Donepezil

Donepezil
Clinical data
Trade names	Aricept, Adlarity, others
Other names	Donepezil hydrochloride (USAN US)
AHFS/Drugs.com	Monograph
MedlinePlus	a697032
License data	US DailyMed: Donepezil;
Pregnancy; category	AU: B3; ;
Routes of; administration	By mouth, transdermal
Drug class	Acetylcholinesterase inhibitor
ATC code	N06DA02 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); BR: Class C1 (Other controlled substances); UK: POM (Prescription only); US: ℞-only; In general: ℞ (Prescription only);
Pharmacokinetic data
Bioavailability	100%
Protein binding	96%, albumin (about 75%) and alpha1-acid glycoprotein (21%).
Metabolism	CYP2D6, CYP3A4, and glucuronidation. Four major metabolites, two of which are active.
Onset of action	Peak plasma levels in 3–4 h.
Elimination half-life	70 hours Around 100 hours in elderly patients.
Duration of action	With daily dosing, steady-state concentration is reached in 15–21 days.
Excretion	0.11–0.13 (L/h/kg); excreted mostly by the kidneys. Around 17% is excreted unchanged in the urine. About 15% to 20% is excreted in feces. Steady-state clearance is similar at all ages.
Identifiers
	IUPAC name (RS)-2-[(1-Benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one;
CAS Number	120014-06-4 ;
PubChem CID	3152;
IUPHAR/BPS	6599;
DrugBank	DB00843 ;
ChemSpider	3040 ;
UNII	8SSC91326P;
KEGG	D07869 ;
ChEBI	CHEBI:53289 ;
ChEMBL	ChEMBL502 ;
PDB ligand	E20 (PDBe, RCSB PDB);
CompTox Dashboard (EPA)	DTXSID8048317 ;
ECHA InfoCard	100.125.198
Chemical and physical data
Formula	C24H29NO3
Molar mass	379.500 g·mol−1
3D model (JSmol)	Interactive image;
Chirality	Racemic mixture
	SMILES O=C2c1cc(OC)c(OC)cc1CC2CC4CCN(Cc3ccccc3)CC4;
	InChI InChI=1S/C24H29NO3/c1-27-22-14-19-13-20(24(26)21(19)15-23(22)28-2)12-17-8-10-25(11-9-17)16-18-6-4-3-5-7-18/h3-7,14-15,17,20H,8-13,16H2,1-2H3 ; Key:ADEBPBSSDYVVLD-UHFFFAOYSA-N ;
	(verify)

Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's type.^[3]^[4]^[8] It appears to result in a small benefit in mental function and ability to function.^[9] Use, however, has not been shown to change the progression of the disease.^[10] Treatment should be stopped if no benefit is seen.^[11] It is taken by mouth or via a transdermal patch.^[3]^[4]^[8]

Donepezil is a centrally acting reversible acetylcholinesterase inhibitor and structurally unrelated to other anticholinesterase agents.^[8]^[5] Common side effects include nausea, trouble sleeping, aggression, diarrhea, feeling tired, and muscle cramps.^[8]^[11] Serious side effects may include abnormal heart rhythms, urinary incontinence, and seizures.^[8]

Donepezil was approved for medical use in the United States in 1996.^[8] It is available as a generic medication.^[11] In 2022, it was the 146th most commonly prescribed medication in the United States, with more than 3 million prescriptions.^[12]^[13]

Medical uses

Alzheimer's disease

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.^[14] The UK National Institute for Clinical Excellence (NICE) recommends donepezil as an option in the management of mild to moderate Alzheimer's disease.^[15] The person should, however, be reviewed frequently and if there is no significant benefit it should be stopped.^[15] 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.^[16]

Other

Lewy body dementia: Some studies have shown benefits of donepezil for the treatment of cognitive and behavioral symptoms in Lewy body dementia.^[5]
Traumatic brain injury: Some research suggests an improvement in memory dysfunction in patients with traumatic brain injury with donepezil use.^[5]
Vascular dementia: Studies have shown that donepezil may improve cognition in patients with vascular dementia but not overall global functioning.^[5]
Dementia associated with Parkinson disease: Some evidence suggests that donepezil can improve cognition, executive function, and global status in Parkinson disease dementia.^[5]

