Pharmacotherapy for Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia among North Americans. It affects approximately 1% of 60-year-olds and increases in prevalence to 30% by age 85.¹ It is a costly disease in terms of the financial and emotional burden on society and on individual families, and it is often the primary cause of nursing home admissions. The main pharmacologic approach is to limit cognitive and functional decline.

The classic early clinical signs of AD include impairment in memory, language, and visuospatial function.² Patients progress from the loss of higher-function activities, such as handling personal finances and navigating trips across town, to the inability to maintain personal hygiene. Behavioral and mood disturbances eventually may progress to psychosis and agitation in more-advanced AD.³

Antioxidants

In 1997, a study using alpha-tocopherol (vitamin E) indicated that the antioxidant might delay the time to death or placement in a nursing home by 4.5 to 7.5 months.⁴ Despite the concerns regarding the validity of the study and a lack of further data to support the benefits of vitamin E, many patients may self-medicate with high doses of vitamin E, and they should be counseled on the potential toxicities. Vitamin C also is a common self-medication therapy, but it may be safer because it is not a lipid-soluble vitamin as is alpha-tocopherol.

Cholinesterase Inhibitors

Cholinesterase inhibitors are thought to work by increasing cholinergic function through blocking the metabolism of acetylcholine, and they may lead to increased synaptic levels of acetylcholine. Three agents are still in common use for mild-to-moderate AD: donepezil, rivastigmine, and galantamine (Table). Tacrine is used rarely because of its potential hepatotoxicity.

The most common side effects of cholinesterase inhibitors are related to gastrointestinal (GI) disturbance (nausea, vomiting, and diarrhea). Donepezil has a lower incidence of GI side effects and may be more tolerable. The nausea and vomiting can be greatly reduced by initiating the medication at the lowest dose and waiting 4 weeks before increasing the dose. Whereas donepezil may be started at its minimum effective dose of 5 mg qd, galantamine and rivastigmine are initiated at lower doses and should be increased after 4 weeks. The minimum effective dose of galantamine is 8 to 12 mg bid. The minimum effective dose of rivastigmine is 3 to 6 mg bid.

Other common side effects of cholinesterase inhibitors include weight loss, insomnia, abnormal dreams, muscle cramps, bradycardia, syncope, and fatigue.

Donepezil should be used with caution in patients with active GI disorders, in those with a history of ulcer disease, or in those concomitantly taking nonsteroidal anti-inflammatory drugs (NSAIDs).⁵ Donepezil may cause cardiovascular side effects in 1 of 100 to 1 of 1000 patients and rarely leads to hematologic abnormalities, including anemia and thrombocytopenia.⁵

Galantamine should be used with caution in patients with GI ulcer, seizure disorder, asthma, and chronic obstructive pulmonary disease.⁶ Potent inhibitors of the cytochrome P450 3A4 may decrease the metabolism of galantamine and lead to symptoms of toxicity. These symptoms include bradycardia, collapse, convulsions, defecation, GI cramping, hypotension, lacrimation, muscle fasciculations, muscle weakness, QT prolongation, respiratory depression, salivation, severe nausea, sweating, torsades de pointes, urination, ventricular tachycardia, and vomiting.

Rivastigmine may cause a slightly higher incidence of nausea (47%), vomiting (31%), dizziness (21%), and headache (17%), compared with the other cholinesterase inhibitors.⁷

Cholinesterase inhibitor therapy produces minimal improvement in cognition, as measured by the Alzheimer's Disease Assessment Scale. Studies suggest, however, that their benefit is in helping patients maintain the ability to perform activities of daily living and in potentially delaying placement in a nursing home.⁸ Yet, there have been no clinical trials using cholinesterase inhibitors in patients with mild-to-moderate AD, and there has been minimal research on moderate-to-severe AD patients residing in long-term care facilities. Theoretically, continuation of therapy within the nursing home setting may decrease behavior disturbances related to AD. The cost-effectiveness of cholinesterase inhibitors beyond delaying placement in a nursing home requires further investigation.

Discontinuing cholinesterase inhibitor therapy may result in abrupt loss of effect.

N-Methyl-D-Aspartate (NMDA) Antagonist

Memantine is theorized to be a noncompetitive NMDA receptor antagonist, similar in proposed mechanism to amantadine, rimantadine, and ketamine. Memantine has been approved for moderate-to-severe AD. The initial dose is 5 mg qd, and the drug can be titrated weekly by 5 mg qd to a maximum of 10 mg bid. Food does not appear to alter the 100% oral bioavailability of this agent.⁹ Memantine is renally excreted, and thus, for patients with impaired renal function, the maximum daily dose is 10 mg.¹⁰ The drug has been shown to have no effect on cytochrome P450 metabolism in vitro, and it is unlikely to have significant hepatic drug-drug interactions.⁶ Concomitant use of amantadine, ketamine, and dextromethorphan should be avoided because of the theoretical additive effect at the NMDA receptors.

In clinical trials of memantine, the incidence rates for adverse events did not differ significantly from those with placebo. The most common adverse effects include dizziness, headache, hallucinations, insomnia, confusion, and constipation.

When memantine was added to donepezil therapy, community- dwelling patients temporarily stabilized or achieved a modest improvement in daily function before continuing to decline.¹¹ Minimal or no change was seen in 72% of the patients taking memantine and donepezil, in comparison with 62% of the patients taking placebo and donepezil. There appears to be no increase in the frequency or severity of side effects when memantine is used in combination with cholinesterase inhibitors.¹² The combination may not be beneficial in all patients, however, and patients'families should evaluate the benefit of adding memantine.

Behavior and Mood Therapy

As mentioned earlier, behavior and mood disturbances are very common in patients with AD. Atypical antipsychotic agents?such as risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole?may be used for patients exhibiting agitation or psychosis. Mood stabilizers (divalproex sodium and carbamazepine) or antidepressants may be beneficial. These medications may have hepatic drug-drug interactions with galantamine, however.

Conclusion

Alzheimer's disease is a progressive, debilitating condition that, without effective pharmacologic treatment, will continue to be an emotional and financial burden in North America. Cholinesterase inhibitors have been shown to slow the progression of cognitive and functional decline in patients living in the community. Memantine may be useful in moderate-to-severe AD and can be beneficial when used in combination with cholinesterase inhibitors.

Dr. DeKorte is director of pharmacy education and training and manager of clinical pharmacy services at George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah. She is also clinical assistant professor of pharmacy practice at the University of Utah.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@mwc.com.