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Pesticide is a world that is consisted of 2 parts: • Pest = unwanted creature or living • Cide = killing or elimination • Pesticides include several categories such as hebicides, insecticides, fungicides, bacteriocides, etc. • The 3 major groups to be studied in our course are: Insecticides: organophophates. Herbicides: paraquat. Rodenticides: anticoagulants Dr. TAHAR ABDULAZIZ MD, PhD
ORGANOPHOSPHATE TOXICITY • Garden and household pesticides, and in agriculture. • Formulations include liquids, sprays, and powders. • In veterinary medicine they are found in pedicullicide lotions. • Shampoos, aqueous and alcoholic lotions are also used as human pedicullicides and scabicides. • Organophosphate nerve agents may be used as chemical warfare agents. An example was sarin used in the Tokyo subway attacks of 1995. • Parathion is an organophosphate insecticide that is widely used in agriculture in Libya. Dr. TAHAR ABDULAZIZ MD, PhD
Mechanism of Toxicity • OP bind ChE and inhibit its function excess of ACh in synapses and NMJ muscarinic and nicotinic symptoms and signs. • Excess ACh in the synapse can lead to 3 sets of symptoms and signs: • At postganglionic muscarinic synapses lead to SLUDGE/BBB. • At nicotinic motor end plates causes persistent depolarization of skeletal muscle resulting in fasciculations, progressive weakness, and hypotonicity. • OP cross the blood-brain barrier, they may cause seizures, respiratory depression, and CNS depression for reasons not completely understood. • OP bind to RBC cholinesterase & plasma cholinesterase (pseudocholinesterase) in the serum. • The kinetics of the enzyme will reach zero within 10 hours i.e. all enzyme will be in the form of OP-AchE complex, this situation is called aging phenomenon. Dr. TAHAR ABDULAZIZ MD, PhD
Causes Dr. TAHAR ABDULAZIZ MD, PhD
Ach & AChE Dr. TAHAR ABDULAZIZ MD, PhD
Clinical Manifestations • Pesticides can rapidly be absorbed through the skin, lungs, GI tract, and mucous membranes. • Symptoms usually occur within a few hours after GI ingestion and appear almost immediately after inhalational exposure. Dr. TAHAR ABDULAZIZ MD, PhD
cholinergic toxic syndrome 1- Muscarinic effects: SLUDGE/BBB mnemonic S = Salivation L = LacrimationU = Urination D = Defecation G = GI symptoms E = Emesis B = Bronchorrhea B = Bronchospasm B = Bradycardia 2- Nicotinic effects at neuromuscular junctions and autonomic ganglia: weakness, fasciculations, and paralysis. 3- CNS effects may lead to seizures and CNS depression. Dr. TAHAR ABDULAZIZ MD, PhD
Plasma cholinesterase (pseudocholinesterase) & RBC cholinesterase levels • Laboratory evidence of OP poisoning may be obtained by measuring decreases in: • Plasma pseudocholinesterase (PChE) and • RBC acetylcholinesterase (RChE) activities • Significant depression of enzyme activity may occur but still fall within the “normal” range. • It is most helpful if the patient had a pre-exposure baseline measurement for comparison (eg, as part of a workplace health surveillance program). TAHAR ABDULAZIZ MD, PhD (tsoleman@yahoo.com)
a. The RChE activity provides a more reliable measure of the toxic effect; a 25% or greater depression in activity from baseline generally indicates a true exposure effect. b. PChE activity is a sensitive indicator of exposure but is not as specific as RChE activity PChE may be depressed due to genetic deficiency medical illness chronic organophosphate exposure PChE activity usually recovers within weeks after exposure RChEmay recover after several months • Carbamate poisoning produces reversible AchE inhibition, and spontaneous recovery of enzyme activity may occur within several hours, making these tests less useful. Dr. TAHAR ABDULAZIZ MD, PhD
Treatment Dr. TAHAR ABDULAZIZ MD, PhD