Adverse effects

In clinical trials the most common adverse events leading to discontinuation were nausea, diarrhea, and vomiting.^[3]^[17] 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.^[3]^[5]

Donepezil, like other cholinesterase inhibitors, can cause nightmares due to enhanced activation of the visual association cortex during REM sleep.^[5] Dosing donepezil in the morning can reduce the frequency of nightmares.^[5]

Precautions

Donepezil should be used with caution in people with heart disease, cardiac conduction disturbances, chronic obstructive pulmonary disease, asthma, severe cardiac arrhythmia and sick sinus syndrome.^[3]

People with peptic ulcer disease or taking NSAIDs should use with caution because increased risk of gastrointestinal bleeding was noted.^[3] 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.^[3]

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.^[18]^[19]

Mechanism of action

Donepezil binds and reversibly inhibits enzymes called cholinesterases, especially acetylcholinesterase, thus inhibiting hydrolysis of acetylcholine. This increases acetylcholine concentrations at cholinergic synapses.^[5]

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.^[20]^[21]

In addition to its actions as an acetylcholinesterase inhibitor, donepezil has been found to act as a potent agonist of the σ₁ receptor (K_i = 14.6 nM), and has been shown to produce specific antiamnestic effects in animals mainly via this action.^[22]

Some noncholinergic mechanisms have also been proposed.^[5] Donepezil upregulates the nicotinic receptors in the cortical neurons, adding to neuroprotective activity.^[5] It inhibits voltage-activated sodium currents reversibly and delays rectifier potassium currents and fast transient potassium currents, although this action is unlikely to contribute to clinical effects.^[5]

Synergy

Donepezil was claimed to act synergistically with an agent called FK962 [283167-06-6]^[23] & FK960 [133920-70-4].^[24] {potential activation of somatostatinergic neurotransmission} However, the development was discontinued after Phase II "since the data reviewed did not indicate clear efficacy of the compound for the treatment of mild to moderate Alzheimer's disease."^[25]

Stereochemistry

Donepezil medications are racemates.^[26]

Enantiomers
(R)-Donepezil	(S)-Donepezil

History

Research leading to the development of donepezil began in 1983, at Eisai, and in 1996, Eisai received approval from the United States Food and Drug Administration (FDA) for donepezil under the brand Aricept, which it co-marketed with Pfizer.^[28] The team at Eisai was led by Hachiro Sugimoto.^[29]

As of 2011, Aricept was the world's best-selling Alzheimer's disease treatment.^[30] The first generic donepezil became available in November 2010, with the US FDA approval of a formulation prepared by Ranbaxy Labs.^[31]

Research

Donepezil has been tested in other cognitive disorders, including Lewy body dementia,^[32] and vascular dementia,^[33] but it is not currently approved for these indications. Donepezil has also been found to improve sleep apnea in people with Alzheimer's.^[34] It also improves gait in people with mild Alzheimer's.^[35]

Donepezil has also been studied in people with mild cognitive impairment, schizophrenia, attention deficit disorder, post-coronary artery bypass surgery cognitive impairment,^[36] cognitive impairment associated with multiple sclerosis, CADASIL syndrome, and Down syndrome. A three-year National Institutes of Health trial in people with mild cognitive impairment reported donepezil was superior to placebo in delaying rate of progression to dementia during the initial 18 months of the study, but this was not sustained at 36 months.^[37] In a secondary analysis, a subgroup of individuals with the apolipoprotein E4 genotype showed sustained benefits with donepezil throughout the study.^[38] At this time, though, donepezil is not indicated for prevention of dementia.

Cognitive enhancement

Donepezil has shown mixed results for improving cognitive abilities in healthy individuals.^[39]^[40]^[41]^[42] 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 T_max (210 minutes after dosing).^[41] 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.^[42]

ADHD

The addition of donepezil with existing ADHD medications has shown mixed results.^[43] In those with Tourette syndrome and ADHD, donepezil may reduce tics while it had no effect on ADHD's symptoms.^[43]

Pervasive developmental disorder

Donepezil, along with other cholinesterase inhibitors, is suggested as having potential for trouble behaviors: irritability, hyperactivity, and difficulty in social communication which are typically seen in those with pervasive developmental disorder, pervasive developmental disorder not otherwise specified, and autism-spectrum disorder.^[43]

Anorexia nervosa

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.^[44] 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.^[45] However, no trial to date supports this hypothesis.

