July/August 2013

Medications Target Alzheimer’s Disease

By Mark D. Coggins, PharmD, CGP, FASCP
Today’s Geriatric Medicine
Vol. 6 No. 4 P. 6

Current FDA-approved medications that help to manage Alzheimer’s disease (AD) symptoms and slow its progression include cholinesterase inhibitors (CIs) and N-methyl-D-aspartate antagonists (NMDAs).1

Most guidelines recommend including these medications as part of the care plan for AD patients with no contraindications as long as the patient and his or her caregivers are carefully educated on the medications’ risks and benefits and the appropriateness of their use remains under evaluation. Patients and families should be educated on expected benefits associated with using these medications with realistic therapy goals in mind.

The effectiveness of these medications often is unpredictable and highly variable among patients; however, these medications can help many patients with AD-related symptoms while providing them with comfort, dignity, and independence for a longer period of time and encouraging and assisting caregivers as well.2

CIs
CIs improve memory and cognitive function by increasing the availability of acetylcholine in the central nervous system by blocking the degradation of acetylcholine by the enzyme acetylcholinesterase.

In general, all of the CIs have demonstrated benefits in slowing the rate of cognitive and functional decline while reducing disturbances and caregiver stress.2,3 Patients with mild to moderate AD may see improvements in retaining new information when taking a CI.4 CIs also have been shown to alleviate some targeted troubling behaviors that contribute to caregiver stress, such as verbal repetition.5,6

CI selection often is based on a particular medication’s side effect profile. The most common side effects with CIs are nausea, vomiting, diarrhea, weight loss, and loss of appetite.2 These side effects typically are transient and may be minimized by slowly increasing the dose. Because CIs can cause syncope, patients should be monitored for risk of falls.

NMDAs
Memantine (Namenda) is the first and only approved NMDA medication. It reduces overexcitation of glutamate receptors, helping to preserve glutamatergic neurotransmission in the brain to slow the rate of cognitive decline.2 Memantine generally is well tolerated and is unlikely to cause adverse gastrointestinal effects that are commonly experienced with CIs.7

Namenda XR, a once-a-day extended-release capsule form of memantine, is currently being marketed. The capsules can be given with or without food and can be taken intact or opened and sprinkled on applesauce.

When switching from the Namenda to Namenda XR formulation, patients receiving 10 mg of Namenda twice daily should be converted to Namenda XR 28 mg once daily, with the switch being made the day following the last day the 10-mg Namenda tablet was taken.8 Patients with severe renal impairment (creatinine clearance of 5 to 29 mL/min as calculated by the Cockcroft Gault equation) should receive reduced maximum dosing of 5 mg twice daily of Namenda or if using Namenda XR, 14 mg once daily.8,9

Importance of Early Treatment
CIs and NMDAs are most effective when started early in the disease course and used persistently without treatment gaps. Therefore, early recognition of AD and evaluation of treatment effectiveness are essential.10 Early treatment provides the opportunity to attain maximum benefits during AD’s early and later stages.11 Aggressive treatment may maximize patient function and independence. Doses should be increased to the maximum tolerated amount to increase the potential for efficacy.

Studies have shown that patients experience a greater decline in cognition when CI therapy is delayed. One study involving rivastigmine (Exelon) demonstrated that patients receiving rivastigmine had significantly less cognitive decline at month six compared with those patients who did not receive the drug, with this benefit continuing to be noted through the 52-week trial.12

Delaying Nursing Home Placement
CI use in some patients has been shown to help delay the need for nursing home placement. AD patients taking ≥ 5 mg/day of donepezil (Aricept) have been shown to have a significant delay in nursing home placement. Patients taking donepezil for nine to 12 months reduced the time to temporary nursing home placement for a dementia-related incident by 21 months and by approximately 18 months for permanent nursing home placement.13

In a US government-funded observational study, memantine combined with a CI was associated with a threefold delay in time to nursing home admission compared with CI monotherapy.14 Another study of memantine reported that patients with moderate to severe AD had enhanced autonomy in activities of daily living after 28 weeks of therapy. Memantine-treated patients were reported to delay transition to the dependent stages of the disease.15

Combination Therapy
Combination therapy (CI and memantine) has been found to be more beneficial in slowing the rate of cognitive decline than CI therapy alone. The benefits of combination therapy may be sustained for at least two years.16 Memantine use alone and with CIs has shown moderate improvements in behavioral symptoms, including agitation, aggression, irritability, liability, and delusions.17

Discontinuing Therapy
Clinicians often struggle with when to discontinue AD medications. Before discontinuing, clinicians must consider that losses in cognition that occur following discontinuation of six weeks or longer may not be reversed when therapy is reinstated. These medications often are discontinued when patients are admitted to the hospital, and failure to restart these medications on discharge can have tremendous negative implications for these patients.

Recommendations to discontinue these medications should be made if the patient experiences any of the following:

• fails monotherapy with two or more CIs, memantine, and combination therapy;

• demonstrates loss of clinical effect, manifested by accelerated and progressive cognitive deterioration;

• demonstrates intolerance (unmanageable drug-related side effects); or

• deteriorates to the point of having no meaningful social interactions or quality of life as determined by caregivers and health care providers.

Coconut Oil Debate
Coconut oil and a related medical food, Axona, are being promoted as AD treatments, and their use has gained significant media visibility.

