Acetylcholinesterase inhibitors (AChE-Is) are the first class of agents specifically approved by the US Food and Drug Administration (FDA) for the treatment of AD (). Tacrine (Cognex) was approved in 1993 followed by approval of donepezil (Aricept) in 1996, rivastigmine (Exelon) in 2000, and galantamine (Reminyl, Razadyne) in 2001. Memantine (Namenda)—an NMDA receptor antagonist—approval followed in 2004 (). Tacrine had a short half-life requiring administration every 4 hours and had substantial associated hepatotoxicity, requiring frequent monitoring of liver enzymes. These limitations were not present with later AChE-Is. Tacrine is rarely used, is no longer available in many countries, and will not be discussed here.
Timeline of approved treatments for Alzheimer disease.
All AChE-Is share the characteristic of inhibiting acetylcholinesterase and each of these agents has additional distinctive pharmacologic aspects. AChE-Is are thought to bind acetylcholinesterase in the synaptic cleft so that acetylcholine released from the presynaptic cholinergic terminal has an increased residence time within the synapse and is more likely to interact with the postsynaptic cholinergic receptor. The enhanced postsynaptic activity renders more normal the function of the cholinergic system.
Donepezil is a selective AChE-I, rivastigmine is a mixed acetylcholinesterase and butyrylcholinesterase inhibitor, and galantamine is described as having an allosteric nicotinic modulating effect as well as being an AChE-I. The clinical consequences of the differential pharmacology of the AChE-Is, if any, are unknown.
For purposes of drug development, patients were identified for AChE-I clinical trials as having mild to moderate AD by requiring a MMSE (Folstein et al. 1975
) score between ten and 26 in most trials. All AChE-Is are approved for treatment of mild to moderate AD. In the clinical development of donepezil, trials of patients with moderate to severe AD were conducted and established efficacy of this agent in patients with MMSE scores of 0–15. Donepezil is approved for mild, moderate, and severe AD.
To meet the criteria for approval by the FDA as a treatment for AD, an agent must be shown in two well-conducted trials to be statistically significantly superior to placebo on a test of cognition (regarded as the central feature of AD) and a global scale or an assessment of ADL (Schneider 2008) The usual measure of cognition in mild to moderate AD is the ADAS-Cog (Rosen et al. 1984
). In patients with moderate to severe AD the cognitive measure most commonly used is the Severe Impairment Battery (SIB) (Schmitt et al. 1997
). The global outcome used in most AChE-I trials is the CIBIC+ (Schneider et al. 1997
). ADL scales used in AChE-I trials include the ADCS ADL scale (Galasko et al. 1997
) or the DAD (Gelinas et al. 1999
). Changes in behavior are commonly measured as secondary outcomes in AChE-I clinical trials, and the most commonly used instrument is the Neuropsychiatric Inventory (NPI) (Cummings et al. 1994
). Pharmacoeconomic data are collected in some trials using the Resource Utilization in Dementia (RUD) scale (Wimo and Winblad 2003
). Most clinical trials of AChE-Is have been 6 months in duration; some have been as short as 3 months and some as long as 2 years (AD2000 Collaborative Group 2004
The responses to treatment with different AChE-Is have overlapping confidence intervals (CI), and no individual cholinesterase inhibitor has been shown to be superior to others in terms of efficacy. The mean response on the ADAS-cog is approximately 2.0 points with CI of 1.5–2.5 points (Birks 2006
). The response on the CIBIC+ is usually in the range of 1.9 (CI 1.3–3.0) on a scale in which 4 represents no change. 3, 2 and 1 represent mild, moderate and marked improvement, and 5, 6, and 7 represent mild, moderate, and marked worsening (Whitehead et al. 2004
). A two-point (CI 0.5–2.5) drug–placebo difference is common at trial conclusion on the ADCS ADL and a two-point (CI 0.5–4.0) drug–placebo difference on the NPI total score is common at trial conclusion. Approximately 25% of patients have a measurable improvement on the ADAS-Cog compared to 15% of patients on placebo. In addition to the drug–placebo difference in improvement, AChE-Is produce a delay in decline that affects as many as 80% of patients participating in a clinical trial (Geldmacher et al. 2006
). Improvement on the ADAS-Cog is taken as an indication of improvement in the core clinical features of AD, whereas a drug–placebo difference in CIBIC+ or an ADL scale is accepted as a measure of clinically meaningful improvement. As noted, most clinical trials of AChE-Is are 6 months in duration and establish benefit for 6 months of therapy; some 1-year trials (Winblad et al. 2001
) or 2-year trials (AD2000 Collaborative Group 2004
) have been conducted and continued to show a drug–placebo difference at study conclusion. These observations support the long-term use of AChE-Is in the treatment of AD.
