Donepezil, commonly known by its brand name Aricept, is a cornerstone medication for managing the cognitive symptoms of Alzheimer's disease [1.6.4]. It belongs to a class of drugs called cholinesterase inhibitors, which work by increasing the levels of acetylcholine, a key neurotransmitter for memory and thinking, in the brain [1.6.4]. While beneficial, its mechanism of action also makes it susceptible to numerous drug interactions that can either diminish its effectiveness or increase the risk of serious side effects. Therefore, patients and caregivers must be vigilant about all other medications being taken, including over-the-counter drugs and supplements [1.4.2, 1.5.5].
How Donepezil Works and Why Interactions Occur
Donepezil functions by inhibiting acetylcholinesterase, the enzyme that breaks down acetylcholine [1.6.4]. This results in higher concentrations of acetylcholine available for nerve cell communication. Drug interactions can occur through two primary pathways:
- Pharmacodynamic Interactions: This happens when another drug has an opposing (antagonistic) or additive (synergistic) effect on the body. For example, a drug that blocks acetylcholine will directly counteract donepezil [1.6.1].
- Pharmacokinetic Interactions: This involves one drug affecting the absorption, metabolism, or excretion of another. Donepezil is metabolized by liver enzymes CYP2D6 and CYP3A4. Drugs that induce these enzymes can lower donepezil levels, while inhibitors can increase them, potentially leading to toxicity [1.4.5].
Major Drug Classes to Avoid or Use with Caution
It is crucial to discuss all medications with a healthcare provider before starting or stopping any treatment. The following are some of the most significant drug classes known to interact with donepezil.
Anticholinergic Medications
This is the most direct and contradictory interaction. Anticholinergic drugs work by blocking acetylcholine, the very neurotransmitter donepezil aims to increase [1.6.1]. Taking them together can negate the therapeutic benefits of donepezil, potentially worsening cognitive symptoms [1.2.3]. Many common over-the-counter and prescription medications have anticholinergic properties.
- Examples: Diphenhydramine (Benadryl), oxybutynin (for bladder control), dicyclomine (for IBS), and benztropine (for Parkinson's disease) [1.2.2, 1.2.6].
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Both donepezil and NSAIDs can increase the production of stomach acid, which raises the risk of gastrointestinal bleeding and peptic ulcers [1.5.1, 1.5.5]. The combined use significantly amplifies this risk, especially in older adults [1.5.2]. Caution is advised even with low-dose aspirin [1.4.6].
- Examples: Ibuprofen (Advil, Motrin), naproxen (Aleve), aspirin, diclofenac, and meloxicam [1.4.4, 1.5.6]. Paracetamol (Tylenol) is generally considered a safer alternative for pain relief [1.4.6].
Cardiovascular Drugs
Donepezil can slow the heart rate (bradycardia) and affect the heart's electrical conduction, including prolonging the QTc interval [1.2.3, 1.7.2]. When combined with other medications that have similar effects, the risk of dangerous heart rhythm problems like torsades de pointes, fainting (syncope), and atrioventricular (AV) block increases [1.7.2, 1.7.4, 1.7.6].
- Beta-Blockers: Atenolol, metoprolol, propranolol [1.4.5].
- Other Heart Rhythm Medications: Amiodarone, sotalol, dronedarone, digoxin, diltiazem, and verapamil [1.2.3, 1.2.6].
Antipsychotic and Antidepressant Medications
Certain antipsychotics can increase the risk of severe extrapyramidal symptoms (uncontrolled movements, muscle rigidity) when taken with donepezil [1.2.3]. Additionally, some antipsychotics and antidepressants can also prolong the QTc interval, compounding the cardiac risks [1.7.2].
- Antipsychotic Examples: Haloperidol, quetiapine, risperidone, ziprasidone [1.2.3, 1.4.4].
- Antidepressant Examples: Citalopram, escitalopram, amitriptyline [1.7.2].
Anesthesia and Muscle Relaxants
Donepezil can interact with neuromuscular blocking agents used during surgery. It can prolong the muscle-relaxing effect of depolarizing agents like succinylcholine [1.4.5]. Conversely, it may cause resistance to non-depolarizing agents like rocuronium, making adequate muscle relaxation difficult to achieve during anesthesia [1.8.2]. It is vital to inform the surgical and anesthesia team that a patient is taking donepezil well before any procedure [1.8.1].
Other Medications
- Anticonvulsants: Drugs like carbamazepine, phenytoin, and phenobarbital can increase the metabolism of donepezil, reducing its effectiveness [1.4.5].
- Antifungals: Ketoconazole and itraconazole can inhibit donepezil's metabolism, increasing its levels and the risk of side effects [1.3.3, 1.4.3].
- Corticosteroids: Co-administration, particularly at high doses, may lead to an additive effect causing muscle weakness [1.2.3].
- Herbal Supplements: St. John's wort can decrease the effectiveness of donepezil and should be avoided [1.4.2, 1.4.6].
Comparison Table of Key Donepezil Interactions
| Drug Class/Medication | Examples | Potential Interaction/Risk |
|---|---|---|
| Anticholinergics | Diphenhydramine, Oxybutynin, Benztropine | Directly opposes donepezil's action, reducing its effectiveness [1.6.1, 1.2.6]. |
| NSAIDs | Ibuprofen, Naproxen, Aspirin | Increased risk of stomach ulcers and gastrointestinal bleeding [1.5.5, 1.4.4]. |
| Cardiovascular Drugs | Metoprolol, Amiodarone, Diltiazem | Additive effect can lead to dangerously slow heart rate (bradycardia) and heart rhythm problems [1.2.3, 1.4.5]. |
| QTc-Prolonging Drugs | Citalopram, Quetiapine, Ziprasidone | Increased risk of life-threatening cardiac arrhythmias like Torsades de Pointes [1.7.2, 1.2.6]. |
| Neuromuscular Blockers | Succinylcholine, Rocuronium | Potentiates the effect of succinylcholine; may cause resistance to rocuronium during anesthesia [1.4.5, 1.8.2]. |
| CYP450 Inducers | Carbamazepine, Phenytoin, Rifampin | Decreases blood levels and effectiveness of donepezil [1.4.5, 1.3.3]. |
| CYP450 Inhibitors | Ketoconazole, Itraconazole | Increases blood levels of donepezil, raising the risk of side effects [1.3.3, 1.4.3]. |
Conclusion
Managing medications for a person with Alzheimer's disease requires careful coordination. The potential for drug interactions with donepezil is extensive, ranging from reducing its cognitive benefits to causing serious cardiac or gastrointestinal harm. The best strategy for safety is maintaining a complete and updated list of all medications, including over-the-counter products and supplements, and regularly reviewing it with a doctor or pharmacist. Never add, stop, or change a medication dose without professional medical guidance. Proactive communication is the key to safely navigating treatment with donepezil.
For more information, consult authoritative sources such as the National Institute on Aging.
