Cholinesterase inhibitor explained

Use:Alzheimer's disease
Biological Target:Cholinesterase
Mechanism Of Action:Enzyme inhibitor
Atc Prefix:N06#N06DA Anticholinesterases
Medicinenet:cholinesterase_inhibitors

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]

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

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.

Pyridostigmine is used in the treatment of myasthenia gravis.[11]

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

See also: 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.[12]

Binding affinity

Acetylcholinesterase inhibitors

Donepezil, phenserine, huperzine A, and BW284c51 are selective AChE inhibitors.[13] [14]

Butyrylcholinesterase inhibitor

Tetra (monoisopropyl) pyrophosphoramide (Iso-OMPA) and ethopropazine are selective BChE inhibitors.[13]

AChE and BChE inhibitor

Paraoxon and rivastigmine are both acetylcholinesterase inhibitors and butyrylcholinesterase inhibitors.[13] [14] [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.[14]

Chemical weapons

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 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

Notes and References

  1. Book: English . Brett A. . Webster . Andrew A. . Primer on the Autonomic Nervous System . Acetylcholinesterase and its Inhibitors . Elsevier . 2012 . 978-0-12-386525-0 . 10.1016/b978-0-12-386525-0.00132-3 . 631–633.
  2. Book: Deutch . Ariel Y. . Roth . Robert H. . From Molecules to Networks . Pharmacology and Biochemistry of Synaptic Transmission . Elsevier . 2014 . 978-0-12-397179-1 . 10.1016/b978-0-12-397179-1.00007-5 . 207–237.
  3. Colovic . Mirjana B. . Krstic . Danijela Z. . Lazarevic-Pasti . Tamara D. . Bondzic . Aleksandra M. . Vasic . Vesna M. . Acetylcholinesterase Inhibitors: Pharmacology and Toxicology . Current Neuropharmacology . Bentham Science Publishers Ltd. . 11 . 3 . 2013-04-01 . 1570-159X . 24179466 . 3648782 . 10.2174/1570159x11311030006 . 315–335.
  4. Web site: Cholinesterase Inhibitors (Medical Use & WMD) . PharmWiki . . 24 August 2020.
  5. Mandour . Raafat . Environmental Risks of Insecticides Cholinesterase Inhibitors . Toxicology International . 2013 . 20 . 1 . 30–34 . . 10.4103/0971-6580.111556 . 23833435 . 3702124 . free .
  6. Book: Budson . Andrew E. . Solomon . Paul R. . Memory Loss, Alzheimer's Disease, and Dementia . Cholinesterase Inhibitors . Elsevier . 2016 . 978-0-323-28661-9 . 10.1016/b978-0-323-28661-9.00016-0 . 160–173.
  7. Khoury . Rita . Rajamanickam . Jayashree . Grossberg . George T. . An update on the safety of current therapies for Alzheimer's disease: focus on rivastigmine . Therapeutic Advances in Drug Safety . SAGE Publications . 9 . 3 . 2018-01-08 . 2042-0986 . 29492246 . 5810854 . 10.1177/2042098617750555 . 171–178.
  8. Book: Forrester . John V. . Dick . Andrew D. . McMenamin . Paul G. . Roberts . Fiona . Pearlman . Eric . The Eye . General and ocular pharmacology . Elsevier . 2016 . 978-0-7020-5554-6 . 10.1016/b978-0-7020-5554-6.00006-x . 338–369.e1 . 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. 10.1038/d41586-019-03686-y. Novichok nerve agents banned by chemical-weapons treaty. 2019. Castelvecchi. Davide. Nature. 33244185.
  10. 10.1080/24734306.2018.1475151. Novichok agents: A historical, current, and toxicological perspective. 2018. Chai. Peter R.. Hayes. Bryan D.. Erickson. Timothy B.. Boyer. Edward W.. Toxicology Communications. 2. 1. 45–48. 30003185. 6039123.
  11. Book: WHO Model Formulary 2008 . 2009 . 9789241547659 . ((World Health Organization)) . Stuart MC, Kouimtzi M, Hill SR . 10665/44053 . World Health Organization . World Health Organization . 429 .
  12. Web site: 2012. Prescribing information : Aricept. live. 6 May 2021. FDA access data. Eisai Inc. and Pfizer Inc.. https://web.archive.org/web/20160221204009/http://www.accessdata.fda.gov:80/drugsatfda_docs/label/2012/020690s035,021720s008,022568s005lbl.pdf . 2016-02-21 .
  13. Book: Waiskopf . Nir . Soreq . Hermona . Handbook of Toxicology of Chemical Warfare Agents . Cholinesterase Inhibitors . Elsevier . 2015 . 978-0-12-800159-2 . 10.1016/b978-0-12-800159-2.00052-x . 761–778.
  14. Book: Hersen, Michel . Comprehensive handbook of personality and psychopathology . limited . John Wiley . Hoboken, New Jersey . 2006 . 978-0-471-75725-2 . 63041762 . 514 . Tertiary source.
  15. Ali TB, Schleret TR, Reilly BM, Chen WY, Abagyan R . Adverse Effects of Cholinesterase Inhibitors in Dementia, According to the Pharmacovigilance Databases of the United-States and Canada . PLOS ONE . 10 . 12 . e0144337 . 2015 . 26642212 . 4671709 . 10.1371/journal.pone.0144337 . 2015PLoSO..1044337A . free .
  16. News: 2 September 2020. Alexei Navalny was poisoned 'using Novichok' nerve agent, say German government. Telegraph Media Group Limited.

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