Which cholinesterase inhibitor for early dementia?
Consider drug differences, patient factors to find a good match.
Mechanism. Donepezil inhibits the enzyme acetylcholinesterase, and rivastigmine inhibits acetylcholinesterase and butyrylcholinesterase. Galantamine inhibits acetylcholinesterase and shows allosteric modulation of the presynaptic nicotinic receptor.
Data indicating that rivastigmine is particularly effective in patients with rapidly progressive illness is consistent with the possible advantage of inhibiting both butyrylcholinesterase and acetylcholinesterase. It has been argued that galantamine’s binding to nicotinic receptors modulates their function, which may enhance acetylcholine release.
Among the three agents, only rivastigmine shows a consistent, linear dose-response relationship. It is rapidly and extensively metabolized, primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite (autohydrolysis). Minimal metabolism occurs via the major cytochrome P (CYP)-450 isoenzymes. Donepezil and galantamine are metabolized by isoenzymes 2D6 and 3A4 and undergo glucuronidation.7
Drug interactions. Because rivastigmine avoids hepatic metabolism, interactions with drugs metabolized by CYP-450 isoenzymes have not been reported.8
Donepezil interacts with ketoconazole and quinidine, which inhibit donepezil metabolism and increase mean donepezil concentrations. Galantamine interacts with ketoconazole, paroxetine, and erythromycin, which increase mean galantamine concentrations.9
Administration. Donepezil and extended-release galantamine are given once daily because of their long half-lives, whereas regular galantamine and rivastigmine are taken twice daily with meals to minimize GI effects (Table 2). Nausea and vomiting can occur with any of the ChEIs but are more common and troublesome with rivastigmine and galantamine.
Table 2
How to use cholinesterase inhibitors for patients with dementia
| Drug | Recommended dosing | Possible side effects | Titration | Administration |
|---|---|---|---|---|
| Tacrine | Initial: 40 mg/d Maximum: 160 mg/d | Liver damage causing increase in ALT levels, GI effects (nausea, indigestion, vomiting, diarrhea, abdominal pain), skin rash | Dosage can be increased every 4 weeks | Divide into four doses; take on empty stomach |
| Donepezil | Initial: 5 mg/d Maximum: 10 mg/d | GI effects (nausea, diarrhea, vomiting, loss of appetite), insomnia, muscle cramps, fatigue | Increase dosage after 4 weeks | Once daily in morning or at bedtime |
| Rivastigmine | Initial: 3 mg/d Maximum: 12 mg/d | GI effects (nausea, vomiting, loss of appetite, weight loss, diarrhea, heartburn) | Increase dosage every 4 weeks | Twice daily after meals |
| Galantamine (regular, ER) | Initial: 8 mg/d Maximum: 24 mg/d | GI effects (nausea, vomiting, diarrhea, weight loss), possible increased mortality risk in patients with MCI | Increase dosage every 4 weeks | Regular: Twice daily after meals ER: Once daily after a meal |
| ALT: alanine transferase | ||||
| ER: extended-release formulation | ||||
| MCI: mild cognitive impairment | ||||
Efficacy In Early AD
In controlled clinical trials, all four ChEIs have significantly improved cognition, behavior, and activities of daily living in patients with mild-to-moderate AD.10-12 Tacrine—the first FDA-approved ChEI—is rarely used because its associated hepatoxicity requires ongoing liver enzyme monitoring.13 Among the other three:
Donepezil. A review of 16 trials involving 4,365 participants10 found significant benefits in cognitive functioning, activities of daily living, and behavior in persons with mild, moderate, or severe AD who were treated with donepezil for 12, 24, or 52 weeks.
Rivastigmine improved or maintained cognitive function, activities of daily living, and behavior for up to 52 weeks in patients with mild to moderate AD, according to a review of studies from 1995 to 2002.11 GI irritation was the most common adverse effect. Giving rivastigmine for up to 2 years may reduce the cost of caring for patients with AD, mostly by delaying nursing home placement.
Galantamine has beneficial effects on cognition, global function, activities of daily living, and behavior in patients with AD, vascular dementia, and AD with cerebrovascular components, according to a review of clinical studies.12 Adverse events are generally mild to moderate, transient, and gastrointestinal.
Efficacy In Other Dementias
In addition to their FDA-approved use for mildto-moderate AD, ChEIs also have been studied in persons with other types of dementia and mild cognitive impairment (MCI).
Dementia with Lewy bodies. Rivastigmine given with flexible titration from 6 to 12 mg/d improved behavior in 120 patients with Lewy body dementia.14 In the double-blind, multicenter study, patients taking rivastigmine, mean 9.7 mg/d for 20 weeks, were less apathetic and anxious and had fewer delusions and hallucinations than did those taking placebo. The drug was judged to be safe and well tolerated.
Vascular dementia. Patients with vascular dementia showed improved cognition and global function when treated with donepezil, 5 or 10 mg/d, for up to 24 weeks. Donepezil was well tolerated in this combined analysis of two randomized, placebo-controlled trials.15
Kumar et al16 compared two rivastigmine dosages in patients with mild-to-moderate AD, some of whom also had vascular dementia risk factors. Patients were randomly assigned to placebo, low-dose rivastigmine (1 to 4 mg/d), or high-dose rivastigmine (6 to 12 mg/d) for 26 weeks. Cognition, activities of daily living, and disease severity improved with rivastigmine in patients with or without vascular risk factors. Greater benefit was seen with high-dose than low-dose rivastigmine and in patients with AD plus vascular risk factors than in those with AD alone.
