Alzheimer’s Therapy: Acetylcholinesterase Inhibitors

By | April 15, 2015

Overview. Acetylcholinesterase inhibitors are the only drugs approved for the treatment of mild to moderate Alzheimer’s disease in the major markets. acetylcholinesterase inhibitors do not cure Alzheimer’s disease but do alleviate the cholinergic deficit observed in Alzheimer’s disease patients. Cognitive symptoms are occasionally improved but most often are only stabilized by the drugs ().

Studies also show a modest effect of these drugs on functional and behavioral symptoms found in Alzheimer’s disease. These studies are detailed in the drug-specific sections that follow.

The relative efficacy of the acetylcholinesterase inhibitors has not been determined. Because only open-label comparator studies have been conducted, analysis of these agents’ comparative efficacy is inconclusive. A meta-analysis found no significant difference in efficacy between different acetylcholinesterase inhibitors ().

Mechanism of Action. The role of acetylcholinesterase inhibitors in the treatment of Alzheimer’s disease is based on the cholinergic hypothesis, which attributes the cognitive deficits seen in Alzheimer’s disease patients to a reduction in the levels of the cholinergic neurotransmitter acetylcholine (acetylcholine), as discussed in the “Pathophysiology” section and shown in Figure “Mechanism of action of acetylcholinesterase inhibition”. acetylcholine synthesis in cholinergic neurons is catalyzed by choline acetyltransferase (choline acetyltransferase) and results from the transfer of an acetyl group of acetyl-coenzyme A (acetyl CoA) to choline. The synthesized acetylcholine is then stored in several hundred vesicles at the end of cholinergic neurons until the neuron is stimulated by a nerve impulse to release the contents of the vesicles (up to 20 million acetylcholine molecules) into the synaptic cleft. In the synaptic cleft, most of the acetylcholine binds to acetylcholine receptors (i.e., muscarinic or nicotinic receptors) on other (postsynaptic) neurons. This neurotransmitter binding initiates signaling in the postsynaptic neuron, which is essential for brain function. Cholinergic neurons in the forebrain project to the hippocampus, a region that is critical for learning and memory tasks. In addition, cholinergic neurons project to regions of the cortex responsible for higher-order processing. The loss of cholinergic neurons seen in Alzheimer’s disease patients is what accounts for decline in cognitive functions and higher-order processing abilities, such as judgment and reasoning. Any unbound acetylcholine in the synaptic cleft — both the acetylcholine molecules that never bind to acetylcholine receptors and those that are released after signal transduction — is hydrolyzed by the enzyme acetylcholinesterase (), releasing choline that neurons then reabsorb to use in synthesizing more acetylcholine.

According to the cholinergic hypothesis, the cognitive decline in Alzheimer’s disease results from the death of cholinergic neurons seen in the forebrain of these individuals. With fewer neurons producing acetylcholine, the concentration of acetylcholine available in the synaptic cleft is drastically reduced in Alzheimer’s disease patients. Furthermore, the loss of cholinergic neurons contributes to neuropsychiatric manifestations of Alzheimer’s disease because these neurons project onto other aminergic neurons (e.g., serotonergic and dopaminergic neurons). If these aminergic neurons lose their cholinergic input, symptoms such as depression and psychosis arise. By inhibiting the degradation of acetylcholine, acetylcholinesterase inhibitors effectively increase the concentration of acetylcholine available to participate in neuronal signaling. The drugs accomplish this by targeting acetylcholinesterase (in the case of donepezil [Eisai/Pfizer’s Aricept] and galantamine [Shire Pharmaceuticals/Janssen Pharmaceutica’s Razadyne]) or by targeting butyrylcholinesterase (BuChE) (in the case of rivastigmine [Novartis’s Exelon, Sigma Tau/Esteve’s Prometax]) to augment the effective concentration of acetylcholine in the synaptic cleft of cholinergic neurons. Unlike the older AChEI tacrine, the cholinergic action of donepezil, rivastigmine, and galantamine is largely limited to the brain, which causes fewer side effects ().

