From the Guidelines
Cholinesterase inhibitors, such as donepezil and galantamine, pose significant risks to patients, including gastrointestinal side effects, cardiovascular risks, and neurological effects, as evidenced by a 2021 study published in the Mayo Clinic Proceedings 1. The most common adverse reactions associated with cholinesterase inhibitors are gastrointestinal in nature, including:
- Nausea
- Vomiting
- Diarrhea
- Loss of appetite These side effects are dose-dependent, with higher doses typically causing more severe reactions, as reported in a 2008 study published in the Annals of Internal Medicine 1. Cardiovascular risks associated with cholinesterase inhibitors include:
- Bradycardia (slow heart rate)
- Syncope (fainting)
- Increased risk of bradyarrhythmia, as noted in the 2021 study 1 Neurological effects may include:
- Headaches
- Dizziness
- Insomnia
- Rarely, seizures Additionally, cholinesterase inhibitors can exacerbate respiratory conditions like asthma or COPD due to increased bronchial secretions, and drug interactions are possible, especially with medications that affect heart rate or have anticholinergic properties, as discussed in the 2008 study 1. The risks associated with cholinesterase inhibitors must be carefully weighed against their potential benefits, particularly in patients with advanced dementia, where the lack of long-term benefit is a concern, as highlighted in the 2021 study 1.
From the FDA Drug Label
Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved
- Risks of cholinesterase inhibitors include:
- Cholinergic crisis
- Severe nausea and vomiting
- Salivation
- Sweating
- Bradycardia
- Hypotension
- Respiratory depression
- Collapse
- Convulsions
- Increasing muscle weakness
- Death (if respiratory muscles are involved) 2
- Diarrhea
- Abdominal pain
- Dizziness
- Tremor
- Headache
- Somnolence
- Confusional state
- Hyperhidrosis
- Hypertension
- Hallucinations
- Malaise 2
- Fatal outcome has been rarely reported with rivastigmine 2 and may occur with other cholinesterase inhibitors like donepezil 3
From the Research
Risks of Cholinesterase Inhibitors
The use of cholinesterase inhibitors is associated with several risks, including:
- Peripheral cholinergic adverse effects, such as nausea, vomiting, dizziness, diarrhea, and abdominal pain, which are common for these inhibitors, with an incidence ranging between 7 to 30% 4
- Hepatotoxicity, which is associated with tacrine, with increased liver enzyme values observed in 49% of patients with Alzheimer's disease treated with this drug 4
- Cardiovascular effects, including a small but significant increase in the risk of syncope and bradycardia, as well as occasional reports of QT prolongation and torsades de pointes ventricular tachycardia 5
- Adverse events, such as nausea and/or vomiting, diarrhea, dizziness, headache, and hypertension, which are more common with donepezil 10 mg and galantamine 16 to 24 mg than with placebo 6
Comparison of Risks
A network meta-analysis found that donepezil 10 mg has the greatest effect on cognition, but at the cost of adverse effects, while galantamine 16 to 24 mg is probably associated with a slight excess of adverse events over placebo 6. Rivastigmine had the lowest ranking of the cholinesterase inhibitors in both benefit and harm estimates, but this may reflect possibly inadequate doses received by some trial participants and small trial sample sizes 6.
Drug-Specific Risks
- Tacrine is associated with hepatotoxicity and has a higher incidence of adverse events due to its lower bioavailability and shorter elimination half-life 4
- Donepezil has a longer elimination half-life and is administered once daily, but is associated with a higher risk of adverse events, particularly at higher doses 4, 6
- Galantamine is probably associated with a slight excess of adverse events over placebo, but has a similar efficacy to donepezil 6
- Rivastigmine has a lower incidence of adverse events, but its efficacy is less certain due to limited data 6