Donepezil
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| Clinical data |
| Trade names |
Aricept |
| AHFS/Drugs.com |
Monograph |
| MedlinePlus |
a697032 |
Pregnancy
category |
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Routes of
administration |
By mouth (tablets) |
| ATC code |
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| Legal status |
| Legal status |
- US: ℞-only
- In general: ℞ (Prescription only)
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| Pharmacokinetic data |
| Bioavailability |
100% |
| Protein binding |
96% |
| Biological half-life |
70 hours |
| Excretion |
0,11-0,13 (l/h/kg) |
| Identifiers |
IUPAC name
- (RS)-2-[(1-Benzyl-4-piperidyl)methyl]- 5,6-dimethoxy-2,3-dihydroinden-1-one
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| CAS Number |
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| PubChem CID |
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| IUPHAR/BPS |
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| DrugBank |
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| ChemSpider |
|
| UNII |
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| KEGG |
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| ChEBI |
|
| ChEMBL |
|
| PDB ligand |
|
| ECHA InfoCard |
100.125.198 |
| Chemical and physical data |
| Formula |
C24H29NO3 |
| Molar mass |
379.492 g/mol |
| 3D model (Jmol) |
|
| Chirality |
Racemic mixture |
SMILES
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O=C2c1cc(OC)c(OC)cc1CC2CC4CCN(Cc3ccccc3)CC4
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InChI
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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 Y
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Key:ADEBPBSSDYVVLD-UHFFFAOYSA-N Y
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| (verify) |
Donepezil, marketed under the trade name Aricept, is a medication used in the palliative treatment of Alzheimer's disease.[1][2] Donepezil is used to improve cognition and behavior of people with Alzheimer's, but does not slow the progression of or cure the disease.[3]
Common side effects include loss of appetite, gastrointestinal upset, diarrhea, difficulty sleeping, vomiting, or muscle cramping.[4]
It was developed by Eisai and Pfizer and is sold as a generic by multiple suppliers. Donepezil acts as a centrally acting reversible acetylcholinesterase inhibitor.[5]
Contents
- 1 Medical uses
- 2 Adverse effects
- 3 Mechanism of action
- 4 History
- 5 Research
- 6 References
- 7 External links
Medical uses
Alzheimer's disease
There is no evidence that donepezil or other similar agents alters the course or progression of Alzheimer's disease (AD). 6 to 12-month controlled studies have shown modest benefits in cognition and/or behavior.[3] The UK National Institute for Clinical Excellence (NICE) recommends donepezil as an option in the management of mild to moderate Alzheimer's disease.[6] The person should, however, be reviewed frequently and if there is no significant benefit it should be stopped.[6] In 2006 the U.S. Food and Drug Administration also approved donepezil for treatment of mild, moderate and severe dementia in Alzheimer's disease.[7]
Adverse effects
In clinical trials the most common adverse events leading to discontinuation were nausea, diarrhea, and vomiting.[8][9] Other side effects included difficulty sleeping, muscle cramps and anorexia. Most side effects were observed in patients taking the 23 mg dose compared to 10 mg or lower doses. Side effects improved with continued use.[10]
Precautions
Donepezil should be used with caution in people with heart disease, cardiac conduction disturbances, chronic obstructive pulmonary disease, asthma, severe cardiac arrhythmias and sick sinus syndrome.[10]
People with peptic ulcer disease or taking NSAIDS should use caution because increased risk of gastrointestinal bleeding was noted.[10] 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.[10]
Mechanism of action
Donepezil binds and reversibly inactivates the cholinesterases, thus inhibiting hydrolysis of acetylcholine. This results in an increased 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.[11][12] It is noted that the hippocampal formation plays an important role in the processes of control of attention, memory and learning. Just the severity of the loss of cholinergic neurons of the central nervous system (CNS) has been found to correlate with the severity of cognitive impairment.
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.[13]
History
Donepezil inhibiting
Torpedo californica acetylcholinesterase. See
Proteopedia 1eve.
