Organophosphate and Carbomate Insecticides PDF

Organophosphate and Carbomate Insecticides pesticides  Pesticides are group of chemicals used for killing of undesirable pests (both plants & animals).  Classified as  insecticides  rodenticides  fungicides  herbicides Organophosphorus compounds Are used as liq...

Organophosphate and Carbomate Insecticides pesticides  Pesticides are group of chemicals used for killing of undesirable pests (both plants & animals).  Classified as  insecticides  rodenticides  fungicides  herbicides Organophosphorus compounds Are used as liquid or powder. They are absorbed by ingestion, Inhalation or through the skin  Organophosphates and carbomates are used extensively throughout the world.  are involved in about 3 million cases of human poisoning and cause about 40.000 death.  Ach synthesis : choline acetyl transferase Choline + Acetyl CO A Ach (cytoplasm of nerve ending) Acetyl choline esterase Acetyl choline choline + acetate AchE cluster in post synaptic membrane of cholinergic synapse plasma AchE called false AchE capable to hydrolyzing Ach but has different properties Ach receptors  2main types: Muscarinic receptors on smooth muscles & gland, they block by atropine Nicotinic receptors (in sympathetic ganglia small amount of Ach stimulate post ganglion neurons, large amount block transmission of impulses from pre to post neurons) which subdivided to those found in neuromuscular junction & in autonomic ganglia Both receptor are found in large number in the brain. Pathophysiology :  OPCs & carbamate bound to active site of AchE & inhibit it so increase Ach in synapse & neuromuscular junction causing muscarinic & nicotinic s/s. High Ach in post ganglionic muscarinic synapse causes parasympathetic activity of smooth muscles (GIT, lung, heart, bladder & secretary gland) & increase activity of post ganglionic sympathetic receptors for sweat glands…(SLUDGE/BBB).  High Ach at nicotinic motor endplate cause persistent depolarization of skeletal muscles with fasciculations, progressive weakness & hypotonicity. OPs cross BBB causing seizures, respiratory depression & CNS depression. Acute poisoning occurs in: Self-ingestion or injection. Accidental poisoning -due to contamination of food stuff. Swallow of liquid preparations kept at home by children. Dermal contamination due to user ignorance to wear protective clothing. Action:-  Organophosphates and carbomates act by inhibiting cholinesterases  accumulation of acetylcholine at central and peripheral cholinergic nerve endings, including neuromuscular junctions.  Carbomates produce relatively short lived inhibition of cholinesterase, since the carbomate enzyme complex tends to dissociate spontaneously.  Factors Which Determine the Speed of Onset and Severity of Poisoning:- The rate of phosphorylation of the enzyme The rate of spontaneous hydrolysis of the phosphorylated enzyme and release of active enzyme (reactivation).  The rate of ageing of the phosphorylated enzyme complex by the process of dealkylation of the organophosphate component. Once this happens, reactivation is impossible.  Difference between OPs & carbamate is that carbamate hydrolyzed from AchE site within 24 hrs, OPs undergo aging which occur when phosphorlated AchE loses an alkyl side chain & becoming irreversibly inactivated.  Manifestations of Poisoning:- local.  Blistering and redness of the skin  Eye splashes lead to miosis and blurring of vision. Systemic.  The speed of onset depends on the route and magnitude of exposure.  The features of organophosphate and carbomate poisoning are a mixture of peripheral muscarinic effects of excess acetylcholine on  the gastrointestinal tract  bronchi  Heart  bladder  sweat, salivary and lacrimal glands nicotinic actions at neuromuscular junctions and sympathetic ganglia and CNS effects.  