Anticholinergic drugs are used to treat conditions such as Parkinson's disease, depression, nausea and vomiting, chronic obstructive pumonary disease (COPD), and pain. They work by blocking acetylcholine, a neurotransmitter found throughout the parasympathetic nervous system, which exerts its effects on the muscles via the motor neurons (Chancellor et al, 2012). In certain conditions, such as bladder instability or gastrointestinal disturbance, some drugs are prescribed specifically for their anticholinergic properties. Acetylcholine inhibits smooth muscle function in the gastrointestinal and urinary tracts, and in the lungs. An example of anticholinergic effects in the peripheral nervous system is reduced secretions, which can cause slowed gastrointestinal motility. This can lead to constipation, urinary retention, increased risk of infection, blurred vision, and increased heart rate. Anticholinergic effects on the central nervous system include sedation, confusion, poor concentration, agitation, hallucinations and cognitive decline (Tune, 2001). In the brain, acetylcholine is one of the chemicals that enable messages to be passed between neurons. Acetylcholine is thought to be one of the key neurotransmitters involved in memory and learning, and is much reduced in Alzheimer's disease. Older adults are more susceptible to anticholinergic effects as there is a reduction in the acetylcholine neurones and receptors in the brain with age (Pasina et al, 2013).
Anticholinergic drugs are commonly prescribed for a wide range of medical issues. Fox et al (2014) found that between 20-50% of older adults are prescribed at least one anticholinergic drug. Older adults are more susceptible to the unwanted effects of these drugs, and these effects are related to negative health outcomes (PrescQIPP, 2016).
Anticholinergic burden is the consequence of taking multiple medications with anticholinergic properties, and older adults with comorbidities are at increased risk for this (Salahudeen et al, 2015). Tune (2001) alludes to the ‘vicious circle’ of prescribing in response to side-effects of medications, also called ‘prescribing cascade’ (Rochon and Gurwitz, 2017). An example of this would be an older adult becoming constipated as a result of anticholinergic treatment for bladder instability. Constipation can cause agitation, particularly in those with cognitive impairment, because of the discomfort it causes. Agitation is sometimes treated using antipsychotic medication, which in itself has anticholinergic effects, thereby initiating the cascade.
Reviews of anticholinergic burden
In their review of 46 studies looking at the impact of anticholinergic burden on functioning, Fox et al (2014) found the strongest association between high anticholinergic load and adverse cognitive outcomes. There was little support from the literature that these drugs increase the risk of Mild Cognitive Impairment (MCI) developing into dementia. The majority of the studies reported a relationship between increased anticholinergic burden and reduced physical function, suggesting that avoiding anticholinergic drugs may preserve function and reduce the risk of adverse events such as falls. Chew et al (2008) looked at 107 medications commonly prescribed to older adults, and found that drugs blocking the muscarinic (cholinergic) receptors cause ‘impairment in various cognitive functions, including working memory, episodic memory, processing speed and praxis’, which in turn may lead to decline in physical functioning and falls.
In their comparison of different anticholinergic measurement scales, Dauphinot et al (2017) found that, in patients with dementia, anticholinergic exposure was associated with functional decline. When treating and managing behavioural disorders in dementia, psychotropic drugs are commonly used, such as small doses of antipsychotics for agitation and aggression. Such drugs have a high anticholinergic burden, therefore leading to an increase in central anticholinergic side-effects, such as sedation and confusion. The review also found that reduced performance on Mini Mental State Examination (MMSE) was associated with an increased anticholinergic burden. The authors suggested that the ‘optimisation of drugs prescription’, as well as the use of therapeutic alternatives, could be helpful (Dauphinot et al, 2017). ‘Medicines optimisation’ is a patient-focused, holistic approach, which involves conducting a review of an individual's prescription, to avoid the patient taking unnecessary drugs (Royal Pharmaceutical Society, 2013).