References

^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
^ "Donepezil Hydrochloride 10 mg Film-coated tablets". Electronic Medicines Compendium. Archived from the original on 8 September 2022. Retrieved 8 September 2022.
^ ^a ^b ^c ^d ^e ^f ^g ^h "Aricept- donepezil hydrochloride tablet, film coated Aricept ODT- donepezil hydrochloride tablet, orally disintegrating". DailyMed. 23 December 2021. Retrieved 15 March 2022.
^ ^a ^b ^c "Adlarity- donepezil hydrochloride patch". DailyMed. 11 March 2022. Retrieved 19 June 2022.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u Kumar A, Sharma S (2020). "Donepezil". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 30020629. Retrieved 12 April 2020.
^ ^a ^b ^c ^d ^e ^f Seltzer B (October 2005). "Donepezil: a review". Expert Opinion on Drug Metabolism & Toxicology. 1 (3). Informa Healthcare: 527–536. doi:10.1517/17425255.1.3.527. PMID 16863459. S2CID 32689288. 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. ISBN 978-0-12-380884-4. ISSN 1871-5125. PMID 22469221. S2CID 206178636. 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]. {{cite book}}: |journal= ignored (help)
^ ^a ^b ^c ^d ^e ^f "Donepezil Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 4 February 2019.
^ Birks JS, Harvey RJ (June 2018). "Donepezil for dementia due to Alzheimer's disease". The Cochrane Database of Systematic Reviews. 2018 (6): CD001190. doi:10.1002/14651858.CD001190.pub3. PMC 6513124. PMID 29923184.
^ Swedish Council on Health Technology Assessment (June 2008). "Dementia – Caring, Ethics, Ethnical and Economical Aspects: A Systematic Review". SBU Systematic Reviews. PMID 28876770.
^ ^a ^b ^c British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 300. ISBN 978-0-85711-338-2.
^ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
^ "Donepezil Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
^ Steele LS, Glazier RH (April 1999). "Is donepezil effective for treating Alzheimer's disease?". Canadian Family Physician. 45: 917–919. PMC 2328349. PMID 10216789.
^ ^a ^b "Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease | Guidance and guidelines | NICE". www.nice.org.uk. 23 March 2011. Retrieved 4 February 2019.
^ "FDA Approves Expanded Use of Treatment for Patients With Severe Alzheimer's Disease". FDA (Press release). 13 October 2006. Archived from the original on 10 July 2009.
^ Noetzli M, Eap CB (April 2013). "Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease". Clinical Pharmacokinetics. 52 (4): 225–241. doi:10.1007/s40262-013-0038-9. PMID 23408070. S2CID 1686999.
^ "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.
^ "Table 4. NHS Guideline" (PDF). p. 6 of 11. Archived from the original (PDF) on 31 December 2019. Re-titration following AChEI missed doses or planned treatment breaks
^ Davies P, Maloney AJ (December 1976). "Selective loss of central cholinergic neurons in Alzheimer's disease". Lancet. 2 (8000): 1403. doi:10.1016/s0140-6736(76)91936-x. PMID 63862. S2CID 43250282.
^ Kása P, Rakonczay Z, Gulya K (August 1997). "The cholinergic system in Alzheimer's disease". Progress in Neurobiology. 52 (6): 511–535. doi:10.1016/s0301-0082(97)00028-2. PMID 9316159. S2CID 8460305.
^ Maurice T, Su TP (November 2009). "The pharmacology of sigma-1 receptors". Pharmacology & Therapeutics. 124 (2): 195–206. doi:10.1016/j.pharmthera.2009.07.001. PMC 2785038. PMID 19619582.
^ 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. PMID 21130801. S2CID 26055819.
^ 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. PMID 12151024. S2CID 35007246.
^ "Astellas Discontinues Development of Alzheimer's Disease Compound FK962" (PDF). Astrellas. 18 July 2006. Retrieved 3 September 2023.
^ 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, ISBN 978-3-946057-10-9, S. 178.
^ Proteopedia 1eve
