Organophosphorous insecticides
- 1. ORGANOPHOSPHOROUS INSECTICIDES ORGANIC ESTERS OF PHOSPHOROUS 1
- 2. • The first OP compound synthesized in 1854 by Philipe de Clermont was tetraethyl pyrophosphate • Gerhard Schrader led the exploration of OP compounds that could be used as insecticides • One of the earliest OP insecticides synthesized by Schrader was Parathion • After WWII, thousands of OPs have been synthesized in the search for compounds with species selectivity, i.e. more toxic to insects and less toxic to mammals (malathion) 2
- 3. USES • INSECTICIDES & INSECTICIDE SYNERGISTS • ACARICIDES & RODENTICIDES • SOIL NEMATICIDES • FUNGICIDES & HERBICIDES • DEFOLIANTS • INSECT REPELLANTS • CHEMOSTERILANTS • WAR FARE AGENTS GENERAL FORMULA 3
- 4. •All OP compounds have a pentavalent phosphorus atom & a characteristic phosphoryl bond (P=O) or thiophosphoryl bond (P=S) •OP compounds have two alkyl substituents and a leaving group, which is more labile to hydrolysis than the alkyl group •OPs are esters of phosphoric acid with varying combinations of O, C, S or N •OPs that are derivatives of phosphoric or phosphonic acid possess anti- AChE activity, unlike derivatives of phosphinic acid 4
- 5. •Some OPs (such as dichlorvos, monocrotophos, & trichlorfon) are direct AChE inhibitors •Those of phosphorothioates type (such as bromophos, diazinon, fenthion, & parathion) possess minimal or no anti-AChE & require desulfuration to the analogous oxon before acquiring anti-AChE activity •OPs which are used as defoliants (s,s,s-tributyl phosphorotrithioate & s,s,s-tributyl phosphorotrithioite) & herbicides (glyphosate & gluphosinate) are of very low mammalian toxicity 5
- 6. CLASSIFICATION BASED ON CHEMICAL STRUCTURE •PHOSPHATES AND PYROPHOSPHATES: Paraoxon, Tetraethyl Pyrophosphate (TEPP), Schraden, Dichlorvos •PHOSPHOROTHIOATES: Parathion, Fenthion, Diazinon,ronnel •PHOSPHONATES:Trichlorfon •PHOSPHORAMIDATES: Phospholan, Mephospholan •PHOSPHOROTHIOLATES: Echothiophate, Profenphos •PHOSPHOROHALIDES: Diisopropyl Fluorophosphate (DFP), Sarin •PHOSPHOROCYANIDES: Tabun 6
- 7. CLASSIFICATION (BASED ON STRUCTURE) 7
- 8. DIRECT ACTING •Contain P=O •Directly inhibit AChE •TEPP, dichlorvos, trichlorfon INDIRECT ACTING •Phosphorothioates (P=S) •Inactive anti-AChE •Require activation to oxons •Malathion, parathion, fenthion CLASSIFICATION (BASED ON MODE OF ACTION) 8
- 9. FACTORS AFFECTING TOXICITY Compound Storage- contamination, heat induced isomerisation & pH changes Ambient temperature Species Age Interaction Formulation Impurities Other factors 9
- 10. TOXICOKINETICS •Gain entry into the body mainly through oral, dermal, or inhalation •Lipid soluble, so absorbed from all body surfaces; do not accumulate in any particular tissue •Well distributed in tissue throughout the body •May follow either activation or detoxification, or both •Some transformed to quaternary compounds- cannot enter brain (phosphoroamidates) 10
- 11. •In liver esterases convert OP compounds to water soluble metabolites- rapidly excreted in urine •Hydrolysis of ester linkage markedly reduces its toxicity •Chlorinated Ops are more lipid soluble & residues persist for long time •Residues are detected in the feces, saliva & milk 11
- 12. MECHANISM OF ACTION • Inhibit the enzyme AChE within nerve tissue & at the neuromuscular junctions • ChE are serine hydrolases that catalyze the breakdown of ACh through an acyl-transfer, where water is the acceptor molecule to which the substrate acyl moiety is transferred • A serine O of the active site of ChEs carries out a nucleophilic attack on the electrophilic C of the carbonyl group of ACh, resulting in an acetylated enzyme intermediate & release of choline • Deacetylation occurs when an attacking water molecule (hydroxyl ion) acts as a more effective nucleophile, thereby releasing acetate 12
