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Adverse Effects of Acetylcholinesterase
Inhibitors
Adverse Effects of Acetylcholinesterase Inhibitors
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Issue Number: Volume 19 - Number 1 - January 2011 [1]
Section: Feature
Citation:
Clinical Geriatrics 2011;19(1):27-30.
PatelTable1.png [2]
PatelTable2.png [3]
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Authors:
Birju B. Patel, MD, FACP, and N. Wilson Holland, MD, FACP
Introduction
Dementia is an underrecognized and underdiagnosed condition in the rapidly growing elderly
population. It is estimated that approximately 24 million people worldwide had dementia in
2005.
1
Alzheimers disease is the most common type of dementia, accounting for 60% to 80% of
all dementia cases.
2
In the United States alone, 5.3 million people have Alzheimers disease
and someone develops Alzheimers disease every 70 seconds. It is the seventh leading cause of
death in this country. The annual healthcare system costs are estimated at $172 billion.2 Our
healthcare system is increasingly impacted by the silver tsunami. The U.S. Census Bureau
estimates that the elderly population will double to an estimated 80 to 90 million individuals by
the year 2050.
3
Acetylcholinesterase inhibitors (AChEIs) are typically prescribed to treat symptoms of cognitive
and functional decline in patients with Alzheimers disease and other dementias.
4,5
In 1993,
tacrine hydrochloride became the first AChEI approved by the U.S. Food and Drug
Administration (FDA) for the treatment of Alzheimers disease, but it was later primarily replaced
by second-generation AChEIs due to more favorable side-effect profiles and safety concerns;
there have been reports of hepatotoxicity with tacrine use.
6
There are currently three second-
generation AChEIs approved by the FDA: donepezil hydrochloride (1997); rivastigmine tartrate
(2000); and galantamine hydrobromide (2001; Table I). Donepezil is labeled for use in all stages
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of dementia. Galantamine and rivastigmine are labeled for use in mild-to-moderate dementia.
[2]
As the use of these AChEIs increases, there are ongoing controversies about their
cost-effectiveness and modest efficacy.
7-10
By inhibiting the cholinesterase enzyme from
breaking down acetylcholine (ACh), these agents lead to increased synaptic levels of ACh.
Although these medications are intended to increase cholinesterase activity specifically in the
brain, the side effects manifest as symptoms that can be expected from both central and
peripheral cholinergic excess. Many clinicians are not aware of the array of potential side effects
of these medications (Table II).
[3]
This article discusses the side effects, tolerability, and precautions in the use of AChEIs. The
following case vignettes illustrate some adverse effects of these medications.
Case 1
Dr. B was an 88-year-old man who had had dementia for several years. His medical history
included serial transient ischemic attacks and prostate cancer. A computed tomography (CT)
scan of his brain showed lacunar infarcts and small vessel ischemic changes. Dr. B was initially
started on donepezil 5 mg daily, and this was increased after several months to 10 mg daily
Approximately 3 months into his treatment, he started having loose, watery stools up to 6 times
per day. The patient had no abdominal pain, fever, chills, or recent history of travel. His
laboratory evaluation showed a normal chemistry profile and normal thyroid studies. Stool
studies were performed, results of which were also unremarkable. Because of the severity of his
diarrhea, his family made an appointment for him to see a local gastroenterologist. Dr. B
underwent a colonoscopy, which was unrevealing other than the finding of noninflamed
diverticula. His wife also noticed that he had developed rhinorrhea during this period of time. He
subsequently presented to a geriatric primary care clinic, and donepezil was discontinued. Dr. B
was seen in follow-up 2 weeks later, and both the rhinorrhea and diarrhea had completely
resolved.
Case 2
Mr. R was an 85-year-old man with a history of hypertension, severe osteoarthritis, and
asbestosis, as well as a several-month history of increasing confusion. Results of laboratory
studies were unremarkable, including normal thyroid-stimulating hormone and vitamin B12
levels. A CT scan of the brain showed small vessel ischemic changes and chronic lacunar
infarcts in the internal capsule. A baseline electrocardiogram was not obtained, but chest
roentgenography showed pleural plaques. Cognitive testing revealed moderate dementia, and
he was started on galantamine 4 mg twice daily, which was titrated to 8 mg twice daily after 6
weeks.
