Chemicals which prevent breakdown of acetylcholine and butyrylcholine
Acetylcholine
Sarin molecule, C4H10FO2P
Tetraethyl pyrophosphate molecule, C8H20O7P2
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]
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 [ edit ]
Common side effects of one ChEI include insomnia , nausea and vomiting , accidental injury, headache , dizziness , bradycardia , hypotension , ecchymosis , and sleep disturbance.[ 13]
Acetylcholinesterase inhibitors [ edit ]
Donepezil , phenserine , huperzine A , and BW284c51 are selective AChE inhibitors.[ 14] [ 11]
Butyrylcholinesterase inhibitor [ edit ]
Tetra (monoisopropyl) pyrophosphoramide (Iso-OMPA ) and ethopropazine are selective BChE inhibitors.[ 14]
AChE and BChE inhibitor [ edit ]
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 [ edit ]
Galantamine might be less well tolerated than donepezil and rivastigmine.[ 11]
Assassination Attempt [ edit ]
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]
Institute, National; (UK), Care Excellence (2019-12-27). Cholinesterase inhibitors and memantine for dementia . Retrieved 2019-12-27 .
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 . 24 (3). Springer Science and Business Media LLC: 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 .
^ 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 .
^ 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 .
^ 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 . 11 (3). Bentham Science Publishers Ltd.: 315–335. doi :10.2174/1570159x11311030006 . ISSN 1570-159X . PMC 3648782 . PMID 24179466 .
^ "Cholinesterase Inhibitors (Medical Use & WMD)" . PharmWiki . Tulane University School of Medicine . Retrieved 24 August 2020 .
^ Mandour, Raafat (2013). "Environmental Risks of Insecticides Cholinesterase Inhibitors" . Toxicology International . 20 (1). United States National Library of Medicine : 30–34. doi :10.4103/0971-6580.111556 . PMC 3702124 . PMID 23833435 .
^ a b c d e 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 .
^ a b 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 . 9 (3). SAGE Publications: 171–178. doi :10.1177/2042098617750555 . ISSN 2042-0986 . PMC 5810854 . PMID 29492246 .
^ 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.
^ Castelvecchi, Davide (2019). "Novichok nerve agents banned by chemical-weapons treaty". Nature . doi :10.1038/d41586-019-03686-y . PMID 33244185 .
^ 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 .
^ a b c d 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 .
^ 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 .
^ "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 .
^ a b c 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 .
^ 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 .
^ "Alexei Navalny was poisoned 'using Novichok' nerve agent, say German government" . Telegraph Media Group Limited. 2 September 2020.