Selectivity of Cholinesterase Inhibition

The deterioration in cognitive function that is characteristic of Alzheimer’s disease is related to a reduction in cholinergic transmission in the basal forebrain, and the appearance of neurofibrillatory tangles and plaques containing β-amyloid (Aβ). Some plaques are neurotoxic and contain acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). AChE consists of different molecular forms: G1, G2 and G4. In the cortex and hippocampus, G4 is located presynaptically and comprises about 70 to 80% of the AChE present. The remainder is in the G1 form which is present in postsynaptic neurons. G4 is the predominant type of AChE that is reduced in Alzheimer’s disease. Skeletal muscle contains mainly G4 and G2. Eight cholinesterase inhibitors that reduce the inactivation of acetylcholine (ACh) have been tested in placebo-controlled trials in patients with Alzheimer’s disease. All these agents were found to improve cognitive function, or delay its rate of decline, in a significant proportion of patients. Tacrine, eptastigmine and rivastigmine also significantly improved activities of daily living. Furthermore, most of these drugs increased cerebral blood flow and glucose metabolism, parameters that are decreased in the basal forebrain of individuals with Alzheimer’s disease. This latter effect may contribute to the therapeutic effect of cholinesterase inhibitors and may delay the formation of Aβ. Currently available cholinesterase inhibitors differ in the incidence and severity of adverse effects produced at clinical doses. Reversible liver damage, seen with tacrine and velnacrine, and cholinergic hyperactivity, such as nausea, vomiting and muscle cramps, with these and other drugs can prevent the attainment of an optimum dose. The selectivity of cholinesterase inhibitors for AChE versus BuChE, and for the different molecular forms of AChE, may have an influence on both therapeutic and adverse effects. Donepezil and galantamine (galanthamine) are selective inhibitors of AChE, while the other agents also inhibit BuChE. The adverse effects associated with cholinergic hyperactivity are not due to blockade of BuChE as previously suggested, since they are seen with the AChE-selective inhibitors and not with those inhibitors that only inhibit BuChE. The advantage of nonselective inhibitors is that they may also increase ACh levels by inhibiting BuChE in glial cells. Selective inhibitors of the G1 form of AChE, such as rivastigmine, are more likely to elevate ACh levels in the brain of patients with Alzheimer’s disease and may be less likely to cause skeletal muscle cramps than nonselective inhibitors such as metrifonate.