Medication: Donepezil (Aricept)
Released: 1996
Pronunciation: don ep e zil / AIR e cept
Mascot / mnemonic: “Donnie Pez is Air except” (for an Alzheimer’s brain)
❖ Cholinergic drug
❖ Cholinesterase inhibitor
❖ Cognitive enhancer
FDA-approved for
❖ Alzheimer’s dementia, mild–moderate
❖ Alzheimer’s dementia, moderate–severe
Donepezil (Aricept) is the #1 prescribed medication for treatment of dementia. Aricept works as a cholinergic agent by inhibiting the acetylcholinesterase (AChE) enzyme. It is FDA-approved for Alzheimer’s disease of any severity. It has better evidence for mild Alzheimer’s than the other cholinesterase inhibitors.
Donepezil is generally well tolerated, but about 10% quit due to nausea, vomiting, or diarrhea. Think SLUDGE cholinergic effects. The gastrointestinal issues usually do not persist past a couple of weeks. It may slow heart rate. Bradycardia is a cholinergic effect. Other potential side effects are agitation and vivid dreams.
Aricept has a long half-life of about 3 days. It is dosed at bedtime but is non-sedating. It does not cause weight gain, and the 23 mg dose is associated with weight loss.
After the patient is established on donepezil, the NMDA receptor antagonist memantine (Namenda) is often added. Namzaric is a branded capsule containing both Namenda (memantine ER) and Aricept.
A strategic combination of donepezil with a peripherally acting anticholinergic such as solifenacin (Vesicare, approved for overactive bladder) can allow high doses of donepezil to be used. Solifenacin blocks donepezil’s dose-limiting gastrointestinal side effects without impairing cognition. This strategy only works with anticholinergics without CNS effects—otherwise the cholinergic cognitive benefit of donepezil would be blocked.
Donepezil interactions
Pharmacodynamic interactions
❖ Avoid combining with anticholinergics (with CNS effects) due to opposing mechanism of action.
❖ Cholinergic toxicity (SLUDGE syndrome) is possible when combined with cholinergics such as bethanechol (Urecholine)
❖ Strategic combination with a peripheral anticholinergic (without CNS effects) can ameliorate GI distress.
❖ Caution with beta blockers (propranolol, metoprolol, etc) due to aggregate risk of bradycardia.
❖ Lowers seizure threshold
Pharmacokinetic interactions
❖ 2D6 substrate - link to CYP2D6 mnemonic system
❖ 3A4 substrate (minor) - link to CYP3A4 mnemonic system
Donepezil dosing / pearls:
5 mg HS x 4 weeks then 10 mg HS, which is the target dose for mild Alzheimer’s dementia. Maximum dose is 23 mg HS (intended for moderate to severe dementia) which should not be used until the patient has tolerated 10 mg for 3 months.
If given with solifenacin at 15 mg, donepezil can be titrated to 40 mg HS without causing gastrointestinal distress (Chase et al, 2017). Solifenacin would be started at 10 mg QD x 1 week, then 15 mg QD, which is a high dose.
Consider moving donepezil to AM dosing if it causes insomnia or disturbing dreams.
Monitor for bradycardia.
The usual next step is the addition of memantine (Namenda).
Consider switching to the rivastigmine patch (Exelon transdermal) if cognitive decline continues past 6 to 9 months.
If donepezil is stopped, it should be tapered over 4 weeks, but be advised that cognitive functioning may plummet, possibly irrecoverably.