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Drugs for Alzheimer's Disease.

The Alzheimer's Association (2009a) estimates 5.9 million Americans are living with Alzheimer's dementia (AD). AD is the most common form of dementia in the United States, accounting for 50%-70% of the cases of dementia. The number of Americans living with the disease is expected to rise to 11-16 million in the year 2050 (Smith, 2009). Alzheimer's disease is currently the seventh leading cause of death in the United States (Alzheimer's Association, 2009a). AD is progressive and fatal; its exact cause is unknown, but research has demonstrated a clear connection between the affected cells in the amygdala, hippocampus, areas around the hippocampus, and "the cortical pathways involved in catecholaminergic, seritonergic and cholinergic transmission" (Alzheimer's Association 2009b, para. 2). In the hippocampus and neocortex, the neurons that convey acetylcholine suffer the most deterioration, resulting in a reduction of acetylcholinesterase (ACHE). This leads to the deterioration of cognitive and behavioral function that is the primary symptom of Alzheimer's disease (Bender, 2005).

The reduction of AChE is seen in advanced stages of the disease, as is a reduction of choline acetyltransferase (Bender, 2005). Butyrylcholinesterase (BuChE), which is related to acetylcholinesterase, is distributed widely in the nervous system. It is important in cholinergic neurotransmission, and also is thought to be involved in neurodegenerate diseases (Darvesh, Hopkins, & Geula, 2006). BuChE is present in both the cortical and limbic areas of the brain, and is increased in Alzheimer's disease (Bender, 2005). Alzheimer's disease also has two known hallmarks of pathology: plaques and neurofibrillary tangles. "Plaques are extracellular deposits of abnormally processed amyloid precursor protein, and tangles are intracellular accumulations of the cytoskeletal protein tau" (Alzheimer's Association, 2009b, para. 3). These plaques and tangles are seen in advanced disease. Along with the depletion of acetyltransferase, their presence correlates with the cognitive decline of the disease state (Bassil & Grossberg, 2009). The cause of acetyltransferase depletion and formation of plaques and tangles is not clearly known. Many hypotheses are being explored, including abnormal amyloid processing, cardiovascular risk factors, tau formation, and inflammation and disruption of cell signaling pathways (Alzheimer's Association, 2009b).

Drug therapy for Alzheimer's disease is currently aimed at slowing the progression of the disease and managing the symptoms of the cognitive decline. In this article, the two classes of drugs currently approved by the Food and Drug Administration for treatment of Alzheimer's disease will be reviewed: the cholinesterase inhibitors (ChEls) and the single N-methyl-D-aspatate (NMDA) receptor antagonist, the drug memantine (Clip and Save Drug Chart, 2009).

Cholinesterase Inhibitors

The cholinesterase inhibitor drugs increase the level of acetylcholine, which assists with memory, judgment, and other cognitive functions. The cholinesterase inhibitors maintain the amount of circulating acetylcholine, which is thought to compensate for the loss of functioning brain cells (Alzheimer's Association, 2009c). Four cholinesterase inhibitor drugs are approved by the FDA and available in the United States: donepezil (Aricept[TM]), galantamine (Razadyne[TM]), rivastigmine (Exelon[TM]), and tacrine (Cognex[TM]) (Alzheimer's Association 2009c). Tacrine has experienced significantly less use then the other three ChEls for two reasons, the need for multiple daily dosing and its significant risk of heptatoxicity (Alzheimer's Association 2009c; Bassil & Grossberg 2009; Rodda & Walker 2008).

Donepezil is the most popularly prescribed ChEl. It is also the only drug indicated for all stages of Alzheimer's disease: mild, moderate, and severe (Smith, 2009). Donezpezil is a "reversible and noncompetitive ChEI, and a far more selective inhibitor of acetylcholinesterase than of butyrylcholinesterase" (Bassil & Grossberg, 2009, p. 296), assisting in memory and learning tasks by increasing the level of acetylcholine in the brain. Smith (2009) cited a 3-year study with donepezil in which patients showed clinical improvements when the drug was started early in clinical treatment versus patients for whom therapy was delayed. Aisen, Souder, and Treinkman (2005) also reported significant improvement in cognitive function in patients treated with donepezil over a 24-week study period compared to placebo-treated patients. Donepezil is prescribed in initial daily dosing of 5 mg at bedtime, increasing the dose to 10 mg after 4-6 weeks of therapy. Because the drug is 96% protein bound, the patient must maintain adequate hydration while on therapy (Turkoski, Lance, & Bonfiglio, 2009). Current research is exploring once-a-month dosing by subcutaneous injection in the belief that this regimen will help maintain a steady state of the drug in a patient population with known memory problems; it also will reduce caretaker burden of daily drug therapy (Smith, 2009). Adverse effects of donepezil include gastrointestinal side effects, such as nausea, anorexia, and diarrhea, as well as muscle cramping, headache, fatigue, and dizziness (Bassil & Grossberg, 2009; Turkoski et al., 2009).

