Is Combining an Anticholinergic with a Cholinesterase Inhibitor a Good Strategy for High-Level CNS Cholinesterase Inhibition?

Abstract

The currently approved cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) produce gastrointestinal toxicity which limits dosing to that which produces only about 25% to 35% CNS cholinesterase inhibition in Alzheimer’s patients undergoing treatment, below the minimum therapeutic target of about 40% to 50% CNS inhibition considered necessary to treat cognitive impairment. A recent strategy for producing high-level CNS acetylcholinesterase (AChE) inhibition (50% or higher) is to co-administer a muscarinic anticholinergic with the AChE inhibitor to block the dose-limiting cholinergic overstimulation of the gastrointestinal system, allow more robust AChE inhibition in the CNS, and improve efficacy in the treatment of Alzheimer’s disease. Unfortunately, most common muscarinic anticholinergics, including solifenacin, readily penetrate the CNS and are directly associated with long-term exacerbation of the underlying neuropathology of Alzheimer’s disease and increased brain atrophy. The co-administration of an anticholinergic with an AChE inhibitor is a rational strategy for improving efficacy in the symptomatic treatment of dementia, but there are significant long-term risks that have not yet been considered. For long-term safety against accelerating the underlying disease processes in Alzheimer’s, anticholinergics used to increase the tolerability of AChE inhibitors should not penetrate, or have very limited penetration, of the blood-brain-barrier. Neurotrophic-mediated mechanisms by which cholinergic drugs may affect neurodegeneration in Alzheimer’s disease are explored and improved treatment options are suggested.

Optimizing treatment for older adults with depression

“…48 However, this and other peripheral pro-cholinergic side effects can be managed by adding a peripheral-acting anticholinergic (such as trospium) rather than stopping the acetylcholinesterase inhibitor. 50…”

“…48 However, this and other peripheral pro-cholinergic side effects can be managed by adding a peripheral-acting anticholinergic (such as trospium) rather than stopping the acetylcholinesterase inhibitor. 50 Alternatives for Parkinsonism. Managing depression (often complicated by psychosis) in this context usually requires the input of a specialist such as a geriatric psychiatrist.…”

Amyloid β, Lipid Metabolism, Basal Cholinergic System, and Therapeutics in Alzheimer’s Disease

“…Similarly, less white matter loss was found, as well as a decrease in ventricular enlargement only in women, and with no apparent effect on hippocampal volume [ 238 , 239 ]. It has also been reported that rivastigmine, unlike other AChEIs, is able to preserve both neocortical white matter and gray matter, and the antineurodegenerative effects of rivastigmine in the white matter could be the result of inhibition of both AChE as well as BuChE [ 235 , 239 , 240 ]. Inhibition of both cholinesterases has beneficial effects on cognition, global function, behavioral symptoms, and executive functions.…”