In a two-year longitudinal study of 13 000 men and women over 65 years of age, Fox et al (2011) found similar outcomes to Dauphinot et al (2017). They found that 47% of participants were taking medications that had potential anticholinergic properties and 4% were taking medications with definite anticholinergic properties. The drugs prescribed were ranked based on strength of anticholinergic activity and scored 0 (nil effect) to 3 (severe effect), using the Anticholinergic Cognitive Burden (ACB) scale (Boustani et al, 2008). The key findings of this study are shown in Table 1. Cognition was measured using the MMSE, with the main outcome measure being a decline in MMSE score at two years. They concluded that anticholinergic activity appears to increase the risk of both cognitive impairment and mortality in older adults.
Table 1: Key findings of two-year longitudinal study of use of anticholinergic drugs and cognitive impairment in older adults
| 20% of those taking anticholinergic drugs with a total burden score of 4+ had died by the end of the two year study, compared with 7% of those taking no anticholinergic drugs |
| For every additional burden point, the odds of dying increased by 26% |
| Those taking anticholinergic drugs with a combined score of 5+ scored 4% lower in cognitive function tests than those taking no anticholinergic drugs |
| Increased risks of anticholinergic drugs were shown to be cumulative |
| Those who were older, of lower social class, or had a greater number of health conditions tended to take the most anticholinergic drugs. |
From: Fox et al, 2011
Measuring Anticholinergic Burden
There is no single standard scale to aid the measurement of anticholinergic burden. The adverse effects of anticholinergics increase with larger drug doses, and multiple low-level anticholinergic drugs can add up to the same burden (or greater) as a single high-level drug (PrescQipp, 2016)
The Anticholinergic Risk Scale (ARS) is a means of ‘estimating the extent to which an individual patient may be at risk of anticholinergic adverse events’ and was developed by Rudolph et al (2008) using a review of the 500 most prescribed medications by a geriatrician and two geropharmacists. It ranks a total of 49 drugs according to their anticholinergic potential on a scale of 0 (limited/none) to 3 (very strong potential). Higher ARS scores were shown to be associated with adverse anticholinergic effects.
The ACB Scale (Boustani et al, 2008) was designed as a tool to aid in identifying the severity of adverse effects of anticholinergic drugs, particularly on cognition. It was developed from a systematic review of medical literature looking at medicines with known anticholinergic effects. The scale includes 88 drugs which are ranked 0-3 (0=no anticholinergic property known; 1=potential effect on cognition (given its affinity with muscarinic receptors in vitro); 2=moderate-severe effect on cognition but not causing confusion; 3=moderate-severe effect on cognition and causing confusion). In a comparison with the ACB Scale, Pasina et al (2013) found the ARS to be more specific than the ACB in ‘capturing medication associated with a higher degree of cognitive and functional impairment’. Both scales supported the hypothesis that the cumulative effects of anticholinergic drugs have a negative impact on the functioning of a sample of older adults. The scales' lists of medication differed in terms of the number of drugs included and the scoring of some medications, for example ACB scale includes drugs that have only serum anticholinergic activity, such as furosemide and warfarin, which have no clinically relevant cognitive effects.
The ARS was altered in several ways in 2014 to produce the modified ARS (mARS; Sumukadas et al, 2014). It was updated to include newer drugs available in the United Kingdom (drugs not available in the UK have been excluded). Medications rated as ‘moderate to severe risk’ on other scales, such as the ACB, were added, as well as those listed in the British National Formulary as having significant anticholinergic properties. It also now includes therapeutic alternatives, to assist the prescriber in optimising treatment.
Rudolph et al (2008) suggest that the primary use for the risk scale would be as a tool to identify patients in hospital who are at risk of developing adverse anticholinergic reactions, and as an educational aid to assist clinicians in identifying anticholinergic drugs, which would inform their prescribing decisions. The scale is easy to use as a reference tool; it provides the user with therapeutic alternatives to drugs causing anticholinergic burden.
