Organophosphates

Mechanism of Action and Application

OPs bind to the OH group of serine in the esteratic site of acetylcholinesterase. This covalent bond is very strong, and its hydrolysis takes hundreds of hours. In fact, virtually irreversible inhibition of the enzyme occurs, leading to an excess of acetylcholine accumulation in the synapses.

In medicine, OPs (e.g., armin, echothiopate) are used only topically for the treatment of glaucoma—they cause miosis and lower intraocular pressure. Echothiopate is characterized by hydrophilicity: it poorly penetrates through the conjunctiva, so the risk of systemic effects is minimal, and its aqueous solutions are stable.

OPs are widely used outside of medicine:

• Insecticides: malathion, parathion. In the organisms of insects and mammals, they undergo bioactivation (replacement of a sulfur atom with oxygen) and turn into highly toxic metabolites (malaoxon, paraoxon).
• Chemical warfare agents: soman.

Path in the Body and Clinical Presentation of Poisoning

Due to high lipophilicity, OPs are easily absorbed even through intact skin, mucous membranes, and lungs. They accumulate in adipose tissue, integrate into cell membranes, and settle on vascular endothelium and erythrocytes. The poison is excreted with bile, but is reabsorbed in the intestine (enterohepatic circulation), which leads to its prolonged presence in the body and the risk of repeated intoxications.

Acute poisoning is accompanied by total excitation of M- and N-cholinergic receptors due to an excess of acetylcholine.

Muscarinic agonist effects (parasympathetic stimulation):

• Eyes: marked miosis (pinpoint pupil), lacrimation.
• Secretion: profuse sweating, hypersalivation, abundant mucus in the bronchi.
• Respiration: bronchospasm and asphyxia.
• Gastrointestinal tract and kidneys: vomiting, abdominal cramps, diarrhea, involuntary urination.
• Heart: bradycardia, drop in blood pressure.

Nicotinic and central effects:

• Vessels and heart: stimulation of sympathetic ganglia, adrenal glands, and the vasomotor center can cause tachycardia and an increase in blood pressure.
• Muscles: initially twitching (fasciculations), then paralysis due to persistent depolarization of the postsynaptic membrane.
• CNS: confusion, psychomotor agitation, convulsions, coma. Death results from respiratory center paralysis.

Detoxification and Antidote Therapy

In case of poisoning, it is important to quickly remove the poison: from the skin — with a dry swab (without rubbing) and washing with sodium bicarbonate solution or soapy water; from the GI tract — with gastric lavage, sorbents, and laxatives; from the blood — with forced diuresis, hemodialysis, or hemosorption.

Specific treatment includes two directions:

1. Blockade of muscarinic receptors. The main drug is atropine. It is administered intravenously in high doses to relieve peripheral parasympathetic effects.
2. Enzyme reactivation. Cholinesterase reactivators are used. They contain an oxime group that is attracted to the phosphorus of the poison. The oxime detaches the OP residue from the enzyme (dephosphorylation), restoring acetylcholinesterase activity.

There is the problem of «aging of the complex»: over time, the bond between the poison and the enzyme becomes stronger, and reactivators become useless. Therefore, they must be administered in the first hours.

Among reactivators, the following are distinguished:

• Quaternary ammonium compounds (dipyroxime, alloxime). They poorly cross the blood-brain barrier and act mainly in the periphery.
• Tertiary amines (isonitrosine). They easily penetrate the CNS, relieving both peripheral and central symptoms.

These drugs are administered parenterally in a hospital setting and are strictly contraindicated in poisoning by reversible inhibitors (carbamates).

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Detailed mechanism of interaction between reactivators and the phosphoryl residue
• Features of malathion and parathion bioactivation
• Comparison of dipiroxim and isonitrozine pharmacokinetics
• Mechanism of sustained depolarization of the skeletal muscle postsynaptic membrane

Other topics in the section «Drugs acting on cholinergic synapses»

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