Assessing the Risks and Benefits of Cholinesterase Inhibitors for Alzheimer Disease

“One day, I had trouble remembering how to get home from work,” reports your patient in her early-60s, as she attempts to hide her embarrassment and frustration at your questions. In addition to memory difficulties, you notice that she’s had some weight loss, and her grooming is not quite up to her usual standards.

Whether you are a primary care or a specialist provider, this kind of patient report should immediately trigger consideration of the warning signs of Alzheimer disease. Approximately 5.3 million Americans have Alzheimer disease,¹ and some primary care physicians may encounter up to 16 patients each month with Alzheimer disease or a related dementia.² Alzheimer disease is recognized as the sixth-leading cause of death among adults in the United States and is the only disease listed in the top 10 that cannot be cured, prevented, or even slowed.³
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Diagnosing early-stage Alzheimer disease and managing it over its progressive course can be a daunting task. To date, only symptomatic therapies for Alzheimer disease are available, and none of the drug interventions have an impact on disease progression, neuronal damage, or death.^4,5 Alzheimer disease is a progressive disease, which means that the symptoms and care plan change over time.

The effects of current drug treatment are modest, so it may be difficult to tell if Alzheimer disease interventions are helping to reduce symptoms. Thus, the patient, caregiver, and treatment team should be well-aligned on their goals and expectations for Alzheimer treatment, and it is incumbent upon the clinician caring for the patient to clearly spell out the risks and benefits of a treatment plan.

Patients who are treated early in the course of Alzheimer disease have the best chance of maintaining the highest possible functional and cognitive ability for the longest period of time. If pharmacologic approaches are warranted, medications should be carefully selected to target specific problem behaviors, and the benefits of the medications should be considered in the context of their adverse event profile. The cost impact on the patient should also be discussed.

Pharmacologic Treatments for Alzheimer Disease

Currently available medications for patients with Alzheimer disease include cholinesterase inhibitors, which are used for mild-to-moderate Alzheimer disease and work by preventing the breakdown of acetylcholine, a neurotransmitter believed to be important for memory and learning.^6-8 These drugs do not reverse Alzheimer disease, nor do they halt or slow nerve cell destruction.

The improvements associated with cholinesterase inhibitors may be modest, and the drugs may lose their effect over time as Alzheimer disease progresses and the brain produces less acetylcholine. Cholinesterase inhibitors treat symptoms related to memory, thinking, language, judgment, and other thought processes, and these drugs can delay the worsening of symptoms for about 6 to 12 months, on average, in about one-half of the people who take them.⁹ Cholinesterase inhibitors can also improve some neuropsychiatric symptoms that may coexist with cognitive decline, such as agitation or apathy.¹⁰

By comparison, memantine (Namenda) is an example of the second type of agent, an N-methyl-D-aspartate (NMDA) receptor antagonist used to treat moderate-to-severe Alzheimer disease. Memantine regulates the neurotransmitter glutamate by binding to NMDA receptors located on the surface of brain cells.¹¹ Glutamate is among the most prevalent amino acids found in the body, and, at optimal concentrations, is known to play a unique role as a neurotransmitter in learning and memory.¹² When glutamate levels drop too low, an individual is at greater risk for developing cognitive problems. Alternatively, when glutamate levels are too high, nerve cells become overstimulated, which can lead to cell death.¹³ NMDA antagonists may be used in combination with cholinesterase inhibitors because of their different mechanisms of action. 

According to existing guidelines, cholinesterase inhibitors are considered first-line agents when treating mild-to-moderate cases of Alzheimer disease.² Three cholinesterase inhibitors are currently available and approved by the US Food and Drug Administration for treating the symptoms of Alzheimer disease:

      - Donepezil (brand names: Aricept, Aricept ODT)

      - Rivastigmine (brand names: Exelon, Exelon Patch)

      - Galantamine (brand names: Razadyne, Razadyne ER)

There is also a combination donepezil/memantine extended-release product (Namzaric) currently available for the treatment of moderate-to-severe Alzheimer disease in patients stabilized on donepezil 10 mg once daily.

The cholinesterase inhibitors are reviewed here for their known benefits and risks in treating patients with Alzheimer disease. Consideration of specific drug choice should include the patient’s individual response to treatment and drug tolerability, dosage form preference, physician experience, and cost to the patient.