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- 16. •Interact only with the esteratic site of AChE •The complex formed is very stable as it doesn’t undergo rapid hydrolysis •Restoration of AChE synthesis of new enzyme several weeks •Also inhibit butyryl choline esterse & neurotoxic esterase 16
- 17. • Binding of AChE by different OPs varies in affinity and reversibility • After binding, the enzyme is ‘phosphorylated’, and thus inhibited & is regarded as ‘irreversible’ • Irreversible inhibition of AChE causes accumulation of ACh in the neuromuscular junction, parasympathetic postganglionic terminals in smooth muscles, cardiac muscle & glands PHOSPH ORYLAT ION REACTI VATION AGING REGENE RATION 4 STAGES OF AChE INHIBITION 17
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- 19. CLINICAL SIGNS MUSCARINIC SIGNS •Profuse salivation & sweating • Lacrimation & pupil constriction • Serous or seromucous nasal discharge, bradycardia •Increased respiratory sounds due to bronchoconstriction & excess bronchial secretions, coughing •Pronounced gastrointestinal sounds, colic and diarrhoea due to increased gastrointestinal motility •Vomiting & frequent urination NICOTINIC SIGNS •Muscle fasciculation • Tremors •Twitching •Spasm & hypertonicity causing a stiff gait or rigid stance CNS EFFECTS •Effects vary with species •Severe CNS depression •Anxiety, restlessness & hyperactivity death due to respiratory failure, •Bronchoconstriction &convulsions may be life threatening SLUDD SYNDROME 19
- 20. •Mechanism of action is not very clear •Not due to anti-AChE activity •Polyneuritis, demyelination, sensory disturbances, muscle weakness, tenderness, depressed tendon reflexes, lower and upper motor neuron paralysis CHRONIC OP POISONING 20
- 21. OPIDN/OPIDP • Esters of phosphorus-containing acids produce delayed neurotoxic effects • Tri-o-cresyl phosphate (TOCP) was known to produce delayed neurotoxic effects in man and chicken, characterized by ataxia and weakness of the limbs, developing 10– 14 days after exposure- OPIDN • Renamed as OPIDP now • OPIDP is characterized by distal degeneration of long- and large diameter motor & sensory axons of both peripheral nerves &spinal cord • Among all animal species hen appears to be the most sensitive & used as an animal model • TOCP and certain other compounds have minimal or no anti-AChE property, however they cause phosphorylation & aging of a protein in neurons called neuropathy target esterase (NTE) leading to OPIDP 21
- 22. Post mortem findings •Non specific •Pulmonary edema, congestion, •Coagulative necrosis in liver, cerebral edema •Patches of necrosis in skeletal muscle •Intestinal tract may be dilated & filled with fluid Diagnosis •History •Clinical signs •Estimation of AChE in blood & tissues 22
- 23. TREATMENT •Combined use of atropine sulfate and pyridine-2- aldoxime methochloride (2-PAM) •Before instituting antidotal therapy, monogastric animals, such as dog, should be given gastric lavage •Animals of any species can be given activated charcoal to stop further absorption of insecticides •Animals should be washed thoroughly with water if they are exposed to insecticides dermally •Intravenous (iv) fluid therapy is always beneficial 23
- 24. •Oxygen therapy if cyanosis & dyspnoea are prominent •Washing the animal with plenty of water & detergent • Administration of mineral oil • Keeping the animal quiet & comfortable CONTRAINDICATIONS Neuromuscular blocking Drugs Anesthetics Atropine in cyanotic cats 24