A 75-year-old patient with Alzheimer's disease is on donepezil 10 mg/day. He develops intolerable gastrointestinal side effects. Which mechanism of action explains both the therapeutic benefit and the GI adverse effects of donepezil?
- A NMDA receptor antagonism reducing excitotoxicity in the gut
- B Serotonin reuptake inhibition causing GI dysmotility
- C Dopamine receptor blockade causing nausea via the CTZ
- D Acetylcholinesterase inhibition → increased ACh → muscarinic stimulation in GI tract ✓
Explanation
Donepezil is a reversible, selective acetylcholinesterase (AChE) inhibitor. By blocking AChE, it increases synaptic acetylcholine in the central cholinergic projections from the nucleus basalis of Meynert (basal forebrain), thereby improving cognition and slowing Alzheimer's progression. However, the same increase in peripheral ACh stimulates muscarinic M3 receptors in the GI tract, causing nausea, vomiting, diarrhoea, and abdominal cramps. These are the most common side effects limiting compliance. Memantine (NMDA antagonist) is the alternative used in moderate-severe Alzheimer's and does not cause GI side effects via this mechanism.
Reference: Kaplan & Sadock's Synopsis of Psychiatry, 11th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.