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 (USFDA) for donepezil under the brand Aricept, which it co-marketed with Pfizer.[14] The team at Eisai was led by Hachiro Sugimoto[15]
As of 2011, Aricept was the world's best-selling Alzheimer's disease treatment.[16] The first generic donepezil became available in November 2010 with the USFDA approval of a formulation prepared by Ranbaxy Labs.[17] In April 2011 a second generic formulation, from Wockhardt, received tentative USFDA marketing approval.[18]
Research
Donepezil has been tested (off label) in other cognitive disorders, including Lewy body dementia,[19] and vascular dementia,[20] but it is not currently approved for these indications. Donepezil has also been found to improve sleep apnea in Alzheimer's patients.[21] It also improves gait in patient with mild Alzheimer's Disease.[22]
Donepezil has also been studied in patients with mild cognitive impairment, schizophrenia, attention deficit disorder, post-Coronary artery bypass surgery cognitive impairment,[23] cognitive impairment associated with multiple sclerosis, CADASIL syndrome, and Down syndrome. A three-year National Institutes of Health trial in patients 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. In a secondary analysis, a subgroup of individuals with the apolipoprotein E4 genotype showed sustained benefits with donepezil throughout the study.[24] At this time, though, donepezil is not indicated for prevention of dementia.
References
- ^ "aricept". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
- ^ Lee, J.-H.; Jeong, S.-K.; Kim, B. C.; Park, K. W.; Dash, A. (2015-05-01). "Donepezil across the spectrum of Alzheimer's disease: dose optimization and clinical relevance". Acta Neurologica Scandinavica. 131 (5): 259–267. ISSN 1600-0404. PMID 25690270. doi:10.1111/ane.12386.
- ^ a b Steele LS, Glazier RH (April 1999). "Is donepezil effective for treating Alzheimer's disease?". Can Fam Physician. 45: 917–9. PMC 2328349 . PMID 10216789.
- ^ "ARICEPT 23mg - Prescribing and Patient Info". www.aricept.com. Retrieved 2015-11-03.
- ^ Birks J, Harvey RJ (2006). Birks, Jacqueline, ed. "Donepezil for dementia due to Alzheimer's disease". Cochrane Database Syst Rev (1): CD001190. PMID 16437430. doi:10.1002/14651858.CD001190.pub2.
- ^ a b https://www.nice.org.uk/guidance/TA217/chapter/1-Guidance
- ^ FDA Press Release 2006
- ^ "www.accessdata.fda.gov" (PDF).
- ^ Noetzli M, Eap CB (Apr 2013). "Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease". Clin Pharmacokinet. 52 (4): 225–41. PMID 23408070. doi:10.1007/s40262-013-0038-9.
- ^ a b c d Aricept (donepezil hydrochloride) package insert. Woodcliff Lake, NJ: Eisai Co., Ltd.; 2010 Nov.
- ^ Davies P, Maloney AJ (December 1976). "Selective loss of central cholinergic neurons in Alzheimer's disease". Lancet. 2 (8000): 1403. PMID 63862. doi:10.1016/s0140-6736(76)91936-x. Retrieved 2014-12-23.
- ^ Kása P, Rakonczay Z, Gulya K (August 1997). "The cholinergic system in Alzheimer's disease". Prog. Neurobiol. 52 (6): 511–35. PMID 9316159. doi:10.1016/s0301-0082(97)00028-2. Retrieved 2014-12-23.
- ^ Maurice, Tangui; Su, Tsung-Ping (2009). "The pharmacology of sigma-1 receptors". Pharmacology & Therapeutics. 124 (2): 195–206. ISSN 0163-7258. doi:10.1016/j.pharmthera.2009.07.001.
- ^ Rodrigues Simões, MC; et al. (January 2014). "Donepezil: an important prototype to the design of new drug candidates for Alzheimer's disease". Mini Rev Med Chem. 14 (1): 2–19. PMID 24251806. doi:10.2174/1389557513666131119201353.
- ^ Shimbun, Yomiuri. "Developed the magic bullet for Alzheimer's disease after overcoming many difficulties : People : Chuo Online : YOMIURI ONLINE" (Chuo University Gakuin Jihou, Issue 464). Japan News. Retrieved 11 January 2017.
- ^ Kanoko Matsuyama (25 April 2011). "Eisai Aricept Patch for Alzheimer’s Isn’t Ready for Approval". Bloomberg. 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.