AD dementia is preceded by a period of cognitive impairment in which patients show decline in episodic memory and other cognitive abilities, but the changes are not sufficiently severe to reach the criteria for dementia. This clinical syndrome has been called mild cognitive impairment (MCI) (Petersen et al. 2001
). Clinical trials of AChE-Is for the treatment of cognitive deficits of MCI have been uniformly negative (Jelic et al. 2006
). It is now recognized that MCI is an etiologically heterogeneous state with only approximately 60–70% of patients having underlying AD (Jicha et al. 2006
). The lack of response to AChE-Is in MCI may reflect the absence of an AD-type pathophysiology in a substantial number of patients included in the trial. In the ADCS MCI study, there was a drug–placebo benefit in favor of donepezil in MCI patients who were apolipoprotein E4 carriers, a group likely to have a high underlying rate of AD pathophysiology (Petersen et al. 2001
). This suggests that prodromal AD may respond to treatment by AChE-Is. However, many of the patients enrolled in MCI trials could also have fulfilled criteria for AD.
Gastrointestinal side effects are common in patients placed on AChE-Is. Anorexia, nausea, vomiting, diarrhea, and weight loss may occur and should be monitored in patients treated with these agents. In addition, cholinergic influences may slow heart rate and bradycardia is a contraindication to use of AChE-Is. Occasional patients have experienced changes in urinary function. Muscle cramps have been reported with donepezil and abnormalities in dreaming also have been reported with donepezil.
Donepezil has a half-life of 70 hours and is administered once daily (). It is 96% protein bound with 100% bioavailability; it is metabolized by 2D6 and 3A4 cytochrome P450 enzymes. Treatment is begun with 5 mg/day and, if the patient shows no intolerance, the dose is advanced to 10 mg/day usually after 1 month. A 23 mg once-daily dose has recently been approved for use in patients with moderate to severe AD (Okamura et al. 2008
). Acetylcholinesterase positron emission tomography (PET) studies suggest that the 10 mg dose produces an approximately 60% inhibition of central acetylcholinesterase (Okamura et al. 2008
). Rivastigmine has a peripheral half-life of 1.5 hours and a central half-life of 8 hours. The capsules are given twice daily and, when administered as the patch formulation, the patch is replaced once daily. Rivastigmine is not metabolized through the cytochrome P450 system; it is 40% protein bound and has 40% bioavailability. Rivastigmine is initiated in an oral dose of 1.5 mg orally twice daily and, as tolerance is determined, advanced to 3 mg, 4.5 mg, and 6 mg twice daily for a total target dose of 12 mg/day. Titration is typically at 1-month intervals and is determined by patient tolerance for the agent. The transdermal patch formulation of rivastigmine is initiated at a patch strength of 4.6 mg and advanced to 9.5 mg after 1 month if no intolerance is observed. Galantamine has a half-life of 7 hours and is given twice daily, unless the extended release formulation is used and administered once daily. Galantamine is initiated at a dose of 4 mg twice daily (8 mg/day in a single dose for the extended release formulation) and advanced to 16 and 24 mg/day at 1-month intervals. Galantamine is metabolized by the cytochrome P450 enzymes 2D6 and 3A4. It is 18% protein and has 90% bioavailability.
Characteristics of cholinesterase inhibitors
There are conflicting data as to whether AChE-Is have any disease-modifying properties with respect to AD. They affect disease course by improving symptoms and delaying decline as described above. Basic science observations suggest that enhancement of cholinergic function may reduce the generation of β-amyloid protein (Kimura et al. 2005
). Some imaging studies have suggested less brain atrophy over time in patients treated with AChE-Is (Krishnan et al. 2003
). In addition, some long-term observations suggest less decline in patients treated with AChE-Is or combination therapy of AChE-Is with memantine compared to patients not receiving therapy with these agents (Lopez et al. 2009
; Rountree et al. 2009
). Other clinical and imaging studies, however, suggest no disease-modifying benefit from treatment with AChE-Is (Jack et al. 2008
; Schneider and Sano 2009
). Disease-modifying effects, if present, must be small in magnitude.
Patients intolerant to one AChE-I may be able to tolerate an alternate cholinesterase inhibitor and the effort to keep patients on therapy should be made when intolerance occurs. Patients started on an oral medication might be switched to patch therapy or vice versa. Patients showing no efficacy in response to treatment with one cholinesterase inhibitor (uninterrupted continuing decline of cognition) may also be switched to another. Any benefit from switching in this circumstance however is not established.
Continuing benefit from use of AChE-Is has been shown in trials lasting up to 2 years, among patients followed over that length of time (AD2000 Collaborative Group 2004
). In addition, patients with severe AD—not previously treated with AChE-Is—respond to treatment with AChE-Is, and donepezil is approved for treatment in this advanced phase of the disease. These observations suggest that long-term treatment with AChE-Is may continue to provide benefit. When AChE-Is are discontinued because the patient or the clinician believe that no further benefit is possible, patients should be observed for cognitive decline, loss of ADL, or emergent behavioral disturbances (Holmes et al. 2004
). If adverse cognitive, functional, or behavioral changes occur soon after discontinuation then physicians and patients should consider whether the patient had been benefiting from treatment and whether to reinitiate medications at the starting doses.