Donepezil

Structural formula
Structural formula of the racemate (* stereocenter)
General
Non-proprietary name	Donepezil
other names	( RS ) -1-Benzyl-4 - [(5,6-dimethoxyindan-1-on-2-yl) methyl] piperidine DL -1-Benzyl-4 - [(5,6-dimethoxyindan-1-on-2-yl) methyl] piperidine (±) -E-2020
Molecular formula	C 24 H 29 NO 3
External identifiers / databases
CAS number 120014-06-4 120011-70-3 ( hydrochloride ) EC number 601-651-9 ECHA InfoCard 100.125.198 PubChem 3152 ChemSpider 3040 DrugBank DB00843 Wikidata Q415081
Drug information
ATC code	N06 DA02
Drug class	Antidementia drugs
Mechanism of action	reversible inhibition of acetylcholinesterase
properties
Molar mass	379.49 g · mol -1
Physical state	firmly
Melting point	211–212 ° C ( hydrochloride )
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS hazard labeling no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Donepezil is a medicine used in the treatment of certain forms of mild to moderate forgetfulness ( dementia ). It intervenes in the nervous conduction of excitation in the brain and is supposed to improve memory and thinking.

Clinical information

Application areas (indications)

Donepezil is approved for the symptomatic treatment of mild to moderate dementia of the Alzheimer's type . It can relieve the symptoms of dementia and stop the symptoms from progressing for some time. The effect has been shown to be statistically significant in scientific clinical studies using various measurement methods , but it is very low. In the case of severe Alzheimer's dementia, it is considered to be the second choice in the form of so-called off-label use outside of the drug approval . Donepezil is also occasionally used in vascular dementia without a drug approval and is considered the first choice for this. Its effectiveness in treating mild cognitive impairments , often harbingers or first signs of dementia, is considered minimal and poorly documented. There is evidence that donepezil is effective in Alzheimer's dementia in the severe stage of the disease on cognition, everyday functions and overall clinical impression, and of galantamine on cognition. Further treatment of previously treated patients who enter the severe stage or initial treatment of patients in the severe stage may be recommended. (Recommendation grade B, evidence level Ib, guideline adaptation SIGN 2006). There is evidence of the effectiveness of donepezil on cognition and overall clinical impression in Parkinson's disease dementia. (Recommendation grade B, evidence level Ia, guideline adaptation MOH 2007).

Contraindications (contraindications)

Donepezil is at a known hypersensitivity to the active substance or other piperidine - derivatives such as domperidone , contraindicated . In patients with peptic ulcers, cardiac arrhythmias ( sick sinus syndrome , supraventricular conduction abnormalities), syncope , seizures, obstructive pulmonary diseases (eg. As bronchial asthma , chronic obstructive pulmonary disease ), bladder obstruction or regular use of nonsteroidal anti-inflammatory drugs such as aspirin or naproxen , are subject to special Precautions and the use of donepezil are subject to a risk-benefit assessment.

Monitoring

Since donepezil may be ineffective for the individual and should be discontinued after 15 to 20 weeks in this case, the possible improvement in cognitive performance must be monitored. Patients should also be monitored for possible gastrointestinal complaints (which may indicate gastric ulcers or gastrointestinal bleeding ) and for their ECG (which may indicate newly developed cardiac arrhythmias ). Therefore, a comparative ECG should be taken before starting therapy.

Interactions

Due to its effect on acetylcholine metabolism, donepezil may show pharmacodynamic interactions with other drugs with effects on the acetylcholine system. These include in particular muscle relaxants such as succinylcholine , anticholinergics and acetylcholine agonists. Pharmacodynamic interactions with beta blockers are also possible.

Since donepezil is metabolized via the cytochrome P450 enzyme system , there is, at least in theory, the possibility of an interaction with substances that can inhibit or induce this enzyme system. Experimentally, CYP3A4 inhibitors such as ketoconazole and erythromycin , and CYP2D6 inhibitors such as fluoxetine , can inhibit the breakdown of donepezil and thus lead to an increase in the blood plasma level of the active ingredient. On the other hand, enzyme inducers such as rifampicin , phenytoin , carbamazepine and alcohol can accelerate the breakdown of donepezil and thus lower its plasma level. However, the extent of these interactions and their clinical relevance has not been sufficiently investigated.

Side effects

The more common undesirable effects seen with donepezil use include diarrhea, nausea and headache (frequency> 10%). Infections, loss of appetite, hallucinations , agitation, anxiety , syncope , dizziness , insomnia, fatigue, pain, injuries, gastrointestinal complaints, including vomiting, rash, itching, muscle cramps and urinary incontinence were also common (1 to 10%) .