Mr. R presented to the emergency department (ED) with syncope several months after the
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galantamine was titrated. Initial workup in the ED revealed type II second-degree atrioventricular
block and bradycardia. Telemetry monitoring for 48 hours showed no significant arrhythmias. An
echocardiogram revealed normal systolic function and mild diastolic dysfunction. The patient
was evaluated by a cardiologist, who felt that the likely cause of his syncope was type II second-
degree atrioventricular block associated with galantamine. Galantamine was subsequently
discontinued.
Side Effects of Acetylcholinesterase Inhibitors
The cholinergic hypothesis of age and Alzheimers diseaserelated cognitive deficits states that
decreased levels of ACh in the brain lead to cognitive deficits.
11
The most common cholinergic
side effects of AChEIs involve the gastrointestinal tract. These side effects are usually mild and
have been reported to occur in approximately 20% of patients taking these medications.
12
Among the side effects reported in the package inserts of currently available second-
generation AChEIs are nausea (11%-47%), vomiting (10%-31%), diarrhea (5%-19%), and
anorexia (4%-17%).
13
These gastrointestinal side effects are relatively well known by
clinicians,
14
and can be minimized with the use of longer titration periods and the administration
of these medications with food.
15
There are also lesser-known side effects associated with AChEIs, occurring in fewer than 5% of
patients, that clinicians who care for elderly patients should be aware of.
16
Some of these side
effects can be life-threatening, and include rhinitis, fatigue, leg cramps, insomnia, abnormal
dreams, myasthenia, asthenia, tremor, dizziness, headaches, bradycardia, orthostatic
hypotension, syncope, urinary incontinence, seizures, gastrointestinal hemorrhage,
extrapyramidal symptoms, and, very rarely, liver dysfunction including hepatitis.
17,18
There have
been some reports of hallucinations, aggressive behavior, and agitation, which resolved on dose
reduction or discontinuation of treatment.
13
Severe vomiting with esophageal rupture has also
been reported with the use of rivastigmine.
19
Precautions in the Use of Acetylcholinesterase Inhibitors
Clinicians should be cautious when prescribing AChEIs to patients with previous hypersensitivity
or adverse reactions to these medications. Patients with a history of bradycardia, heart block,
and syncope are at a much higher risk of adverse effects from central and peripheral muscarinic
stimulation resulting in a vagotonic effect on the heart. In a recent study by Gill et al,
20
hospital
visits for syncope were more frequent in those who were taking AChEIs versus controls (31.5 vs
18.6 events per 1000 patient-years). Furthermore, those who were taking AChEIs were more
likely to have hospital visits for bradycardia, permanent pacemaker insertion, and hip fracture.
Syncope can lead to hospitalization, increased healthcare costs, and increased risk of falls and
fractures in the elderly.
20
Cholinergic agents can reduce the seizure threshold; therefore, AChEIs should be prescribed
with a great deal of caution in those with a history of seizure disorder and chronic alcoholism.
Excessive stimulation of nicotinic receptors can lead to muscle cramps and weakness. Patients
who are at risk of developing gastrointestinal ulcers and those who are taking nonsteroidal
anti-inflammatory drugs should be carefully followed for symptoms due to the increased
secretion of gastric acid stimulated by increased levels of ACh. Asthma and chronic obstructive
pulmonary disease can also be exacerbated with the use of AChEIs due to increased bronchial
secretions. Rarely, these medications can cause bladder outflow obstruction and urinary
incontinence.
21
Weight loss, usually due to the gastrointestinal side effects, is also a concern.
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Patients with low body weight should be carefully evaluated for risks versus benefits prior to
initiating treatment with these agents.
