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Organophosphorus_and_carbamate poisoning

Dr. R. S. Verster BVSc, BVSc (Hons), MSc e-mail Insecticides are used on a massive scale worldwide and it is thus inevitable thataccidental poisoning of humans and animals will occur. Organophosphors andcarbamates are responsible for a substantial number of poisoning cases. Intentionalpoisonings are often committed by criminals, who insert aldicarb granules inside meatbaits. A survey in 2003 in Gauteng confirmed that this unacceptable practice causedillness and death of many dogs. The treatment of such cases is usually based on arudimentary understanding of the poison and the objective of this article is to broaden thescope of knowledge of the pathophysiology, diagnosis and holistic management of suchcases. 2. Physiological mechanism of acetylcholine A quick review is necessary to understand the role of this neurotransmitter. Acetylcholineacts as the neurotransmitter between nerve footplates and innervated cells of autonomicganglia, the adrenal medulla, parasympathetic neuroeffector junctions, some sympatheticneuroeffector junctions, somatic neuromuscular junctions and certain regions of thecentral nervous system. Acetylcholine produces excitation in some tissues e.g. smoothmuscle of the gastrointestinal tract, but causes inhibitory responses in other tissues e.g.
myocardium. Depolarisation of the postsynaptic membrane is characterized by anincrease in permeability of the membrane to both Na+ and K+ ions, resulting in excitatoryeffects. On the other hand, inhibitory effects are due to hyperpolarization of themembrane caused by a selective increase in membrane permeability to K+, but not Na+.
Acetylcholine is able to combine with the esterophilic and anionic sites of bothmuscarinic and nicotinic receptors due to its molecular structure. The duration of actionof acetylcholine is limited, due to the inactivation by acetylcholinesterases. The organophosphor’s phosphate radical binds to the active site (the serine hydroxylgroup) of acetylcholinesterase. This binding is considered irreversible as after a period oftime aging (caused by dealkylation of the organophosphorus moiety on the inhibitedenzyme) occurs. Phosphorylated enzymes are inactive and unable to hydrolyzeacetylcholine at the synaptic - and myoneural junctions. The consequence is theaccumulation of acetylcholine with prolonged effects at the receptors. Plasmacholinesterase activity takes 4 - 6 weeks to return to baseline levels and erythrocyteacetylcholinesterase activity may take up to 5 - 7 weeks.
A sub-acute syndrome, referred to as organophosphor-induced delayed neuropathy(OPIDN) may occur 7 - 14 days after exposure, but occasionally up to 21 days later. It ischaracterized by an asymmetrical sensory-motor axonopathy as result of the inhibition of neuropathy target esterase (or neurotoxic esterase [NTE]), which is different fromacetylcholinesterase. Only neurotoxic organophosphors bind irreversibly, by means of phosphorylation, toNTE. This process starts with hydrolysis of an ester or amide bond, leaving an ionizedacidic group on the phosphorus atom. If exposure to an appropriate neurotoxicorganophosphor results in more than 70 % inhibition of NTE, OPIDN usually follows.
Not all organophosphors are neurotoxic, although they can also bind to NTE. As such,these non-neurotoxic organophosphors may paradoxically prevent neurotoxic effects bycompeting for NTE and do not undergo “aging”. The most severe clinical sign associated with OPIDN is paralysis of the limbs, whilemoderate cases show high-stepping gait and ataxia with the absence of pain.
Histologically, the lesion involves a process known as Wallerian degeneration of the longaxons of the peripheral nerves, as well as the ascending and descending tracts of thespinal cord. There is a loss of the myelin sheath, proliferation of Schwann cells withmacrophage accumulation. The thick myelinated fibres are more affected than the thinunmyelinated fibres. Carbamates react with the serine group on acetylcholinesterase to yield a carbamylationof the serine hydroxyl group. The carbamylation of acetylcholinesterase is reversible andthe carbamylated complex will hydrolyze in time, usually within 48 hours. This isdifferent from the organophosphors, which bind the esterases irreversibly and newenzyme is only resynthesized after 20 – 30 days. The accumulated acetylcholine excessively stimulates cholinergic receptors (muscarinic,nicotinic and in the central nervous system). Muscarinic effects such as salivation,lacrimation, urination, vomiting, diarrhoea, bradycardia, bronchoconstriction withexcessive bronchial secretions and miosis are dominant. Nicotinic effects manifest astremors, muscle stiffness, weakness and paralysis. Central nervous system effectsinclude restlessness, confusion, ataxia, convulsions and cardiorespiratory depression.
Mortalities are commonly attributed to respiratory failure.
Post-mortem findings are mostly non-specific (e.g. congestion and cyanosis) and notconsistent. Lesions include rupture of large bronchi, pulmonary oedema and emphysemaand petechiation of some organs. Other lesions that have been reported are pancreatitisand enteritis in dogs and myopathy of the diaphragmatic and intercostal muscles in severecases. 8. Diagnosis of organophosphor and carbamate poisoning The history and clinical signs are important criteria in the diagnosis of suspectedpoisoning. Confirmation of toxicity can be obtained by analyzing the stomach or rumencontents for the presence of the organophosphors or carbamates. Determination of bloodcholinesterase activity is also a good indicator of organophosphor poisoning as itquantifies enzyme activity.
