What is an acetylcholinesterase inhibitor? How do they work?
More than a mouthful, acetylcholinesterase inhibitors (AChEIs) are the most commonly prescribed class of medications for cognitive decline in those with dementia, Parkinson’s-related dementia, and other degenerative brain disease.
Acetylcholine, a chemical in our brain, is thought to play a key role in helping us think clearly and concentrate, in regulating our own behavior (like agitation), and can help in managing feelings of anxiety. Acetylcholine is thought to be decreased in patients with neurocognitive disorders, like dementia. AChEIs work by increasing acetylcholine available in the brain, by blocking a protein that breaks it down.
What diseases are AChEIs used for? How effective are these medications?
Three AChEIs are approved to treat Alzheimer’s disease; the three include Aricept®(donepezil), Razadyne®(galantamine) , and Exelon® (rivastigmine). They are all equally effective in treating Alzheimer’s disease. In the clinical trials, all three medications were associated with mild improvements in cognitive function, behavior, and activities of daily living (like being able to get dressed and eat). It is important to note that, although these medications are shown to help improve scores in these areas, they do not slow the progression of dementia, prolong life, or prevent nursing home admission.
What side effects can be seen with AChEIs?
The most common side effects are nausea, vomiting, and diarrhea. Because it can cause these stomach issues, the medication is associated with weight loss too, which could be concerning in people who are frail or already low weight. AChEIs can also cause dizziness, headaches, or worsen urine incontinence problems, like an enlarged prostate, or breathing problems, like asthma. Lastly it can increase the risk of falls in people with a slow heart rate (“bradycardia”) or other cardiac rhythm problems.
When to stop AChEIs?
This is a controversial topic. It’s important to make sure that the benefits of continuing the AChEIs (like mild improvement in cognition for some) outweigh potential harms (like the potential side effects discussed above). Whether to stop and when to stop will likely be an ongoing conversation with the individual’s medical team, especially as their dementia progresses over time.
For instance, sometimes this medication will be stopped if it hasn’t shown any benefit, if the individual is experiencing intolerable side effects, or if their dementia becomes severe enough that it is unclear if the medication is still helping.
What to expect when stopping AChEIs
Although rare, there are some reports of people experiencing withdrawal symptoms, which includes anxiety and worsening of dementia symptoms, including hallucinations and delusions, when stopping AChEIs abruptly. In these case reports, the medication was restarted at low doses and the symptoms resolved. Because of this risk, when stopping an AChEI, often the medication is slowly decreased over weeks to minimize the impact of this change and the person is closely monitored during this time.
Despite a slow decrease of the medication, sometimes a person can experience a worsening of their dementia symptoms anyway. This may be because the medication was benefiting the person in some ways, and now it’s not on board. Many large studies have evaluated whether there are harms in stopping the medication in the short and long term. In a large 2021 analysis, researchers pooled the evidence from 7 different trials and evaluated the effect of continuing vs stopping AChEIs. The researchers found that those who stopped the medication experienced more cognitive decline in the short term (2 months or less), but there were no differences in intermediate and long-term changes in cognition (a year after). This may mean that the person may lose the benefit of the medication when it is stopped, but in the long term, the individual may have a similar decline anyway. Researchers also found there were no differences in daily functioning, mortality, and nursing home admission between those who continued or stopped AChEIs. Because stopping is a hard decision for everyone, it is so important to talk to your medical team.
How to stop?
The specific plan for stopping your AChEI will be determined by your medical team. Generally, they will avoid stopping cold turkey. Instead, the dose is typically reduced by 25% to 50% every 1 to 2 weeks (sometimes even 4 weeks!). This can be done by reducing the oral medication dose (cutting the medication in half or quarters or picking up a lower dose from the pharmacy) or changing to a lower dose patch.
It is very important to consider the caregivers’ ability to monitor the individual when stopping AChEIs. Because of this, it is important to find a few, not stressful weeks to stop this medication. For instance, it may be more stressful to make this change during the holidays.
What symptoms should I monitor for?
Withdrawal symptoms can start 3 to 7 days after the AChEI is stopped and can take up to 3 weeks to resolve. Look for changes that might be subtle, like difficulty concentrating, insomnia, and fluctuating mood, to more obvious, like hallucinations, delusions, altered consciousness, and agitation.
Who should I talk to, if my loved one experiences withdrawal?
Call your medical team. Often, if the withdrawal symptoms are distressing, they could consider slowing the dose decrease or re-starting the medication at the lowest possible dose. They could decide it would be safer to use dementia medication from another class or that there is no benefit to be had from dementia medications anymore, due to disease severity. If restarting the AChEI is not possible or inappropriate, other medications may be started temporarily to help manage symptoms.
Prepared by Garbo McDermott-Grossman, PharmD
References
- “Deprescribing Cholinesterase Inhibitors.” www.primaryhealthtas.com.au, Dec. 2022, www.primaryhealthtas.com.au/wp-content/uploads/2023/03/A-guide-to-deprescribing-cholinesterase-inhibitors.pdf.
- Donepezil. Package insert. Eisai Inc; 2012.
- “FF #354 Deprescribing Cholinesterase Inhibitors at the End-of-Life.” Palliative Care Network of Wisconsin, 11 Nov. 2024, www.mypcnow.org/fast-fact/deprescribing-cholinesterase-inhibitors-at-the-end-of-life/.
- Greiman, Tristyn L et al. “Adverse outcomes of abrupt switch and discontinuation of acetylcholinesterase inhibitors in dementia with Lewy bodies: Case report and literature review.” The mental health clinician vol. 9,5 309-314. 4 Sep. 2019, doi:10.9740/mhc.2019.09.309
- Moo, Lauren R et al. “Unexpected Findings During Double-blind Discontinuation of Acetylcholinesterase Inhibitor Medications.” Clinical therapeutics vol. 43,6 (2021): 942-952. doi:10.1016/j.clinthera.2021.05.010
- Parsons, Carole et al. “Withdrawal or continuation of cholinesterase inhibitors or memantine or both, in people with dementia.” The Cochrane database of systematic reviews vol. 2,2 CD009081. 3 Feb. 2021, doi:10.1002/14651858.CD009081.pub2