An online tool, the Reference Anticholinergic Burden Scale (2019), provides users with a calculation of the anticholinergic burden score. These calculations used the highest scores where there was discrepancy between values (SIGN, 2015). The site is for ‘information purposes only’, however but may be beneficial to clinicians when reviewing medications on the ward. It is easy to navigate, and gives a quick calculation of the AC burden. It makes the assessment scale easily accessible in practice.
Once a patient has been identified as being at risk of developing adverse anticholinergic effects, a clinician should consider whether action needs to be taken to reduce this risk. PrescQIPP (2016) has made some recommendations in managing these cases, as shown in Table 2. In addition to stopping medication with suspected anticholinergic-induced cognitive impairment, repeating and comparing the MMSE to measure any improvement would be beneficial.
Table 2: Recommended actions in reducing anticholinergic burden
| General: |
| Identify older adults living with frailty on anticholinergic drugs |
| Minimise use of anticholinergic drugs where possible |
| If mARS score is 3 or more (either a single drug or combination of scores), informed decision should be made to either discontinue medication or switch to lower scoring anticholinergic drug/from a different classdrugs |
| Review at regular intervals for efficacy/tolerance |
| Those who were older, of lower social class, with the greater number of health conditions tended to take the most anticholinergic drugs. |
| Review medication in older people that have had a fall/are at increased risk of falls (as part of multifactorial risk assessment) |
| Use supportive polypharmacy resources |
| In patients with dementia: |
|---|
| Medication review to identify and minimise use of drugs which ay impact negatively on cognition |
| Avoid anticholinergic drugs with Acetylcholinesterase Inhibitors, such as donepezil. |
| If suspicion of anticholinergic-induced cognitive impairment, conduct MMSE (Folstein, 1975) and consider stopping/switching if confirmed/clinically appropriate. |
From: PrescQIPP, 2016
Anticholinergic burden in patients-a study
Background
The study aimed to explore whether anticholinergic burden was a feature in the presentation of patients referred to the MHL service. This team is based in an acute hospital of 1200 beds, and receives referrals from a variety of specialities including medicine for older people, orthopaedics, stroke rehabilitation, general medicine, respiratory and renal. The role of older person's practitioners is to review individuals primarily over the age of 65 with acute mental health needs. The team provides assessments, diagnosis and treatment recommendations, as well as supporting with complex discharge planning. Approximately one-quarter of referrals are for the assessment of individuals with cognitive impairment/confusion (as specified on referral) as reported by Trust data (Southern Health analytics Tableau database, 2019, data on file). There are also many patients in hospital assessed as being a fall risk, or who have been admitted as the result of a fall in the community. Anticholinergic agents can lead to falls because of sedation and dizziness, as well as blurred vision.
Methods
Two scoping exercises were undertaken. First, a retrospective review of referrals for older people to the Mental Health Liaison Service between January and March 2018, where the referral reason was ‘confusion and/or cognitive impairment’. Data was taken from the electronic patient record system. The team received a total of 222 referrals in this three month period; 65 referrals from this period were reviewed (29% of referrals received). This is a relatively small number, and doesn't reflct the number of patients we see with dementia and cognitive impairment overall. The aim of the study was to see whether there was a link between new confusion/changed confusion levels and anticholinergic burden.
Second, a review of drug charts of 30 inpatients in the older person's department of the acute hospital was conducted. The review looked at the elements in Table 3. 30 drugs charts were reviewed, with an equal gender split. The individuals were inpatients on two of the older people's medicine wards, and drug charts were randomly selected by picking notes from alternate beds.
