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
Drug class Acetylcholinesterase inhibitor
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

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

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] However, no trial to date supports this hypothesis.

Related Research Articles

<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">Galantamine</span> Neurological medication

Galantamine is a type of acetylcholinesterase inhibitor. 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, sold under the brand name Namenda among others, 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">Eisai (company)</span> Japanese pharmaceutical company

Eisai Co., Ltd. is a Japanese pharmaceutical company headquartered in Tokyo, Japan. It has some 10,000 employees, among them about 1,500 in research. Eisai is listed on the Tokyo Stock Exchange and is a member of the Topix 100 and Nikkei 225 stock indices.

<span class="mw-page-title-main">Milnacipran</span> Antidepressant

Milnacipran is a serotonin–norepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of fibromyalgia. It is not approved for the clinical treatment of major depressive disorder in the US, but it is in other countries.

<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 also an antagonist of the NMDA-receptor. 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 dementia due to Alzheimer's disease. It includes both memory and non-memory impairments. About 50 percent of people diagnosed with MCI have Alzheimer's disease and go on to develop Alzheimer's dementia within five years. MCI can also serve as an early indicator for other types of dementia, although MCI may remain stable or even remit.

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<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

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Memantine/donepezil, sold under the brand name Namzaric among others, 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.
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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].{{cite book}}: |journal= ignored (help)
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