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词条 Acetylcholinesterase inhibitor
释义

  1. Mechanism of action

  2. Uses

  3. Side effects

  4. Titration phase

  5. Examples

     Reversible inhibitor  Comparison table  Quasi-irreversible inhibitor 

  6. See also

  7. References

  8. External links

{{Distinguish|ACE inhibitor}}

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).

Mechanism of action

Organophosphates like TEPP and sarin inhibit cholinesterases, enzymes that hydrolyze the neurotransmitter acetylcholine.

The active centre of cholinesterases feature two important sites, namely the anionic site and the esteratic site. After the binding of acetylcholine to the anionic site of the cholinesterase, the acetyl group of acetylcholine can bind to the esteratic site. Important amino acid residues in the esteratic site are a glutamate, a histidine, and a serine. These residues mediate the hydrolysis of the acetylcholine.

At the esteratic site the acetylcholine is cleaved, which results in a free choline moiety and an acetylated cholinesterase. This acetylated state requires hydrolysis to regenerate itself.[1][2]

Inhibitors like TEPP modify the serine residue in the esteratic site of the cholinesterase.

This phosphorylation inhibits the binding of the acetyl group of the acetylcholine to the esteratic site of the cholinesterase. Because the acetyl group can’t bind the cholinesterase, the acetylcholine can’t be cleaved. Therefore the acetylcholine will remain intact and will accumulate in the synapses. This results in continuous activation of acetylcholine receptors, which leads to the acute symptoms of TEPP poisoning.[3] The phosphorylation of cholinesterase by TEPP (or any other organophosphate) is irreversible. This makes the inhibition of the cholinesterase permanent.[1][2]

The cholinesterase gets irreversible phosphorylated according to the following reaction scheme

In this reaction scheme the E indicates the cholinesterase, PX the TEPP molecule, E*PX the reversible phosphorylated cholinesterase, k3 the reaction rate of the second step, EP the phosphorylated cholinesterase and X the leaving group of the TEPP.

The irreversible phosphorylation of the cholinesterase occurs in two steps. In the first step the cholinesterase gets reversibly phosphorylated. This reaction is very fast. Then the second step takes place. The cholinesterase forms a very stable complex with TEPP, in which TEPP is covalently bound to the cholinesterase. This is a slow reaction. But after this step the cholinesterase is irreversibly inhibited.[1]

The time dependent irreversible inhibition of the cholinesterase can be described by the following equation.[1]

In this formula, E is the remaining enzyme activity, E0 is the initial enzyme activity, t is the time interval after mixing of the cholinesterase and the TEPP, KI is the dissociation constant for cholinesterase-TEPP complex (E*PX) and I is the TEPP concentration.

The reaction mechanism and the formula above are both also compatible for other organophosphates. The process occurs in the same way.

Furthermore, certain organophosphates can cause OPIDN, organophosphate-induced delayed polyneuropathy. This is a disease, which is characterized by degeneration of axons in the peripheral and central nervous system. This disease will show a few weeks after contamination with the organophosphate. It is believed that the neuropathy target esterase (NTE) is affected by the organophosphate which induces the disease. However, there are no references found, which indicate that TEPP is one of the organophosphates that can cause OPIDN.[4]

Uses

Acetylcholinesterase inhibitors:[5]

  • 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)[6]
    • To treat Alzheimer's disease, the Lewy body dementias 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.[7]
    • To treat cognitive impairments in patients with schizophrenia. There is some evidence to suggest efficacy in treating positive, negative and affective symptoms.[8][9][10]
    • 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.[11][12]

Side effects

  • Diarrhea
  • Headache
  • Insomnia
  • Nausea
  • Vomiting
  • Abdominal pain
  • Lack of appetite
  • Yellowed skin
  • Dizziness
  • Slow heartbeat
  • Sudden or substantial weight loss
  • Weakness
Potential side effects of acetylcholinesterase inhibitors[13][14]
mild – usually goes away potentially serious

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, increase lower esophageal sphincter (LES) tone
  • SLUDGE syndrome.
  • Actions on the neuromuscular junction will result in prolonged muscle contraction.
  • The effects of neostigmine on postoperative nausea and vomiting are controversial and there is not a clear linkage in clinical practice, however, there is good evidence to support the reduction in risk when anticholinergic agents are administered.[15]

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.[16] This also prevents accidental overdose and is therefore recommended when initiating treatment with drugs that are extremely potent and/or toxic (drugs with a low therapeutic index).

