Irreversible Anticholinesterases (Organophosphorus Compound)
The organophosphorus compounds are powerful inhibitors of cholinesterase. The organophosphorus compounds are the organic esters of phosphoric acid. They inhibits the pseudocholinesterase more powerfully than true cholinesterase. The pharmacological effects of organophosphorus compounds are similar to acetylcholine. As this compounds are highly lipid soluble, so they can cross blood brain barrier & produces CNS toxicity.
The organophosphorus compound can be absorbed by practically all the routes including the G.I tract. These are inactivated in the body by oxidation & hydrolysis the metabolized products are excreted through urine.
Therapeutic use of organophosphorus compounds are limited due to their prolong action & toxicity. These compounds are generally used as insecticide or pesticides. The compound currently favoured for topical use is echothiophate in the concentration of 0.06% for the treatment of glaucoma. The reduction in the intraocular tension with this drug persists for 1 – 3 weeks following a single instillation. The compound however produces a marked ciliory spasm, brow ache, headache, & blurring of vision. The major drawback of long – acting anticholinergic agents is the risk of development of cataract following their prolonged use (6 months or more).
The important organophosphorus compounds are –
1. Therapeutically useful– Diisopropyl fluorophosphate (DEP), Metrifonate, Echothiophate.
2. Insecticides – Fenthion, Malathion, Mipafox, Octamethylpyrophosphoramide (OMPA), Sumithion, Monocrotophos.
3. Highly toxic nerve gases – Tabun, Sarin.
Organophosphorus compound poisoning:
Poisoning with organophosphorus compound occurs to person, who are engaged in spraying insecticide in agriculture fields or it may be accident i.e. constipation of agricultural products, sprayed with insecticide or due to internal ingestion for suicidal purpose.
Both muscarinic & nicotinic actions & symptoms are observed. Due to their muscarinic effect the symptoms are miosis, spasms of accommodation, headache, bronchospasms, increased salivation & bronchial secretion. On ingestion anorexia, nausea, vomiting, abdominal cramp, diarrhoea are generally symptoms of poisoning.
Due to its nicotinic effect the symptoms are muscular fatigue, weakness, fasciculation, twisting of skeletal muscle, tachycardia or bradycardia due to its effects on CNS, there is convulsion, confusion, coma & ultimately death due to respiratory paralysis.
As recommended by the WHO expert committee, “The treatment must be instituted rapidly in order to prevent a fatal outcome.”
1. Remove soiled clothes.
2. Wash soiled skin, eyes.
3. Nurse in prone position.
4. Clear mouth & throat.
5. Gastric lavageis immediate required if the poison has been ingested.
6. Atropine 2mg is given I.M or I.V route immediately & repeated every 15 – 60 minutes until there is dryness of mouth & heart rate is normalized.
7. Artificial respiration, oxygen inhalation is required.
8. Treatment of shock & prophylactic antibiotics are given.
9. Diazepam is some time used in case of convulsion.
10. Some agents like pralidoxime, obidoxime reactivating substances is also used in the treatment of poisoning.
11. Continued vigilance as a relapse may occur as late as a week after apparent recovery.
It is a cholinesterase reactivators.
Mechanism of action: The irreversible inhibition of cholinesterase produced by the organophosphorus compounds is due to phosphorylation of the esteratic site of the enzyme. Oximes are drugs which combine with the phosphoryl groups of these phosphorylated esteratic sites forming soluble complex. This results in setting free the esteratic site & a reactivation of the enzyme.
Uses: The oximes are practically effective in reversing the neuromuscular paralysis due to organophosphorus compounds where atropine is ineffective.
Oximes are mainly metabolized in the liver & the breakdown products are eliminated in urine.
Adverse Effects: They may produce local irritation, drowsiness, giddiness, blurred vision, diplopia, tachycardia & hypotension.
Preparations & dosage:
Pyridine – 2 aldoxime chloride (P – 2 – Am, pralidoxime)injected I.V slowly in the dose of 1gm. The dose can be repeated after 1 – 2 hours.
The maximum total dose is 12gm in 24 hours.
Obidoxime chloride is more potent than pralidoxime. It is given I.V in the dose of 3 – 6mg/kg. The dose can be repeated every 20 minutes.