Advocates describe AD as “diabetes of the brain” and believe the brain utilizes the ketones provided by coconut oil better than glucose, therefore improving cognitive function. Other theories suggest these ketones help prevent amyloid plaques and reduce the inflammatory responses associated with neurodegeneration. Still others speculate that ketones may improve free radical-mediated pathologies associated with AD.

Skepticism surrounds coconut oil use for treating AD, and the Alzheimer’s Association has stated that “every day we hear magical claims of products promising relief. Coconut oil, for example, is touted by a physician in Florida as having a miraculous impact on her husband. While the ketones in coconut oil are being widely studied for dementia and are a key ingredient in an FDA-approved food product for memory loss, there is no scientific evidence that coconut oil helps with Alzheimer’s.”

The University of South Florida Health Byrd Alzheimer’s Institute has announced a pilot study beginning this year to evaluate the potential benefits of coconut oil for mild to moderate AD, which may help improve ketones’ credibility and recognition as a possible AD treatment.

Without additional clinical research, it is difficult to recommend coconut oil at this time for AD treatment. However, as seen with traditional treatments, therapies’ effectiveness and benefits often vary among patients. AD patients and their families who choose to use coconut oil or Axona should start with low doses and gradually increase to avoid adverse gastrointestinal effects. It also is important that a patient’s health care provider is made aware of the use of these treatments to help monitor for adverse effects and effectiveness and possibly increased lipid levels.

— Mark D. Coggins, PharmD, CGP, FASCP, is a director of pharmacy services for more than 300 skilled nursing centers operated by Golden Living and a director on the board of the American Society of Consultant Pharmacists. He was recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
1. Thies W, Bleiler L; Alzheimer’s Association. 2013 Alzheimer’s disease facts and figures. Alzheimers Dement. 2013;9(2):208-245.

2. Alzheimer’s Disease medications fact sheet. National Institute on Aging website. http://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-medications-fact-sheet. Last updated May 21, 2013. Accessed May 11, 2013.

3. Rodda J, Morgan S, Walker Z. Are cholinesterase inhibitors effective in the management of the behavioral and psychological symptoms of dementia in Alzheimer’s disease? A systematic review of randomized, placebo-controlled trials of donepezil, rivastigmine and galantamine. Int Psychogeriatr. 2009;21(5):813-824.

4. Crowell TA, Paramadevan J, Abdullah L, Mullan M. Beneficial effect of cholinesterase inhibitor medications on recognition memory performance in mild to moderate Alzheimer’s disease: preliminary findings. J Geriatr Psychiatry Neurol. 2006;19(1):13-15.

5. Asp E, Cloutier F, Fay S, et al. Verbal repetition in patients with Alzheimer’s disease who receive donepezil. Int J Geriatr Psychiatry. 2006;21(5):426-431.

6. Rockwood K, Fay S, Jarrett P, Asp E. Effect of galantamine on verbal repetition in AD: a secondary analysis of the VISTA trial. Neurology. 2007;68(14):1116-1121.

7. Kwak YT, Han IW, Suk SH, Koo MS. Two cases of discontinuation syndrome following cessation of memantine. Geriatr Gerontol Int. 2009;9(2):203-205.

8. Namenda XR. Drugs.com website. http://www.drugs.com/pro/namenda-xr.html. Last updated April 2013.

9. Namenda tablets/oral solution. Forest Pharmaceuticals website. http://www.frx.com/pi/Namenda_pi.pdf. Accessed May 15, 2013.

10. Seltzer B. Cholinesterase inhibitors in the clinical management of Alzheimer’s disease: importance of early and persistent treatment. J Int Med Res. 2006;34(4):339-347.

11. Homma A, Imai Y, Tago H. Long-term safety and efficacy of donepezil in patients with severe Alzheimer’s disease: results from a 52-week, open-label, multicenter, extension study in Japan. Dement Geriatr Cogn Disord. 2009;27(3):232-239.

12. Doraiswamy PM, Krishnan KR, Anand R, et al. Long-term effects of rivastigmine in moderately severe Alzheimer’s disease: does early initiation of therapy offer sustained benefits? Prog Neuropsychopharmacol Biol Psychiatry. 2002;26(4):705-712.

13. Geldmacher DS, Provenzano G, McRae T, Mastey V, Ieni JR. Donepezil is associated with delayed nursing home placement in patients with Alzheimer’s disease. J Am Geriatr Soc. 2003;51(7):937-944.

14. Lopez OL, Becker JT, Wahed AS, et al. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009;80(6):600-607.

15. Rive B, Vercelletto M, Damier FD, Cochran J, Francois C. Memantine enhances autonomy in moderate to severe Alzheimer’s disease. Int J Geriatr Psychiatry. 2004;19(5):458-464.

16. Atri A, Shaughnessy LW, Locascio JJ, Growdon JH. Long-term course and effectiveness of combination therapy in Alzheimer disease. Alzheimer Dis Assoc Disord. 2008;22(3):209-221.

17. Gauthier S, Wirth Y, Möbius HJ. Effects of memantine on behavioural symptoms in Alzheimer’s disease patients: an analysis of the neuropsychiatric inventory (NPI) data of two randomized, controlled studies. Int J Geriatr Psychiatry. 2005;20(5):459-464.