Cholinesterase inhibitor

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).[1][2][3]

Not to be confused with Acetylcholinesterase inhibitor, anti-cholinergic, or Cholinergic.
Cholinesterase inhibitor
Drug class
Class identifiers
UseAlzheimer's disease
ATC codeN06#N06DA Anticholinesterases
Mechanism of actionEnzyme inhibitor
Biological targetCholinesterase
Clinical data
Drugs.comDrug Classes
WebMDMedicineNet 
External links
MeSHD002800
Legal status
In Wikidata
Acetylcholine
Sarin molecule, C4H10FO2P
TEPP molecule, C8H20O7P2

ChEIs may be used as drugs for Alzheimer's and myasthenia gravis, and also as chemical weapons and insecticides.[4][5] Side effects when used as drugs may include loss of appetite, nausea, vomiting, loose stools, vivid dreams at night, dehydration, rash, bradycardia, peptic ulcer disease, seizures, weight loss, rhinorrhea, salivation, muscle cramps, and fasciculations.[6][7]

ChEIs are indirect-acting parasympathomimetic drugs.[8]

ChEls are widely used as chemical weapons. Since November 2019 the group of ACheIs known as Novichoks have been banned as agents of warfare under the Chemical Weapons Convention.[9] Novichok agents are neurotoxic organophosphorus compounds and are considered more potent than VX gas, also a neurotoxic organophosphorus compound.[10]

Medical use
Further information: Donepezil § Medical uses

While 4 ChEIs are approved in the US for the treatment of Alzheimer's Disease, only three of these are available commercially.[6] The three available are rivastigmine, donepezil, and galantamine, while tacrine is not.[6] They are generally used to treat Alzheimer's disease and dementia.[6] If a benefit occurs, it is generally during the second or third month after starting.[6]

It is difficult to determine which ChEI has greater efficacy, due to design flaws in head-to-head comparison studies.[11]

Pyridostigmine is used in the treatment of myasthenia gravis.[12]

Neostigmine is used in combination with a muscarinic antagonist to reverse the effects of non-depolarizing muscle relaxants e.g. rocuronium bromide

Cholinesterase inhibitor toxicity
Further information: Organophosphate poisoning and cholinergic crisis

Common side effects of one ChEI include insomnia, nausea and vomiting, accidental injury, headache, dizziness, bradycardia, hypotension, ecchymosis, and sleep disturbance.[13]

Binding affinity

Acetylcholinesterase inhibitors

Donepezil, phenserine, huperzine A, and BW284c51 are selective AChE inhibitors.[14][11]

Butyrylcholinesterase inhibitor

Tetra (monoisopropyl) pyrophosphoramide (Iso-OMPA) and ethopropazine are selective BChE inhibitors.[14]

AChE and BChE inhibitor

Paraoxon and rivastigmine are both acetylcholinesterase inhibitors and butyrylcholinesterase inhibitors.[14][11][7]

In 2015, the United States Food and Drug Administration's Adverse Event Reporting System database compared rivastigmine to the other ChEI drugs donepezil and galantamine found that rivastigmine was associated with a higher frequency of reports of death as an adverse event.[15]

Acetylcholinesterase inhibitors and nicotinic receptor modulator
See also: Allosteric modulator and nicotinic receptor

Galantamine might be less well tolerated than donepezil and rivastigmine.[11]

Chemical weapons
Further information: Chemical weapon

Alleged Assassination Attempt

Cholinesterase inhibitors came to a public attention in 2020 when Russian opposition and dissent figure Alexei Navalny was treated in Berlin Charité hospital for alleged poisoning by a Russian-made nerve agent which is known since 2019 as belonging to the Novichok agents subgroup of ChEI.[16]

See also

Further reading
  • Institute, National; (UK), Care Excellence (2019-12-27). Cholinesterase inhibitors and memantine for dementia. Retrieved 2019-12-27. {{cite book}}: |website= ignored (help)
  • Parsons, Chris G.; Danysz, Wojciech; Dekundy, Andrzej; Pulte, Irena (2013-05-09). "Memantine and Cholinesterase Inhibitors: Complementary Mechanisms in the Treatment of Alzheimer's Disease". Neurotoxicity Research. Springer Science and Business Media LLC. 24 (3): 358–369. doi:10.1007/s12640-013-9398-z. ISSN 1029-8428. PMC 3753463. PMID 23657927.
  • Meng, Yan‑Hong; Wang, Pan‑Pan; Song, Ya‑Xue; Wang, Jian‑Hua (2019-03-01). "Cholinesterase inhibitors and memantine for Parkinson's disease dementia and Lewy body dementia: A meta‑analysis". Experimental and Therapeutic Medicine. 17 (3): 1611–1624. doi:10.3892/etm.2018.7129. ISSN 1792-0981. PMC 6364145. PMID 30783428. Retrieved 2019-12-27.

