Cholinesterase inhibitors with potential or established clinical effects can be classified as follows:
Pharmacodynamics. Rivastigmine is an acetylcholinesterase inhibitor that facilitates cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurons. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits associated with Alzheimer disease. Rivastigmine is a carbamate derivative that binds to the steric site of the acetylcholinesterase and dissociates slowly; thus, it provides a longer duration of action than tacrine and donepezil, which are short-acting agents, because binding to acetylcholinesterase is hydrolyzed within minutes. In addition to acetylcholinesterase, rivastigmine inhibits butylcholinesterase, and as a result of this dual inhibition, it can optimize cholinergic function. Rivastigmine markedly inhibits cerebrospinal fluid acetylcholinesterase after a single oral dose of 3 mg; it also has central nervous system selectivity over the peripheral inhibition of acetylcholinesterase.
An oral 3 mg dose decreases acetylcholinesterase activity in cerebrospinal fluid by approximately 40% within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer disease, inhibition of acetylcholinesterase in cerebrospinal fluid by rivastigmine was found to be dose-dependent up to 6 mg given twice a day (the highest dose tested).
Alterations in the clinical and cognitive status of patients receiving rivastigmine are paralleled by changes in regional cerebral blood flow as measured by SPECT. These values are enhanced in responders and reduced in nonresponders.
Various studies indicate that rivastigmine improves cognition and activities of daily living in patients with dementia associated with Parkinson disease, resulting in a clinically meaningful benefit (Moretti et al 2007).
Pharmacokinetics. Important points pertaining to pharmacokinetics include the following: