Donepezil

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Donepezil
Donepezil skeletal.svg
Clinical data
Trade names Aricept, Adlarity, others
Other namesDonepezil hydrochloride (USAN US)
AHFS/Drugs.com Monograph
MedlinePlus a697032
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth, transdermal
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 100% [5] [6]
Protein binding 96%, albumin (about 75%) and alpha1-acid glycoprotein (21%). [6] [5]
Metabolism CYP2D6, CYP3A4, and glucuronidation. [5] Four major metabolites, two of which are active. [6] [5]
Onset of action Peak plasma levels in 3–4 h. [6] [5]
Elimination half-life 70 hours [7] Around 100 hours in elderly patients. [5]
Duration of action With daily dosing, steady-state concentration is reached in 15–21 days. [6] [5]
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. [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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.125.198 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H29NO3
Molar mass 379.500 g·mol−1
3D model (JSmol)
Chirality Racemic 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 Yes check.svgY
  • Key:ADEBPBSSDYVVLD-UHFFFAOYSA-N Yes check.svgY
   (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]

Contents

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 is a centrally acting reversible acetylcholinesterase inhibitor and structurally unrelated to other anticholinesterase agents. [8] [5]

Donepezil was approved for medical use in the United States in 1996. [8] It is available as a 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

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 (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. [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 Structural Formula V1.svg
(R)-Donepezil		 (S)-Donepezil Structural Formula V1.svg
(S)-Donepezil

History

Donepezil inhibiting Torpedo californica acetylcholinesterase AChE inhibited by donepezil 1EVE.png
Donepezil inhibiting Torpedo californica acetylcholinesterase
10 mg Aricept pill Aricept 10mg 000195lg.jpg
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 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 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 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]

Related Research Articles

<span class="mw-page-title-main">Dementia</span> Long-term brain disorders causing impaired memory, thinking and behavior

Dementia is the general name for a decline in cognitive abilities that impacts a person's ability to perform everyday activities. This typically involves problems with memory, thinking, and behavior. Aside from memory impairment and a disruption in thought patterns, the most common symptoms include emotional problems, difficulties with language, and decreased motivation. The symptoms may be described as occurring in a continuum over several stages. Dementia ultimately has a significant effect on the individual, caregivers, and on social relationships in general. A diagnosis of dementia requires the observation of a change from a person's usual mental functioning and a greater cognitive decline than what is caused by normal aging.

Vascular dementia (VaD) is dementia caused by problems in the blood supply to the brain, resulting from a cerebrovascular disease. Restricted blood supply (ischemia) leads to cell and tissue death in the affected region, known as an infarct. The three types of vascular dementia are subcortical vascular dementia, multi-infarct dementia, and stroke related dementia. Subcortical vascular dementia is brought about by damage to the small blood vessels in the brain. Multi-infarct dementia is brought about by a series of mini-strokes where many regions have been affected. The third type is stroke related where more serious damage may result. Such damage leads to varying levels of cognitive decline. When caused by mini-strokes, the decline in cognition is gradual. When due to a stroke, the cognitive decline can be traced back to the event.

<span class="mw-page-title-main">Cholinergic</span> Agent which mimics choline

Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word "choline" describes the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin. Choline also prevents fat deposits in the liver and facilitates the movement of fats into cells.

<span class="mw-page-title-main">Physostigmine</span> Chemical compound

Physostigmine is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean and the fruit of the Manchineel tree.

<span class="mw-page-title-main">Tacrine</span> Chemical compound

Tacrine is a centrally acting acetylcholinesterase inhibitor and indirect cholinergic agonist (parasympathomimetic). It was the first centrally acting cholinesterase inhibitor approved for the treatment of Alzheimer's disease, and was marketed under the trade name Cognex. Tacrine was first synthesised by Adrien Albert at the University of Sydney in 1949. It also acts as a histamine N-methyltransferase inhibitor.

<span class="mw-page-title-main">Galantamine</span> Neurological medication

Galantamine is used for the treatment of cognitive decline in mild to moderate Alzheimer's disease and various other memory impairments. It is an alkaloid extracted from the bulbs and flowers of Galanthus nivalis, Galanthus caucasicus, Galanthus woronowii, and other members of the family Amaryllidaceae, such as Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata. It can also be produced synthetically.

<span class="mw-page-title-main">Memantine</span> Medication used to treat Alzheimers disease

Memantine is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth.

<span class="mw-page-title-main">Huperzine A</span> Chemical compound

Huperzine A is a naturally-occurring sesquiterpene alkaloid compound found in the firmoss Huperzia serrata and in varying quantities in other food Huperzia species, including H. elmeri, H. carinat, and H. aqualupian. Huperzine A has been investigated as a treatment for neurological conditions such as Alzheimer's disease, but a 2013 meta-analysis of those studies concluded that they were of poor methodological quality and the findings should be interpreted with caution. Huperzine A inhibits the breakdown of the neurotransmitter acetylcholine (ACh) by the enzyme acetylcholinesterase. It is commonly available over the counter as a nutritional supplement and marketed as a memory and concentration enhancer.

