donepezil + tacrine

Donepezil + tacrine is a combination of two small molecule acetylcholinesterase inhibitors, both previously used in the treatment of Alzheimer's disease. Donepezil selectively and reversibly inhibits acetylcholinesterase, increasing levels of acetylcholine in the brain and thereby improving cognitive function in patients with Alzheimer's disease[1][4][9][10]. Tacrine also acts as a reversible inhibitor of cholinesterases (primarily acetylcholinesterase), leading to increased synaptic concentrations of acetylcholine[3][6][8]. Both drugs aim to counteract the cholinergic deficit characteristic of Alzheimer's disease. Tacrine was withdrawn from many markets due to hepatotoxicity concerns, but it remains an important historical agent in this class. The rationale for combining these agents would be to enhance cholinergic neurotransmission through dual inhibition at different binding sites or via additive/synergistic effects; however, such combinations are not standard clinical practice due to overlapping toxicity profiles and lack of evidence for superior efficacy over monotherapy.