Alzheimer's disease (AD) is a neurodegenerative disease that progressively leads to dementia, psychiatric abnormalities, and cognitive impairment and contributes to the ultimate demise of the patient. Plaques and tangles are the 2 characteristic neuropathology findings in patients with AD. The accumulation of beta-amyloid peptide between neurons creates plaques that become inflamed and damage surrounding neurons. The normal processing of beta-amyloid and its precursor proteins becomes impaired, allowing for this accumulation to occur. These alterations in beta-amyloid processing may occur as a result of genetic, environmental, and comorbid disease state factors.1,2
Neurofibrillary tangles are the result of hyperphosphorylated tau proteins linking together to form filaments within the neuron. These filaments may become dense, compromising microtubular function and, ultimately, the neuron's ability to function. Hyperphosphorylation of tau proteins occurs as a result of altered genetics and other factors yet to be discovered.1 It is unknown whether the development of plaques results from filament formation. Inflammation also is a significant component in the advancement of AD, yet anti-inflammatory agents have not demonstrated a treatment benefit to date.3,4
The net effect of the pathology is a loss of functioning neurons. The loss of cholinergic neurons results in impaired memory, learning, attention, behavior, planning, initiative, social activity, and activities of daily living, to name just a few. These symptoms present considerable challenges for caregivers, physicians, therapists, and society. Caregivers of patients with AD suffer from increased levels of stress and higher rates of depression.5,6 The social and financial costs of AD are significant, estimated at $27,000 per patient per year in medical and custodial expenses. The economic impact of new therapies designed to 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 for symptom delay in mild-to-moderate AD is the cholinesterase inhibitors. Tacrine (Cognex; Parke-Davis), the first agent introduced, has a limited role in therapy because of potential hepatotoxicity concerns and the need for frequent laboratory monitoring. Donepezil (Aricept; Eisai/Pfizer), rivastigmine (Exelon; Novartis), and galantamine (Reminyl; Janssen) are the other 3 members of the class. They vary slightly in their pharmacologic properties, yet they have demonstrated a similar impact on patient outcomes.
Cholinergic side effectssuch as nausea, vomiting, diarrhea, and anorexiamay 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, side effects may be increased when therapy is resumed, making it prudent to reinitiate therapy at a lower dose. It is important to remember that galantamine should not be administered to patients with severe hepatic or renal impairment.
The newest agent to come to market, memantine (Namenda; Forest Laboratories), is a low-moderate affinity N-methyl-D-aspartate receptor antagonist that is hypothesized to block abnormal signaling of the excitatory amino acid, glutamate. Abnormal glutamatergic activity is thought to contribute to the development of AD pathology. Memantine is FDA-approved for the treatment of moderate-to-severe AD and is available in Europe. This medication now extends the ability to pharmacologically treat patients with more severe deterioration, as cholinesterase inhibitors are approved only for the treatment of mild-to-moderate disease.
In clinical studies, memantine provided benefit in patients receiving memantine monotherapy or in; combination therapy in those already taking the cholinesterase inhibitor, donepezil. Recent results with memantine in AD patients ranging in severity from mild to moderate suggest that memantine is efficacious in earlier stages of the disease as 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 urine and produces minimal inhibition of CYP 450 enzymes; thus no pharmacokinetic interactions with drugs metabolized by these enzymes are expected. Several studies have demonstrated a lack of interaction with coadministration of memantine and donepezil, a cholinesterase inhibitor metabolized via the CYP 450 system. Although preclinical studies with memantine have demonstrated a lack of interaction in vitro between memantine and cholinesterase inhibitors, coadministration of memantine and either rivastigmine or galantamine has not been rigorously studied in humans. Therefore, it is recommended that clinicians monitor patients receiving either galantamine or rivastigmine together with memantine until formal evaluations are available.
Memory clinics and behavioral therapy have been established to assist patients, families, and caregivers in managing specific symptoms or behaviors associated with AD. Many resources are available for patients and caregivers to learn about the disease process, treatments, and daily activities that may be affected in the different stages of the disease. Safety concerns also need to be addressed to prevent patients with AD from causing accidental harm to themselves or others. Examples include securing sharp objects, as well as providing boundaries in the living environment, trimming fingernails frequently, and removing jewelry to ensure safe hygiene.
A number of treatments and alternative therapies (Sidebar) currently are under investigation for the treatment and prevention of AD. Pharmacologic interventions developed to date have a clear role in delaying disease progression, but their effects are not permanent. Science has yet to find treatments that provide sustained benefits beyond those achieved by current therapies or a treatment that can reverse the disease process. Genetic influences and other potential risk factors for the development of AD also are targets for investigation and modification in the future. As further developments are made, patients and caregivers will turn to pharmacists, as representatives of the health care team, as a resource for new information.
Dr. Huxtable is an assistant professor of pharmacy practice at Midwestern University College of PharmacyGlendale, Glendale, Ariz.
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