Alzheimer's Disease: A Review of Available Treatments
Alzheimer's disease (AD) is a neurodegenerative diseasethat progressively leads to dementia, psychiatricabnormalities, and cognitive impairment andcontributes to the ultimate demise of the patient. Plaquesand tangles are the 2 characteristic neuropathology findingsin patients with AD. The accumulation of beta-amyloidpeptide between neurons creates plaques that becomeinflamed and damage surrounding neurons. The normalprocessing of beta-amyloid and its precursor proteinsbecomes impaired, allowing for this accumulation tooccur. These alterations in beta-amyloid processing mayoccur as a result of genetic, environmental, and comorbiddisease state factors.1,2
Neurofibrillary tangles are the result of hyperphosphorylatedtau proteins linking together to form filamentswithin the neuron. These filaments may become dense,compromising microtubular function and, ultimately, theneuron's ability to function. Hyperphosphorylation of tauproteins occurs as a result of altered genetics and other factorsyet to be discovered.1 It is unknown whether thedevelopment of plaques results from filament formation.Inflammation also is a significant component in theadvancement of AD, yet anti-inflammatory agents havenot demonstrated a treatment benefit to date.3,4
The net effect of the pathology is a loss of functioningneurons. The loss of cholinergic neurons results inimpaired memory, learning, attention, behavior, planning,initiative, social activity, and activities of daily living, toname just a few. These symptoms present considerablechallenges for caregivers, physicians, therapists, and society.Caregivers of patients with AD suffer from increasedlevels of stress and higher rates of depression.5,6 The socialand financial costs of AD are significant, estimated at$27,000 per patient per year in medical and custodialexpenses. The economic impact of new therapies designedto delay the progression of symptoms is not fully understood,due to the complex nature of assessing their impact.
The first class of agents proven to be efficacious forsymptom delay in mild-to-moderate AD is the cholinesteraseinhibitors. Tacrine (Cognex; Parke-Davis), thefirst agent introduced, has a limited role in therapybecause of potential hepatotoxicity concerns and the needfor frequent laboratory monitoring. Donepezil (Aricept;Eisai/Pfizer), rivastigmine (Exelon; Novartis), and galantamine(Reminyl; Janssen) are the other 3 members of theclass. They vary slightly in their pharmacologic properties,yet they have demonstrated a similar impact on patientoutcomes.
Cholinergic side effects—such as nausea, vomiting, diarrhea,and anorexia—may occur with any of these agents,requiring slow dose titration to improve patient tolerance.If therapy is interrupted for as little as a few days, sideeffects may be increased when therapy is resumed, makingit prudent to reinitiate therapy at a lower dose. It is importantto remember that galantamine should not be administeredto patients with severe hepatic or renal impairment.
The newest agent to come to market, memantine(Namenda; Forest Laboratories), is a low-moderate affinityN-methyl-D-aspartate receptor antagonist that ishypothesized to block abnormal signaling of the excitatoryamino acid, glutamate. Abnormal glutamatergic activityis thought to contribute to the development of ADpathology. Memantine is FDA-approved for the treatmentof moderate-to-severe AD and is available in Europe. Thismedication now extends the ability to pharmacologicallytreat patients with more severe deterioration, ascholinesterase inhibitors are approved only for the treatmentof mild-to-moderate disease.
In clinical studies, memantine provided benefit inpatients receiving memantine monotherapy or in; combinationtherapy in those already taking the cholinesteraseinhibitor, donepezil. Recent results with memantine in ADpatients ranging in severity from mild to moderate suggestthat memantine is efficacious in earlier stages of the diseaseas well.
In AD patients, memantine treatment is safe and well tolerated,with an adverse events profile comparable to placebo.Memantine is primarily excreted unchanged in urineand produces minimal inhibition of CYP 450 enzymes; thusno pharmacokinetic interactions with drugs metabolized bythese enzymes are expected. Several studies have demonstrateda lack of interaction with coadministration ofmemantine and donepezil, a cholinesterase inhibitor metabolizedvia the CYP 450 system. Although preclinical studieswith memantine have demonstrated a lack of interaction invitro between memantine and cholinesterase inhibitors,coadministration of memantine and either rivastigmine orgalantamine has not been rigorously studied in humans.Therefore, it is recommended that clinicians monitorpatients receiving either galantamine or rivastigmine togetherwith memantine until formal evaluations are available.
Memory clinics and behavioral therapy have been establishedto assist patients, families, and caregivers in managingspecific symptoms or behaviors associated with AD. Manyresources are available for patients and caregivers to learnabout the disease process, treatments, and daily activities thatmay be affected in the different stages of the disease. Safetyconcerns also need to be addressed to prevent patients withAD from causing accidental harm to themselves or others.Examples include securing sharp objects, as well as providingboundaries in the living environment, trimming fingernailsfrequently, and removing jewelry to ensure safe hygiene.
A number of treatments and alternative therapies(Sidebar) currently are under investigation for the treatmentand prevention of AD. Pharmacologic interventionsdeveloped to date have a clear role in delaying disease progression,but their effects are not permanent. Science hasyet to find treatments that provide sustained benefitsbeyond those achieved by current therapies or a treatmentthat can reverse the disease process. Genetic influences andother potential risk factors for the development of AD alsoare targets for investigation and modification in the future.As further developments are made, patients and caregiverswill turn to pharmacists, as representatives of the healthcare team, as a resource for new information.
Dr. Huxtable is an assistant professor of pharmacy practice atMidwestern University College of Pharmacy—Glendale,Glendale, Ariz.
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