Cholinesterase reactivator

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Pralidoxime molecule Pralidoxime-2D-skeletal.png
Pralidoxime molecule

Cholinesterase reactivators are drugs that reverse the inhibition of cholinesterase by organophosphates or sulfonates. [1] They are used as antidote for treating organophosphate insecticide and nerve agent poisoning. [2] Organophosphates are used industrially in agricultural pesticides, and globally as agents of chemical warfare. [3] Discovered in 1955, Pralidoxime was the first cholinesterase reactivator used as an antidote to OP neurotoxicity and remains the most commonly used reactivator. [3] Cholinesterase reactivators are indicated for anticholinesterase toxicity and cholinergic crisis, the signs of which are contained within the mnemonic DUMBELS : Diarrhea/diaphoresis, urinary frequency, miosis, bronchospasm/bronchorrhea, emesis, lacrimation, and salivation. [4] Death may occur due to the blockage of nicotinic receptors of muscle fibers at the neuromuscular junction, causing paralysis of the muscles of respiration. [5]

Contents

Mechanism of action

Acetylcholinesterase Inhibitors Acetylcholinesterase Inhibitors.svg
Acetylcholinesterase Inhibitors

Organophosphates lead to toxicity by forming a strong covalent bond in the active site of AChE. OPs phosphorylate the serine residue in the active site of AChE, irreversibly inhibiting the enzyme, thereby allowing acetylcholinesterase to accumulate in the synaptic cleft of ACh receptors. [6]

Drugs in the oxime class (e.g., Pralidoxime) reactivate AChE by removing the OP. Oximes have a higher affinity for phosphorylation than the serine residue in the AChE active site, causing the OP to detach from the AChE enzyme, freeing its active site and restoring function. After the OP detaches from AChE, it phosphorylates the oxime, forming an OP-oxime compound that hydrolyzes within the synapse. [6]

Because oximes function primarily at nicotinic receptors, it must be co-administered with a muscarinic antagonist such as atropine. [6] Nicotinic symptoms relieved by Pralidoxime include muscle weakness and paralysis. [6]

Guideline recommendations

In the treatment of organophosphate toxicity, cholinesterase reactivators such as Pralidoxime reactivate inhibited AChE at peripheral nicotinic receptors. Since AChE mediates effects on both nicotinic and muscarinic receptors, cholinesterase reactivators are co-administered with muscarinic antagonists, primarily atropine. Atropine resolves OP-induced cholinergic toxicity at muscarinic receptors in addition to aiding in central nervous system signs like bradycardia, respiratory depression, and bronchoconstriction. [7]

Pralidoxime should be administered within 24 to 48 hours of OP poisoning, after which point the strong covalent bond of OP in the active site of AChE may be completely irreversible. [6]

See also

Related Research Articles

Nerve agents, sometimes also called nerve gases, are a class of organic chemicals that disrupt the mechanisms by which nerves transfer messages to organs. The disruption is caused by the blocking of acetylcholinesterase (AChE), an enzyme that catalyzes the breakdown of acetylcholine, a neurotransmitter. Nerve agents are irreversible acetylcholinesterase inhibitors used as poison.

<span class="mw-page-title-main">Acetylcholine</span> Organic chemical and neurotransmitter

Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.

<span class="mw-page-title-main">Chlorfenvinphos</span> Chemical compound

Chlorfenvinphos is an organophosphorus compound that was widely used as an insecticide and an acaricide. The molecule itself can be described as an enol ester derived from dichloroacetophenone and diethylphosphonic acid. Chlorfenvinphos has been included in many products since its first use in 1963. However, because of its toxic effect as a cholinesterase inhibitor it has been banned in several countries, including the United States and the European Union. Its use in the United States was discontinued in 1991.

<span class="mw-page-title-main">Galantamine</span> Neurological medication

Galantamine is a type of acetylcholinesterase inhibitor. It is an alkaloid extracted from the bulbs and flowers of Galanthus nivalis, Galanthus caucasicus, Galanthus woronowii, and other members of the family Amaryllidaceae, such as Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata. It can also be produced synthetically.

Obidoxime is a member of the oxime family used to treat organophosphate poisoning. Oximes are drugs known for their ability to reverse the binding of organophosphorus compounds to the enzyme acetylcholinesterase (AChE).

A cholinergic crisis is an over-stimulation at a neuromuscular junction due to an excess of acetylcholine (ACh), as a result of the inactivity of the AChE enzyme, which normally breaks down acetylcholine.

<span class="mw-page-title-main">Pralidoxime</span> Chemical compound used as antidote for nerve agent poisoning

Pralidoxime or 2-PAM, usually as the chloride or iodide salts, belongs to a family of compounds called oximes that bind to organophosphate-inactivated acetylcholinesterase. It is used to treat organophosphate poisoning in conjunction with atropine and either diazepam or midazolam. It is a white solid.

