WordNet

a substance that retards or stops an activity
an enzyme that hydrolyses acetylcholine (into choline and acetic acid)

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抑制する人(物) / 化学反応抑制剤

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/09/14 20:28:23」(JST)

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Acetylcholine

Acetylcholinesterase

Acetylcholinesterase inhibition

An acetylcholinesterase inhibitor (often abbreviated AChEI) or anti-cholinesterase is a chemical or a drug that inhibits the acetylcholinesterase enzyme from breaking down acetylcholine, thereby increasing both the level and duration of action of the neurotransmitter acetylcholine. Acetylcholinesterase inhibitors are classified as reversible, irreversible, or quasi-irreversible (also called pseudo-irreversible).^[1]

Uses

Acetylcholinesterase inhibitors:^[2]

Occur naturally as venoms and poisons
Are used as weapons in the form of nerve agents
Are used as insecticides
Are used medicinally:
- To treat myasthenia gravis. In myasthenia gravis, they are used to increase neuromuscular transmission.
- To treat glaucoma
- To treat postural tachycardia syndrome
- As an antidote to anticholinergic poisoning
- To reverse the effect of non-depolarising muscle relaxants
- To treat neuropsychiatric symptoms of diseases such as Alzheimer's disease, particularly apathy
- To increase chances of lucid dreaming (by prolonging REM sleep)^[3]
- To treat Alzheimer's disease, Lewy Body Dementia and Parkinson's disease. In these neurodegenerative conditions AChEIs are primarily used to treat the cognitive (memory and learning deficits mostly) symptoms of dementia. These symptoms are attenuated due to the role of acetylcholine in cognition in the CNS. There is some evidence to suggest that AChEIs may attenuate psychotic symptoms (especially visual hallucinations) in Parkinson's disease.^[4]
- To treat cognitive impairments in patients with schizophrenia. There is some evidence to suggest efficacy in treating positive, negative and affective symptoms.^[5]^[6]^[7]
- As a treatment for autism and to increase the percentage of Rapid eye movement sleep in autistic children, in line with the mechanism by which they encourage lucid dreaming.^[8]^[9]

Side effects

Potential side effects of acetylcholinesterase inhibitors^[10]^[11]
mild – usually goes away	potentially serious
Diarrhea Headache Insomnia Nausea Vomiting	Abdominal pain Lack of appetite Yellowed skin Dizziness Slow heartbeat Sudden or substantial weight loss Weakness

Some major effects of cholinesterase inhibitors:

Actions on the parasympathetic nervous system, (the parasympathetic branch of the autonomic nervous system) may cause bradycardia, hypotension, hypersecretion, bronchoconstriction, GI tract hypermotility, and decrease intraocular pressure.
SLUDGE syndrome.
Actions on the neuromuscular junction will result in prolonged muscle contraction.

Administration of reversible cholinoesterase inhibitors is contraindicated with those that have urinary retention due to obstruction.

Titration phase

When used in the central nervous system to alleviate neurological symptoms, such as rivastigmine in Alzheimer's disease, all cholinesterase inhibitors require doses to be increased gradually over several weeks, and this is usually referred to as the titration phase. Many other types drug treatments may require a titration or stepping up phase. This strategy is used to build tolerance to adverse events or to reach a desired clinical effect.^[12] This also prevents accidental overdose and is therefore recommended when initiating treatment with drugs that are extremely potent and/or toxic (drugs with a low therapeutic index).

Examples

Reversible inhibitor

Compounds which function as reversible competitive or noncompetitive inhibitors of cholinesterase are those most likely to have therapeutic uses. These include:

Some organophosphates not listed under "Irreversible" below
Carbamates
- Physostigmine
- Neostigmine
- Pyridostigmine
- Ambenonium
- Demecarium
- Rivastigmine
Phenanthrene derivatives
- Galantamine
Caffeine – noncompetitive (also an Adenosine receptor antagonist)^[13]^[14]
Rosmarinic acid - ester of Caffeic acid. Found in plants species of Lamiaceae family.^[15]
Alpha-Pinene - noncompetitive reversible ^[16]^[17]
Piperidines
- Donepezil
Tacrine, also known as tetrahydroaminoacridine (THA')
Edrophonium
Huperzine A^[18]^[19]
Ladostigil
Ungeremine^[20]
Lactucopicrin