Benefits Linked With the Use of Cholinesterase Inhibitors for Alzheimer Disease

A large number of randomized controlled trials have been conducted to evaluate the effectiveness of cholinesterase inhibitors on both the symptoms and course of Alzheimer disease. Results from several systematic reviews suggest that the medications all demonstrate a similar modest benefit, with no evidence of dementia prevention in those with mild cognitive impairment, although they vary in terms of their mechanisms of action, recommended dosing, and risk for side effects.^4,14-16

Patients taking cholinesterase inhibitors generally show some improvement on measures of functional impairment and cognitive ability. Additionally, Alzheimer disease patients taking cholinesterase inhibitors exhibit slower decline on these measures than those taking placebo.^4,5 Clinical trials have shown that there are no differences in effectiveness of cholinesterase inhibitors in terms of age, sex, or ethnicity.

Donepezil, one of the generally well-tolerated cholinesterase inhibitors, is the only Alzheimer drug approved for all stages of the disease. Donepezil is noted for its high specificity for acetylcholinesterase inhibition and its limited activity within peripheral tissue, such as cardiac tissue or smooth muscle of the gut.¹⁷ Its efficacy has been evaluated in a number of clinical trials, with results suggesting that donepezil has a small, dose-dependent effect on cognitive abilities, daily functioning, and behavior.¹⁸ No consistent effect was found in terms of the impact of donepezil on ratings of patients’ quality of life across these studies.

Rivastigmine is a carbamate derivative and, in contrast to the other 2 cholinesterase inhibitors, is considered to be a slowly reversible inhibitor of acetylcholinesterase.¹⁹ Moreover, its low protein-binding characteristics mean that rivastigmine has very minimal potential for significant interactions with other drugs, which is a critical feature for medications intended for use among aging and elderly patients who are more commonly prescribed multiple drugs for other medical illnesses.²⁰

Findings from efficacy studies indicate that rivastigmine may be beneficial for patients with mild-to-moderate Alzheimer disease, as those receiving the drug demonstrated slightly better outcomes in terms of rate of decline in cognitive function and daily functioning compared with those receiving placebo.²¹ Rivastigmine has also received support for its beneficial effects in terms of reducing the rate of decline in cognitive ability and daily functioning for patients with moderately severe Alzheimer disease.²² For patients with comorbid behavioral disorders, rivastigmine has been shown to have beneficial effects on impairing behavioral symptoms to the degree that some patients were able to reduce their dosage of antipsychotic medications.²³

Galantamine has been used for decades in humans for anesthesia and to treat symptoms of neuropathic pain.²⁴ Galantamine has received support for its efficacy in providing benefits in terms of global clinical function, behavioral symptoms, and daily functioning to patients with mild-to-moderate Alzheimer disease, compared with placebo.²⁵ In addition, long-term studies have suggested that galantamine may significantly reduce mortality and long-term decline in cognitive abilities and daily function.²⁶

However, the efficacy outcomes of these agents for Alzheimer disease are modest at best. Moreover, these medications are intended to treat the symptoms of the disease only, and they are not curative. It is important for clinicians to counsel families on realistic expectations, as it is very possible for patients to exhibit no notable changes in symptoms. In fact, the American Geriatrics Society (AGS) recommended against use of cholinesterase inhibitors in an update to the American Board of Internal Medicine (ABIM)’s Choosing Wisely Campaign, stating that “although some clinical trials suggest that cholinesterase inhibitors may improve cognitive testing results, it is now unclear whether these changes are ‘clinically meaningful’ based on available data. Since no studies have investigated the benefits of cholinesterase inhibitors beyond a year or the risks/benefits of long-term therapy, the AGS expert panel advised that clinicians, patients, and their caregivers discuss treatment goals and the likelihood of adverse effects before beginning treatment, and that they adjust therapy if the desired effects are not achieved within 12 weeks.”²⁷

In addition to setting reasonable expectations, clinicians should consider the full medical history of the patient prior to prescribing medication for cognition deterioration. As Ging-Yuek Robin Hsiung, MD, of the Vancouver Coastal Health Research Institute concluded in a review of Alzheimer disease drug treatment, ²⁸ “Before pharmacological intervention is instituted, it is important that sources of excess disability and comorbidity be eliminated or reduced. Comorbid medical and psychiatric conditions, such as depression and delirium, should be recognized and appropriately treated.”