Table 3 Elements considered in drug chart review
| Age | Older adults are more susceptible to the adverse anticholinergic effects (Pasine et al, 2013) anticholinergic effects (Pasine et al, 2013) |
| Evidence of cognitive impairment; whether there is a diagnosis of dementia/subtype | Anticholinergic exposure in individuals with dementia can cause a decline in functional ability (Dauphinot et al, 2017) |
| Presence of delirium during admission | This may continue to exacerbate confusion levels and risk of falls in older people (NICE, 2010) |
| History of falls | AC Burden can contribute to falls risk (Tune, 2001) |
| Prescribed medication | Admitted with; new; discontinued (and reason) |
| Total number of medications | Polypharmacy itself can lead to confusion and increased falls risk (Scottish Government, 2018) |
| Total number of psychotropic drugs | One of the ‘high risk’ classes of medication in terms of causes of confusion and falls (Scottish Government, 2018) |
| mARS score |
Finally, a further review was conducted to establish whether there was a three-way correlation between increased mARS score with increased numbers of medication and increased risk of falls.
Results
In the review of referrals, the average patient age was 83 years, with over two-thirds (n=45) being female. The average number of medications prescribed was seven (range 2-16 medicines), with one patient taking 16 different medicines. Of the 38 individuals assessed, 66% had an identified diagnosis of dementia or cognitive impairment and 73% were recorded as having a history of falls. Eighteen individuals scored against the mARS, with the average score being 2 (maximum score = 4).
Thirteen of the patients were taking 10 or more medications. Although this was only a small number, there did appear to be a correlation between an increased mARS score with and increased number of medications (Figure 1). The remainder of those assessed were on an average of six medications, with an average mARS score of less than one.
In the review of drug charts, the average patient age was 87 years. The average number of medications prescribed was seven (range 1-14 medicines), with two patients prescribed 14 drugs. 43% showed evidence of cognitive impairment (with 53% of these patients having a pre-existing diagnosis of dementia). 56% of patients were at risk of falls. When assessed against the mARS, 50% scored, with the average being 2.3; the maximum score was 8.
Again, the data suggested that there was a correlation between increased numbers of medications and higher levels of anticholinergic burden (Figure 2). The remainder of the patients assessed were taking an average of four medications, and had an average mARS score of 0.
In the review of a three-way correlation, four individuals were found to score in all three domains, as shown in Table 4. One individual had a mARS score greater than three, was prescribed 12 medications, experienced recurrent falls and had cognitive impairment.
Table 4 Review of three-way correlation
| Age | Gender | Diagnosis | Falls history | No. prescribed medications | mARS score |
|---|---|---|---|---|---|
| 86-95 | F | Cognitive Impairment | <3 in 12months | 5 | 2 |
| 76-85 | M | Mixed Dementia | <3 in 12months | 8 | 2 |
| 86-95 | F | Alzheimer's Disease | <3 in 12months | 10 | 2 |
| 86-95 | F | Cognitive Impairment | <3 in 12months | 12 | 6 |
Case Study
A 78 year old patient was referred to the MHL service for a medication review in relation to psychotropic drugs, as she was experiencing:
- Reduced mobility
- Constipation
- Multifactorial falls (12 in the preceding year)
- Known postural hypotension
- Parkinsonism — likely drug-induced
- Polypharmacy.
In total, she was prescribed 18 medications, including five psychotropic drugs:
- Lithium 400mg nocte
- Venlafaxine 112.5mg daily
- Amitriptyline 30mg nocte
- Flupentixol 500mcg tds
- Chlorpromazine 50mg daily.
Guidelines for the management of depression support the augmentation of lithium with an antidepressant (NICE, 2017). In this case, amitriptyline was being used as an aid for sleep rather than as an additional antidepressant agent. The use of an antipsychotic alongside an antidepressant is also supported for treatment of depression, psychotic or non-psychotic, however guidance recommends the use of atypical drugs such as quetiapine or olanzapine (Taylor et al, 2015). She was also prescribed solifenicin, an antimuscarinic drug to treat an unstable bladder.