Comparison table

Comparison of reversible acetylcholinesterase inhibitors
Inhibitor	Duration	Main site of action	Clinical use	Adverse effects
Edrophonium	short (10 min.)^[21]	neuromuscular junction^[21]	diagnosis of myasthenia gravis^[21]
Neostigmine	medium (1–2 hrs.)^[21]	neuromuscular junction^[21]	Reverse neuromuscular block (intravenously)^[21] Treat myasthenia gravis (orally)^[21]	visceral^[21]
Physostigmine	medium (0.5-5 hrs.)^[21]	postganglionic parasympathetic^[21]	treat glaucoma (eye drops)^[21]
Pyridostigmine	medium (2–3 hrs.)^[21]	neuromuscular junction^[21]	Treat myasthenia gravis (orally)^[21]
Dyflos	long^[21]	postganglionic parasympathetic^[21]	historically to treat glaucoma (eye drops)^[21]	toxic^[21]
Echothiophate (irreversible)	long^[21]	postganglionic parasympathetic^[21]	treat glaucoma (eye drops)^[21]	systemic effects^[21]
Parathion (irreversible)	long^[21]	none^[21]	toxic^[21]

Quasi-irreversible inhibitor

Compounds which function as quasi-irreversible inhibitors of cholinesterase are those most likely to have use as chemical weapons or pesticides. These include:

Organophosphates
- Echothiophate
- Diisopropyl fluorophosphate
- Cadusafos
- Chlorpyrifos
- Cyclosarin
- Dichlorvos
- Dimethoate
- Metrifonate (irreversible)
- Sarin
- Soman
- Tabun
- VX
- VE
- VG
- VM
- Diazinon
- Malathion
- Parathion

Carbamates
- Aldicarb
- Bendiocarb
- Bufencarb
- Carbaryl
- Carbendazim
- Carbetamide
- Carbofuran
- Carbosulfan
- Chlorbufam
- Chloropropham
- Ethiofencarb
- Formetanate
- Methiocarb
- Methomyl
- Oxamyl
- Phenmedipham
- Pinmicarb
- Pirimicarb
- Propamocarb
- Propham
- Propoxur