References
  1. English, Brett A.; Webster, Andrew A. (2012). "Acetylcholinesterase and its Inhibitors". Primer on the Autonomic Nervous System. Elsevier. pp. 631–633. doi:10.1016/b978-0-12-386525-0.00132-3. ISBN 978-0-12-386525-0.
  2. Deutch, Ariel Y.; Roth, Robert H. (2014). "Pharmacology and Biochemistry of Synaptic Transmission". From Molecules to Networks. Elsevier. pp. 207–237. doi:10.1016/b978-0-12-397179-1.00007-5. ISBN 978-0-12-397179-1.
  3. Colovic, Mirjana B.; Krstic, Danijela Z.; Lazarevic-Pasti, Tamara D.; Bondzic, Aleksandra M.; Vasic, Vesna M. (2013-04-01). "Acetylcholinesterase Inhibitors: Pharmacology and Toxicology". Current Neuropharmacology. Bentham Science Publishers Ltd. 11 (3): 315–335. doi:10.2174/1570159x11311030006. ISSN 1570-159X. PMC 3648782. PMID 24179466.
  4. "Cholinesterase Inhibitors (Medical Use & WMD)". PharmWiki. Tulane University School of Medicine. Retrieved 24 August 2020.
  5. Mandour, Raafat (2013). "Environmental Risks of Insecticides Cholinesterase Inhibitors". Toxicology International. United States National Library of Medicine. 20 (1): 30–34. doi:10.4103/0971-6580.111556. PMC 3702124. PMID 23833435.
  6. Budson, Andrew E.; Solomon, Paul R. (2016). "Cholinesterase Inhibitors". Memory Loss, Alzheimer's Disease, and Dementia. Elsevier. pp. 160–173. doi:10.1016/b978-0-323-28661-9.00016-0. ISBN 978-0-323-28661-9.
  7. Khoury, Rita; Rajamanickam, Jayashree; Grossberg, George T. (2018-01-08). "An update on the safety of current therapies for Alzheimer's disease: focus on rivastigmine". Therapeutic Advances in Drug Safety. SAGE Publications. 9 (3): 171–178. doi:10.1177/2042098617750555. ISSN 2042-0986. PMC 5810854. PMID 29492246.
  8. Forrester, John V.; Dick, Andrew D.; McMenamin, Paul G.; Roberts, Fiona; Pearlman, Eric (2016). "General and ocular pharmacology". The Eye. Elsevier. pp. 338–369.e1. doi:10.1016/b978-0-7020-5554-6.00006-x. ISBN 978-0-7020-5554-6. Parasympathomimetics are a group of drugs that act either by directly stimulating the muscarinic receptor, for example pilocarpine, or by inhibiting the enzyme acetylcholinesterase, which hydrolyses the acetylcholine in the synapse.
  9. Castelvecchi, Davide (2019). "Novichok nerve agents banned by chemical-weapons treaty". Nature. doi:10.1038/d41586-019-03686-y. PMID 33244185.
  10. Chai, Peter R.; Hayes, Bryan D.; Erickson, Timothy B.; Boyer, Edward W. (2018). "Novichok agents: A historical, current, and toxicological perspective". Toxicology Communications. 2 (1): 45–48. doi:10.1080/24734306.2018.1475151. PMC 6039123. PMID 30003185.
  11. Hersen, Michel (2006). Comprehensive handbook of personality and psychopathology (Tertiary source). Hoboken, New Jersey: John Wiley. p. 514. ISBN 978-0-471-75725-2. OCLC 63041762.
  12. World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 429. hdl:10665/44053. ISBN 9789241547659.
  13. "Prescribing information : Aricept" (PDF). FDA access data. Eisai Inc. and Pfizer Inc. 2012. Archived (PDF) from the original on 2016-02-21. Retrieved 6 May 2021.
  14. Waiskopf, Nir; Soreq, Hermona (2015). "Cholinesterase Inhibitors". Handbook of Toxicology of Chemical Warfare Agents. Elsevier. pp. 761–778. doi:10.1016/b978-0-12-800159-2.00052-x. ISBN 978-0-12-800159-2.
  15. Ali TB, Schleret TR, Reilly BM, Chen WY, Abagyan R (2015). "Adverse Effects of Cholinesterase Inhibitors in Dementia, According to the Pharmacovigilance Databases of the United-States and Canada". PLOS ONE. 10 (12): e0144337. Bibcode:2015PLoSO..1044337A. doi:10.1371/journal.pone.0144337. PMC 4671709. PMID 26642212.
  16. "Alexei Navalny was poisoned 'using Novichok' nerve agent, say German government". Telegraph Media Group Limited. 2 September 2020.
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