Anticholinergic medications

Anticholinergic drugs are routinely prescribed for many different pathologies, including allergies, depression, urinary incontinence and Parkinson disease. They block the action of acetylcholine – a neurotransmitter involved in learning and memory consolidation.

Recent studies have shown that this class of medication is associated with the development of cognitive decline and can increase the risk of dementia.

In one recent study^[1]patients who used anticholinergic drugs had a higher risk to develop mild cognitive impairment (MCI) in 10 years. Mild cognitive impairment is an early stage of Alzheimer’s disease. The authors also found that the risk was even higher in patients carrying the APOE4 gene, who used this type of drugs. The APOE4 gene is a genetic risk factor to Azheimer’s disease (you can read more at Genetic section).

Acetylcholine is a neurotransmitter, that is, a chemical message released by nerve cells in order to send signals to other cells, such as neurons, muscle cells, and glandular cells. It can be found at different places toward nervous system, and performs different functions, such as:

• Neuromuscular junctions – activates muscle contraction of both striated and smooth muscles
• Autonomic nervous system – it is the main neurotransmitter of the parasympathetic nervous system
• Brain – neurotransmitter and neuromodulator with an important role in increasing wakefulness, maintaining attention, learning and memory.

Although many anticholinergic drugs are most usually prescribed for severe disease like depression, Parkinson disease and psychiatric disorders, some of them can be bought without prescription, and include many over-the-counter medications commonly used (table 1).

Another important fact to pay attention is the so called “anticholinergic burden” – that is the cumulative effect of taking multiple medicines with anticholinergic properties. Some drugs used in other indications (Table 1) are not classified as anticholinergic drugs because this is not their main action. However, these still have a more or less strong anticholinergic activity. Because each drug has a slightly different effect, it may therefore be more or less likely to cause cognitive decline. The anticholinergic activity of a drug can be ranking, ranging from no anticholinergic activity (=0) to high anticholinergic activity (=3) (see also table 2)

It turns out that the concomitant use of many drugs with low anticholinergic activity can lead to a cumulative anticholinergic effect and consequently to a high anticholinergic burden^[2].

Drugs such as antibiotics, corticosteroids, anti-acids and diuretics can have low anticholinergic effects. Unfortunately, elderly people are usually prescribed many medications at the same time, which is also called polypharmacy. These patients are then significantly more susceptible to anticholinergic burden and its negative side effects, including an increased risk of dementia^[3].

In table 2 you can find a list with the most common used medication and their classification according to anticholinergic activity. It can be used to calculate anticholinergic burden.

Conclusion:

Anticholinergic drugs can increase risk of developing mild cognitive impairment, especially in patients carrying the APOE4 gene. Some drugs, although not classified as anticholinergics, can have anticholinergic activity ranging from low to high. The concomitant use of many drugs with different ranges of anticholinergic activity can raise the “anticholinergic burden” and increase the risk of dementia. These facts underscore the adverse impact of anticholinergic medications on cognition, particularly among individuals with elevated risk for AD. Physicians should carefully evaluate whether the benefit of using anticholinergic medications outweighs the risk of developing cognitive impairment and be aware of the cumulative negative effect of multiple drugs with anticholinergic activity. Also, any patient who obtains these drugs without a prescription from a pharmacy because of other indications should be informed about these adverse effects by the pharmacist, and should make a careful cost-benefit assessment for themselves in order not to expose themselves unnecessarily to a higher risk of dementia. Especially people who are also exposed to other dementia risk factors should definitely make this effort.

Table 1: Frequently used anticholinegic drugs – adapted from Ancelin ML et al.^[4]

Table 2: Overview of anticholinergic activity of some usually prescribed drugs. Adapted from Kiesel EK et al.^[5]

1. ↑ Weigand AJ, Bondi MW, Thomas KR, Campbell NL, Galasko DR, Salmon DP, Sewell D, Brewer JB, Feldman HH, Delano-Wood L; Alzheimer’s Disease Neuroimaging Initiative. Association of anticholinergic medications and AD biomarkers with incidence of MCI among cognitively normal older adults. 2020 Oct 20;95(16):e2295-e2304.
2. ↑ 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.
3. ↑ Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study.JAMA Intern Med. 2015;175(3):401-407.
4. ↑ 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):455-459.
5. ↑ Kiesel EK, Hopf YM, Drey M. An anticholinergic burden score for German prescribers: score development.BMC Geriatr. 2018;18(1):239. Published 2018 Oct 11. doi:10.1186/s12877-018-0929-6