TABLE Relative Efficacy and Safety Profiles for Key Therapies Prescribed for the Treatment of Alzheimer’s Disease

Donepezil (Aricept) Rivastigmine (Exelon) Galantamine (Reminyl) Memantine (Namenda)
Approved Indications Mild to moderate Alzheimer’s disease Mild to moderate Alzheimer’s disease Mild to moderate Alzheimer’s disease Moderate to severe Alzheimer’s disease
Mechanisms of Action AChEl AChEl, BuChE inhibitor AChEl, Nicotinic acetylcholine receptor modulator, Antioxidant NMDA antagonist
Efficacy in Mild to Moderate Alzheimer’s disease
Study length 30 weeks (1 study) 26 weeks (2 studies) 26 weeks (2 studies) 26 weeks (1 study)
Mean treatment-placebo difference in ADAS-cog score change scores at study end 3.1 (a) 2.6, 4.9 (b) 3.1, 3.9 (c) (p = 0.003) (e)
Mean treatment-placebo differences in CIBIC-plus scores at study end 0.39 (a) 0.35, 0.41 (b) 0.28, 0.34 (c) (p = 0.004) (e)
Efficacy in Moderate-to-Severe Alzheimer’s disease
Study length 24 weeks (1 study) 52 weeks (1 study) N/A 28 weeks (1 study)
Mean treatment-placebo difference in ADCS-ADL change scores at study end N/A N/A N/A 3.4 (d)
Mean treatment-placebo difference in SIB scores N/A N/A N/A 5.7 (d)
Mean treatment-placebo difference in IADL + scale scores at study end 6.83 (f) N/A N/A N/A
Mean treatment-placebo difference in PSMS + scale 1.32 (f) N/A N/A N/A
Mean treatment-placebo difference in ADAS-cog change scores at study end N/A 5.3 ± 1.5 (g) N/A N/A
Mean treatment-placebo differences in CIBIC-plus scores at study end N/A 0.35±0.06P) N/A 0.3 (d)
Discontinuation rates over placebo for approved indications 8% (a) 10% (b) 3 times higher than placebo (c) Same as placebo
Most common side effects as listed in package inserts:
Nausea 5% 35% 13% 0%
Vomiting 2% 25% 9% 1%
Anorexia 2% 14% 6% 0%
Dizziness 2% 10% 3% 2%
Diarrhea 5% 8% 2% N/A
Weight decrease 2% 2% 5% 0%
Headache 1% 5% 3% 3%
Abdominal pain < 1% 7% 1% N/A
Approved dosage forms Tablet; Rapid-disintegration tablet Capsule; Oral solution Tablet, Oral solution Tablet
Dosage frequency Once daily Twice daily Twice daily Twice daily
Titration schedule 4-6 weeks 4-6 weeks 4-8 weeks 3 weeks

aValues correspond to 10 mg dose.

bData from two studies represented. Values correspond to 6-12 mg dose group.

cData from two studies represented. Values correspond to a 24mg dose.

dValue corresponds to 20 mg dose.

Statistical significance over placebo from a forthcoming 2004 study. Value corresponds to 20 mg dose.

fValue corresponds to 5-10 mg dose from a 2001 study.

gValues correspond to a 24 mg dose from a 2005 study.

AChEl = acetylcholinesterase inhibitor;

ADAS-cog = Alzheimer’s Disease Assessment Scale-Cognitive Subscale;

N/A = comparable data not available.

Formulation. All acetylcholinesterase inhibitors are available in oral tablet formulations that can be taken once daily (donepezil) or twice daily (rivastigmine and galantamine). Liquid formulations, which are perceived by some caregivers as easier to administer, are available for rivastigmine and galantamine. A rapid-disintegration tablet formulation of donepezil, also designed for easier administration, was launched in Japan in July 2004.

Companies continue to pursue development of more convenient AChEI formulations. While these formulations offer an added advantage of convenience for caretakers, who would not need to administer the drug as often, ultimately these new formulations may not impact market sales as much as the drug manufacturers hope — the convenience of the dosing form (liquid, tablet, patch) is less of an issue than the drug’s efficacy and side effects.

In December 2003, Eisai filed with the FDA for both liquid and rapid-disintegration tablet formulations of donepezil. In October 2004, Eisai received FDA approval for the rapid-disintegration tablet in the United States. In Europe, Eisai submitted a marketing authorization application (MAA) for a rapid-disintegration tablet and a liquid formulation of donepezil in December 2003 and May 2004, respectively. In 2005, Janssen launched a once-daily (extended-release) formulation of galantamine (Razadyne ER) in the United States and Europe. Novartis is developing a once-daily transdermal formulation of rivastigmine that is currently in Phase III trials and is scheduled to be submitted to the FDA in 2006.

Alzheimer’s Therapy: Donepezil

Alzheimer’s Therapy: Rivastigmine

Alzheimer’s Therapy: Galantamine