Onchidal
Coumarins

References

^ Pohanka, M (2012). "Acetylcholinesterase inhibitors; a patent review (2008–present)". Expert Opinion on Therapeutic Patents. 22 (8): 871–886. doi:10.1517/13543776.2012.701620. PMID 22768972.
^ Colovic, MB; Krstic, Danijela Z.; Lazarevic-Pasti, Tamara D.; Bondzic, Aleksandra M.; Vasic, Vesna M. (2013). "Acetylcholinesterase Inhibitors: Pharmacology and Toxicology". Current Neuropharmacology. 11 (3): 315–335. doi:10.2174/1570159X11311030006. PMC 3648782. PMID 24179466.
^ Yuschak, Thomas (2006). Advanced Lucid Dreaming: The Power of Supplements. Lulu. ISBN 1430305428.
^ Taylor, D; Paton, C; Shitij, K (2012). Maudsley Prescribing Guidelines in Psychiatry (11th ed.). West Sussex: Wiley-Blackwell. ISBN 978-0-47-097948-8.
^ Singh, J; Kour, K; Jayaram, MB (January 2012). "Acetylcholinesterase inhibitors for schizophrenia". The Cochrane Database of Systematic Reviews. 1: CD007967. doi:10.1002/14651858.CD007967.pub2. PMID 22258978. Lay summary.
^ Choi, KH; Wykes, T; Kurtz, MM (September 2013). "Adjunctive pharmacotherapy for cognitive deficits in schizophrenia: meta-analytical investigation of efficacy". The British Journal of Psychiatry. 203 (3): 172–178. doi:10.1192/bjp.bp.111.107359. PMID 23999481.
^ Ribeiz, SR; Bassitt, DP; Arrais, JA; Avila, R; Steffens, DC; Bottino, CM (April 2010). "Cholinesterase Inhibitors as Adjunctive Therapy in Patients with Schizophrenia and Schizoaffective Disorder A Review and Meta-Analysis of the Literature". CNS Drugs. 24 (4): 303–317. doi:10.2165/11530260-000000000-00000. PMID 20297855.
^ Buckley, A. W.; Sassower, K.; Rodriguez, A. J.; Jennison, K.; Wingert, K.; Buckley, J.; Thurm, A.; Sato, S.; Swedo, S. (2011). "An Open Label Trial of Donepezil for Enhancement of Rapid Eye Movement Sleep in Young Children with Autism Spectrum Disorders". Journal of Child and Adolescent Psychopharmacology. 21 (4): 353–357. doi:10.1089/cap.2010.0121. PMC 3157749. PMID 21851192.
^ Handen, B. L.; Johnson, C. R.; McAuliffe-Bellin, S.; Murray, P. J.; Hardan, A. Y. (2011). "Safety and Efficacy of Donepezil in Children and Adolescents with Autism: Neuropsychological Measures". Journal of Child and Adolescent Psychopharmacology. 21 (1): 43–50. doi:10.1089/cap.2010.0024. PMC 3037196. PMID 21309696.
^ Consumer Reports; Drug Effectiveness Review Project (May 2012). "Evaluating Prescription Drugs Used to Treat: Alzheimer's Disease Comparing Effectiveness, Safety, and Price" (PDF). Best Buy Drugs. Consumer Reports: 2. Retrieved 1 May 2013. , which claims Alzheimer's Association guidance as a source
^ Inglis, F. (2002). "The tolerability and safety of cholinesterase inhibitors in the treatment of dementia". International journal of clinical practice. Supplement (127): 45–63. PMID 12139367.
^ Inglis, F (2002). "The tolerability and safety of cholinesterase inhibitors in the treatment of dementia". International journal of clinical practice. Supplement (127): 45–63. PMID 12139367.
^ Karadsheh, N; Kussie, P; Linthicum, DS (1991). "Inhibition of acetylcholinesterase by caffeine, anabasine, methyl pyrrolidine and their derivatives". Toxicology letters. 55 (3): 335–42. doi:10.1016/0378-4274(91)90015-X. PMID 2003276.
^ Pohanka, M (2014). "The effects of caffeine on the cholinergic system.". Mini Reviews in Medicinal Chemistry. 14 (6): 543–549. doi:10.2174/1389557514666140529223436. PMID 24873820.
^ Vladimir-Knežević, Sanda; Blažeković, Biljana; Kindl, Marija; Vladić, Jelena; Lower-Nedza, Agnieszka D.; Brantner, Adelheid H. (2014-01-09). "Acetylcholinesterase Inhibitory, Antioxidant and Phytochemical Properties of Selected Medicinal Plants of the Lamiaceae Family". Molecules. 19 (1): 767–782. doi:10.3390/molecules19010767.
^ Miyazawa, Mitsuo; Yamafuji, Chikako (2005-03-09). "Inhibition of acetylcholinesterase activity by bicyclic monoterpenoids". Journal of Agricultural and Food Chemistry. 53 (5): 1765–1768. doi:10.1021/jf040019b. ISSN 0021-8561. PMID 15740071.
^ Perry, Nicolette S. L.; Houghton, Peter J.; Theobald, Anthony; Jenner, Peter; Perry, Elaine K. (2000-07-01). "In-vitro Inhibition of Human Erythrocyte Acetylcholinesterase by Salvia lavandulaefolia Essential Oil and Constituent Terpenes". Journal of Pharmacy and Pharmacology. 52 (7): 895–902. doi:10.1211/0022357001774598. ISSN 2042-7158. PMID 10933142.
^ Bauer, Brent A. Alzheimer's disease. mayoclinic.com
^ Wang, BS; Wang, H; Wei, ZH; Song, YY; Zhang, L; Chen, HZ (2009). "Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis". Journal of neural transmission (Vienna, Austria : 1996). 116 (4): 457–65. doi:10.1007/s00702-009-0189-x. PMID 19221692.
^ Rhee IK, I; Appels N; Hofte B; Karabatak B; Erkelens C; Stark LM; Flippin LA; Verpoorte R (November 2004). "Isolation of the Acetylcholinesterase Inhibitor Ungeremine from Nerine bowdenii by Preparative HPLC Coupled On-Line to a Flow Assay System". Biological & Pharmaceutical Bulletin. 27 (11): 1804–1809. doi:10.1248/bpb.27.1804. PMID 15516727.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x ^y Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 156

