Anticholinergic burden: where to from here?

This is the final article in a series on anticholinergic burden. Check out part 1 and part 2.

THERE is a cable car that runs all the way up the second tallest mountain in the Alps, 3.8 km above the town of Chamonix. The view is something to be seen: the summit overlooks France, Italy and Switzerland. But what is equally spellbinding is the cable car’s history. Opening in 1955, it was built by people traversing extreme peaks in treacherous icy conditions. Its very existence – and the vision to create it in the first place – was a great example of optimism and endeavour.

Back on terra firma here in sunny Australia, working as a doctor, we face peaks and barriers of our own (albeit less frosty and cinematic). In the past 2 weeks (here, here), I have shared some thoughts on how a well meaning and clinically pertinent concept – the anticholinergic burden of medication – proves harder to use in real-life than hoped. This is nobody’s fault; it has just evolved and meandered along this way.

To sum up my last two articles, the earliest anticholinergic burden scales (taken collectively) can be contradictory, hard to access and incomplete (not all drugs in the pharmacopoeia are listed).

Trying then to employ tools to help our patients steer clear of iatrogenic harm can feel a bit like scaling a medical mountain.

One of the most sapping things for doctors is that we are somewhat teased. On the one hand, we have copious older patients harmed by medicines; on the other, we learn with hope about ideas such as the anticholinergic burden (identifying questionable drugs, and even quantifying the severity of the problem). We put faith in these published concepts, hoping they represent definitive weapons in our fight against iatrogenesis. But if we subsequently realise that the clinical utility of a scale or tool is less than we’d hoped, and stop using it, we are stuck.

Consequently, deprescribing and medicine rationalisation remains as tricky as ever. Going further, I wonder whether small clinical disappointments such as this contribute ever-so-slightly to doctor burnout – the “death by 1000 paper cuts” or “many tiny betrayals of purpose”.

As a song once said, “I’m a believer”

That said, humans built Alpine cable cars, flew to the Moon and designed smartphones. And so, despite the difficulty we face with concepts such as the anticholinergic burden, the fires of optimism need not yet be fully extinguished.

I foresee a bright day when we hold whizzing, user-friendly applications in our hands as clinicians, allowing us to better recognise “problem” medicines and to quantify how much the patient may be at risk. Accordingly, I wanted to share a future vision of what an all-singing-and-dancing e-tool could look like in this regard.

To start with, it would be built on four principles.

It needs to expand past the anticholinergic burden of the pharmacopeia

What is our big picture vision here? Older people are the main protagonists in the iatrogenesis story, and so I’d argue it boils down to “let’s help doctors become aware of medications increasing the risk of falling or causing cognitive impairment”.

In this regard, it is germane to ponder that drugs can compromise older people in far-reaching ways – well beyond simply their anticholinergic activity. Consider:

• sedation (drugs such as valproate, topiramate, levetiracetam, pregabalin);
• hypotension;
• hypoglycaemia (especially sulphonylureas and insulin, versus reduced renal function);
• lowered seizure thresholds;
• muscle catabolism or myopathy (eg, statins, fibrates, prednisolone);
• hyponatraemia (eg, most antidepressants); and,
• drug-related parkinsonism (eg, metoclopramide, prochlorperazine).

As such, clearly there’s more to (iatrogenic) life than just anticholinergics. Taking this idea that harm can flow from a number of angles, it is noteworthy that wide-ranging lists of medications already exist – such as the STOPP criteria and the revised Beers list – flagging drugs probably best avoided in geriatric patients.

Notwithstanding, in an ideal world, we’d have a single tool able to broadly identify problematic drugs in older people, and to put numerical scores on attendant risk. In some ways, the Australian drug burden index stands out in this sense; it is a tool designed to transcend beyond just anticholinergic drugs, with sedatives added into its calculation. Unfortunately, however, use of the drug burden index has had its own acknowledged issues in terms of bedside utility.

It needs to be genuinely user-friendly and electronic

In the past, I used to print original anticholinergic scales on scrap paper for clinical use (before I stopped using them out of frustration). Some of the older scales were also not easily found; they were buried within academic papers or hidden behind a paywall. But nobody wants to carry disparate paper copies of drug-related scales these days, and so, clearly, it’d be best if tools designed to flag questionable drugs were produced in the form of a computerised program or app. Although it would be no small feat to design a mobile program capturing a wide array of risky drugs in older people (beyond anticholinergics), it may still be possible in the future.

There should be ongoing work to demystify the singular issue of anticholinergic burden

Even though we’d really like to quantify the risk of drugs from varying modes of adverse effects (sedation, hypotension, myopathy etc), this needn’t mean the vagaries of the anticholinergic burden concept itself should stop being studied: ongoing collaborative work is definitely needed to help more clearly define when drugs are truly anticholinergic or otherwise.

