Cholinesterase Inhibitors and Alzheimer Disease
Article Outline
Dementia is a very common problem, and Alzheimer disease (AD) is the most common cause of dementia. More than 24 million people in the world have dementia, and the number is rising as the population ages. AD is a terrible disease that causes impaired cognition and function in the patient and much suffering on the part of the caregivers. It is the fifth leading cause of death in the United States.1
Cholinesterase inhibitors (ChEIs) are the only drugs indicated for use in mild to moderate AD. The drugs are documented to be effective for the cognitive aspect of the disease, in which they are regarded as modestly effective. It is controversial how meaningful this effect is, particularly if the effect is cost effectiveness, because these medications are expensive.2 However, it is generally not the cognitive symptoms of dementia that cause the most distress or institutionalization; it is the neuropsychiatric symptoms that have the tremendous impact on quality of life.
There are no medications currently approved for the neuropsychiatric symptoms of dementia. Because they are approved for AD, ChEIs have been tried with mixed results, with no clear benefit emerging. In particular, Howard3 found no benefit in using them to treat agitation. There are 3 cholinesterase inhibitors in common use: donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne, formerly Reminyl). All increase cholinergic transmission by inhibiting cholinesterase at the synaptic cleft. While the exact mechanism of action is different, the drugs appear to be equally effective.4
Guidelines from the Alzheimer's Disease Management Council (ADMC) Clinical Consensus Panel describe the use of ChEIs in AD management and recommend that they be started early. Titrate dosage upward slowly. If one is not effective or causes intolerable side effects, another ChEI may be tried.4 Discontinuing the medication causes resurgence of symptoms.
Because there is no cure for AD, the goal of drug therapy is symptomatic: a temporary improvement; stabilization; or less-than-expected decline of cognitive, functional, or behavioral symptoms. This can be measured by a variety of assessment tools, including cognitive instruments, measures of functioning, and assessments of activities of daily living. The Mini-Mental State Examination, commonly used for screening for dementia, is not sensitive enough to detect changes. The large number of different assessment tools adds to the confusion over the efficacy of ChEIs, as a patient may improve in one area of functioning but not another.5
Gastrointestinal (GI) adverse effects, such as nausea, vomiting, diarrhea, anorexia, weight loss, and dyspepsia, are common with ChEIs and may occur when medication is started, requiring careful dose titration. Donepezil appears to have a lower incidence of GI adverse effects than the other 2 ChEIs. That fact, plus its once-daily dosing, have made it a frequent drug choice. Oral rivastigmine must be given with food twice a day. A transdermal patch of rivastigmine has recently been approved by the Food and Drug Administration. This dosage form may cause less nausea and vomiting than the oral dose. Galantamine is also given twice a day.5
The other adverse effects of ChEIs have received less attention. The fact sheet from the Alzheimer's Association mentions only the GI side effects.6 These other effects include fatigue, insomnia, muscle cramps, dizziness, asthenia (weakness), and syncope. Some of these symptoms may be hard to assess in patients with dementia who have difficulty expressing themselves.
Syncope is a serious adverse effect, causing fall-related injuries. ChEIs have cardiovascular effects augmenting vagal tone and promoting bradycardia, which may lead to syncope. Gill et al1 found increased rates of syncope, bradycardia, hip fracture, and need for pacemaker insertion with the use of ChEIs.
Off-label use of atypical antipsychotics to manage behaviors in dementia has been common. Research shows some evidence of efficacy.7 However, the FDA has determined that these drugs are associated with an increase in risk of mortality and stroke, and requires a black box warning to that effect.
Where does this leave the clinician? It is recommended that clinicians identify target symptoms/behaviors. Conduct a careful assessment for a remedial cause of the behavior, then try nonpharmacologic interventions. Symptom severity can help determine treatment. There are times when a patient's condition is intolerable and clearly requires pharmacological intervention. Most of the time the situation is less clear. ChEIs can be tried; antipsychotics may be preferred. This is where the input of the caregiver is important.
The clinician must carefully weigh benefits versus risks of the pharmacological treatment. This deliberation must include evaluating the devastating effect of the disease on the patient and his or her family. In the case of ChEIs, the assessment must include the risk of weakness, dizziness, and syncope, with a high potential for resultant falls and injury.
References
- Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors . Arch Intern Med . 2009;169(9):867–873
- . Attainment of treatment goals by people with Alzheimer's disease receiving galantamine: a randomized controlled trial . Can Med Assoc J . 2006;174(8):1099–1105
- Donepezil for the treatment of agitation in Alzheimer's disease . N Engl J Med . 2007;357(14):1382–1392
- . Effective pharmacologic management of Alzheimer's disease . Am J Med . 2007;120:388–397
- Diagnosis and treatment of dementia: nonpharmacologic and pharmacologic therapy for mild to moderate dementia . Can Med Assoc J . 2008;179(10):1019–1026
- . FDA-Approved Treatments for Alzheimer's. Topic Sheet . Available at: www.alz.org
- The dementia antipsychotic withdrawal trial (Dart-AD): long-term follow-up of a randomized placebo-controlled trial . Lancet Neurol . 2009;8:151–157
Suggestions for topics are welcome.
PII: S1555-4155(10)00030-9
doi:10.1016/j.nurpra.2010.01.009
© 2010 American College of Nurse Practitioners. Published by Elsevier Inc. All rights reserved.