Rivastigmine is a ChEI indicated for mild-to-moderate AD as well as mild-to-moderate dementia related to Parkinson's disease (Bassil & Grossberg, 2009). It is an equal inhibitor of acetylcholinesterase and butyrylcholinesterase. Bender (2005) reported results of a 6-month study in which patients treated with rivastigmine demonstrated an improvement on the Alzheimer's disease assessment cognitive subscale. Similar to studies with donepezil, the rate of cognitive decline was altered favorably when patients were started earlier on therapy. Dosing for rivastigmine starts at 1.5 mg twice daily for 3 weeks, increasing to 3 mg twice daily with a maximum dose of 6 mg in two divided doses. The drug is 40% protein bound (Turkoski et al., 2009). Adverse gastrointestinal effects of rivastigmine are nausea, vomiting, diarrhea, anorexia, and abdominal pain. These effects were most significant during the titration phase of drug therapy (Bassil & Grossberg, 2009). Other adverse effects are dizziness and headache, with less common effects being fatigue, insomnia, and confusion (Turkoski et al., 2009). In a 26-week study with rivastigmine, Smith (2009) reported 95% of patients experienced an adverse effect; only 19% discontinued the drug due to the adverse effects. In addition, patients who received the drug three times a day versus twice a day had significantly fewer gastrointestinal side effects and improved tolerability of the drug (Bassil & Grossberg 2009). A transdermal delivery system patch was developed, decreasing gastrointestinal side effects, assisting with drug therapy adherence, and improving efficacy with earlier improvement and improved cognitive scores (Bassil & Grossberg, 2009).

Galantamine (Razadyne[TM], marketed as Reminyl[TM] in other countries) is approved for treating patients with mild-to-moderate Alzheimer's disease (Bassil & Grossberg, 2009). Galantamine inhibits acetylcholinesterase "to slow acetylcholine hydrolysis and may also modulate presynaptic nicotinic receptors activation, thereby increasing neurotransmitter concentrations in the synaptic cleft" (Bassil & Grossberg, p. 300). Bender (2005) reported findings of a 36-month study in which patients treated with galantamine had 50% less cognitive loss than untreated patients. Aisen and colleagues (2005) also reported patients treated with galantamine during a 12-month trial maintained cognitive scores relative to their baseline scores. Galantamine is dosed at 4 mg twice daily for 4 weeks, increasing to 8 mg twice daily with a maximum dose of 12 mg twice daily. It also is available as an extended release tablet, with dosing starting at 8 mg per day and increasing to 24 mg a day (Turkoski et al., 2009). Reported adverse gastrointestinal effects include nausea, vomiting, anorexia, and diarrhea. Other adverse effects are dizziness, headache, weight loss, and urinary tract infection. Adverse effects were not significantly different with the immediate release versus the extended release formulation of the drug, with the exception of fewer days of reported nausea; no difference was seen in patients with vomiting (Bassil & Grossberg, 2009).

Tacrine (Cognex[TM]) is a centrally acting cholinesterase inhibitor which slows the degradation of acetylcholine in the cerebral cortex. However, it has been associated with hepatotoxicity and is now rarely used because three other ChEls have a better safety profile (Bassil & Grossberg, 2009; Turkoski et al., 2009).

NMDA Receptor Antagonist

Memantine (Namenda[TM]) is the only NMDA receptor antagonist approved in the United States. It is used to treat moderate-to-severe Alzheimer's disease. The FDA declined approval for treatment of mild AD in 2005 (Alzheimer's Association, 2009c).

Memantine regulates the activity of glutamate, which works in memory and learning. Excess levels of glutamate can cause disruption and death to nerve cells. Memantine is believed to protect cells from excessive glutamate by blocking the NMDA receptors (Alzheimer's Association, 2009c; Bassil & Grossberg, 2009). This action may help preserve or even improve learning, and acts as a neuroprotective defense system (Aisen et al., 2005). Smith (2009) reported results of a 12-week trial of memantine with patients with severe Alzheimer's disease; patients treated with memantine demonstrated a significant improvement in cognitive function. Bassil and Grossberg (2009) also cited a 28-week study in which patients with moderate-to-severe Alzheimer's disease who received memantine demonstrated significant improvement on functional, cognitive, and global functioning scales. Memantine also is being studied with ChEls to assess if combination therapy is superior to monotherapy. A study by Rountree and colleagues (2009) found combination therapy was superior to monotherapy. The study also demonstrated long-term use of Alzheimer's drug therapy had significant impact on the rate of decline on cognitive, global, and activity of daily living functioning. Dosing of memantine starts at 5 mg daily, increasing to a target dose of 20 mg per day. Amounts greater than 5 mg must be given in divided doses. Memantine is 40% protein bound. Adverse effects include dizziness, confusion, headache, constipation, and cough (Turkoski et al., 2009).

