Letters to the Editor

Prescribing Cholinesterase Inhibitors for Alzheimer Disease: Timing Matters


Am Fam Physician. 2018 Jun 1;97(11):700.

Original Article: Alzheimer Disease: Pharmacologic and Nonpharmacologic Therapies for Cognitive and Functional Symptoms

Issue Date: June 15, 2017

See additional reader comments at: https://www.aafp.org/afp/2017/0615/p771.html

To the Editor: As subspecialists in geriatric psychiatry and pharmacy, we appreciate this concise and informative review of pharmacologic and nonpharmacologic therapies for Alzheimer disease. We would, however, like to make a suggestion regarding the information in Table 1 on administration of cholinesterase inhibitors. The authors recommend administering donepezil (Aricept) at bedtime and other oral cholinesterase inhibitors, specifically galantamine (Razadyne) and rivastigmine (Exelon), once or twice daily depending on whether the formulation is extended release.

The most common adverse effects of cholinesterase inhibitors include nausea, diarrhea, vomiting, decreased appetite, dyspepsia, anorexia, muscle cramps, fatigue, insomnia, dizziness, headache, and asthenia.13 Taking these medications with food, preferably a full meal, can mitigate these gastrointestinal effects. Therefore, we recommend taking cholinesterase inhibitors with food whenever possible to improve tolerability. Furthermore, administering these medications with a meal delays drug absorption, which reduces the peak plasma and brain concentrations, thereby decreasing the risk of all acute adverse effects.4 Fortunately, the package inserts for galantamine and rivastigmine recommend dosing with meals.2,3 However, the package insert for donepezil mentions only nightly dosing.1 When donepezil is administered nightly, plasma levels of the drug peak in three to four hours,5 likely contributing to the incidence of insomnia and abnormal dreams.

The only justification we are aware of for nightly dosing is that peak blood levels and their accompanying adverse effects would occur while patients are asleep and, therefore, would go unnoticed. However, nausea can rouse one from sleep, and another common adverse effect, bradycardia, could predispose patients to nocturnal falls when moving from the bed to the toilet.

We recommend administering donepezil in the morning with a meal, and oral forms of galantamine and rivastigmine once or twice daily, depending on the formulation, with meals.

Author disclosure: No relevant financial affiliations.


show all references

1. Aricept [package insert]. Woodcliff Lake, N.J.: Esai; 2016. http://www.aricept.com/. Accessed July 17, 2017....

2. Razadyne [package insert]. Titusville, N.J.: Janssen Pharmaceuticals; 2013. https://www.janssenmd.com/pdf/razadyne/razadyne_pi.pdf. Accessed July 18, 2017.

3. Exelon [package insert]. East Hanover, N.J.: Novartis Pharmaceuticals; 2013. https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/exelon.pdf. Accessed July 18, 2017.

4. Grossberg GT. Cholinesterase inhibitors for the treatment of Alzheimer's disease: getting on and staying on. Curr Ther Res Clin Exp. 2003;64(4):216–235.

5. Tiseo PJ, Rogers SL, Friedhoff LT. Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration. Br J Clin Pharmacol. 1998;46(suppl 1):13–18.

Editor's Note: This letter was sent to the authors of “Alzheimer Disease: Pharmacologic and Nonpharmacologic Therapies for Cognitive and Functional Symptoms,” who declined to reply.


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