- ^ Staff Writer (25 April 2011). "Wockhardt Obtains US FDA Nod For Generic Version Of Aricept Tablets". RTTNews. Retrieved 25 April 2011.
- ^ Rojas-Fernandez CH (February 2001). "Successful use of donepezil for the treatment of dementia with Lewy bodies". Ann Pharmacother. 35 (2): 202–5. PMID 11215841. doi:10.1345/aph.10192.
- ^ Malouf R, Birks J (2004). Malouf, Reem, ed. "Donepezil for vascular cognitive impairment". Cochrane Database Syst Rev (1): CD004395. PMID 14974068. doi:10.1002/14651858.CD004395.pub2.
- ^ 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): 677–83. PMID 18198262. doi:10.1378/chest.07-1446.
- ^ Montero-Odasso, Manuel; Muir-Hunter, Susan W.; Oteng-Amoako, Afua; Gopaul, Karen; Islam, Anam; Borrie, Michael; Wells, Jennie; Speechley, Mark (2015-01-01). "Donepezil improves gait performance in older adults with mild Alzheimer's disease: a phase II clinical trial". Journal of Alzheimer's disease: JAD. 43 (1): 193–199. ISSN 1875-8908. PMID 25079803. doi:10.3233/JAD-140759.
- ^ Doraiswamy PM (2007). "Donepezil for cognitive decline following coronary artery bypass surgery: a pilot randomized controlled trial.". Psychopharmacology Bulletin. 40 (2): 54–62. PMID 17514186.
- ^ Petersen, RC; Thomas, RG; Grundman, M; Bennett, D; Doody, R; Ferris, S; Galasko, D; Jin, S; Kaye, J; Levey, A; Pfeiffer, E; Sano, M; van Dyck, CH; Thal, LJ; Alzheimer's Disease Cooperative Study Group (June 9, 2005). "Vitamin E and donepezil for the treatment of mild cognitive impairment.". The New England Journal of Medicine. 352 (23): 2379–88. PMID 15829527. doi:10.1056/nejmoa050151.
External links
- Brenner, George D.; George M. Brenner (2000). Pharmacology. Philadelphia: W. B. Saunders. ISBN 0-7216-7757-6.
- Acting Editor-in-Chief Louise Welbanks. (2000). Compendium of Pharmaceuticals and Specialities, 2000 (25th ed.). Canadian Pharmaceutical Assn. ISBN 0-919115-76-4.
- Official Aricept product site
- Aricept entry at Drugs.com
- 3D Molecular structure of Donepezil
- Acetylcholinesterase: A gorge-ous enzyme Article describing structure of target enzyme acetylcholinesterase at PDBe
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Psychoanaleptics: Antidementia agents (N06D)
|
| AChE inhibitors |
- Donepezil
- Galantamine
- Huperzine A (Huperzia serrata)
- Rivastigmine
- Tacrine
|
| BACE inhibitors |
- Lanabecestat
- Semagacestat
- Verubecestat
|
| Others |
- Bifemelane
- Ergoloid
- Meclofenoxate (centrophenoxine)
- Memantine
- Nicergoline
|
|
Acetylcholine receptor modulators
|
|
Receptor modulators
|
| mACh |
- Agonists: 77-LH-28-1
- AC-42
- AC-260,584
- Aceclidine
- Acetylcholine
- AF30
- AF150(S)
- AF267B
- AFDX-384
- Alvameline
- AQRA-741
- Arecoline
- Bethanechol
- Butyrylcholine
- Carbachol
- CDD-0034
- CDD-0078
- CDD-0097
- CDD-0098
- CDD-0102
- Cevimeline
- Choline
- cis-Dioxolane
- Ethoxysebacylcholine
- Itameline
- LY-593,039
- L-689,660
- LY-2,033,298
- McNA343
- Methacholine
- Milameline
- Muscarine
- NGX-267
- Ocvimeline
- Oxotremorine
- PD-151,832
- Pilocarpine
- RS86
- Sabcomeline
- SDZ 210-086
- Sebacylcholine
- Suberyldicholine
- Talsaclidine
- Tazomeline
- Thiopilocarpine
- Vedaclidine
- VU-0029767
- VU-0090157
- VU-0152099
- VU-0152100
- VU-0238429
- WAY-132,983
- Xanomeline
- YM-796
- Antagonists: 3-Quinuclidinyl benzilate
- 4-DAMP
- Aclidinium bromide
- Anisodamine
- Anisodine
