Mechanism of Action and Clinical Uses
Organophosphates bind to the serine OH-group in the esteratic site of acetylcholinesterase. This covalent bond is extremely stable, and its hydrolysis takes hundreds of hours. This results in virtually irreversible enzyme inhibition, leading to an accumulation of excess acetylcholine in synapses.
In medicine, OPs (such as armin and echothiophate) are used only topically to treat glaucoma—they induce miosis and lower intraocular pressure. Echothiophate is hydrophilic, meaning it penetrates the conjunctiva poorly, minimizing the risk of systemic effects, and its aqueous solutions are stable.
OPs are widely used outside of medicine:
- Insecticides: malathion, parathion. In the bodies of insects and mammals, they undergo bioactivation (substitution of a sulfur atom with oxygen) to form highly toxic metabolites (malaoxon, paraoxon).
- Chemical warfare agents: soman.
Toxicokinetics and Clinical Presentation of Poisoning
Due to their high lipophilicity, OPs are readily absorbed even through intact skin, mucous membranes, and the lungs. They accumulate in adipose tissue, integrate into cell membranes, and deposit on vascular endothelium and erythrocytes. The poison is excreted in bile but reabsorbed in the intestine (enterohepatic circulation), leading to prolonged retention in the body and a risk of secondary intoxications.
Acute poisoning is characterized by generalized overstimulation of M- and N-cholinergic receptors due to excess acetylcholine.
Muscarinic (M-cholinomimetic) effects (parasympathetic overactivation):
- Eyes: marked miosis (pinpoint pupils), lacrimation.
- Secretions: profuse sweating, salivation, excessive bronchial secretions.
- Respiratory: bronchospasm and asphyxia.
- Gastrointestinal and renal: vomiting, abdominal cramps, diarrhea, involuntary urination.
- Cardiovascular: bradycardia, hypotension.
Nicotinic (N-cholinomimetic) and central effects:
- Cardiovascular and vascular: stimulation of sympathetic ganglia, adrenal glands, and the vasomotor center can cause tachycardia and hypertension.
- Muscular: initially twitching (fasciculations), followed by paralysis due to persistent depolarization of the postsynaptic membrane.
- CNS: confusion, psychomotor agitation, seizures, coma. Death results from respiratory center paralysis.
Detoxification and Antidote Therapy
In case of poisoning, rapid decontamination is crucial: remove the poison from the skin using a dry wipe (without rubbing) followed by washing with sodium bicarbonate solution or soapy water; from the GI tract via gastric lavage, adsorbents, and laxatives; from the blood via forced diuresis, hemodialysis, or hemoperfusion.
Specific treatment involves two main approaches:
- Blockade of muscarinic receptors. The primary drug is atropine. It is administered intravenously in high doses to control peripheral parasympathetic symptoms.
- Enzyme reactivation. Cholinesterase reactivators are administered. They contain an oxime group that is attracted to the phosphorus moiety of the poison. The oxime detaches the OP residue from the enzyme (dephosphorylation), restoring acetylcholinesterase activity.
There is a phenomenon known as "complex aging": over time, the chemical bond between the enzyme and the OP hardens, rendering reactivators ineffective. Therefore, they must be administered within the first few hours.
Reactivators include:
- Quaternary ammonium compounds (pralidoxime/dipyroxime, aloxime). They cross the blood-brain barrier poorly and act primarily in the periphery.
- Tertiary amines (isonitrozine). They readily penetrate the central nervous system, alleviating both peripheral and central symptoms.
These drugs are administered parenterally in a hospital setting and are strictly contraindicated in poisonings caused by reversible inhibitors (carbamates).