Most Common Adverse Effects of Acetylcholinesterase Inhibitors
The two most common adverse effects of acetylcholinesterase inhibitors like donepezil are gastrointestinal symptoms and bradycardia.
Gastrointestinal Symptoms (CORRECT ANSWER)
Gastrointestinal adverse effects are by far the most frequently reported side effects of cholinesterase inhibitors and represent the primary reason for treatment discontinuation. 1, 2, 3
- Nausea occurs with a relative risk of 2.54 compared to placebo, making it one of the most common adverse effects 2, 4
- Diarrhea has a relative risk of 2.57, occurring significantly more often than placebo 2, 4
- Anorexia demonstrates the largest effect size among GI symptoms with a relative risk of 3.21 2, 4
- Vomiting is also frequently reported, particularly during dose initiation 1, 3, 5
The FDA drug label confirms that nausea, diarrhea, and vomiting are the most common adverse reactions, occurring at frequencies of at least 5% in patients receiving 10 mg/day and at twice the placebo rate 3. These effects are dose-related, with higher incidence at 10mg compared to 5mg dosing 2, 4.
Bradycardia/Bradyarrhythmia (CORRECT ANSWER)
Cardiovascular effects, particularly bradyarrhythmia, represent a serious and common adverse effect of cholinesterase inhibitors due to their cholinomimetic mechanism. 1, 4
- The Mayo Clinic Proceedings guideline specifically lists bradyarrhythmia as an adverse effect of cholinesterase inhibitors like donepezil 1
- Complete atrioventricular block and ventricular tachyarrhythmia have been documented with donepezil use 6
- Caution is advised in patients with pre-existing bradycardia 7
Why the Other Options Are INCORRECT
Anxiety (INCORRECT)
- Anxiety is not listed among the common adverse effects in any guideline or FDA labeling 1, 2, 4, 3
- In fact, agitation (not anxiety) may initially increase but typically subsides after the first few weeks of therapy 2, 4
Sedation (INCORRECT)
- Sedation is not a characteristic adverse effect of cholinesterase inhibitors 1, 3
- The opposite is more common: insomnia occurs in approximately 9% of patients treated with donepezil versus 6% with placebo 3
- Somnolence occurs in only 2% of patients, which is not considered a major adverse effect 3
Clinical Pearls for Adverse Effect Management
- GI effects can be minimized by starting at 5mg daily and gradually increasing to 10mg after 4-6 weeks 2, 4, 5
- Taking donepezil with food reduces gastrointestinal adverse effects 2
- Unlike tacrine (another cholinesterase inhibitor), donepezil does not cause hepatotoxicity and does not require liver function monitoring 2, 5
- Withdrawal rates due to adverse events ranged from 0% to 57% in treatment groups, with nausea, diarrhea, and vomiting being the most common reasons for discontinuation 3