Cholinesterase inhibitors can be reversible, pseudo-irreversible, or irreversible. In reversible inhibition, the inhibitor molecule is bound to the enzyme molecule for a short period of time, after which the inhibitor and enzyme molecules dissociate and enzyme activity is restored. In pseudo-irreversible inhibition, the inhibitor molecule binds to the enzyme molecule, but the bond is more slowly broken down, delaying the return of enzyme activity to normal. Irreversible inhibitors bind permanently to the enzyme, and thus the enzyme does not become available again.

Tacrine, donepezil, and galantamine are reversible cholinesterase inhibitors. Although rivastigmine is considered a reversible cholinesterase inhibitor, its extended interactions with cholinesterase have been referred to as “pseudo-irreversible”.

Cholinesterase inhibitors can also be characterized as selective for acetylcholine-depleted areas of the central nervous system. Animal studies show that tacrine is a nonselective acetylcholinesterase (AChE) inhibitor, donepezil and rivastigmine are brain selective, but there is evidence to suggest that rivastigmine is also brain-region selective—ie, selective for the cerebral cortex and hippocampus, areas mainly involved in cognitive function Galantamine is a selective, reversible AChE inhibitor.

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.

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.