Risks Associated With Use of Cholinesterase Inhibitors Among Alzheimer Patients

All 3 cholinesterase inhibitors share a similar profile of adverse effects. More than one-half of patients may experience some type of side effects due to drug treatment, with the most common side effects reported as nausea, vomiting, diarrhea, weight loss, and dizziness.^{5, 8, 19} However, adverse effects of cholinesterase inhibitors are generally dose-dependent and, thus, can be mitigated using a slow titration schedule up to the goal maintenance dosing level.

Some patients may experience severe symptoms of nausea, vomiting, diarrhea, and indigestion, particularly when they have first started taking the medication, but these types of side effects are relatively uncommon.⁸ These symptoms may be reduced by reminding the patient to take cholinesterase inhibitors with food. For cases of severe gastrointestinal side effects, it is recommended that the clinician consider using the rivastigmine transdermal patch in order to by-pass the digestive tract.

Prescribing cholinesterase inhibitors to treat symptoms of Alzheimer disease may incite symptomatic bradycardia and syncope, which then increases the risk for fall-related injuries, including fractured hip.⁸ In fact, one study found that dementia patients being treated with cholinesterase inhibitors were seen more frequently in the hospital for syncope, bradycardia, permanent pacemaker insertion, and hip fracture, than control patients (ie, 31.5 versus 18.6 visits per 1000 person-years).²⁹ It is important to have a baseline electrocardiogram prior to prescribing cholinesterase inhibitors and to consider these risks when prescribing cholinesterase inhibitors to older adults.

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carefully review a list of all the patient’s current medications. Patients are often prescribed cholinesterase inhibitors in conjunction with an anticholinergic drug, whose mechanisms of action counteract each other. Patients who are already taking a medication with anticholinergic effects, such as tricyclic antidepressants (eg, nortriptyline, amitriptyline), diphenhydramine, and oxybutynin (frequently prescribed for bladder spasticity), may experience cognitive dysfunction by combining these medications with a cholinesterase inhibitor. All centrally acting anticholinergic drugs should be reduced in dosage and gradually eliminated before a patient is prescribed a cholinesterase inhibitor.

Another prescribing consideration is cost, as Alzheimer drugs are not inexpensive. Depending upon drug choice, the agents can cost the patient several hundred dollars per month, with costs varying based upon choice of drug and formulation; use of the generic medication; insurance plan reimbursement; copay; availability of drug discount cards; and other variables.³⁰ Clinicians should engage the patient and their caregiver in an honest dialogue of the affordability of treatment prior to finalizing a treatment plan.

The ongoing use of cholinesterase inhibitors for a period of 26 weeks, particular orally administered rivastigmine (6 to 12 mg), is commonly associated with gastrointestinal adverse events that appear to be attributed to the rapid increase in acetylcholine.^21,31,32 The use of the rivastigmine patch formulation provides a continuous delivery of the drug that is associated with a significant improvement in symptoms of Alzheimer disease.^31,33 Furthermore, donepezil has demonstrated very good tolerability when it is taken for 24 weeks.³⁴ Therefore, if severe adverse events are experienced, dosage adjustments or switching to a different cholinesterase inhibitor can be beneficial for the patient. 

Conclusion

The memory loss, thinking and reasoning problems, and daily functioning declines experienced by individuals with Alzheimer disease are progressive and highly challenging to the patient, caregiver, and treatment team. Use of cholinesterase inhibitors may offer symptomatic treatment for patients with mild-to-moderate Alzheimer disease. However, these agents should be considered in light of the fact that many patients show minimal meaningful benefit from cholinesterase inhibitors but may still experience side effects and significant drug costs. It is essential to establish open dialogue with the patient to set treatment expectations, evaluate effectiveness within 12 months of treatment initiation, and participate in shared decision-making with the entire treatment team.

Sarah Williams, PhD, and Takeesha Roland Jenkins, MS, MS, are medical writers at HE Institute, located in Ponte Vedra Beach, Florida.

References

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