Adverse Effects of Acetylcholinesterase Inhibitors
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 Alzheimer’s 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 Alzheimer’s disease and someone develops Alzheimer’s 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 Alzheimer’s 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 Alzheimer’s 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 of dementia. Galantamine and rivastigmine are labeled for use in mild-to-moderate dementia.
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).
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 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 Alzheimer’s disease–related 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. 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 Alzheimer’s 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 provider’s 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.
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.
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