This isn’t to say that nobody has tried, on the contrary. For example, a systematic review from Ecuador in 2013 tried to resolve the discrepancies between the earlier anticholinergic scales (circa 2006–2011). The authors reviewed seven older published scales; however, they also used famed pharmacology textbook Martindale both to ensure they didn’t miss any medications and as a method of resolving any large discrepancies in opinion between scales. They ultimately classified 100 drugs as anticholinergic (47 “high potency” and 53 “low potency”). A possible problem, however, is that Martindale may not be the most appropriate tool for identifying adverse drug effects; for instance, these may be better sought from the SIDER database or the Meyler’s text. Like all before them, the authors also noted a pesky group of discrepant drugs whose scores for anticholinergic burden vary wildly in the literature, stating that “for future research, it is recommendable to clarify the real anticholinergic potency of drugs like alprazolam, colchicine, digoxin, frusemide and metoclopramide”.

In other words, they concluded that the jury remains out on a cluster of medicines regarding their “real” anticholinergic activity (whatever real might mean).

And so indeed we do need future research into the idea of antimuscarinic activity of drugs – it could be clinically important. But it is not clear what form this would take.

I do wonder if, one day, there will be future attempts to study all modern drugs using the “test tube” method summarised last week (ie, that performed by Chew and colleagues to quantify laboratory level antimuscarinic potencies of drugs). To date, Chew’s group was the last to conduct a large in vitro analysis of individual drugs at clinically relevant concentrations, but they published results for only 107 drugs and as far back as 2008 (ie, before newer drugs such as apixaban and empagliflozin). In any case, time will tell, and easier said than done.

Nevertheless, the upshot for the development of a comprehensive drug–risk tool for older people in this context is that it would need to be malleable and frequently updated. If future pharmacological studies change the way we view properties of medications (such as their anticholinergic activity), any computer program we use at the bedside must have the ability to change its inner data or settings.

Individual countries would need to use their own version of the tool

The original anticholinergic scales tended only to contain medicines that were available in their country of origin. This basically means that you – as a doctor trying to use a scale in your Australian clinic in 2019 – may notice some of your patient’s medications are missing. This is a much bigger issue than one might think; after the aforementioned systematic review from Ecuador, one group overseas observed that 36% of all the drugs said to be potently anticholinergic in the list of 100 medicines were not actually available in their country.

As such, it is clear that “one size does not fit all” when using anticholinergic or other drug-toxicity scales – it seems geography very much matters. And so finally, any comprehensive drug–risk application in the future must be adaptable to individual countries.

Imagine a shiny computerised application is born

It might be possible to conjure a future vision of an electronic program designed to recognise potential iatrogenic risk. It would allow an older patient’s medications and doses to be entered, and would then flag the presence of questionable medicines, both qualitatively (ie, “drug ‘x’ increases risk of falls and confusion”) and quantitatively (ie, “the risk is low, medium, high”). Ultimately, it would be able to generate a paper or electronic report summarising its clever conclusions.

But then what? How would such a hypothetical drug–risk app be best used in an operational sense? Who would control it? Where would it be stationed? I’d suggest the following final thoughts:

• First, we should give the tool to pharmacists. Whether in the community (providing home medicine reviews) or in hospital wards (advising doctors PRN), pharmacists would be well placed to take ownership over an app determining the potential for harm as they uncover the patient’s medicine regime during initial assessment;
• from there, they would be tasked with distributing the reports generated to the treating doctors with whom they work;
• that said, it is absolutely vital that doctors receiving a report maintain faith in its utility (a report would essentially say “dear doctor, your patient may be at risk from x number of the drugs prescribed”). Without medical buy-in, the whole process falls down rapidly. To illustrate, let’s imagine a pharmacist gives a report (flagging a high anticholinergic burden) to a ward registrar, based on prescription of olanzapine, digoxin and inhaled tiotropium. The registrar then wonders whether they are being prodded into ceasing these medicines. However, if the patient has established morbidity from bipolar, heart failure, atrial fibrillation and chronic obstructive pulmonary disorder, stopping any of these drugs – simply in response to theoretical anticholinergic burden – could be unwise. At that point, trust in the tool would evaporate for the doctor if they believed it represented an edict from the ward pharmacist to deprescribe all the flagged medications;
• accordingly, success in translating the app to clinical use depends on pharmacists filtering the reports through senior doctors – those grasping that the reports are not orders telling doctors to deprescribe wildly out of context, but instead simply act as stimulators of thought. Geriatricians and clinical pharmacologists would be well placed to do this. This leadership role would be as important as the tool itself.

I hope this three-part series of articles has helped you. Grappling with the realities of quantifying medication risk (using anticholinergic scales as an exemplar) has proven to be unexpectedly rocky so far; I wish it had been a smooth cable car ride to the peak. That said, when we use clinical tools or concepts – yet later realise they are imperfect – true positive change probably best comes from authentic narrative about the problems from the shop floor. Let’s see what happens in the future.

Dr Toby Commerford is a consultant geriatrician at Royal Adelaide Hospital, is course coordinator for geriatrics at the University of Adelaide’s Rural School, and practises remote and rural outreaches to Port Augusta and Murray Mallee. He is also the lead singer in a rock band.

The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or InSight+ unless so stated.