Atropine Atropine is a pure muscarinic antagonist that competes with ACh at the muscarinic receptor. Atropine is most commonly given in intravenous (IV) form at the recommended dose of 2-5 mg for adults and 0.05 mg/kg for children with a minimum dose of 0.1 mg to prevent reflex bradycardia. Atropine may be repeated every 5-10 minutes. Severe organophosphate poisonings often require hundreds of milligrams of atropine. Observation of 3 major signs: • dryness of mouth • flushing of face • dilatation of pupils. Dr. TAHAR ABDULAZIZ MD, PhD
Oximes {Pralidoxime (2-PAM)}: Organophosphates bind and phosphorylate one of the active sites of AChE and inhibit the functionality of this enzyme. Oximes bind to the organophosphate, causing the compound to break its bond with AChE. Most of the effects are on the peripheral nervous system because entry into the CNS is limited. The WHO protocol for oxime therapy is recommended for any patient with clinically significant poisoning. Dr. TAHAR ABDULAZIZ MD, PhD
Difference between OP & Carbamates Dr. TAHAR ABDULAZIZ MD, PhD
Complications: 1- Intermediate syndrome (1-4 DAYS AFTER) sudden respiratory paresis, with weakness in cranial nerves and proximal-limb and neck flexor muscles. 2- OP-induced delayed neurotoxicity (OPIDN) (9-14 DAYS) A sensorimotorpolyneuropathy with distal motor weakness and sensory paresthesias in the lower extremities, which may progress proximally and eventually affect the upper extremities. 3- Pancreatitis Pancreatitis has been reported as a rare complication. One case series reported that 12.76% of OP poisonings were associated with acute pancreatitis, though this has not been the experience in other series. Dr. TAHAR ABDULAZIZ MD, PhD
PARAQUAT TOXICITY • Non-selective, water soluble herbicide (weed killer). • It is used since 1962. • It is available as an aqueous concentrate and in granular formulations • In Libya there are 2 compounds: • Gramaxone (yellowish liquid) • Weedol (granulation form) Dr. TAHAR ABDULAZIZ MD, PhD
Pathophysiology • Paraquat is very toxic when ingested. The exact mechanisms of toxicity is not fully understood. • The lethal dose is 1-4 grams. • Lungs are the main target of paraquat due to active, energy-dependent uptake by alveolar type I and II cells. • Skin absorption is poor. Inhalation is a possible route of toxicity Dr. TAHAR ABDULAZIZ MD, PhD
Ingestion is the most common route of toxicity: • Mild: ingestion of less than 20 mg/Kg body weight. • Moderate to severe: ingestion of 20-40 mg/Kg. p • Very severe: ingestion of more than 40 mg/Kg. death may occur within 24 hours but never after more than 7 days. Dr. TAHAR ABDULAZIZ MD, PhD
Mechanism of toxicity • Paraquat may cause lesions in the lung by a mechanism known as redox cycling. These compounds are reduced by cytochrome P450 reductase forming a free radical. • Free radical with tissue macromolecules, one molecule of oxygen is reduced to superoxide that can then be converted to other toxic oxygen species. • These reactive compounds may cause peroxidation of cellular membranes. • The specific toxicity of paraquat to the lung results from the uptake of this compound by lung due to high pulmonary oxygen tension. Dr. TAHAR ABDULAZIZ MD, PhD
Formatio of superoxide radical by PQ Dr. TAHAR ABDULAZIZ MD, PhD
Toxicity may occur through oxidation/reduction cycle producing peroxides and free radicals. • Free radicals are chemical elements that may be positively or negatively charged or neutral but possess a single unpaired electron Dr. TAHAR ABDULAZIZ MD, PhD
Clinical Manifestations Dr. TAHAR ABDULAZIZ MD, PhD
Management • There is no specific treatment; supportive therapy is important. • Gastric lavage with AC • Gastric lavage with aqueous suspension of clay (Fuller Earth or Bentonite clay). • To avoid excessive oxygen administration as this may aggravate lipid peroxidation reactions in the lungs. Significant hypoxemia to be treated with supplemental oxygen; only the lowest oxygen concentration necessary to achieve a pO2 of about 60 mm. • Charcoal hemoperfusion • Hemodialysisanf forced diuresis are not effective Dr. TAHAR ABDULAZIZ MD, PhD