^ 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. PMID 24251806.
^ "Developed the magic bullet for Alzheimer's disease after overcoming many difficulties (Hachiro Sugimoto)". Chuo University Gakuin Jihou (ChuOnline). Archived from the original on 15 February 2020. Retrieved 11 January 2017.
^ Matsuyama K (25 April 2011). "Eisai Aricept Patch for Alzheimer's Isn't Ready for Approval". Bloomberg. Archived from the original on 5 November 2012. Retrieved 25 April 2011.
^ "Ranbaxy gets FDA nod for Alzheimer's drug". The Indian Express. New Delhi, India: Indian Express Group. 30 November 2010. IndianExpress.com. Retrieved 25 April 2011.
^ Rojas-Fernandez CH (February 2001). "Successful use of donepezil for the treatment of dementia with Lewy bodies". The Annals of Pharmacotherapy. 35 (2): 202–205. doi:10.1345/aph.10192. PMID 11215841. S2CID 24685121.
^ Malouf R, Birks J (2004). Malouf R (ed.). "Donepezil for vascular cognitive impairment". The Cochrane Database of Systematic Reviews (1): CD004395. doi:10.1002/14651858.CD004395.pub2. PMID 14974068.
^ Moraes W, Poyares D, Sukys-Claudino L, Guilleminault C, Tufik S (March 2008). "Donepezil improves obstructive sleep apnea in Alzheimer disease: a double-blind, placebo-controlled study". Chest. 133 (3): 677–683. doi:10.1378/chest.07-1446. PMID 18198262. Archived from the original on 14 April 2013.
^ 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. PMID 25079803.
^ 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. PMID 17514186.
^ Jelic V, Kivipelto M, Winblad B (April 2006). "Clinical trials in mild cognitive impairment: lessons for the future". Journal of Neurology, Neurosurgery, and Psychiatry. 77 (4): 429–438. doi:10.1136/jnnp.2005.072926. PMC 2077499. PMID 16306154.
^ Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, et al. (Alzheimer's Disease Cooperative Study Group) (June 2005). "Vitamin E and donepezil for the treatment of mild cognitive impairment". The New England Journal of Medicine. 352 (23): 2379–2388. doi:10.1056/nejmoa050151. PMID 15829527.
^ Chuah LY, Chee MW (October 2008). "Cholinergic augmentation modulates visual task performance in sleep-deprived young adults". The Journal of Neuroscience. 28 (44): 11369–11377. doi:10.1523/JNEUROSCI.4045-08.2008. PMC 6671517. PMID 18971479.
^ Silver MA, Shenhav A, D'Esposito M (December 2008). "Cholinergic enhancement reduces spatial spread of visual responses in human early visual cortex". Neuron. 60 (5): 904–914. doi:10.1016/j.neuron.2008.09.038. PMC 2640421. PMID 19081383.
^ ^a ^b Zaninotto AL, Bueno OF, Pradella-Hallinan M, Tufik S, Rusted J, Stough C, et al. (August 2009). "Acute cognitive effects of donepezil in young, healthy volunteers". Human Psychopharmacology. 24 (6): 453–464. doi:10.1002/hup.1044. PMID 19637397. S2CID 22391336.
^ ^a ^b Balsters JH, O'Connell RG, Martin MP, Galli A, Cassidy SM, Kilcullen SM, et al. (8 September 2011). "Donepezil impairs memory in healthy older subjects: behavioural, EEG and simultaneous EEG/fMRI biomarkers". PLOS ONE. 6 (9): e24126. Bibcode:2011PLoSO...624126B. doi:10.1371/journal.pone.0024126. PMC 3169575. PMID 21931653.
^ ^a ^b ^c Elbe D (2019). Clinical handbook of psychotropic drugs for children and adolescents. Boston, MA: Hogrefe. pp. 366–69. ISBN 978-1-61676-550-7. OCLC 1063705924.
^ Favier M, Janickova H, Justo D, Kljakic O, Runtz L, Natsheh JY, et al. (December 2020). "Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating". The Journal of Clinical Investigation. 130 (12): 6616–6630. doi:10.1172/JCI138532. PMC 7685731. PMID 33164988.
^ Halabe Bucay A (May 2009). "Donepezil (aricept) as a treatment for anorexia nervosa: a very feasible therapeutic possibility". Expert Opinion on Investigational Drugs. 18 (5): 569–571. doi:10.1517/13543780902810360. PMID 19388874. S2CID 72686919.