Antidotes in Organophosphate Poisoning

Mechanism of toxic action of OPs

Organophosphates belong to the group of irreversible acetylcholinesterase inhibitors. Under normal conditions, this enzyme, located in the synaptic cleft, catalyzes the hydrolysis of the neurotransmitter acetylcholine into choline and acetic acid.

Upon entering the body, OP toxins attack the enzyme by phosphorylating serine in the active site of acetylcholinesterase. This results in the formation of an extremely stable, virtually non-hydrolyzable complex. The bond becomes irreversible, and enzyme activity either recovers extremely slowly or not at all. Consequently, acetylcholine ceases to be degraded and accumulates in massive quantities in the synapses, causing continuous and pathological receptor stimulation.

Atropine as a specific antidote

When the toxic agent is known, a key component of etiotropic treatment is specific (antidote) therapy. In poisoning with OPs and muscarine, atropine (a belladonna alkaloid) is used.

Atropine acts at the molecular level as a competitive inhibitor of M-cholinergic receptors (muscarinic acetylcholine receptors). The sequence of its action is as follows:

1. The drug binds to the active site of the M-cholinergic receptor.
2. It physically prevents the binding of the natural mediator—acetylcholine—which has become overly abundant due to the action of OPs.
3. It blocks nerve impulse transmission in parasympathetic synapses.

Clinically, this manifests as the relief of poisoning symptoms. For example, at the ocular level, the circular muscle of the iris (pupillary sphincter) relaxes, leading to mydriasis (pupil dilation).

What to do in case of atropine overdose?

Since atropine is a competitive inhibitor, its effects can be overcome. The main goal in antidote overdose is to artificially increase the concentration of acetylcholine in the synaptic cleft. Increasing the substrate concentration will predictably displace the inhibitor (atropine) from its binding to the receptor.

Second-order antidotes here are reversible acetylcholinesterase inhibitors:

• Physostigmine
• Proserine (neostigmine)

They form only a temporary bond with the enzyme, blocking the breakdown of acetylcholine. This allows endogenous neurotransmitter to accumulate to a level sufficient to displace atropine molecules.

Other types of antidote therapy

In addition to atropine, clinical toxicology employs other specific and functional antagonists to treat acute drug poisonings:

• Flumazenil (Flumazenilum, Anexate) is a competitive antagonist of benzodiazepine receptors. It is administered intravenously by drip in overdoses of benzodiazepines and Z-drugs (e.g., zolpidem). It blocks allosteric receptors, preventing agonists from binding to the GABA-A receptor complex, thereby eliminating CNS depression (drowsiness, ataxia, coma).
• Naloxone is an opioid receptor blocker. It is administered intramuscularly or intravenously to restore respiration in morphine and other opioid poisonings.
• Neostigmine is used for decurarization in non-depolarizing muscle relaxant overdoses. The mechanism is based on the inhibition of acetylcholinesterase and the accumulation of acetylcholine, which displaces the muscle relaxant from the receptor.

Class and exam questions

What else to study on this topic

• Plasma cholinesterase (butyrylcholinesterase) as a second target of anticholinesterase agents.
• Classification of reversible inhibitors by chemical structure (carbamic acid derivatives and others).
• Use of galantamine, donepezil, and rivastigmine in neurodegenerative conditions (Alzheimer's disease, Parkinson's disease).
• The danger of bemegride use in severe hypnotic poisonings and the risk of hypoxic neuronal damage.
• Use of atropine in anesthesiology for premedication and prevention of reflexive cardiac arrest.

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.