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a substance that retards or stops an activity

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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）』「2015/06/12 22:08:59」(JST)

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Acetylcholine

Acetylcholinesterase

Acetylcholinesterase inhibition

An acetylcholinesterase inhibitor (often abbreviated AChEI) or anti-cholinesterase is a chemical 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]
Piperidines
- Donepezil
Tacrine, also known as tetrahydroaminoacridine (THA')
Edrophonium
Huperzine A^[15]^[16]
Ladostigil
Ungeremine^[17]
Lactucopicrin

Comparison table

Comparison of reversible acetylcholinesterase inhibitors
Inhibitor	Duration	Main site of action	Clinical use	Adverse effects
Edrophonium	short (10 min.)^[18]	neuromuscular junction^[18]	diagnosis of myasthenia gravis^[18]
Neostigmine	medium (1–2 hrs.)^[18]	neuromuscular junction^[18]	Reverse neuromuscular block (intravenously)^[18] Treat myasthenia gravis (orally)^[18]	visceral^[18]
Physostigmine	medium (0.5-5 hrs.)^[18]	postganglionic parasympathetic^[18]	treat glaucoma (eye drops)^[18]
Pyridostigmine	medium (2–3 hrs.)^[18]	neuromuscular junction^[18]	Treat myasthenia gravis (orally)^[18]
Dyflos	long^[18]	postganglionic parasympathetic^[18]	historically to treat glaucoma (eye drops)^[18]	toxic^[18]
Ecothiopate (irreversible)	long^[18]	postganglionic parasympathetic^[18]	treat glaucoma (eye drops)^[18]	systemic effects^[18]
Parathion (irreversible)	long^[18]	none^[18]	toxic^[18]

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. edit
^ 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. edit
^ 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. edit
^ 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.
^ 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

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1. 脳血管性認知症の治療および予防 treatment and prevention of vascular dementia
2. 軽度認知機能障害：予後および治療 mild cognitive impairment prognosis and treatment
3. 麻酔後回復室（PACU）における心血管の障害 cardiovascular problems in the post anesthesia care unit pacu
4. 重症筋無力症の治療 treatment of myasthenia gravis
5. 抗コリン剤中毒 anticholinergic poisoning

English Journal

Pathology supported genetic testing and treatment of cardiovascular disease in middle age for prevention of Alzheimer's disease.

Kotze MJ, van Rensburg SJ.SourceDivision of Anatomical Pathology, Faculty of Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg, 7505, South Africa, maritha@sun.ac.za.
Metabolic brain disease.Metab Brain Dis.2012 Sep;27(3):255-66. Epub 2012 Apr 19.
Chronic, multi-factorial conditions caused by a complex interaction between genetic and environmental risk factors frequently share common disease mechanisms, as evidenced by an overlap between genetic risk factors for cardiovascular disease (CVD) and Alzheimer's disease (AD). Single nucleotide poly
PMID 22552896

Acetylcholinesterase inhibition activity of acetylated depsidones from Lobaria pulmonaria.

Pejin B, Tommonaro G, Iodice C, Tesevic V, Vajs V.Sourcea Department of Organic Chemistry, Faculty of Chemistry , University of Belgrade , Serbia.
Natural product research.Nat Prod Res.2012 Sep;26(17):1634-7. Epub 2011 Oct 10.
As part of our ongoing project of new acetylcholinesterase inhibitors from lower marine and terrestrial species, a phytochemical investigation was conducted on a foliose lichen, Lobaria pulmonaria (L.) Hoffm. (Lobariaceae), from Bosnia and Herzegovina. The study led to the isolation of a mixture of
PMID 21985528