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)[17]
  • Rosmarinic acid - ester of Caffeic acid. Found in plants species of family Lamiaceae.[18]
  • Alpha-Pinene - noncompetitive reversible [19][20]
  • Piperidines
    • Donepezil
  • Tacrine, also known as tetrahydroaminoacridine (THA')
  • Edrophonium
  • Huperzine A[21][22]
  • Ladostigil
  • Ungeremine[23]
  • Lactucopicrin
  • Acotiamide
  • Hybrid/bitopic ligands[24]

Comparison table

Comparison of reversible acetylcholinesterase inhibitors
InhibitorDurationMain site of actionClinical useAdverse effects
Edrophonium short (10 min.)[25] neuromuscular junction[25] diagnosis of myasthenia gravis[25]
Neostigmine medium (1–2 hrs.)[25] neuromuscular junction[25]
  • Reverse neuromuscular block (intravenously)[25]
  • Treat myasthenia gravis (orally)[25]
 visceral[25]
Physostigmine medium (0.5-5 hrs.)[25] postganglionic parasympathetic[25] treat glaucoma (eye drops)[25]
Pyridostigmine medium (2–3 hrs.)[25] neuromuscular junction[25]
  • Treat myasthenia gravis (orally)[25]
Dyflos long[25] postganglionic parasympathetic[25] historically to treat glaucoma (eye drops)[25] toxic[25]
Echothiophate (irreversible) long[25] postganglionic parasympathetic[25] treat glaucoma (eye drops)[25] systemic effects[25]
Parathion (irreversible) long[25] none[25] toxic[25]

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:

{{colbegin}}
  • 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
  • Onchidal
  • Coumarins
{{colend}}

