Treatment

Recognition of the cholinergic deficit associated with AD has given rise to a number of medications that facilitate cholinergic neurotransmission. Benefits demonstrated by giving intravenous physostigmine, a short half-life inhibitor of acetylcholinesterase

(AChE), led to the development of longer half-life, orally administered AChE inhibitors (AChEI). These medications have been shown to significantly improve cognition when compared to placebo, and this effect can be maintained for years. AChEIs are also useful psychotropic drugs in patients with AD: Improvements in apathy, hallucinations, and other neuropsychiatry symptoms have been shown (Cummings, 2000).

Tacrine was the first AChEI to be widely used clinically. Tacrine is a nonselective AChEI; because it inhibits both AChE and butyrylcholinesterase, the cholinesterase predominant outside the central nervous system, tacrine is associated with significant cholinergic side effects including nausea, vomiting, and diarrhea. Another significant side effect of tacrine is hepatotoxicity; this necessitates discontinuation of the drug in some users, but users developing this side effect can be rechallenged with the drug. Significant side effects, four times a day dosing, and newer AChEIs have relegated tacrine to a secondary position among the AChEIs. Donepezil is a more selective inhibitor of AChE and can be taken once daily. Rivastigmine, a derivative of physostigmine, is also a more specific inhibitor of AChE. Cholinergic side effects necessitate slow titration (over weeks) when starting patients on rivastigmine. Rivastigmine is dosed twice daily. Galantamine is both an AChEI and an allosteric modulator of the cholinergic nicotinic receptor. Galantamine is given twice daily.

A number of pharmacological approaches to AD have focused on intervention in the disease process itself. In women, estrogen is probably a neurotrophin that facilitates synaptogenesis and learning. Studies have suggested that postmenopausal estrogen supplementation in women can decrease the risk of developing AD, but other factors present in the estrogen-using population confound these results. It is unclear if estrogen is helpful in women who have developed AD (Cholerton et al., 2002). Several epidemiological studies have likewise suggested that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDS) may decrease the risk of developing AD. However, clinical trials of corticosteroids and COX inhibitors have not supported this finding (Pasinetti, 2002). Lipoprotein oxidation and subsequent cellular membrane damage has been posited as a pathogenic mechanism in AD, and the use of oxygen-free radical scavengers such as vitamins E and C has been investigated. In a study of the effects of vitamin E, illness progression in AD patients was noted to be slowed (Sano, 1997). As research on the usefulness of estrogen, NSAIDS, and vitamins is still evolving, general recommendations regarding the use of these substances cannot be made at this time.

The potential utility of N-menthy-D-aspartate (NMDA) antagonists in the treatment of AD has been suggested by the finding of the overstimulation of NMDA receptors by glutamate in neurodegenerative disorders. One NMDA antagonist, memantine, has demonstrated significant clinical benefit in the treatment of moderate to severe AD (Reisberg et al., 2003) providing hope for treatment of the disease in its later stages.

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