Organophosphates: poisoning and management.: Organophosphates: poisoning and management. Prepared by : Belal A El- Dabour PHOSPHORUS:: PHOSPHORUS: Phosphorus is essential for the human body. in bones and teeth (hydroxyapatite- a Calcium Phosphate salt). Phosphorylation and DE phosphorylation of sugars and proteins Phosphorus is a component of DNA & RNA. ATP,NADH & NADPH Phospholipids that form all cell membranes . Acid-Base balance. Industrial Uses:: Industrial Uses: Organophosphates are widely employed both in natural and synthetic applications because of the ease with which organic groups can be linked together . They are the basis of many insecticides, herbicides, and nerve gases. The are also widely used as solvents , plasticizers & extreme pressure additives . Medically important uses:: Medically important uses: Organophosphate pesticides degrade rapidly by hydrolysis on exposure to sunlight, air, and soil. Their ability to degrade made them an attractive alternative to the persistent organochloride pesticides, such as DDT. Although organophosphates degrade faster than the organochlorides , they have greater acute toxicity , posing risks to people who may be exposed to large amounts Insecticides & Nerve Gases : Organophosphate pesticides (as well as sarin and VX nerve agent) irreversibly inactivate acetylcholinesterase , which is essential to nerve function in insects, humans, and many other animals. Organophosphate pesticides affect this enzyme in varied ways, and thus in their potential for poisoning . Concepts:: Concepts: Insecticides posses the Thiophosphoryl P=S functionality. Thiophosphoryl compounds are not active inhibitors of acetyl cholinesterase in either mammals or insects; in mammals, metabolism tends to remove lipophilic side groups from the phosphorus atom while in insects it tends to oxidize the compound, thus removing the terminal sulfur and replacing it with a terminal oxygen, which allows the compound to more efficiently act as an acetylcholinesterase inhibitor . Nerve Gases were modified to contain thetetraethyl pyrophosphate Group which made them readily toxic, e.g : Sarin , VX . Slide 6: Some organophosphates are lipid soluble and can dissolve in lipid and produce latent toxic effect. Altogether, over 100,000 OP compounds have been screened for their insecticidal properties, of which over 100 have been developed for commercial use ! How they get into body?: How they get into body? Inhaled Ingested Transdermal occupational Household. Generally oral or respiratory exposures result in signs or symptoms within three hours. while symptoms of toxicity from dermal absorption may be delayed up to 12 hours. Toxicology:: Toxicology: Some critical proportion of the tissue enzyme mass must be inactivated by phosphorylation before symptoms and signs of poisoning become manifest. At sufficient dosage, loss of enzyme function allows accumulation of Ach peripherally at / cholinergic neuroeffector junctions (muscarinic effects), skeletal nerve-muscle junctions, and autonomic ganglia (nicotinic effects ) as well as centrally . Clinical Features: Clinical Features Ex- posure by inhalation results in the fastest appearance of toxic symptoms, followed by the gastrointestinal route and finally the dermal route. Acute Cholinergic Syndrome: minutes to hours Central Peripheral Muscarinic Peripheral Nicotinic Intermediate Syndrome OPIDN: Delayed peripheral neuropathy Neurocognitive dysfunction Cholinergic Effects – “DUMBELS”: Cholinergic Effects – “DUMBELS” D iarrhoea U rination M iosis B radycardia , Bronchorrhoea , Bronchospasm E mesis L acrimation S alivation The “SLUD” syndrome S alivation, L achrymation, U rination, D efecation Nicotinic Effects: Nicotinic Effects Respiratory difficulty respiratory arrest diaphragmatic weakness Muscle Weakness fasiculations clonus tremor Stimulation of sympathetic nervous system Mydriasis , hypertension, tachycardia re-entrant dysrhythmias cardiorespiratory arrest Further explanation: Further explanation The critical symptoms in management are the respiratory symptoms. Sufficient muscular fasciculations and weakness are oftenobserved as to require respiratory support; respiratory arrest can occur suddenly. Likewise, bronchorrhea and bronchospasm may often impede efforts at adequate oxygenation of the patient . The primary cause of death is respiratory failure , and there usually is a secondary cardiovascular component. The classic cardiovascular sign is bradycardia which can progress to sinus arrest. However, this may be superseded by tachycardia and hypertension from nicotinic ( sympathetic ganglia) stimulation. CNS effects:: CNS effects: Serious Effects Coma Respiratory centre depression. Seizures Other effects Confusion Memory loss Disorientation Delirium Take Notice :: Take Notice : Miosis is often a helpful diagnostic sign since the other signs may be confused with other conditions. Intermediate Syndrome:: Intermediate Syndrome: Some insecticides induce an intermediate syndrome. This syndrome occurs after resolution of the acute cholinergic crisis, generally 24-96 hours after exposure . It is characterized by acute respiratory paresis and muscular weakness, primarily in the facial, neck, and proximal limb muscles. In addition, it is often accompanied by cranial nerve palsies and depressed tendon reflexes. this syndrome lacks muscarinic symptomatology, and appears to result from a combined pre- and post-synaptic dysfunction of neuromuscular transmission. Clinical importance : Clinical importance Delayed respiratory failure leads to death if not aware of it or prepared for it. Symptoms do not respond well to atropine and oximes ; therefore treatment is mainly supportive. Chronic Effects: OPIDN: Chronic Effects: OPIDN OPIDN: Organophosphate induced delayed neuropathy Rarely, certain organophosphates have caused damage to the afferent fibers of peripheral and central nerves and associated with inhibition of neuropathy target esterase (NTE). This delayed syndrome has been termed organophosphate-induced delayed neuropathy (OPIDN), and is manifested chiefly by weakness or paralysis and paresthesia of the