Mild Poisoning: * CNS stimulant effect (nicotinic effects) as  Anxiety  restlessness  insomnia  nightmares  tiredness  dizziness  headache *(muscarinic effects):  Nausea  vomiting  abdominal colic  diarrhea  tenesmus  Increased secretions: sweating excessive salivation lacrimation, urination and diarrhea (SLUD Synd-)  Miosis (pinpoint pupil)  Bronchospasm & bronchorrhea  Moderate Poisoning: *Shows nicotinic effects as:  Twitches, muscle fasciculation's, tremors, paralysis Involving respiratory muscles  Fatigue, generalized weakness sufficient to make walking impossible and speech difficult.  Severe Poisoning: *Impaired consciousness *flaccid paralysis of limb muscles (affecting proximal groups more than distal ones) *Pulmonary edema *cyanosis *convulsions and atrial fibrillation. *Depressed respiration, asphyxia  Diagnosis:- -In absence of history of exposure diagnosis is difficult. -Gastrointestinal symptoms with fever and polymorph leucocytosis may lead to wrong diagnosis of gastroenteritis. -Reduction in activity of cholinesterase confirms the diagnosis. -In severe poisoning activity is reduced to less than 10% of normal activity.  Management:- Removal of clothing and washing of contaminating skin with soap and water. Gastric lavage. Blood sample to measure cholinesterase activity Removal of respiratory secretions and correction of hypoxia. Replacement of fluid loss due to vomiting, diarrhea and pulmonary oedema.  Atropine is the drug of choice. Given in a dose of 2 mg intravenously every 10-30 minutes / adult till relief is obtained or signs of atropinization are obvious. (Children 0.02- 0.05 mg/Kg). Diazepam (5-10 mg I/V) to reduce anxiety and restlessness. Mortality rate up to 25% in severe poisoning. oximes Oxime compounds are used as antidotes for nerve agents. A  nerve agent inactivates acetylcholinesterase molecules by phosphorylation of the molecule. Oxime compounds can reactivate acetylcholinesterate by attaching to the phosphorus atom and forming an oxime-phosphonate which then splits away from the acetylcholinesterase molecule. The most effective oxime nerve-agent antidotes are pralidoxime (also known as 2-PAM),  Late complications and acute intoxication include: Cranial nerves and brain stem lesions developed 1-4 days. Peripheral neuropathy due to axonal degeneration starts 2-3 weeks after exposure. Insomnia, inability to concentrate and depression. Paraquat (Bipyridyl Compound) Paraquat is the trade name for N,N′-dimethyl- 4,4′-bipyridinium dichloride, one of the most widely used herbicides in the world. A large majority (93%) of fatalities from paraquat poisoning are cases of intentional self- administration, i.e., suicides. Fatal dose 4 mg/kg Paraquat Pure paraquat, when ingested, is highly toxic to mammals, including humans; potentially leading to acute respiratory distress syndrome (ARDS), and there are no specific antidotes. However, fuller's earth or activated charcoal is an effective treatment, if taken in time. Death may occur up to 30 days after ingestion C.P. of Paraquat poisoning Stage (1) 1 – 5 days Local corrosive action - hemoptysis - ulceration of mucous membranes - nausea, diarrhea - oliguria  C.P. of Paraquat poisoning Stage (2) 2 – 8 days Signs of liver, kidney, cardiac damage - jaundice - fever - tachycardia - myocarditis - respiratory distress, cyanosis - elevated BUN, serum bilirubin C.P. of Paraquat poisoning Stage (3) 3 – 14 days Pulmonary fibrosis - cough, dyspnea, tachpnea - edema, pleaural effusion - atelectasis - low arterial O tension 2 - increased alveolar O tension 2 gradient - respiratory failure  Paraquat Herbicides Diquat 2,4dichlorophenoxyacetic acid Color : Blue-green emetic agent  GSH GSSG.. O2 O2 O H Paraquat Lung Lipid peroxidation Type I and II pneumocyte cell death & alveolitis Lung fibrosis paraquat 1. Basic life support 2. Prevent absorption 2.1 Gastric lavage O2 2.2 Fuller’s earth 2.3 MOM 30 ml q 6 hrs 2.4 Skin decontamination 3. Increase elimination 3.1 Hemodialysis/ Hemoperfusion 4. Modification of tissue toxicities 4.1 Modulate inflammatory responses - Cyclophosphamide 5mg/kg/day IV divided to every 8 hr - Dexamethazone 10 mg IV q 8 hr - Chlorphenairamine 4 mg 1 tab po qid 4.2 Prevent oxidation - Vit C (500mg/amp) 6 g/day IV - Vit E (400 i.u./ tab) 2 tabs qid - N-acetylcysteine (300mg/amp) 50mg/kg every 8 hr Thank You