Acetylcholinesterase inhibitor

Not to be confused with ACE inhibitor.

Acetylcholine

Acetylcholinesterase

Acetylcholinesterase inhibition

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).

Uses

Acetylcholinesterase inhibitors:

• 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)
  • To treat Alzheimer's disease, Lewy Body Dementia 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.
  • To treat cognitive impairments in patients with schizophrenia. There is some evidence to suggest efficacy in treating positive, negative and affective symptoms.
  • 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.

Side effects

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

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.
• 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. 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.

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)
• Rosmarinic acid - ester of Caffeic acid. Found in plants species of Lamiaceae family.
• Alpha-Pinene - noncompetitive reversible
• Piperidines
  • Donepezil
• Tacrine, also known as tetrahydroaminoacridine (THA')
• Edrophonium
• Huperzine A
• Ladostigil
• Ungeremine
• Lactucopicrin

Comparison table

Comparison of reversible acetylcholinesterase inhibitors

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

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
  • 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

See also

• Pesticide poisoning

External links

• Acetylcholinesterase inhibitors at the US National Library of Medicine Medical Subject Headings (MeSH)
• Acetylcholinesterase: A gorge-ous enzyme QUite Interesting PDB Structure article at PDBe