Acetylcholinesterase inhibitor

Acetylcholine

Acetylcholinesterase

An acetylcholinesterase inhibitor (often abbreviated AChEI) or anti-cholinesterase is a chemical that inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.

Uses

Acetylcholinesterase inhibitors:

• Occur naturally as venoms and poisons
• Are used as weapons in the form of nerve agents
• Are used medicinally:
  • To treat myasthenia gravis. In myasthenia gravis, they are used to increase neuromuscular transmission.
  • To treat Glaucoma
  • To treat Alzheimer's disease
  • To treat Lewy Body Dementia
  • As an antidote to anticholinergic poisoning

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
• Delta9-tetrahydrocannabinol (THC) ^[1]
• Carbamates
  • Physostigmine
  • Neostigmine
  • Pyridostigmine
  • Ambenonium
  • Demarcarium
  • Rivastigmine
• Phenanthrene derivatives
  • Galantamine
• Piperidines
  • Donepezil, also known as E2020
• Tacrine, also known as tetrahydroaminoacridine (THA')
• Edrophonium
• Huperzine A
• Ladostigil
• Ungeremine^[2]

Comparison table

Comparison of reversible acetylcholinesterase inhibitors

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

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 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

Natural Compounds

• Huperzine A
• Galantamine
• Onchidal
• Coumarins

Effects

Some major effects of cholinesterase inhibitors:

• Actions on the autonomic nervous system, that is parasympathetic nervous system will 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.^[4]

See also

• Pesticide poisoning

References

1. ^ Eubanks LM, Rogers CJ, Beuscher AE, et al. (2006). "A molecular link between the active component of marijuana and Alzheimer's disease pathology". Mol. Pharm. 3 (6): 773–7. doi:10.1021/mp060066m. PMC 2562334. PMID 17140265. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2562334. 
2. ^ 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. PMID 15516727. http://www.jstage.jst.go.jp/article/bpb/27/11/1804/_pdf. 
3. ^ ^{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
4. ^ 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. 

External links

• ATSDR Case Studies in Environmental Medicine: Cholinesterase Inhibitors, Including Insecticides and Chemical Warfare Nerve Agents U.S. Department of Health and Human Services
• MeSH Acetylcholinesterase+inhibitors