Acetylcholinesterase Inhibitors

Mechanism of Action

Acetylcholine (ACh) is an important neurotransmitter in the central nervous system, which is involved in functions such as learning, memory and attention. In AD and in dementia associated with Parkinson’s disease, there is a decrease in acetylcholine activity. 

Acetylcholinesterase is an enzyme that hydrolyses acetylcholine into choline and acetate, terminating its action at cholinergic synapses. Inhibition of this enzyme increases the availability and duration of action of acetylcholine at cholinergic synapses.

AChE is the main cholinesterase in the brain whereas butyrylcholinesterase is the present in the brain and peripheral tissues.

• Donepezil is a specific and reversible inhibitor of AChE
• Galantamine is a selective, competitive and reversible inhibitor of AChE, it also increases the action of ACh on nicotinic receptors, likely through binding to an allosteric site on the receptor
• Rivastigmine inhibits both acetylcholinesterase and butyrylcholinesterase. The duration of AchE inhibition is 9 hours. 

Created in BioRender. Boucher, M. (2026) https://BioRender.com/xc2xfoa

Acetylcholinesterase Inhibitors: Mechanism of Action in Alzheimer’s Disease (AD)

Pharmacokinetics

Rivastigmine is also available as a transdermal patch which is useful for patients with swallowing difficulties. Furthermore it provides more gradual drug delivery and generally produces fewer gastrointestinal adverse effects than oral rivastigmine. The following table describes the pharmacokinetic properties of AChE inhibitors. 

Contraindications

• Galantamine is contraindicated in CrCl <9ml/min and in severe hepatic impairment, or in patients who have significant renal and hepatic dysfunction.
• Rivastigmine patch and patients with previous allergic contact dermatitis with rivastigmine patch administration
• All AChE inhibitors are contraindicated in patients with previous hypersensitivity to the active substance or relevant excipients 

Adverse Effects and Cautions

Gastrointestinal

Common adverse effects include nausea, vomiting and loss of appetite, generally these effects get better after a few weeks of taking AChE inhibitors and are dose related. Slow dose escalation can also help to minimise adverse effects. Use of rivastigmine patches is less likely to cause side effects compared to oral administration.

Increased gastric acid secretion may increase the risk of peptic ulceration and gastrointestinal bleeding, therefore caution should be applied in those at risk of developing peptic ulcers.

Respiratory

AChE inhibitors are cautioned in asthma and COPD as they may increase risk of bronchospasm.

Cardiovascular

Increased cholinergic activity can produce vagotonic effects such as bradycardia and heart block, there have also been reports of QTc prolongation and Tosade de Pointes with AChE inhibitors. Therefore caution should be applied to patients with heart block, sick sinus syndrome or patients with or at risk of QT prolongation.

Neurological

Due to the increase in ACh in the central nervous system, AChE inhibitors may cause hallucinations, altered or aggressive behaviour and rarely extrapyramidal symptoms and neuroleptic malignant syndrome.

Donepezil can cause vivid dreams or insomnia. If these occur with bedtime administration, taking the medicine in the morning may help, following advice from the prescriber.

Seizures have also been reported with AChE inhibitors, however this can also be a manifestation of AD.

Skin

Serious skin reactions have been reported with galantamine therapy. Furthermore, application site skin reactions are a common side effect with rivastigmine transdermal patches.

Urological

AChE inhibitors are not recommended in patients with urinary outflow obstruction or post bladder surgery, as generally cholinomimetics may cause bladder outflow obstruction.

Weight Loss

Weight loss can occur during treatment with cholinesterase inhibitors for patients with AD

Interactions

Anticholinergic Effects

Drugs that cause an anticholinergic effect antagonise the actions of AChE inhibitors. For example TCAs and drugs with an antimuscarinic effect may increase risk of falls and cognitive impairment.

Ulcergenic Drugs

Alongside corticosteroids and NSAIDs, there is an increased risk of peptic ulceration. 

Medicines that lower heart rate

Alongside beta blockers or other rate limiting medications such as rate limiting calcium channel blockers and amiodarone, there is risk of bradycardia and/or heart block. 

Medicines that prolong the QT interval

Increased risk of QT prolongation alongside drugs that are also known to cause this effect:

• Certain SSRIs; citalopram, escitalopram
• Macrolide antibiotics 
• Quinolone antibiotics
• Antiarrythmics; amiodarone, sotalol, quinidine

Antipsychotics

There is an increased risk of neuroleptic malignant syndrome when AChE inhibitors are concomitantly prescribed with antipsychotics 

Anaesthetics

Cholinesterase inhibitors may prolong the effects of depolarising neuromuscular blocking agents, such as suxamethonium, and may interfere with the effects of non-depolarising neuromuscular blockers.

CYP mediated interactions

Galantamine is metabolised by CYP2D6 and CYP3A4, therefore when given alongside potent inhibitors of either enzyme there is a risk of increased incidence of cholinergic reactions such as nausea and vomiting. 

Donepezil is also metabolised by CYP2D6 and CYP3A4, so inhibitors or inducers of these enzymes may alter its exposure.

References

1. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019.
2. Hitchings BSc, M., Lonsdale, D., Burrage, D., Baker, E. (2022). The Top 100 Drugs – E-Book. Netherlands: Elsevier.
3. Alzheimer’s disease – Treatment – NHS Accessed 21/10/26
4. Donepezil Hydrochloride 5 mg film-coated tablets. – Summary of Product Characteristics (SmPC) – (emc) | 10107  Accessed 22/10/26
5. Gatalin XL 8mg prolonged release capsules, hard – Summary of Product Characteristics (SmPC) – (emc) | 1271 Accessed 22/10/26
6. Rivastigmine Sandoz 1.5 mg hard capsules – Summary of Product Characteristics (SmPC) – (emc) | 4835 Accessed 22/10/26
7. Exelon 4.6 mg/24h transdermal patch – Summary of Product Characteristics (SmPC) – (emc) | 1185 Accessed 22/10/26