External links

Acetylcholinesterase inhibitors at the US National Library of Medicine Medical Subject Headings (MeSH)
Acetylcholinesterase: A gorge-ous enzyme QUite Interesting PDB Structure article at PDBe

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 認知症治療におけるコリンエステラーゼ阻害剤 cholinesterase inhibitors in the treatment of dementia
2. 認知症の治療 treatment of dementia
3. 有機リン剤およびカルバメート中毒 organophosphate and carbamate poisoning
4. レビー小体型認知症の予後および治療 prognosis and treatment of dementia with lewy bodies
5. 脳血管性認知症の治療および予防 treatment and prevention of vascular dementia

English Journal

Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer's disease.

Chen Y1,2,3, Zhu J4, Mo J4, Yang H4, Jiang X5, Lin H4, Gu K4, Pei Y1, Wu L1, Tan R5, Hou J3, Chen J6, Lv Y1, Bian Y6, Sun H4.
Journal of enzyme inhibition and medicinal chemistry.J Enzyme Inhib Med Chem.2018 Dec;33(1):290-302. doi: 10.1080/14756366.2017.1412314.
PMID 29278947

Structure-activity relationship investigation of benzamide and picolinamide derivatives containing dimethylamine side chain as acetylcholinesterase inhibitors.

Gao XH1, Liu LB2, Liu HR2, Tang JJ2, Kang L2, Wu H3, Cui P3, Yan J3.
Journal of enzyme inhibition and medicinal chemistry.J Enzyme Inhib Med Chem.2018 Dec;33(1):110-114. doi: 10.1080/14756366.2017.1399885.
PMID 29166796

Design, synthesis, and pharmacological evaluation of 2-amino-5-nitrothiazole derived semicarbazones as dual inhibitors of monoamine oxidase and cholinesterase: effect of the size of aryl binding site.

Tripathi RKP1, M Sasi V1, Gupta SK2, Krishnamurthy S2, Ayyannan SR1.
Journal of enzyme inhibition and medicinal chemistry.J Enzyme Inhib Med Chem.2018 Dec;33(1):37-57. doi: 10.1080/14756366.2017.1389920.
PMID 29098902

Japanese Journal

本邦に於ける治療介入を伴う臨床研究を実施する上での問題点：DASH–PD研究の経験から

神経治療学 34(4), 445-449, 2018
NAID 130006386686

Synthesis of Amide and Ester Derivatives of Cinnamic Acid and Its Analogs: Evaluation of Their Free Radical Scavenging and Monoamine Oxidase and Cholinesterase Inhibitory Activities

Chemical and Pharmaceutical Bulletin 65(11), 1020-1027, 2017-11-01
NAID 120006382837

認知症の初期における薬物療法・非薬物療法 (特集初期・認知症への精神科医療の関わり)

日本精神科病院協会雑誌 = Journal of Japanese Association of Psychiatric Hospitals 36(5), 463-468, 2017-05
NAID 40021223662

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★リンクテーブル★

リンク元	「コリンエステラーゼ阻害薬」
拡張検索	「acetylcholinesterase inhibitors」
関連記事	「inhibitor」「cholinesterase」「cholinesterases」

「コリンエステラーゼ阻害薬」

　　[★]

英: cholinesterase inhibitor cholinesterase inhibitors
同: 抗コリンエステラーゼ薬 anticholinesterase
関: アセチルコリン、アセチルコリン受容体、副交感神経