- Antihistamines (first-generation) (e.g., brompheniramine, chlorphenamine, cyproheptadine, dimenhydrinate, diphenhydramine, doxylamine, mepyramine (pyrilamine), phenindamine, pheniramine, promethazine, tripelennamine, triprolidine)
- Atropine
- Atropine methonitrate
- Atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, zotepine)
- Benactyzine
- Benzatropine (benztropine)
- Benzilylcholine mustard
- Benzydamine
- BIBN 99
- Biperiden
- Bornaprine
- CAR-226,086
- CAR-301,060
- CAR-302,196
- CAR-302,282
- CAR-302,368
- CAR-302,537
- CAR-302,668
- Caramiphen
- Cloperastine
- CS-27349
- Cyclobenzaprine
- Cyclopentolate
- Darifenacin
- DAU-5884
- Dimethindene
- Dexetimide
- DIBD
- Dicyclomine (dicycloverine)
- Ditran
- EA-3167
- EA-3443
- EA-3580
- EA-3834
- Etanautine
- Etybenzatropine (ethybenztropine)
- Flavoxate
- Himbacine
- HL-031,120
- Ipratropium bromide
- J-104,129
- Hyoscyamine
- Mamba toxin 3
- Mamba toxin 7
- Mazaticol
- Mebeverine
- Methoctramine
- Metixene
- N-Ethyl-3-piperidyl benzilate
- N-Methyl-3-piperidyl benzilate
- Orphenadrine
- Otenzepad
- Oxybutynin
- PBID
- PD-102,807
- PD-0298029
- Phenglutarimide
- Phenyltoloxamine
- Pipenzolate bromide
- Piperidolate
- Pirenzepine
- Piroheptine
- Procyclidine
- Profenamine
- Revefenacin
- RU-47,213
- SCH-57,790
- SCH-72,788
- SCH-217,443
- Scopolamine (hyoscine)
- Sofpironium bromide
- Solifenacin
- Telenzepine
- Tetracyclic antidepressants (e.g., amoxapine, maprotiline, mianserin, mirtazapine)
- Timepidium bromide
- Tiotropium bromide
- Tolterodine
- Tricyclic antidepressants (e.g., amitriptyline, butriptyline, clomipramine, desipramine, dosulepin (dothiepin), doxepin, imipramine, lofepramine, nortriptyline, protriptyline, trimipramine)
- Trihexyphenidyl
- Tripitamine
- Tropacine
- Tropatepine
- Tropicamide
- Typical antipsychotics (e.g., chlorpromazine, loxapine, thioridazine)
- WIN-2299
- Xanomeline
- Zamifenacin
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| nACh |
- Agonists: 5-HIAA
- A-84,543
- A-366,833
- A-582,941
- A-867,744
- ABT-202
- ABT-418
- ABT-560
- ABT-894
- Acetylcholine
- Altinicline
- Anabasine
- Anatoxin-a
- AR-R17779
- Butinoline
- Butyrylcholine
- Carbachol
- Choline
- Cotinine
- Cytisine
- Decamethonium
- Desformylflustrabromine
- Dianicline
- Dimethylphenylpiperazinium
- Epibatidine
- Epiboxidine
- Ethanol
- Ethoxysebacylcholine
- EVP-4473
- EVP-6124
- Galantamine
- GTS-21
- Ispronicline
- Ivermectin
- Levamisole
- Lobeline
- MEM-63,908 (RG-3487)
- Morantel
- Nicotine (tobacco)
- NS-1738
- PHA-543,613
- PHA-709,829
- PNU-120,596
- PNU-282,987
- Pozanicline
- Rivanicline
- RJR-2429
- Sazetidine A
- SB-206553
- Sebacylcholine
- SIB-1508Y
- SIB-1553A
- SSR-180,711
- Suberyldicholine
- Suxamethonium (succinylcholine)
- TC-1698
- TC-1734
- TC-1827
- TC-2216
- TC-5214
- TC-5619
- TC-6683
- Tebanicline
- Tropisetron
- UB-165
- Varenicline
- WAY-317,538
- XY-4083
- Antagonists: 18-MAC
- 18-MC
- α-Neurotoxins (e.g., α-bungarotoxin, α-cobratoxin, α-conotoxin, many others)
- ABT-126
- Alcuronium
- Allopregnanolone
- Amantadine
- Anatruxonium
- AQW051
- Atracurium
- Barbiturates (e.g., pentobarbital, sodium thiopental)
- Bungarotoxins (e.g., α-bungarotoxin, κ-bungarotoxin)
- Bupropion
- Candocuronium iodide (chandonium iodide)
- Chlorisondamine
- Cisatracurium
- Coclaurine
- Coronaridine
- Cyclopropane
