A deficiency of intact cholinergic neurons, particularly those extending from subcortical areas such as the nucleus basalis of Meynert, has been observed in patients with progressive dementia of the Alzheimer type. Using a rationale similar to that in other CNS degenerative diseases, therapy for enhancing concentrations of cholinergic neurotransmitters in the CNS has been used in mild-to-moderate Alzheimer's disease. Therapeutic strategies are directed at maximizing the ratio of central to peripheral ChE inhibition and using ChE inhibitors in conjunction with selective cholinergic agonists and antagonists.
Donepezil, 5 and 10 mg/day oral doses, may improve cognition and global clinical function and delay symptomatic progression of the disease. The drug is well tolerated in single daily doses; side effects are largely attributable to excessive cholinergic stimulation (nausea, diarrhea, and vomiting). Usually, 5 mg doses are administered at night for 4-6 weeks; if this dose is well tolerated, the dose can be increased to 10 mg daily. Rivastigmine, a long-acting carbamoylating inhibitor, has efficacy, tolerability, and side effects similar to those of donepezil. Galantamine, a recently approved AChE inhibitor, has a side-effect profile similar to those of donepezil and rivastigmine. Tacrine is approved for mild-to-moderate Alzheimer's disease, but a high incidence of hepatotoxicity limits this drug's utility. See Chapter 20 for further discussion of therapies for this disease.
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