See also

  • Pesticide poisoning
  • Parathion S

References

1. ^1 2 3 4 5 {{cite journal |last=Čolović |first=Mirjana B. |last2=Krstić |first2=Danijela Z. |last3=Lazarević-Pašti |first3=Tamara D. |last4=Bondžić |first4=Aleksandra M. |last5=Vasić |first5=Vesna M. |date=2013-05-01 |title=Acetylcholinesterase Inhibitors: Pharmacology and Toxicology |journal=Current Neuropharmacology |volume=11 |issue=3 |pages=315–335 |doi=10.2174/1570159X11311030006 |issn=1570-159X |pmc=3648782 |pmid=24179466}}
2. ^1 {{cite book |url=https://books.google.com/books?id=fRUlBQAAQBAJ |title=Toxic Phosphorus Esters: Chemistry, Metabolism, and Biological Effects |last=O'Brien |first=Richard D. |date=2013-10-22 |publisher=Elsevier |isbn=978-1-4832-7093-7 |language=en}}
3. ^{{cite book |url=https://books.google.com/books?id=RZTVBQAAQBAJ |title=Principles of Toxicology: Environmental and Industrial Applications |last=Roberts |first=Stephen M. |last2=James |first2=Robert C. |last3=Williams |first3=Phillip L. |date=2014-12-08 |publisher=John Wiley & Sons |isbn=978-1-118-98248-8 |language=en}}
4. ^{{cite journal |last=Lotti |first=Marcello |last2=Moretto |first2=Angelo |date=2005-01-01 |title=Organophosphate-induced delayed polyneuropathy |journal=Toxicological Reviews |volume=24 |issue=1 |pages=37–49 |issn=1176-2551 |pmid=16042503 |doi=10.2165/00139709-200524010-00003}}
5. ^{{cite journal|author=Colovic, MB|title=Acetylcholinesterase Inhibitors: Pharmacology and Toxicology|journal=Current Neuropharmacology|year=2013|volume=11|issue=3|pages=315–335|doi=10.2174/1570159X11311030006|last2=Krstic|first2=Danijela Z.|last3=Lazarevic-Pasti|first3=Tamara D.|last4=Bondzic|first4=Aleksandra M.|last5=Vasic|first5=Vesna M.|pmid=24179466|pmc=3648782}}
6. ^{{cite book |last= Yuschak|first= Thomas|title= Advanced Lucid Dreaming: The Power of Supplements|year= 2006|publisher= Lulu|isbn= 978-1430305422}}
7. ^{{cite book | isbn = 978-0-47-097948-8 | title = Maudsley Prescribing Guidelines in Psychiatry | edition = 11th |author1=Taylor, D |author2=Paton, C |author3=Shitij, K | date = 2012 | publisher = Wiley-Blackwell | location = West Sussex }}
8. ^{{cite journal|title=Acetylcholinesterase inhibitors for schizophrenia|journal=The Cochrane Database of Systematic Reviews|volume=1|pages=CD007967|date=January 2012|doi=10.1002/14651858.CD007967.pub2|pmid=22258978|author1=Singh, J|author2=Kour, K|author3=Jayaram, MB|lay-url=http://www.cochrane.org/CD007967/SCHIZ_acetylcholinesterase-inhibitors-versus-antipsychotics-for-schizophrenia-either-alone-or-in-combination-with-antipsychotics|df=}}
9. ^{{cite journal|title=Adjunctive pharmacotherapy for cognitive deficits in schizophrenia: meta-analytical investigation of efficacy|journal=The British Journal of Psychiatry|volume=203|issue=3|pages=172–178|doi=10.1192/bjp.bp.111.107359|pmid=23999481|date=September 2013|author1=Choi, KH |author2=Wykes, T |author3=Kurtz, MM|pmc=3759029}}
10. ^{{cite journal|title=Cholinesterase Inhibitors as Adjunctive Therapy in Patients with Schizophrenia and Schizoaffective Disorder A Review and Meta-Analysis of the Literature|journal = CNS Drugs|date=April 2010|volume=24|issue=4|pages=303–317|doi=10.2165/11530260-000000000-00000|pmid=20297855|author1=Ribeiz, SR |author2=Bassitt, DP |author3=Arrais, JA |author4=Avila, R |author5=Steffens, DC |author6=Bottino, CM }}
11. ^{{Cite journal | last1 = Buckley | first1 = A. W. | last2 = Sassower | first2 = K. | last3 = Rodriguez | first3 = A. J. | last4 = Jennison | first4 = K. | last5 = Wingert | first5 = K. | last6 = Buckley | first6 = J. | last7 = Thurm | first7 = A. | last8 = Sato | first8 = S. | last9 = Swedo | first9 = S. | doi = 10.1089/cap.2010.0121 | title = An Open Label Trial of Donepezil for Enhancement of Rapid Eye Movement Sleep in Young Children with Autism Spectrum Disorders | journal = Journal of Child and Adolescent Psychopharmacology | volume = 21 | issue = 4 | pages = 353–357 | year = 2011 | pmid = 21851192 | pmc =3157749 }}
12. ^{{Cite journal | last1 = Handen | first1 = B. L. | last2 = Johnson | first2 = C. R. | last3 = McAuliffe-Bellin | first3 = S. | last4 = Murray | first4 = P. J. | last5 = Hardan | first5 = A. Y. | title = Safety and Efficacy of Donepezil in Children and Adolescents with Autism: Neuropsychological Measures | doi = 10.1089/cap.2010.0024 | journal = Journal of Child and Adolescent Psychopharmacology | volume = 21 | issue = 1 | pages = 43–50 | year = 2011 | pmid = 21309696 | pmc =3037196 }}
13. ^{{Cite journal |author1 = Consumer Reports |author1-link = Consumer Reports |author2 = Drug Effectiveness Review Project |author2-link = Drug Effectiveness Review Project |date = May 2012 |title = Evaluating Prescription Drugs Used to Treat: Alzheimer's Disease Comparing Effectiveness, Safety, and Price |journal = Best Buy Drugs |page = 2 |url = http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/AlzheimersFINAL.pdf |accessdate = 1 May 2013 |deadurl = no |archiveurl = https://web.archive.org/web/20120905164340/http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/AlzheimersFINAL.pdf |archivedate = 5 September 2012 |df = }}, which claims Alzheimer's Association guidance as a source
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15. ^Barash. Clinical Anesthesia, 7th edition. Pages 552-554.
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17. ^{{cite journal|pmid=2003276|year=1991|last1=Karadsheh|first1=N|last2=Kussie|first2=P|last3=Linthicum|first3=DS|title=Inhibition of acetylcholinesterase by caffeine, anabasine, methyl pyrrolidine and their derivatives|volume=55|issue=3|pages=335–42|journal=Toxicology Letters|doi=10.1016/0378-4274(91)90015-X}}
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20. ^{{Cite journal|title = In-vitro Inhibition of Human Erythrocyte Acetylcholinesterase by Salvia lavandulaefolia Essential Oil and Constituent Terpenes|journal = Journal of Pharmacy and Pharmacology|date = 2000-07-01|issn = 2042-7158|pages = 895–902|volume = 52|issue = 7|doi = 10.1211/0022357001774598|language = en|first = Nicolette S. L.|last = Perry|first2 = Peter J.|last2 = Houghton|first3 = Anthony|last3 = Theobald|first4 = Peter|last4 = Jenner|first5 = Elaine K.|last5 = Perry|pmid = 10933142|df = }}
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23. ^{{cite journal|last=Rhee IK |first=I |author2=Appels N |author3=Hofte B |author4=Karabatak B |author5=Erkelens C |author6=Stark LM |author7=Flippin LA |author8=Verpoorte R |date=November 2004 |title=Isolation of the Acetylcholinesterase Inhibitor Ungeremine from Nerine bowdenii by Preparative HPLC Coupled On-Line to a Flow Assay System |journal=Biological & Pharmaceutical Bulletin |volume=27 |issue=11 |pages=1804–1809 |url=http://www.jstage.jst.go.jp/article/bpb/27/11/1804/_pdf |pmid=15516727 |doi=10.1248/bpb.27.1804 }}{{dead link|date=October 2016 |bot=InternetArchiveBot |fix-attempted=yes }}
24. ^Messerer, R., Dallanoce, C., Matera, C., Wehle, S., Flammini, L., Chirinda, B., . . . Holzgrabe, U. (2017). Novel bipharmacophoric inhibitors of the cholinesterases with affinity to the muscarinic receptors M1 and M2. MedChemComm, 8(6), 1346-1359. doi:10.1039/c7md00149e
25. ^1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 {{cite book |author=Rang, H. P. |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |pages= |isbn=978-0-443-07145-4 |oclc= |doi=}} Page 156

External links

  • {{MeshName|Acetylcholinesterase+inhibitors}}
  • Acetylcholinesterase: A gorge-ous enzyme QUite Interesting PDB Structure article at PDBe
{{Enzyme inhibition}}{{Antidementia}}{{Nootropics}}{{Acetylcholine metabolism and transport modulators}}

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