Cholinesterase Inhibitors

General Pharmacology

Despite their common mechanism of action, the CHE-I are quite different structurally.

Cholinesterase Inhibitors

CHE-I can be characterized by the way that they inhibit acetylcholinesterase - reversible, pseudoirreversible, or irreversible. In the case of reversible inhibition, the inhibitor is bound to the enzyme for a short period of time. Pseudoirreversible inhibition is characterized by a longer-lived inhibitor-enzyme complex, after which the enzyme returns to normal activity. Irreversible inhibitors bind permanently to the enzyme. Certain pesticides exert their toxicity by binding irreversibly to peripheral and central acetylcholinesterase.

There are two types of cholinesterases that can be affected by CHE-I - acetylcholinesterase and butrylcholinesterase. Both enzymes are present in the CNS, with butrylcholinesterase also found in smooth and cardiac muscle, skin and serum. Butrylcholinesterase has been identified in amyloid plaques, leading some researchers to postulate its role in AD-associated neuropathological changes. Because of its presence in the periphery, a high degree of inhibition of butrylcholinesterase may be associated with a greater degree of systemic cholinergic adverse effects, such as nausea and vomiting. The four CHE-I differ in their selectivity for acetylcholinesterase vs. butrylcholinesterase. Donepezil, rivastigmine and galantamine are specific for cholinesterase inhibition in the CNS, however, rivastigmine has been reported to exhibit greater selectivity for two of the brain regions most afflicted in AD - the cortex and the hippocampus. Galantamine, in addition allosterically modulates the nicotinic acetylcholine receptors (nAChR) , thereby augmenting the release of acetylcholine.This dual mechanism of action for galantamine is purported to maximize cholinergic function,which although not proven, may result in improved efficacy over other agents.

The clinical meaning of various differences between CHE-I is unclear; differences in spectrum activity or efficacy for individual agents has been postulated, but not proven conclusively.^7.

The table below provides a comparative pharmacologic overview of tacrine, donepezil, rivastigmine and galantamine. ^{8, 8a.}

Comparison of Cholinesterase Inhibitors

AChE=acetylcholinesterase; BChE=butrylcholinesterase; CYP=cytochrome P-450 enzyme

*rivastigmine's pharmacodynamic half-life is 10 hours