<span class="mw-page-title-main">Azinphos-methyl</span> Chemical compound

Azinphos-methyl (Guthion) is a broad spectrum organophosphate insecticide manufactured by Bayer CropScience, Gowan Co., and Makhteshim Agan. Like other pesticides in this class, it owes its insecticidal properties to the fact that it is an acetylcholinesterase inhibitor. It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act, and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.

<span class="mw-page-title-main">Phosmet</span> Organophosphate non-systemic insecticide

Phosmet is a phthalimide-derived, non-systemic, organophosphate insecticide used on plants and animals. It is mainly used on apple trees for control of codling moth, though it is also used on a wide range of fruit crops, ornamentals, and vines for the control of aphids, suckers, mites, and fruit flies.

<span class="mw-page-title-main">Organophosphate poisoning</span> Toxic effect of pesticides

Organophosphate poisoning is poisoning due to organophosphates (OPs). Organophosphates are used as insecticides, medications, and nerve agents. Symptoms include increased saliva and tear production, diarrhea, vomiting, small pupils, sweating, muscle tremors, and confusion. While onset of symptoms is often within minutes to hours, some symptoms can take weeks to appear. Symptoms can last for days to weeks.

<span class="mw-page-title-main">Chlorethoxyfos</span> Chemical compound

Chlorethoxyfos is an organophosphate acetylcholinesterase inhibitor used as an insecticide. It is registered for the control of corn rootworms, wireworms, cutworms, seed corn maggot, white grubs and symphylans on corn. The insecticide is sold under the trade name Fortress by E.I. du Pont de Nemours & Company.

<span class="mw-page-title-main">Disulfoton</span> Chemical compound

Disulfoton is an organophosphate acetylcholinesterase inhibitor used as an insecticide. It is manufactured under the name Di-Syston by Bayer CropScience. Disulfoton in its pure form is a colorless oil but the technical product used in vegetable fields is dark and yellowish with a sulfur odor. Disulfoton is processed as a liquid into carrier granules. These granules are mixed with fertilizer and clay to be made into a spike, designed to be driven into the ground. The pesticide is absorbed over time by the roots and translocated to all parts of the plant. The pesticide acts as a cholinesterase inhibitor and gives long lasting control.

<span class="mw-page-title-main">Acetylcholinesterase inhibitor</span> Drugs that inhibit acetylcholinesterase

Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level and duration of action of acetylcholine in the central nervous system, autonomic ganglia and neuromuscular junctions, which are rich in acetylcholine receptors. Acetylcholinesterase inhibitors are one of two types of cholinesterase inhibitors; the other being butyryl-cholinesterase inhibitors. Acetylcholinesterase is the primary member of the cholinesterase enzyme family.

<span class="mw-page-title-main">Ethoprophos</span> Chemical compound

Ethoprophos (or ethoprop) is an organophosphate ester with the formula C8H19O2PS2. It is a clear yellow to colourless liquid that has a characteristic mercaptan-like odour. It is used as an insecticide and nematicide and it is an acetylcholinesterase inhibitor.

<span class="mw-page-title-main">Terbufos</span> Chemical compound

Terbufos is a chemical compound used in insecticides and nematicides. It is part of the chemical family of organophosphates. It is a clear, colourless to pale yellow or reddish-brown liquid and sold commercially as granulate.

Carbamate poisoning is poisoning due to exposure to carbamates, which are commonly sold as pesticides around the world. In most respects, it is similar to organophosphate poisoning, though typically less severe or requiring a larger amount of the chemical before symptoms appear.

<span class="mw-page-title-main">Crotylsarin</span> Chemical compound

Crotylsarin (CRS) is an extremely toxic organophosphate nerve agent of the G-series. Like other nerve agents, CRS irreversibly inhibits acetylcholinesterase. However, since the inhibited enzyme ages so rapidly, it can't be reactivated by cholinesterase reactivators.

<span class="mw-page-title-main">Guanitoxin</span> Chemical compound

Guanitoxin (GNT), formerly known as anatoxin-a(S) "Salivary", is a naturally occurring cyanotoxin commonly isolated from cyanobacteria. It is a potent covalent acetylcholinesterase inhibitor, and thus a potent rapid acting neurotoxin which in cases of severe exposure can lead to death. Guanitoxin was first structurally characterized in 1989, and consists of a cyclic N-hydroxyguanidine organophosphate with a phosphate ester moiety.

<span class="mw-page-title-main">Cholinergic blocking drug</span> Drug that block acetylcholine in synapses of cholinergic nervous system

Cholinergic blocking drugs are a group of drugs that block the action of acetylcholine (ACh), a neurotransmitter, in synapses of the cholinergic nervous system. They block acetylcholine from binding to cholinergic receptors, namely the nicotinic and muscarinic receptors.

References

  1. "Cholinesterase Reactivators - MeSH - NCBI". www.ncbi.nlm.nih.gov.
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