5.16:
Anticholinesterase Agents: Poisoning and Treatment
Anticholinesterase agents prevent acetylcholine hydrolysis to enhance cholinergic actions.
Organophosphates—a type of anticholinesterase—interact covalently with AChE, yielding an irreversible phosphorylated enzyme.
It further undergoes aging with the loss of an alkyl group, and the complex formed is resistant to hydrolytic regeneration.
Aging inhibits AChE functioning and promotes acetylcholine accumulation, potentiating cholinergic responses leading to acute toxicity.
The handling of anticholinesterases, such as insecticides, can lead to accidental poisoning, and the symptoms manifest as a result of muscarinic and nicotinic activation.
In organophosphate poisoning, cholinesterase reactivators, such as pralidoxime, are effective before the enzyme undergoes aging. Pralidoxime binds to the anionic site of the enzyme through its charged quaternary nitrogen, while the oxime end reacts with the phosphorus atom. The resulting complex diffuses away, reactivating the enzyme.
The muscarinic symptoms are managed by IV administration of atropine.
Other treatment measures include gastric lavage, maintaining blood pressure, and ensuring airway patency.
5.16:
Anticholinesterase Agents: Poisoning and Treatment
Anticholinesterases, also known as cholinesterase inhibitors, work by blocking the breakdown of acetylcholine, leading to its accumulation in the synaptic cleft. This accumulation indirectly enhances both muscarinic and nicotinic actions. These agents are classified as reversible or irreversible based on their mechanism of action.
Irreversible agents form a strong bond with the cholinesterase enzyme, making it inactive. The breakdown of the phosphorylated enzyme is slower than the carbamylated enzyme, making it difficult for the enzyme to regenerate. Over time, the phosphorylated enzyme can undergo a process called aging, where it loses an alkyl group and becomes less reactive. This aging process prevents enzyme regeneration, resulting in an accumulation of acetylcholine in the synaptic cleft. This exacerbates cholinergic actions and contributes to the toxic effects of irreversible anticholinesterases.
Treating anticholinesterase poisoning involves several measures. Gastric lavage is performed to remove any ingested poison. Maintaining hydration, blood pressure, and airway patency is essential. Diazepam is administered to control convulsions in patients. The muscarinic side effects can be managed by administering intravenous atropine; however, muscle paralysis caused by nicotinic actions cannot be reversed by atropine. In cases of organophosphate poisoning, cholinesterase reactivators such as pralidoxime and obidoxime are used to restore neuromuscular transmission. However, these reactivators are only effective if administered before the aging process begins.