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a medicine that inhibits cholinesterase by combining with it and so has a cholinergic effect

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/01/18 02:01:45」(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]

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]
Ecothiopate (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

Huperzine A
Galantamine
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.
^ 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.
^ 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.
^ 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. 眼筋型重症筋無力症 ocular myasthenia gravis
2. 小児および思春期における注意欠陥多動性障害治療薬の薬理学 pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents
3. 新生児および幼児における神経筋接合部障害 neuromuscular junction disorders in newborns and infants
4. 小児における外眼筋に影響するミオパチー myopathies affecting the extraocular muscles in children

English Journal

Characterization of plasma cholinesterase from the White stork (Ciconia ciconia) and its in vitro inhibition by anticholinesterase pesticides.

Oropesa AL, Gravato C, Sánchez S, Soler F.SourceToxicology Area, School of Veterinary, University of Extremadura, Avda. de la Universidad, s/n, 10003 Cáceres, Spain. Electronic address: aoropesa@unex.es.
Ecotoxicology and environmental safety.Ecotoxicol Environ Saf.2013 Nov;97:131-8. doi: 10.1016/j.ecoenv.2013.07.022. Epub 2013 Aug 17.
Blood plasma cholinesterase (ChE) activity is a sensitive biomarker of exposure to organophosphorus (OP) and carbamate (CB) insecticides in vertebrates. Several studies indicate that more than one ChE form may be present in blood of birds. In this study the predominant ChE activity (acetylcholineste
PMID 23962622

Enzyme inhibitory and antioxidant activities of Viburnum tinus L. relevant to its neuroprotective potential.

Yılmaz BS, Altun ML, Orhan IE, Ergene B, Citoglu GS.SourceDepartment of Pharmacognosy, Faculty of Pharmacy, Ankara University, 06100 Ankara, Turkey.
Food chemistry.Food Chem.2013 Nov 1;141(1):582-8. doi: 10.1016/j.foodchem.2013.03.020. Epub 2013 Mar 13.
In vitro neuroprotective activity of the extracts of Viburnum tinus L. was investigated via inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and tyrosinase (TYRO) by microtitre plate assays. Their antioxidant activity was tested using 2,2-diphenyl-1-picrylhydrazyl (DPPH),
PMID 23768397

A potential target for organophosphate insecticides leading to spermatotoxicity.

Suzuki H, Tomizawa M, Ito Y, Abe K, Noro Y, Kamijima M.SourceDepartment of Occupational and Environmental Health, Graduate School of Medical Sciences, Nagoya City University , Nagoya 467-8601, Japan.
Journal of agricultural and food chemistry.J Agric Food Chem.2013 Oct 16;61(41):9961-5. doi: 10.1021/jf4033365. Epub 2013 Oct 1.
Organophosphate (OP) insecticides as an anticholinesterase also act on the diverse serine hydrolase targets, thereby revealing secondary or unexpected toxic effects including male reproductive toxicity. The present investigation detects a possible target molecule(s) for OP-induced spermatotoxicity (
PMID 24044584

Japanese Journal

Anticholinesterase and β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitory Compounds from the Heartwood of Juniperus chinensis

Chemical and Pharmaceutical Bulletin 63(11), 955-960, 2015
NAID 130005105730

手術終了時の筋弛緩薬拮抗：ネオスチグミンで完全回復できるか？

日本臨床麻酔学会誌 35(2), 257-265, 2015
NAID 130005087404

Microwave-Assisted Synthesis, Molecular Docking, and Cholinesterase Inhibitory Activities of New Ethanediamide and 2-Butenediamide Analogues

Chemical and Pharmaceutical Bulletin 63(3), 210-217, 2015
NAID 130004803778

Related Pictures

MYASTHENIA GRAVIS (quick pearls) | DAILYEM Google Images Anticholinesterase Acetylcholinesterase Inhibitors: Examples & Mechanism | Study.com Cholinergic and Anticholinesterase drugs アセチルコリンエステラーゼ阻害剤とは - goo Wikipedia Cholinesterase Inhibitors in Early Alzheimer’s Disease

★リンクテーブル★

リンク元	「コリンエステラーゼ阻害薬」「cholinesterase inhibitor」「抗コリンエステラーゼ薬」「抗コリンエステラーゼ」
拡張検索	「anticholinesterase agent」

「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

コリンエステラーゼ阻害薬=

アルツハイマー病の治療薬

作用機序

図：GOO.203

活性部位に結合

エドロフォニウムやドネペジルは活性化部位に結合して、酵素の機能を可逆的に失わせる (GOO.204)

エドロフォニウムは四級アミンなので腎臓より速やかに排泄され、持続時間が短い。

酵素ををカルバモイル化

フィゾスチグミンやネオスチグミンは活性化部位に位置するセリン残基のヒドロキシ基にカルバモイル基(NH₂CO-)を転移することで、機能を可逆的に失わせる (GOO.204)

酵素をリン酸化

有機リン化合物系

薬理作用

動態

適応

臨床応用

種類	疾患への適応
ムスカリン作動薬	緑内障、手術後の腸管麻痺、尿閉
コリンエステラーゼ阻害薬	緑内障、手術後の腸管麻痺、尿閉、重症筋無力症の診断・治療、アルツハイマー病
ムスカリン受容体遮断薬	鎮痙薬（消化管、胆管、尿路など）、胃・十二指腸潰瘍、散瞳薬、パーキンソン病、麻酔前投与