Increasing the Tolerability of Acetylcholinesterase Inhibitors
When side effects and tolerability issues are encountered with AChEIs, several techniques can
be useful. Gradual dose titration, as previously mentioned, can be beneficial in patients who are
experiencing gastrointestinal side effects. Lowering the dose and administering these
medications with meals can also be beneficial. Switching the time of administration can be
important; for example, dosing donepezil in the morning or during lunch can be useful in
preventing the vivid, threatening dreams and nightmares that can occur when taking this
medication. If switching an AChEI is necessary, it is important to stop the offending agent and
let the side effects resolve prior to the initiation of another AChEI. Decreasing the dose
temporarily for a few days can also be helpful in increasing tolerability. A 4- to 6-week dose
titration is often necessary to achieve higher dosing while minimizing side effects.
22
Conclusion
It is important for clinicians to be aware of the side effects of AChEIs. There are ongoing debates
about the efficacy, cost-effectiveness, and optimal duration of use of these agents.
23,24
These
medications are currently the mainstay of treatment of dementia and Alzheimers disease, but
should be used with a great degree of caution and ongoing monitoring. The decision to use
specific AChEIs is based on cost, the healthcare providers experience with these medications,
and individual patient tolerability, since all AChEIs have similar efficacy.
25,26
The potential side
effects, efficacy, and cost of these medications should be discussed with patients and their
caregivers. Expected benefits versus potential risks of treatment also have to be discussed and
carefully weighed for patients prior to the initiation of these medications.
27
Several clinical pearls can be gleaned related to the use of AChEIs (Table III). As the case
vignettes demonstrate, knowing the side effects of these types of medications may prevent
unnecessary or invasive workups in the frail, elderly population. Clinicians who care for elderly
patients should always be looking for new symptoms and their possible relationships to
medications. Most importantly, rather than adding more medications to treat side effects,
clinicians should be reducing polypharmacy and stopping the medications that contribute to
untoward effects. Although syncope and dizziness are less frequently reported side effects,
nevertheless, in our experience in a large outpatient geriatric clinic, we have seen numerous
cases of syncope associated with AChEIs. Because of this, one should pay close attention to
orthostatic findings and get baseline electrocardiograms prior to starting these agents.
Physicians and other healthcare practitioners should always remember the basic premise First,
do no harm before initiating any treatment.
[4]
The authors report no relevant financial relationships.
From the Department of Medicine, Division of Geriatrics and Gerontology, Emory University
School of Medicine, Atlanta, GA, and the Department of Geriatrics and Extended Care, Atlanta
VA Medical Center, Decatur, GA.
References
1. Ferri CP, Prince M, Brayne C, et al; Alzheimers Disease International. Global prevalence of
Adverse Effects of Acetylcholinesterase Inhibitors http://clinicalgeriatrics.com/print/4269
4 of 7 11/22/2011 2:33 AM
dementia: A Delphi consensus study. Lancet 2005;366(9503):2112-2117.
2. Alzheimers Association. 2010 Alzheimers disease facts and figures. http://www.alz.org
/documents_custom/report_alzfactsfigures2010.pdf [5]. Accessed December 13, 2010.
3. Census bureau reports worlds older population projected to triple by 2050 [press release].
U.S. Census Bureau Newsroom. June 23, 2009.
4. Birks J. Cholinesterase inhibitors for Alzheimers disease. Cochrane Database Syst Rev
2006;(1):CD005593.
5. Clark CM, Karlawish JH. Alzheimer disease: Current concepts and emerging diagnostic and
therapeutic strategies. Ann Intern Med 2003;138(5):400-410.
6. Watkins PB, Zimmerman HJ, Knapp MJ, Gracon SI, Lewis KW. Hepatotoxic effects of tacrine
administration in patients with Alzheimers disease. JAMA 1994;271(13):992-998.
7. Morden NE, Zerzan JT, Larson EB. Alzheimers disease medication: Use and cost projections
for Medicare Part D. J Am Geriatr Soc 2007;55(4):622-624.
