Donepezil was approved for medical use in the United States in 1996. It is available as a generic medication. In 2020, it was the 112th most commonly prescribed medication in the United States, with more than 5million prescriptions.
There is no evidence that donepezil or other similar agents alter the course or progression of Alzheimer's disease. Six-to-twelve-month controlled studies have shown modest benefits in cognition or behavior. The UK National Institute for Clinical Excellence (NICE) recommends donepezil as an option in the management of mild to moderate Alzheimer's disease. The person should, however, be reviewed frequently and if there is no significant benefit it should be stopped. In 2006, the U.S. Food and Drug Administration (FDA) also approved donepezil for treatment of mild, moderate and severe dementia in Alzheimer's disease.
Lewy body dementia: Some studies have shown benefits of donepezil for the treatment of cognitive and behavioral symptoms in Lewy body dementia.
Traumatic brain injury: Some research suggests an improvement in memory dysfunction in patients with traumatic brain injury with donepezil use.
Vascular dementia: Studies have shown that donepezil may improve cognition in patients with vascular dementia but not overall global functioning.
Dementia associated with Parkinson disease: Some evidence suggests that donepezil can improve cognition, executive function, and global status in Parkinson disease dementia.
In clinical trials the most common adverse events leading to discontinuation were nausea, diarrhea, and vomiting. Other side effects included difficulty sleeping, muscle cramps and loss of appetite. Most side effects were observed in patients taking the 23 mg dose compared to 10 mg or lower doses. Side effects are mild and transient in most patients, lasting up to three weeks and usually improved even with continued use.
Donepezil, like other cholinesterase inhibitors, can cause nightmares due to enhanced activation of the visual association cortex during REM sleep. Dosing donepezil in the morning can reduce the frequency of nightmares.
People with peptic ulcer disease or taking NSAIDs should use with caution because increased risk of gastrointestinal bleeding was noted. Slow heart beat and fainting in people with heart problems were also seen. These symptoms may appear more frequent when initiating treatment or increasing the donepezil dose. Although occurrence of seizures is rare, people who have a predisposition to seizures should be treated with caution.
If daily donepezil has suspended for 7 days or less, restarting at the same dose is recommended, while if the suspension lasts longer than 7 days, retitrate from 5 mg daily is suggested.
Mechanism of action
Donepezil binds and reversibly inactivates the cholinesterases, thus inhibiting hydrolysis of acetylcholine. This increases acetylcholine concentrations at cholinergic synapses.
The precise mechanism of action of donepezil in patients with Alzheimer's disease is not fully understood. Certainly, Alzheimer's disease involves a substantial loss of the elements of the cholinergic system and it is generally accepted that the symptoms of Alzheimer's disease are related to this cholinergic deficit, particularly in the cerebral cortex and other areas of the brain.
In addition to its actions as an acetylcholinesterase inhibitor, donepezil has been found to act as a potent agonist of the σ1 receptor (Ki = 14.6 nM), and has been shown to produce specific antiamnestic effects in animals mainly via this action.
As of 2011, Aricept was the world's best-selling Alzheimer's disease treatment. The first generic donepezil became available in November 2010, with the US FDA approval of a formulation prepared by Ranbaxy Labs.
Donepezil has shown mixed results for improving cognitive abilities in healthy individuals. A 2009 double-blind, placebo controlled study (n=24) investigating Donepezil's effects across a variety of memory tests in reported an improvement in spatial memory accuracy both before (90 minutes after dosing) and at theoretical Tmax (210 minutes after dosing). However, a later 2011 paper featuring two study double-blind, placebo controlled experiments evaluating Donepezil's effects in older but healthy subjects reported impairment after acute (5 hours after dose) and chronic (4 weeks) donepezil administration.
The addition of donepezil with existing ADHD medications has shown mixed results. In those with Tourette syndrome and ADHD, donepezil may reduce tics while it had no effect on ADHD's symptoms.
Donepezil is furthermore suggested as a feasible therapeutic option for anorexia nervosa. Emerging literature reports that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. Based on the physiopathology of anorexia nervosa, namely in terms of cholinergic deficiencies, the effects of donepezil and other drugs that act as cholinesterase inhibitors could thus be effective in the treatment of the disorder.
^ abcdefSeltzer B (October 2005). "Donepezil: a review". Expert Opinion on Drug Metabolism & Toxicology. Informa Healthcare. 1 (3): 527–536. doi:10.1517/17425255.1.3.527. PMID16863459. S2CID32689288. there is a linear relationship between dose and pharmacodynamic effects, measured as red blood cell acetylcholinesterase inhibition and clinical efficacy. Despite being 96% bound to plasma proteins, it has few interactions with other drugs, and the 5-mg dose can be given safely to patients with mild-to-moderate hepatic and renal-disease.
^Asiri YA, Mostafa GA (2010). "Donepezil". Profiles of Drug Substances, Excipients and Related Methodology. Vol. 35. Elsevier. pp. 117–50. doi:10.1016/s1871-5125(10)35003-5. ISBN978-0-12-380884-4. ISSN1871-5125. PMID22469221. Plasma donepezil concentrations decline with a half-life of approximately 70 h. Sex, race, and smoking history have no clinically significant influence on plasma concentrations of donepezil [46–51].
^"Donepezil: MedlinePlus Drug Information". MedlinePlus. 22 December 2019. Retrieved 31 December 2019. If you forget to take a dose of donepezil, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one. If you do not take donepezil, for 1 week or longer, you should call your doctor before starting to take this medication again.
^McCarthy AD, Owens IJ, Bansal AT, McTighe SM, Bussey TJ, Saksida LM (March 2011). "FK962 and donepezil act synergistically to improve cognition in rats: potential as an add-on therapy for Alzheimer's disease". Pharmacology, Biochemistry, and Behavior. 98 (1): 76–80. doi:10.1016/j.pbb.2010.11.019. PMID21130801. S2CID26055819.
^Tokita K, Yamazaki S, Yamazaki M, Matsuoka N, Mutoh S (October 2002). "Combination of a novel antidementia drug FK960 with donepezil synergistically improves memory deficits in rats". Pharmacology, Biochemistry, and Behavior. 73 (3): 511–519. doi:10.1016/S0091-3057(02)00819-5. PMID12151024. S2CID35007246.
^Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, ISBN978-3-946057-10-9, S. 178.
^Rodrigues Simões MC, Dias Viegas FP, Moreira MS, de Freitas Silva M, Riquiel MM, da Rosa PM, et al. (January 2014). "Donepezil: an important prototype to the design of new drug candidates for Alzheimer's disease". Mini Reviews in Medicinal Chemistry. 14 (1): 2–19. doi:10.2174/1389557513666131119201353. PMID24251806.
^Montero-Odasso M, Muir-Hunter SW, Oteng-Amoako A, Gopaul K, Islam A, Borrie M, et al. (January 2015). "Donepezil improves gait performance in older adults with mild Alzheimer's disease: a phase II clinical trial". Journal of Alzheimer's Disease. 43 (1): 193–199. doi:10.3233/JAD-140759. PMID25079803.
^Doraiswamy PM, Babyak MA, Hennig T, Trivedi R, White WD, Mathew JP, et al. (2007). "Donepezil for cognitive decline following coronary artery bypass surgery: a pilot randomized controlled trial". Psychopharmacology Bulletin. 40 (2): 54–62. PMID17514186.