Occasionally there has also been a neuroleptic malignant syndrome (MNS), a potentially life-threatening psychiatric complication, which is why the BfArM is planning to include a corresponding warning in the product information even if the data are still insufficient.

pharmacology

Pharmacodynamics (mechanism of action)

Donepezil belongs to the group of reversible cholinesterase inhibitors . It mediates its effect via the reversible blockade of the active center of the enzyme acetylcholinesterase . By inhibiting this enzyme, Donepezil slows the hydrolytic breakdown of the neurotransmitter acetylcholine into acetate and choline. This increases the acetylcholine concentration in the synaptic gap and acetylcholine receptors can be activated earlier. Medicines with a similar mode of action include: a. Galantamine , rivastigmine and tacrine . The insecticide parathion (E605) also acts on acetylcholinesterase, but it irreversibly inhibits it.

Donepezil has a particularly strong binding affinity for the isoforms of acetylcholinesterase, which occur in the CNS, which reduces the side effects and is said to make the drug more tolerable than other cholinesterase inhibitors.

chemistry

Stereochemistry

Donepezil is a chiral drug with a stereocenter . The racemate , ie the 1: 1 mixture of ( S ) and ( R ) isomers, is used therapeutically , although it is known that the enantiomers have different effects on acetylcholinesterase in vivo and in vitro . Therefore, several analytical methods for the enantioselective analysis of the ( S ) and the ( R ) isomers of donepezil have been developed.

Isomers of donepezil
( R ) isomer	( S ) isomer

Commercial preparations

Aricept (D, A, CH and other countries), Yasnal (D), Memac (IT)

literature

• JS Birks, RJ Harvey: Donepezil for dementia due to Alzheimer's disease. In: The Cochrane database of systematic reviews. Volume 6, 06 2018, S. CD001190, doi : 10.1002 / 14651858.CD001190.pub3 , PMID 29923184 (Review).

Individual evidence

1. ↑ Entry on donepezil. In: Römpp Online . Georg Thieme Verlag, accessed on June 1, 2014.
2. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
3. ↑ ^{a b c d e} Technical information Aricept 5 mg / 10 mg. Eisai GmbH. As of September 2008.
4. ↑ Birks J, Harvey RJ: Donepezil for dementia due to Alzheimer's disease . In: Cochrane Database Syst Rev . No. 1, 2006, p. CD001190. doi : 10.1002 / 14651858.CD001190.pub2 . PMID 16437430 .
5. ^ ^{A b} Jellinger KA: Consensus statement "Dementia" of the Austrian Alzheimer Society and the Austrian Alzheimer League . In: Journal of Neurology, Neurosurgery and Psychiatry . 5, No. 3, 2004, pp. 6-13.
6. ↑ Birks J, Flicker L: Donepezil for mild cognitive impairment . In: Cochrane Database Syst Rev . 3, 2006, p. CD006104. doi : 10.1002 / 14651858.CD006104 . PMID 16856114 .
7. ↑ ^{a b} Guideline Dementia .
8. ↑ Barner EL, Gray SL: Donepezil use in Alzheimer's disease . In: Ann Pharmacother . 32, No. 1, January 1998, pp. 70-77. PMID 9475825 .
9. ↑ Announcement of the BfArM: Donepezil and Neuroleptic Malignant Syndrome (MNS) , January 30, 2013 (PDF).
10. ↑ EMA: PhVWP monthly report on safety concerns, guidelines and general matters (PDF; 295 kB).
11. ↑ Sugimoto H, Iimura Y, Yamanishi Y, Yamatsu K: Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4 - [(5,6-dimethoxy-1-oxoindan-2-yl) methyl] piperidine hydrochloride and related compounds . In: J. Med. Chem. . 38, No. 24, November 1995, pp. 4821-4829. PMID 7490731 .
12. ↑ Pang YP, Kozikowski AP: Prediction of the binding site of 1-benzyl-4 - [(5,6-dimethoxy-1-indanon-2-yl) methyl] piperidine in acetylcholinesterase by docking studies with the SYSDOC program . In: J. Comput. Aided Mol. Des. . 8, No. 6, December 1994, pp. 683-693. PMID 7738604 .
13. ↑ K. Matsui, Y. Oda, H. Nakata, T. Yoshimura: Simultaneous determination of donepezil (aricept) enantiomers in human plasma by liquid chromatography-electrospray tandem mass spectrometry. In: Journal of chromatography. B, Biomedical Sciences and Applications. Volume 729, Numbers 1-2, June 1999, pp. 147-155, PMID 10410937 .
14. ↑ Mahasen A. Radwan, Heba H. Abdine, Bushra T. Al-Quadeb, Hassan Y. Aboul-Enein, Kenichiro Nakashima: Stereoselective HPLC assay of donepezil enantiomers with UV detection and its application to pharmacokinetics in rats , J. Chromatogr. B 830 (2006) 114-119. doi : 10.1016 / j.jchromb.2005.10.031 .

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