Donepezil

Source: Wikipedia, the free encyclopedia.

Donepezil
Clinical data
Trade namesAricept, Adlarity, others
Other namesDonepezil hydrochloride (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa697032
License data
Pregnancy
category
  • AU: B3
Routes of
administration
By mouth, transdermal
ATC code
Legal status
Legal status
alpha1-acid glycoprotein (21%).[6][5]
MetabolismCYP2D6, CYP3A4, and glucuronidation.[5] Four major metabolites, two of which are active.[6][5]
Onset of actionPeak plasma levels in 3–4 h.[6][5]
Elimination half-life70 hours[7] Around 100 hours in elderly patients.[5]
Duration of actionWith daily dosing, steady-state concentration is reached in 15–21 days.[6][5]
Excretion0.11–0.13 (L/h/kg); excreted mostly by the kidneys. Around 17% is excreted unchanged in the urine. About 15% to 20% is excreted in feces.[5][6] Steady-state clearance is similar at all ages.[5]
Identifiers
  • (RS)-2-[(1-Benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one
JSmol)
ChiralityRacemic mixture
  • O=C2c1cc(OC)c(OC)cc1CC2CC4CCN(Cc3ccccc3)CC4
  • 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 checkY
  • Key:ADEBPBSSDYVVLD-UHFFFAOYSA-N checkY
  (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]

Common side effects include nausea, trouble sleeping, aggression, diarrhea, feeling tired, and muscle cramps.

anticholinesterase agents.[8][5]

Donepezil was approved for medical use in the United States in 1996.

generic medication.[11] In 2021, it was the 131st most commonly prescribed medication in the United States, with more than 4 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

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

People with

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 (Ki = 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.

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

Enantiomers

(R)-Donepezil

(S)-Donepezil

History

Donepezil inhibiting Torpedo californica acetylcholinesterase[27]
10 mg Aricept pill

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

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

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 Tmax (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

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]

References

  1. ^ 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.
  2. ^ "Donepezil Hydrochloride 10 mg Film-coated tablets". Electronic Medicines Compendium. Archived from the original on 8 September 2022. Retrieved 8 September 2022.
  3. ^ 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.
  4. ^ a b c "Adlarity- donepezil hydrochloride patch". DailyMed. 11 March 2022. Retrieved 19 June 2022.
  5. ^
    PMID 30020629
    . Retrieved 12 April 2020.
  6. ^ . 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.
  7. . 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].
  8. ^ a b c d e f "Donepezil Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 4 February 2019.
  9. PMID 29923184
    .
  10. .
  11. ^ .
  12. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  13. ^ "Donepezil - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  14. PMID 10216789
    .
  15. ^ 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.
  16. ^ "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.
  17. S2CID 1686999
    .
  18. ^ "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.
  19. ^ "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
  20. S2CID 43250282
    .
  21. .
  22. .
  23. .
  24. .
  25. ^ "Astellas Discontinues Development of Alzheimer's Disease Compound FK962" (PDF). Astrellas. 18 July 2006. Retrieved 3 September 2023.
  26. , S. 178.
  27. ^ Proteopedia 1eve
  28. PMID 24251806
    .
  29. ^ "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.
  30. ^ 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.
  31. New Delhi, India
    : Indian Express Group. 30 November 2010. IndianExpress.com. Retrieved 25 April 2011.
  32. S2CID 24685121
    .
  33. .
  34. PMID 18198262. Archived from the original
    on 14 April 2013.
  35. .
  36. .
  37. .
  38. .
  39. .
  40. .
  41. ^ .
  42. ^ .
  43. ^ .
  44. .
  45. .

Further reading