- Dacuronium bromide
- Decamethonium
- Dehydronorketamine
- Desflurane
- Dextromethorphan
- Dextropropoxyphene
- Dextrorphan
- Diadonium
- DHβE
- Dihydrochandonium
- Dimethyltubocurarine (metocurine)
- Dipyrandium
- Dizocilpine (MK-801)
- Doxacurium
- Encenicline
- Enflurane
- Esketamine
- Fazadinium
- Gallamine
- Halothane
- Hexafluronium
- Hexamethonium (benzohexonium)
- Hydroxybupropion
- Hydroxynorketamine
- Ibogaine
- Isoflurane
- Ketamine
- Kynurenic acid
- Laudexium (laudolissin)
- Levacetylmethadol
- Levomethadone
- Malouetine
- ME-18-MC
- Mecamylamine
- Memantine
- Methadone
- Methorphan (racemethorphan)
- Methyllycaconitine
- Metocurine
- Mivacurium
- Morphanol (racemorphan)
- Neramexane
- Nitrous oxide
- Norketamine
- Pancuronium bromide
- Pempidine
- Pentamine
- Pentolinium
- Phencyclidine
- Pipecuronium bromide
- Progesterone
- Promegestone
- Radafaxine
- Rapacuronium bromide
- Reboxetine
- Rocuronium bromide
- Sevoflurane
- Stercuronium iodide
- Surugatoxin
- Thiocolchicoside
- Toxiferine
- Tramadol
- Trimetaphan camsilate (trimethaphan camsylate)
- Tropeinium
- Tubocurarine
- Vanoxerine
- Vecuronium bromide
- Xenon
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Transporter modulators
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| CHT |
- Inhibitors: Hemicholinium-3 (hemicholine)
- Triethylcholine
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| VAChT |
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Enzyme modulators
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| ChAT |
- Inhibitors: 1-(-Benzoylethyl)pyridinium
- 2-(α-Naphthoyl)ethyltrimethylammonium
- 3-Chloro-4-stillbazole
- 4-(1-Naphthylvinyl)pyridine
- Acetylseco hemicholinium-3
- Acryloylcholine
- AF64A
- B115
- BETA
- CM-54,903
- N,N-Dimethylaminoethylacrylate
- N,N-Dimethylaminoethylchloroacetate
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| AChE |
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| BChE |
- Inhibitors: Cymserine
- Many of the AChE inhibitors listed above
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Release modulators
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| Inhibitors |
- SNAP-25 inactivators: Botulinum toxin (A, C, E)
- VAMP inactivators: Botulinum toxin (B, D, F, G)
- Others: Bungarotoxins (β-bungarotoxin, γ-bungarotoxin)
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| Enhancers |
- LPHN agonists: α-Latrotoxin
- Others: Atracotoxin (e.g., robustoxin, versutoxin)
- Crotoxin
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Others
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Precursors /
prodrugs |
- Adafenoxate
- Choline (lecithin)
- Citicoline
- Cyprodenate
- Dimethylethanolamine
- Glycerophosphocholine
- Meclofenoxate (centrophenoxine)
- Phosphatidylcholine
- Phosphatidylethanolamine
- Phosphorylcholine
- Pirisudanol
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| Cofactors |
- Acetic acid
- Acetylcarnitine
- Acetyl-coA
- Vitamin B5
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See also: Receptor/signaling modulators
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Sigma receptor modulators
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| σR |
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See also: Receptor/signaling modulators
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