8. Neumann PJ, Hermann RC, Kuntz KM, et al. Cost-effectiveness of donepezil in the treatment
of mild or moderate Alzheimers disease. Neurology 1999;52(6):1138-1145.
9. Hauber AB, Gnanasakthy A, Mauskopf JA. Savings in the cost of caring for patients with
Alzheimers disease in Canada: An analysis of treatment with rivastigmine. Clin Ther
2000;22(4):439-451.
10. Ames D, Kaduszkiewicz H, van den Bussche H, Zimmermann T, Birks J, Ashby D. For
debate: Is the evidence for the efficacy of cholinesterase inhibitors in the symptomatic treatment
of Alzheimers disease convincing or not? Int Psychogeriatr 2008;20(2):259-292. Published
Online: February 6, 2008.
11. Cummings JL, Kaufer D. Neuropsychiatric aspects of Alzheimers disease: The cholinergic
hypothesis revisited. Neurology 1996;47(4):876-883.
12. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-
controlled trial of donepezil in patients with Alzheimers disease. Donepezil Study Group.
Neurology 1998;50(1):136-145.
13. Cummings JL. Use of cholinesterase inhibitors in clinical practice: Evidence-based
recommendations. Focus 2004;2(2):239-252.
14. Cummings JL. Use of cholinesterase inhibitors and clinical practice: Evidence-based
recommendations. Am J Geriatr Psychiatry 2003;11(2):131-145.
15. Agronin ME. Alzheimer Disease and Other Dementias: A Practical Guide. 2nd ed.
Philadelphia, PA: Lippincott Williams and Wilkins; 2008.
16. Physicians Desk Reference. 2011. 65th ed. Montvale, NJ: PDR Network; 2010.
17. Inglis F. The tolerability and safety of cholinesterase inhibitors in the treatment of dementia.
Int J Clin Pract Suppl 2002;(127):45-63.
Adverse Effects of Acetylcholinesterase Inhibitors http://clinicalgeriatrics.com/print/4269
5 of 7 11/22/2011 2:33 AM
18. Gauthier S. Cholinergic adverse effects of cholinesterase inhibitors in Alzheimer s disease:
Epidemiology and management. Drugs Aging 2001;18(11):853-862.
19. Novartis Exelon labeling update reflects report of esophageal rupture. The Pink Sheet
2001;63:24.
20. Gill SS, Anderson GM, Fischer HD, et al. Syncope and its consequences in patients with
dementia receiving cholinesterase inhibitors: A population-based cohort study. Arch Intern Med
2009;169(9):867-873.
21. Hashimoto M, Imamura T, Tanimukai S, Kazui H, Mori E. Urinary incontinence: An
unrecognized adverse effect with donepezil. Lancet 2000;356(9229):568.
22. Mimica N, Presecki P. Side effects of approved antidementives. Psychiatr Danub
2009;21(1):108-113.
23. Graff MJ, Adang EM, Vernooij-Dassen MJ, et al. Community occupational therapy for older
patients with dementia and their care givers: Cost effectiveness study. BMJ
2008;336(7636):134-138. Published Online: January 2, 2008.
24. Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and
memantine for treating dementia: Evidence review for a clinical practice guideline. Ann Intern
Med 2008;148(5):379-397.
25. Qaseem A, Snow V, Cross JT Jr, et al; American College of Physicians/American Academy
of Family Physicians Panel on Dementia. Current pharmacologic treatment of dementia: A
clinical practice guideline from the American College of Physicians and the American Academy
of Family Physicians. Ann Intern Med 2008;148(5):370-378.
26. Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase inhibitors in the treatment
of neuropsychiatric symptoms and functional impairment in Alzheimer disease. A meta-analysis.
JAMA 2003;289(2):210-216.
27. Lindstrom HA, Smyth KA, Sami SA, et al. Medication use to treat memory loss in dementia:
Perspectives of persons with dementia and their caregivers. Dementia 2006;5(1):27-50.
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