Mild cognitive impairment (MCI) is a neurocognitive disorder which involves cognitive impairments beyond those expected based on an individual's age and education but which are not significant enough to interfere with instrumental activities of daily living. MCI may occur as a transitional stage between normal aging and dementia, especially Alzheimer's disease. It includes both memory and non-memory impairments. The cause of the disorder remains unclear, as well as both its prevention and treatment, with some 50 percent of people diagnosed with it going on to develop Alzheimer's disease within five years. The diagnosis can also serve as an early indicator for other types of dementia, although MCI may remain stable or even remit.

<span class="mw-page-title-main">Alzheimer's disease</span> Progressive neurodegenerative disease

Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens, and is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation, mood swings, loss of motivation, self-neglect, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.

<span class="mw-page-title-main">Acetylcholinesterase inhibitor</span> Drugs that inhibit acetylcholinesterase

Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level and duration of action of acetylcholine in the central nervous system, autonomic ganglia and neuromuscular junctions, which are rich in acetylcholine receptors. Acetylcholinesterase inhibitors are one of two types of cholinesterase inhibitors; the other being butyryl-cholinesterase inhibitors. Acetylcholinesterase is the primary member of the cholinesterase enzyme family.

<span class="mw-page-title-main">Cholinesterase inhibitor</span> Chemicals which prevent breakdown of acetylcholine and butyrylcholine

Cholinesterase inhibitors (ChEIs), also known as anti-cholinesterase, are chemicals that prevent the breakdown of the neurotransmitter acetylcholine or butyrylcholine. This increases the amount of the acetylcholine or butyrylcholine in the synaptic cleft that can bind to muscarinic receptors, nicotinic receptors and others. This group of inhibitors is divided into two subgroups, acetylcholinesterase inhibitors (AChEIs) and butyrylcholinesterase inhibitors (BChEIs).

<span class="mw-page-title-main">Rivastigmine</span> Chemical compound

Rivastigmine is a cholinesterase inhibitor used for the treatment of mild to moderate Alzheimer's disease. The drug can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects, which typically include nausea and vomiting.

Methanesulfonyl fluoride (MSF) has long been known to be a potent inhibitor of acetylcholinesterase (AChE), the enzyme that regulates acetylcholine, an important neurotransmitter in both the central and peripheral nervous systems.

Aducanumab, sold under the brand name Aduhelm, is a medication designed to treat Alzheimer's disease (AD). It is a monoclonal antibody that targets aggregated forms (plaque) of amyloid beta (Aβ) found in the brains of people with Alzheimer's disease to reduce its buildup. It was developed by Biogen and Eisai. Aducanumab is given via intravenous infusion.

Hachiro Sugimoto is a Japanese chemist and pharmacologist, known for his discovery of Donepezil.

Lecanemab, sold under the brand name Leqembi, is a monoclonal antibody medication used for the treatment of Alzheimer's disease. Lecanemab is an amyloid beta-directed antibody. It is given via intravenous infusion. The most common side effects of lecanemab include headache, infusion-related reactions, and amyloid-related imaging abnormalities, a side effect known to occur with the class of antibodies targeting amyloid.

<span class="mw-page-title-main">Phenserine</span> Chemical compound

Phenserine is a synthetic drug which has been investigated as a medication to treat Alzheimer's disease (AD), as the drug exhibits neuroprotective and neurotrophic effects.

<span class="mw-page-title-main">Neuromuscular drug</span>

Neuromuscular drugs are chemical agents that are used to alter the transmission of nerve impulses to muscles, causing effects such as temporary paralysis of targeted skeletal muscles. Most neuromuscular drugs are available as quaternary ammonium compounds which are derived from acetylcholine (ACh). This allows neuromuscular drugs to act on multiple sites at neuromuscular junctions, mainly as antagonists or agonists of post-junctional nicotinic receptors. Neuromuscular drugs are classified into four main groups, depolarizing neuromuscular blockers, non-depolarizing neuromuscular blockers, acetylcholinesterase inhibitors, and butyrylcholinesterase inhibitors.

Memantine/donepezil, sold under the brand name Namzaric, is a fixed dose combination medication used for the treatment of dementia of the Alzheimer's type. It contains memantine, as the hydrochloride, a NMDA receptor antagonist; and donepezil as the hydrochloride, an acetylcholinesterase inhibitor. It is taken by mouth.

References

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  2. ↑ "Donepezil Hydrochloride 10 mg Film-coated tablets". Electronic Medicines Compendium. Archived from the original on 8 September 2022. Retrieved 8 September 2022.
  3. 1 2 3 4 5 6 7 8 "Aricept- donepezil hydrochloride tablet, film coated Aricept ODT- donepezil hydrochloride tablet, orally disintegrating". DailyMed. 23 December 2021. Retrieved 15 March 2022.
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  7. ↑ 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].
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