Patient and Caregiver Education

The concern is that patients with dementia may not be able to adhere to treatment plans and report adverse effects. This can create a burden on caregivers because approximately 70% of persons with AD live at home with a caregiver who is a family member or friend. Of patients still living in a home setting, 73% currently require assistance with managing and taking their medications (Bassil & Grossberg, 2009).

Ongoing research in the pharmacologic treatment of Alzheimer's disease centers on drug delivery systems that will improve adherence and minimize adverse effects. Other research is exploring when to start and how long to continue drug therapy. As mentioned previously, several studies found significant delay in loss of cognitive function and a possible improvement in cognitive function when drug therapy was started earlier and continued for a long period of time (Aisen et al., 2005; Bassil & Grossberg, 2009; Rountree et al., 2009; Smith, 2009). Rountree and fellow researchers (2009) are also considering combination versus monotherapy in the treatment of AD by maintaining patients on ChEls while adding the NMDA drug to the medication regimen. Their research has demonstrated positive effects even in patients with an advanced state of disease.

The nurse's role in drug therapy for AD centers on the education of the patient and the caregiver. Drug efficacy is improved when the drug is taken on a regular and consistent basis. Treatment adherence and reporting of adverse effects can have a positive impact on the patient's condition as well as the quality of life (Bassil & Grossberg, 2009). Teaching the purpose of drug therapy, helping the patient and caregiver choose the easiest drug delivery system for the individual, investigating possible drug-to-drug interactions, and managing adverse effects can relieve some of the burden of the Alzheimer's disease management.

References

Aisen, P.S., Souder, E., & Treinkman, A. (2005). Utilizing pharmacologic treatment options to improve patient care in Alzheimer's disease. Journal of the American Academy of Nurse Practitioners, 17($1), 1-12. DOI: 10.1111/j.1745-7599.2006.000s1.x

Alzheimer's Association. (2009a). What is Alzheimer's. Retrieved from http://www.alz.org/alzheimers_disease_what_is_alzheimers.asp

Alzheimer's Association. (2009b). Alzheimer's disease. Retrieved from http://www.alz.org/professionals and researchers_professionals and researchers_alzheimers disease_ pr.asp

Alzheimer's Association. (2009c). Cognitive symptoms. Retrieved from http://www.alz.org/ professionals and researchers_cognitive_symptoms.asp#cholinesterase

Bassil, N., & Grossberg, G.T. (2009). Novel regimens and delivery systems in the pharmacological treatment of AIzheimer's disease. CNS Drugs, 23(4), 293-307.

Bender, K.J. (2005). Slowing the progression of Alzheimer's disease: The role of cholinesterase inhibitors. Consultant, 45(3), S5-S11.

Clip & save drug chart, drugs to treat Alzheimer's disease. (2009). Journal of Psychosocial Nursing & Mental Health Services, 47(4), 13-14.

Darvesh, S., Hopkins, D.A., & Geula, C. (2006). Neurobiology of butyrylcholinesterase. Nature Reviews Neuroscience, 4(2), 131-138. DOI: 10.1038/nrn1035

Rodda, J., & Walker, Z. (2008). Ten years of cholinesterase inhibitors. International Journal of Geriatric Psychiatry 24(5), 437-442. DO1:10.1002/gps.2165

Rountree, S.D., Chan, W., Pavlik, V.N., Darby, E.J., Siddiqui, S., & Doody, R.S. (2009). Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease. Alzheimer's Research & Therapy, 21(1), 7.

Smith, D.A. (2009). Treatment in Alzheimer's disease in the long-term-care setting. American Journal of Health-System Pharmacists, 66(10), 899-907. DOI: 10.2146/ajhp070622

Turkoski, B.B., Lance, B.R., & Bonfiglio, ME (2009). Drug information handbook for advanced practice nurses (10th ed.). Hudson, OH: Lexi-Comp.

Lisa A. Cranweli-Bruce, MS, RN, FNPC, is a Clinical Instructor, Byridine E Lewis School of Nursing, College of Health and Human Services, Georgia State University, Atlanta, GA.
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Title Annotation:Nursing Pharmacology
Author:Cranwell-Bruce, Lisa A.
Publication:MedSurg Nursing
Geographic Code:1USA
Date:Jan 1, 2010
Words:2129
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