She had a history of recurrent depression and, on assessment, there was evidence of cognitive impairment, with an MMSE score of 11/30. The anticholinergic burden was calculated using the mARS, and her overall score was 10, indicating a significant effect. On speaking with her and her husband, there was a large amount of ‘record-keeping’ by her husband as to what drugs had been prescribed when, and for what symptoms. However, some of the medications were prescribed for inappropriate reasons, eg chlorpromazine (a first-generation antipsychotic) had been prescribed by a physician for ‘low mood’. The patient reported that she felt sluggish and ‘slowed’, feeling unsteady on her feet and not wanting to move too much as she feared falling. Her husband was aware that her physical health was being affected by her medication regime, however he expressed concern that, by altering the treatment, her mental state would decline. A discussion took place regarding possible medication changes. By spending time with the couple and explaining the impact of anticholinergic burden on both cognitive and physical functioning, both parties could understand the rationale behind the suggestions of change, with the anticipated outcome being some improvements in function. All changes were made with both the patient's and her husband's agreement.
Whilst she remained in hospital, the team reduced and stopped the chlorpromazine, and began reducing the amitriptyline. It was noted that her mental state appeared to improve, in that she became more engaged and animated. The therapy team also noted that her mobility was improving, becoming steadier with her zimmer frame.
By going through the assessment process, liaising with the husband regarding her prescribing history and educating them about the impact of treatment on her physical and mental well-being, the team was able to reduce the burden of anticholinergic activity with some positive results starting to emerge in the short-term. The role of a Non-Medical Prescriber in a liaison service is a privileged position where there is more opportunity to sit with families and discuss their overall treatment in detail. There is a greater ability to include them in the decision-making process around prescribing and de-prescribing, and to discuss the rationale behind the decisions.
Discussion
These scoping exercises give a snapshot of information around the prescribing of medication in older adults in a general hospital, and the probable correlation between high anticholinergic burden, cognitive impairment and falls risk. It also showed that those prescribed a large number of medications are likely to have a higher mARS score.
On completing these exercises it was evident that further education was required for colleagues. A teaching session was delivered to the MHL service, and the assessment proforma now includes the mARS score. This prompts practitioners to look at the whole prescription for an individual, as well as consideration of any prescribing additions made in terms of anticholinergic activity.
A training session has been delivered to the acute hospital's pharmacists, and we are hoping to work collaboratively on a project to incorporate the measurement of Anticholinergic Burden within the process of admission to the acute hospital. A teaching session for junior doctors has been requested, to raise awareness among the treating teams and again prompting consideration in prescribing decisions. I will also be presenting this project at the Trust's Non-Medical Prescribing Conference 2019 to raise awareness in other areas of prescribing and again, encourage consideration of the impact of such drugs on the patient's overall wellbeing.
Conclusion
My recommendation for the acute hospital setting would be that anticholinergic burden is calculated on admission to the acute hospital, so that rationalisation of medication regimes can happen as early as possible in a bid to optimise the individual's functioning. The Modified Anticholinergic Risk Scale needs to be more easily accessible to clinicians on the wards, either in hardcopy, or via the intranet. In collaboration with the pharmacy team, I hope to work with the hospital's IT team in making the Scale available to prescribers. Future studies could involve surveying a range of doctors in the acute hospital to assess their recognition of drugs associated with a high AC Burden, and an assessment of all referrals of older adults to the Mental Health Liaison Service.
Key Points
- Anticholinergic drugs are widely used for both mental and physical health conditions
- Anticholinergic burden negatively impacts physical and mental health in older adults, increasing morbidity
- A correlation is suggested between an increased anticholinergic burden, increased confusion, increased falls rate and the number of medications prescribed
- There is a need for education within the acute hospital medical teams regarding the impact of anticholinergic burden and how it is measured
- The Modified Anticholinergic Risk Scale should be made accessible to ward teams, and measurement of anticholinergic burden needs to be incorporated in the admission process.
CPD reflective questions
- In your area of practice, do the drugs you prescribe have anticholinergic action? Is it something you consider when making a prescribing decision?
- Could review of medication, with access to a measurement tool for anticholinergic burden, become part of your assessment? How could you make it routine?
- Consider a case you have managed where the individual was prescribed anticholinergic drugs: could you have altered the medication regime to reduce the burden and, potentially, improved their well-being?