extremities. persist for weeks to years. Confirmation:: Confirmation: RBC acetylcholinesterase activity: provides a measure of the degree of toxicity. determine the effectiveness of antidote therapy. plasma (or pseudo-) cholinesterase activity: more easily performed. not correlate well with the severity of poisoning. a depression of 25% or more is strong evidence of excessive organophosphate absorption. Slide 20: Wake Up Dude ! Treatment:: Treatment: D o not delay the treatment until laboratory confirmation is obtained. Treatment:General Strategy: Treatment:General Strategy ABCD Drugs Detox . ABCD:: ABCD: As in all emergencies: AIRWAY: Generally OK, but may have bronchoconstriction. BREATHING Due to muscle fasciculations (twitching), the diaphragm may be paralysed, so they is a need to elective intubation and ventilation. Improve tissue oxygenation as much as possible before administering atropine, so as to minimize the risk of ventricular fibrillation . Deliver 100 % oxygen via facemask Continued…: Continued… CIRCULATION : The degree of hypotension depends on relative actions of muscarinic vasodilator effects, and the effects of ACh on the nicotinic receptors in the ANS ganglion, which causes arteriolar vasoconstriction. Treatment is ATROPINE Drugs:: Drugs: Atropine Pralidoxime . Atropine:: Atropine: The objective of atropine antidotal therapy is to antagonize the effects of excessive concentrations of acetylcholine at end-organs having muscarinic receptors . Atropine does not reactivate the cholinesterase enzyme or accelerate disposition of organophosphate. Recrudescence of poisoning may occur if tissue concentrations of organophosphate remain high when the effect of atropine wears off. Atropine is effective against muscarinic manifestations, but it is ineffective against nicotinic actions, specifically muscle weakness and twitching , and respiratory depression. Slide 27: Administer atropine sulfate : intravenously , intramuscularly if intravenous injection is not possible. through an endotracheal tube if initial IV access is difficult to obtain . Depending on the severity of poisoning, doses of atropine ranging from very low to as high as 300 mg per day may be required, or even continuous infusion. administer simultaneously to resuscitation Glycopyrolate may be used as an alternative to Atropine . What if you give too much Atropine?: What if you give too much Atropine? Anticholinergic Syndrome: Hot as hell Blind as a bat Red as a beet Dry as a bone Mad as a hatter . Pralidoxime:: Pralidoxime : Cholinesterase reactivating agent that are effective in treating both muscarinic and nicotinic symptoms. Use within 48 hours after poisoning. Use with concurrent of atropine. Use only for moderate to severe Organophosphate poisoning and not carbamate . can be given orally or as an infusion. Slide 30: Benzodiazepines : (for psychotic symptoms). Furosemide: may be considered if pulmonary edema persists in the lungs even after full atropinization . Other Treatments under investigation:: Other Treatments under investigation: Magnesium Reduces acetylcholine release Blockage pre-synaptic calcium channels Limited human studies Clonidine Decrease the presynaptic synthesis and release of acetylcholine. Central nervous system > peripheral cholinergic synapses Diazepam Diazepam reduces respiratory failure (rats) and cognitive deficit (primates) Postulate “uncoordinated stimulation of the respiratory centres decreases phrenic nerve output”. Contraindications:: Contraindications: The following drugs are contraindicated in nearly all organophosphate poisoning cases: morphine , succinylcholine , theophylline , phenothiazines , and reserpine. Adrenergic amines should be given only if there is a specific indication, such as marked hypotension. Detoxification:: Detoxification: Skin decontamination. Gastrointestinal decontamination. Prophylactics ??? Skin decontamination:: Skin decontamination : In patients who have been poisoned by organophosphate contamination of skin : clothing , hair, and/or eyes, decontamination must proceed concurrently with whatever resuscitative and antidotal measures are necessary to preserve life . Flush the chemical from the eyes with copious amounts of clean water. clothing should be removed and a complete bath and shampoo given while the victim is recumbent, using copious amounts of soap and water. Attendants should wear rubber gloves as vinyl provides no protection against skin absorption. Wash the chemical from skin folds and from under fingernails . Gastrointestinal decontamination:: Gastrointestinal decontamination: In cases of poisoning due to ingestion. Emesis Gastric Lavage Use of Activated charcoal . Prophylaxis ?: Prophylaxis ? Neither Atropine nor Pralidoxime should be used as prophylactic drug . Prophylactic dosage with either atropine or pralidoxime may mask early signs and symptoms of organophosphate poisoning and thus allow the worker to continue exposure and possibly progress to more severe poisoning. Organophosphates as weapons:: Organophosphates as weapons: As a weapon, organophosphates may be spread through the air. It also can be an “agent of opportunity.” This means that someone could explode the vehicle of transportation (truck or train) that is being used to ship the chemical, or destroy tanks that store the chemical. The organophosphates would then be released into the air. History : History Chile 's president Pinochet used Sarin to assasinate some of his opponents. It was used during the first gulf war. It was deployed in Halabjah , leading to a death toll of 5000 Kurds. 1994: The Japanese religious sect Aum Shinrikyo released an impure form of sarin in Matsumoto, Nagano . 1995 : Aum Shinrikyo sect released an impure form of sarin in the Tokyo Subway . Thirteen people died . Slide 40: 1998: In the US, Time Magazine and CNN ran news stories alleging that in 1970 U.S. Air Force A-1E Skyraiders engaged in a covert operation called Operation Tailwind , in which they deliberately dropped sarin -containing weapons on U.S. troops who had defected in Laos . CNN and Time Magazine later retracted the stories and fired the producers responsible.