2. Introduction Organophosphate (OP) compounds are a large group of compounds having potential to irreversibly inhibit the cholinesterases, acetylcholinesterase, and neuropathy target esterase (NTE). Not only used as insecticides and pesticides, but also used as chemical warfare agents, petroleum additives, and industrial plasticizers. Serious human exposure leads to both muscarinic (cholinergic) hyperstimulation and nicotinic receptor stimulation.
4. HISTORY First synthesized in the early 1800s when Lassaigne reacted alcohol with phosphoric acid. 1854- Philip de Clermount described the synthesis of tetraethyl pyrophosphate at a meeting of the French Academy of Sciences. Eighty years later, Lange in Berlin and Schrader, a chemist at Bayer AG, Germany, investigated the use of organophosphates as insecticides. However, the German military prevented the use of organophosphates as insecticides and instead developed an arsenal of chemical warfare agents (ie, tabun, sarin, soman). A fourth agent VX was synthesized in England a decade later. During World War II, in 1941, organophosphates were reintroduced worldwide for pesticide use, as originally intended.
5. HISTORY……. Massive OP intoxication from suicidal and accidental events, such as the Jamaican ginger palsy incident in 1930, led to the discovery of the mechanism of action of organophosphates. In 1995, a religious sect, AumShinrikyo used sarin to poison people on a Tokyo subway. Mass poisonings - 2005, 15 victims were poisoned after accidentally ingesting ethion-contaminated food in a social ceremony in Magrawa, India. Nerve agents have also been used in battle, notably in Iraq in the 1980s. Chemical weapons pose a very real concern in this age of terrorist activity.
6. Epidemiology 3 million cases of pesticide poisoning with 2000 deaths occur worldwide, each year. 1 million serious unintentional poisonings occur every year . 2 million people are hospitalized for suicide attempts with pesticides. -Jeyaratnam J. Acute pesticide poisoning: A major global health problem. World Health Stat Q 1990;43:139-44
7. Worldwide mortality studies report mortality rates from 3-25%. The compounds most frequently involved - malathion, dichlorvos, trichlorfon. Mortality rates depend on Type of compound used Amount ingested General health of the patient Delay in discovery and transport Insufficient respiratory management Delay in intubation Failure in weaning off ventilatory support Complications Severe bronchorrhea Seizures, Weakness, and neuropathy Respiratory failure is the most common cause of death. Mortality/Morbidity
8. INDIAN PERSPECTIVE Agricultural pesticides accounted for 12.8% all cases of poisonings. 2/3 rd of the patients were young adults aged less than 30 years, more than half were males. Attempted suicide was the most common intent for poisoning. Majority of deaths were due to poisoning with monocrotophos and endosulfan. SrinivasRao C, Venkateswarlu V, Surender T, Eddleston M, Buckley NA. Pesticide poisoning in south India: Opportunities for prevention and improved medical management. Trop Med Int Health 2005;10:581-8
9. RISK FACTORS FOR OPP Young age Lower socioeconomic strata Unemployment Unstable emotional relationships Psychiatric disorders Alcohol abuse -Van derHoek W, Konradsen F. Risk factors for acute pesticide poisoning in Sri Lanka. Trop Med Int Health 2005;10:589-96.
10. Intoxication Accidental exposure to agricultural pesticides while spraying, through skin and inhalational route. Ingestion of adulterated fruit, flour, or cooking oil, and wearing contaminated clothing. Choudaryet al ., reported a food-borne outbreak of OP compound poisoning.(The kitchen, in which, food was prepared had been sprayed earlier with malathion).
11. Pathophysiology Inhibition of carboxyl ester hydrolases, particularly acetylcholinesterase (AChE). AChE degrades the neurotransmitter acetylcholine (ACh) into choline and acetic acid. ACh is found in the central and peripheral nervous system, neuromuscular junctions, and red blood cells (RBCs).
12. PATHO……. 3 D IMAGE OF AchE Organophosphates inactivate AChE by phosphorylating the serine hydroxyl group located at the active site of AChE. The phosphorylation occurs by loss of an organophosphate leaving group and establishment of a covalent bond with AChE. Once AChE has been inactivated, ACh accumulates throughout the nervous system, resulting in overstimulation of muscarinic and nicotinic receptors. Clinical effects are manifested via activation of the autonomic and central nervous systems and at nicotinic receptors on skeletal muscle.
