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Alzheimer’s disease (AD) and other dementias, major causes of morbidity and mortality in late life, have significant negative consequences on family caregivers and represent a huge economic burden on society. The Canadian Study of Health and Aging determined that 8% of Canadians who are age 65 years and over met criteria for dementia, with two-thirds of those being caused by AD (1). Further, the incidence of dementia doubles for every 5 years of increased age over 65 years, suggesting that there would be over 60 000 new cases of dementia diagnosed in Canada each year (2). In the absence of interventions to delay onset of these illnesses, we expect over 750 000 patients in Canada with dementia by 2031 (1). The annual cost of caring for patients with dementia has been estimated to range from $9451 per patient with mild disease to $36 794 per patient with severe disease (3), with an average net cost in Canada of about 4 billion dollars (4). With the aging of our society, these illnesses clearly represent a major health problem. Diagnostic classification systems for AD have focused on cognitive impairment, including memory deficits, aphasia, apraxia, agnosia, and disturbances in executive functioning (5,6). The dementias, however, are not simply disorders that cause cognitive impairment. They severely impair instrumental and, eventually, basic activities of daily living (ADL) and cause a multitude of behavioural disturbances that are frequently associated with much greater caregiver burden than are the memory problems. Therefore, a comprehensive management plan would need to consider optimizing general physical health (including sensory organs), improving (also known as enhancing) cognition, delaying illness progression, and treating behavioural disturbances. Assessing and treating physical and emotional problems in caregivers of these patients is also a crucial part of dementia management. Psychiatry has long been in the forefront of diagnosis and management of dementia patients. Still, with the rapid increase in research in the past decade and the introduction of new treatments, we increasingly face having to familiarize ourselves with new medications, such as completely new therapeutic drug classes, often with multiple and conflicting treatment guidelines. This review examines the data on the pharmacologic management of the cognitive and functional impairment caused by AD and other dementias. Although the focus is on drug treatments, it must be emphasized that these are only a small part of the treatment options that are available and that should be used to manage these illnesses. Recent studies on lifestyle interventions, including participation in physical activities (7) and mentally challenging activities (8), have demonstrated significant benefit for improving cognition and delaying illness progression. This review will not cover the management of behavioural and psychological symptoms of dementia (9) nor the management of caregiver stress (10), which have been reviewed elsewhere. MethodsA Medline search of the English literature from January 1980 to May 2002 was conducted, using the following key words: Alzheimer, dementia, therapy, cholinesterase inhibitor, donepezil, rivastigmine, and galantamine. All randomized controlled trials (RCTs) were reviewed, with emphasis on therapeutic options, currently available in Canada. Following a summary of these studies, organized by a purported mechanism of action (for example, cholinesterase inhibitors, hormone replacement therapy, antiinflammatory therapy, and vascular risk factor management) major treatment guidelines are reviewed. Finally, recommendations are provided based on best current evidence. ReviewCholinesterase Inhibitors Deficits in the cholinergic system are one of the best-documented neurochemical disturbances in AD. The activity of choline acetyltransference—the enzyme that converts choline to the neurotransmitter, acetylcholine—is significantly reduced in the cerebral cortex and in the hippocampus of AD patients. The nucleus basalis of Meynert, the main cholinergic input to the hippocampus, amygdala, and neocortex, demonstrates significant neuronal degeneration. These deficits have been shown to correlate with cognitive impairment and, for this reason, have been a target of therapeutic interventions for several years (11). Unfortunately, treatments that involve precursor loading and direct cholinergic agonists have been ineffective or poorly tolerated, but with the use of the cholinesterase inhibitors (ChEI), treatment was shown to be effective with an acceptable side effect profile. These drugs inhibit acetylcholinesterase, the enzyme responsible for the breakdown of acetylcholine, effectively leaving more acetylcholine available in the synapse to interact with postsynaptic receptors. It has now been about 15 years since the publication of the original tacrine study that formally opened the door to AD pharmacotherapy (12). Although this medication was eventually approved for use in the US, poor tolerability and unacceptable hepatotoxicity risk hampered its use, so it was never approved for use in Canada. Subsequently, however, 3 so-called “second-generation ChEIs” (donepezil, rivastigmine, and galantamine) have been approved, based on their efficacy demonstrated in RCTs and their acceptable tolerability profiles (13–28). Donepezil, rivastigmine, and galantamine share several therapeutic properties and have similar side-effect profiles, even though they are pharmacologically distinct agents. As procholinergic drugs, they increase secretions throughout the body, leading to some of their most common side effects, such as nausea, vomiting, and loose stools. Other potential concerns related to cholinergic effects include increasing secretions in the respiratory tract (exacerbating chronic obstructive pulmonary disease [COPD]) and slowing the heart rate. Dizziness and headache are also reported, though these are not uncommon in placebo-treated patients. In the RCTs, dropouts owing to adverse events were actually quite small, approximately 13%, compared with 6% in the placebo-treated patients (unpublished research). Because of these cholinergic effects, clinicians should use caution when prescribing these drugs in patients with a history of COPD, peptic ulcer disease, and certain cardiac conditions; namely, sick-sinus syndrome, supraventricular conduction abnormalities, active coronary artery disease, and congestive heart failure.
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