Alzheimer’s disease is associated with significant losses in cholinergic neurons and decreased concentrations of acetylcholine, a neurotransmitter significantly involved in learning and memory processes. Acetylcholinesterase inhibitors (ACIs) exert pharmacologic effects by increasing availability of intrasynaptic acetylcholine in the presence of intact cholinergic neurons. All available ACIs are FDA-approved in adults for the management of mild to moderate Alzheimer’s dementia, while donepezil is also FDA-approved for management of severe Alzheimer’s disease. Additionally, rivastigmine (Exelon®) is FDA-approved for use in mild-to-moderate dementia associated with Parkinson’s disease.
A combination product containing donepezil and memantine extended-release (Namzaric®) is also FDA-approved for use in patients with moderate to severe Alzheimer’s dementia stabilized on donepezil and memantine. Memantine, a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist, exerts pharmacologic effects by blocking glutamate activity, the key excitatory neurotransmitter in the central nervous system. Glutamate is released into synapses when certain neurons die and activates NMDA receptors, causing over excitation, an influx of calcium ions and, ultimately, death of downstream neurons. NMDA receptor activation is thought to be one of the main causes of neurodegeneration in various types of dementia, including Alzheimer’s-associated dementia. ACI monotherapy and combination therapy recommended dosages are summarized in Table 1 and Table 2, respectively. Dosages exceeding these recommendations will be reviewed.