13. AchE-OP Once an organophosphate binds to AChE, the enzyme can undergo one of the following: Endogenous hydrolysis of the phosphorylated enzyme by esterases or paraoxonases Reactivation by a strong nucleophile such as pralidoxime (2-PAM) Irreversible binding and permanent enzyme inactivation (aging) - Singh G, Khurana D. Neurology of acute organophosphate poisoning. Neurol India 2009;57:119-25
14. Biochemical basis of acute OP poisoning, its reaction with the enzyme acetylcholinesterase, the aging reaction, and reactivation following the administration of oximes
15. CLINICAL FEATURES ACUTE CHOLINERGIC CRISIS INTERMEDIATE SYNDROME DELAYED NEUROPATHY EXTRA PYRAMIDAL,CNS DIPPERS’S FLU
16. Muscarinic syndrome SLUDGE Salivation Lacrimation Urination Diarrhea GI upset Emesis DUMBELS (diaphoresis and diarrhea; urination; miosis; bradycardia, bronchospasm, bronchorrhea; emesis; excess lacrimation; and salivation)
18. Nicotinic syndrome Follows muscarinic syndrome and precedes delayed neuropathy. Referred as 'intermediate syndrome'. Hyperstimulation of the NMJ by acetylcholine initially results in fasciculations, later followed by neuromuscular paralysis which may last for 2-18 days. The paralysis usually involves the ocular, bulbar, neck, proximal limb, and respiratory muscles in that order of severity.
19. Central nervous system syndrome Uncommonly involved in acute OP poisoning and occurs with OP compounds that cross the blood-brain barrier. Depressed mental status and central respiratory drive. In severe poisoning, patients may have convulsive seizures.
20. CHRONIC OP INDUCED NEUROPSYCHIATRIC DISORDERS (COPIND) &EPS BEHAVIOURAL CHANGES IMPAIRED VIGILANCE , INFORMATION PROCESSING , MEMORY DEPRESSION , ANXIETY, IRRITABILITY EPS TREMOR RIGIDITY HYPOKINESIA POOR RESPONSE TO DOPA THERAPY
22. Paralysis Type I: acute paralysis - continued depolarization at the NMJ. Type II (IMS):develop 24-96 hrs after resolution of acute OPP symptoms ,paralysis and respiratory distress,weakness of proximal muscle groups, neck, and trunk, with sparing of distal muscles,Cranial nerve palsies, persists for 4-18 days, may require mechanical ventilation and may be complicated by infections or cardiac arrhythmias. Type III: OP-induced delayed polyneuropathy (OPIDP), occurs 2-3 weeks after exposure to large doses and is due to inhibition of neuropathy target esterase. Distal muscle weakness with relative sparing of the neck muscles, cranial nerves and proximal muscle groups. Recovery can take up to 12 months
25. PERADENIA OPP SCALE-senanayake N ,a scale to asses severity of op intoxication;POPscale.human ex toxicol 1993;12;297-299
26. Diagnosis Based on the characteristic clinical features and history of exposure to a known OP compound. Estimation of serum or RBC cholinesterase level and electrodiagnostic tests . Clinical features of OP poisoning appear when RBC cholinesterase activity is <75% of normal and in clinically overt poisoning it is usually <10%. Serial studies have failed to document a strict relationship between levels of serum cholinesterase and the severity of clinical manifestations and prognosis.
