–36.View ArticleGoogle Scholar
  17. Navila C. Using a “MAP” to steer patients away from medicines-related falls. Clin Pharm. 2013;5:119–21.Google Scholar
  18. Duran CE, Azermai M, Vander Stichele RH. Systematic review of anticholinergic risk scales in older adults. Eur J Clin Pharmacol. 2013;69(7):1485–96.View ArticleGoogle Scholar
  19. Mayer T, Haefeli WE, Seidling HM. Different methods, different results--how do available methods link a patient's anticholinergic load with adverse outcomes? Eur J Clin Pharmacol. 2015;71(11):1299–314.View ArticleGoogle Scholar
  20. Carnahan RM, Lund BC, Perry PJ, Pollock BG, Culp KR. The anticholinergic drug scale as a measure of drug-related anticholinergic burden: associations with serum anticholinergic activity. J Clin Pharmacol. 2006;46(12):1481–6.View ArticleGoogle Scholar
  21. Ancelin ML, Artero S, Portet F, Dupuy AM, Touchon J, Ritchie K. Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study. BMJ. 2006;332(7539):455–9.View ArticleGoogle Scholar
  22. Rudolph JL, Salow MJ, Angelini MC, McGlinchey RE. The anticholinergic risk scale and anticholinergic adverse effects in older persons. Arch Intern Med. 2008;168(5):508–13.View ArticleGoogle Scholar
  23. Han L, Agostini JV, Allore HG. Cumulative anticholinergic exposure is associated with poor memory and executive function in older men. J Am Geriatr Soc. 2008;56(12):2203–10.View ArticleGoogle Scholar
  24. Ehrt U, Broich K, Larsen JP, Ballard C, Aarsland D. Use of drugs with anticholinergic effect and impact on cognition in Parkinson's disease: a cohort study. J Neurol Neurosurg Psychiatry. 2010;81(2):160–5.View ArticleGoogle Scholar
  25. Chew ML, Mulsant BH, Pollock BG, Lehman ME, Greenspan A, Mahmoud RA, Kirshner MA, Sorisio DA, Bies RR, Gharabawi G. Anticholinergic activity of 107 medications commonly used by older adults. J Am Geriatr Soc. 2008;56(7):1333–41.View ArticleGoogle Scholar
  26. Sittironnarit G, Ames D, Bush AI, Faux N, Flicker L, Foster J, Hilmer S, Lautenschlager NT, Maruff P, Masters CL, et al. Effects of anticholinergic drugs on cognitive function in older Australians: results from the AIBL study. Dement Geriatr Cogn Disord. 2011;31(3):173–8.View ArticleGoogle Scholar
  27. Salahudeen MS, Duffull SB, Nishtala PS. Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review. BMC Geriatr. 2015;15:31.View ArticleGoogle Scholar
  28. Aizenberg D, Sigler M, Weizman A, Barak Y. Anticholinergic burden and the risk of falls among elderly psychiatric inpatients: a 4-year case-control study. Int Psychogeriatr. 2002;14(3):307–10.View ArticleGoogle Scholar
  29. Minzenberg MJ, Poole JH, Benton C, Vinogradov S. Association of anticholinergic load with impairment of complex attention and memory in schizophrenia. Am J Psychiatry. 2004;161(1):116–24.View ArticleGoogle Scholar
  30. Whalley LJ, Sharma S, Fox HC, Murray AD, Staff RT, Duthie AC, Deary IJ, Starr JM. Anticholinergic drugs in late life: adverse effects on cognition but not on progress to dementia. J Alzheimers Dis. 2012;30(2):253–61.View ArticleGoogle Scholar
  31. Cancelli I, Valentinis L, Merlino G, Valente M, Gigli GL. Drugs with anticholinergic properties as a risk factor for psychosis in patients affected by Alzheimer's disease. Clin Pharmacol Ther. 2008;84(1):63–8.View ArticleGoogle Scholar
  32. Han L, McCusker J, Cole M, Abrahamowicz M, Primeau F, Élie M. Use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients. Arch Intern Med. 2001;161(8):1099.View ArticleGoogle Scholar
  33. Hilmer SN, Mager DE, Simonsick EM, Cao Y, Ling SM, Windham BG, Harris TB, Hanlon JT, Rubin SM, Shorr RI, et al. A drug burden index to define the functional burden of medications in older people. Arch Intern Med. 2007;167(8):781–7.View ArticleGoogle Scholar
  34. Villalba-Moreno AM, Alfaro-Lara ER, Perez-Guerrero MC, Nieto-Martin MD, Santos-Ramos B. Systematic review on the use of anticholinergic scales in poly pathological patients. Arch Gerontol Geriatr. 2016;62:1–8.View ArticleGoogle Scholar
  35. Summers WK. A clinical method of estimating risk of drug induced delirium. Life Sci. 1978;22(17):1511–6.View ArticleGoogle Scholar
  36. Dauphinot V, Faure R, Omrani S, Goutelle S, Bourguignon L, Krolak-Salmon P, Mouchoux C. Exposure to anticholinergic and sedative drugs, risk of falls, and mortality: an elderly inpatient, multicenter cohort. J Clin Psychopharmacol. 2014;34(5):565–70.View ArticleGoogle Scholar
  37. Salahudeen MS, Chyou TY, Nishtala PS. Serum anticholinergic activity and cognitive and functional adverse outcomes in older people: a systematic review and meta-analysis of the literature. PLoS One. 2016;11(3):e0151084.View ArticleGoogle Scholar
  38. Collamati A, Martone AM, Poscia A, Brandi V, Celi M, Marzetti E, Cherubini A, Landi F. Anticholinergic drugs and negative outcomes in the older population: from biological plausibility to clinical evidence. Aging Clin Exp Res. 2016;28(1):25–35.View ArticleGoogle Scholar
  39. Kersten H, Wyller TB. Anticholinergic drug burden in older people's brain - how well is it measured? Basic Clin Pharmacol Toxicol. 2014;114(2):151–9.View ArticleGoogle Scholar
  40. Aging Brain Program: Anticholinergic Cognitive Burden Scale 2012 Update. https://www.uea.ac.uk/documents/3306616/10940915/Anticholinergics/088bb9e6-3ee2-4b75-b8ce-b2d59dc538c2. Last accessed 3 Oct 2018.
  41. Singh S, Loke YK, Enright P, Furberg CD. Pro-arrhythmic and pro-ischaemic effects of inhaled anticholinergic medications. Thorax. 2013;68(1):114–6.View ArticleGoogle Scholar
  42. Mayer T, Meid AD, Saum KU, Brenner H, Schottker B, Seidling HM, Haefeli WE. Comparison of nine instruments to calculate anticholinergic load in a large cohort of older outpatients: association with cognitive and functional decline, falls, and use of laxatives. Am J Geriatr Psychiatry. 2017;25(5):531–40.View ArticleGoogle Scholar

Copyright

© The Author(s). 2018

Advertisement