27. Draw blood for measurement of RBC and plasma cholinesterase levels prior to treatment with pralidoxime (2-PAM). RBC AChE represents the AChE found on RBC membranes, similar to that found in neuronal tissue. Plasma cholinesterase is a liver acute-phase protein . It is found in CNS white matter, the pancreas and the heart. RBC cholinesterase is the more accurate. Plasma cholinesterase is easier to assay and is more readily available. Falsely depressed levels of RBC cholinesterase can be found in pernicious anemia, hemoglobinopathies, use of antimalarial drugs, and oxalate blood tubes. Falsely depressed levels of plasma cholinesterase are observed in liver dysfunction, low-protein conditions, neoplasia, hypersensitivity reactions, use of certain drugs (succinylcholine, codeine, morphine), pregnancy, and genetic deficiencies ENZYME ESTIMATION
28. Neurophysiological abnormalities A single supramaximal electrical-stimulus-induced repetitive response A decrement-increment response to high frequency (30 and 50 Hz) repetitive nerve stimulation (RNS) A decremental response to high rate (30 and 50 Hz) RNS -Singh G, Khurana D. Neurology of acute organophosphate poisoning. Neurol India 2009;57:119-25
31. EDX in a 28-year-old man with monocrotophos poisoning. 26 Hrs after poisoning . single supramaximal stimulus induced repetitive response was observed and 30 Hz RNS produced a severe decrement (a) in the abductor pollicisbrevis. Partially corrected following the administration of pralidoxime iodide (2 g intravenous).
33. Median CMAP (i), and RNS at 3 Hz (ii) and 30 Hz (iii) before (a) and after (b, c) pralidoxime administration on day 1 of chlorpyrifos poisoning (calibration: 1 division = 5 ms, 5 mV).
34. Organophosphate-induced respiratory failure - Clinical neurophysiology Multifactorial: Respiratory muscle weakness particularly in the diaphragm, central respiratory depression, and pulmonary factors (pulmonary edema, bronchoconstriction, bronchorrhea). EDX can be of help in differentiating between neuromuscular and nonneuromuscular causes . Low amplitude of the diaphragmatic CMAP correlates well with the need for assisted mechanical ventilation and the reduced amplitude improves with amelioration of the neuromuscular transmission deficit .
35. Treatment-principles ABC GASTIC LAVAGE WASHING SKIN WITH SOAP AND WATER TWICE ADMISSION FOR ATLEAST FOR 5 DAYS PRALIDOXIME 500 mgs,TID*7 DAYS ATROPINE -10 mgs /hr SPONGING EVERY 4 HRS ACTIVATED CHARCOAL THROUGH RYLES TUBE 4 HRLY WITH HOLDINGNG FEEDING FOR ATLEAST 96 HRS
36. Atropine The endpoint for atropinization is dried pulmonary secretions and adequate oxygenation. Tachycardia >140/mt and mydriasis must not be used to limit or to stop subsequent doses of atropine. 1-2 mg IV bolus, repeat q1-5min Pediatric-0.05 mg/kg IV, repeat q1-5min Strongly consider doubling each subsequent dose to rapidly stabilize patients with severe respiratory distress
37. Glycopyrrolate Indicated for use as an antimuscarinic agent to reduce salivary, tracheobronchial, and pharyngeal secretions. Does not cross the blood-brain barrier. Can be considered in patients at risk for recurrent symptoms (after initial atropinization) but who are developing central anticholinergic delirium or agitation. Adult;1-2 mg/kg IV Pediatric;0.025 mg/kg IV
38. Pralidoxime Reactivates the phosphorylatedAChE by binding to the OP molecule. Antidote to reverse muscle paralysis but is not effective once the OP compound has bound AChE irreversibly (aged). Current recommendation is administration within 48 h of OP poisoning. Does not significantly relieve depression of respiratory center or decrease muscarinic effects of AChE poisoning, administer atropine concomitantly to block these effects of OP poisoning. Signs of atropinization might occur earlier with addition of 2-PAM to treatment regimen. 2-PAM administration is not indicated for carbamate exposure since no aging occurs.
39. DOSAGE OF PAM Adult 1-2 g (20-40 mg/kg) IV in 100 mL isotonic sodium chloride soln/D5W over 15-30 min; repeat in 1 h if muscle weakness is not relieved; then repeat q3-8h if signs of poisoning recur. Other dosing regimens; continuous drip; start with bolus of 25-50 mg/kg and then 10-20 mg/kg/h Pediatric 20-40 mg/kg in 100 mL isotonic sodium chloride soln/D5W IV over 15-30 min; repeat in 1-2 h if muscle weakness not relieved; repeat q10-12h prn to relieve cholinergic symptoms Other dosing regimens; continuous drip; start with bolus of 25-50 mg/kg (up to 2 g); then 10-20 mg/kg/h (up to 500mg)