Variations in acetylcholinesterase activity between species are too great to establish ageneral reference range and are therefore, a critical factor that influences interpretation oflaboratory results. Thus, a database with normal values is needed for each species.
Erythrocyte acetylcholinesterase inhibition is a useful tool to aid in the diagnosis oforganophosphor poisoning in cattle and sheep, because 90 % or more of the totalcholinesterase is found in the red blood cells. Dogs and cats, on the other hand, havesimilar pseudocholinesterase and acetylcholinesterase activities. Cholinesterases inwhole blood, plasma or brain are inhibited to a similar degree in goats, therefore, anydepression of cholinesterase activity is a reliable index of exposure to organophosphors.
Samples collected during the post mortem examination should therefore include stomach/rumen contents, whole blood (if possible), blood clots, brain, eyes (ocular fluid) and liver.
Reduction of cholinesterase activity to less than 25 % of normal is seen in severe cases,but a 50 % reduction is considered a significant inhibition. Although the determinationof cholinesterase activity is the gold standard for confirmation of organophophorpoisoning it is not reliable to confirm exposure to carbamates, as the cholinesterasesspontaneously reactivate and give false negative results. 9. Treatment of organophosphor and carbamate toxicosis In companion animals it would appear that mild intoxication could be successfullytreated, although the more severe cases usually die, despite intensive treatment. The most important treatment is repeated parenteral administration of atropine at 0.1 - 0.2mg/kg in dogs and cats. The dose of atropine is 0.25 - 0.5 mg/kg in cattle and up to 1 mg/kg in sheep. A total dose of 65 mg is recommended for the average horse. The total doseof atropine in humans is only 2 mg intravenously. Atropine is a competitive antagonist ofacetylcholine. Atropine has no effect on nicotinic receptors and will not counteractmuscle tremors, weakness or paralysis. Diphenhydramine dosed at 1 - 4 mg/kg per osevery 6 - 8 hours may be useful to counteract the nicotinic effects. Even a dose of 5mg/kg diphenhydramine is acceptable.
Enzyme reactivators are useful in the treatment of organophosphor poisoning, but notwith carbamate poisoning, as the acetylcholinesterase inhibition in the latter is reversible,the enzyme will re-activate spontaneously in a short period of time irrespective oftreatment. The reactivators are used in organophosphor poisoning because of stronger andlonger inhibition of acetylcholinesterase. They must, however, be administered within 24hours before “aging” occurs and, preferably, within the first 12 - 18 hours. Pralidoxime chloride (2-PAM) is administered at 10 - 15 mg/kg 2 - 3 times a day in dogs and cats. Thereactivator competes for the phosphate moiety of the organophosphor compound andreleases it from the acetylcholinesterase enzyme. The clinician should also remove the poison to prevent further exposure and absorbtion.
Further absorbtion from the stomach of dogs can be avoided by administering theemetics, apomorphine (0.04 mg/kg i/v or 0.08 mg/kg i/m or s/c or syrup of ipecac (1 - 2ml/kg p.o. [not more than 15 ml in total]). For cats the dosage of syrup of ipecac is 3.3ml/kg p.o. Gastric lavage in small animals or rumenotomy in large animals can also beconsidered.
Adsorbants e.g. activated charcoal 1 - 4 g/kg p.o. are very effective in binding ingestedpesticides. A cathartic must be used at the same time, because activated charcoalbecomes stationary in the gastro-intestinal tract and slowly releases the adsorbed toxin.
The cathartic promotes passage of the activated charcoal and elimination of the adsorbedtoxin via the faeces.
Additional supportive treatment must be given, which could include light anaesthesia ordeep sedation and fluid therapy until the dog has eliminated the poison. References1. Aaron C K, Howland M A1994 Insecticides: Organophosphates and carbamates. In Goldfrank’s Toxicologic Emergencies 5th Edition Goldfrank L R, Florenbaum N E,Lewin N A, Weisman R S Howland M A, Hoffman R S (ed) Appleton & Lange,Norwalk 1105 - 1114 2. Adams H R 1988 Cholinergic pharmacology. Autonomic drugs. In Veterinary Pharmacology and Therapeutics Booth N H, McDonald L E (ed) Iowa StateUniversity Press, Iowa 117 – 123 3. Barret D S, Oehme F W, Kruckenberg S M 1985 A review of organophosphorus ester-induced delayed neurotoxicity. Veterinary and Human Toxicology 27(1): 22 -37 4. Beasley V R, Dorman D C 1990 Management of toxicoses. The Veterinary Clinics of North America: Small Animal Practice 20(2): 307 – 337 5. Blakley B R, Yole M J 2002 Species differences in normal brain cholinesterase activities of animals and birds. Veterinary and Human Toxicology 44(3): 129 - 132 6. Brown J H, Taylor P 1996 Muscarinic receptor agonists and antagonists. In Hardman J G, Limbard L E (chief-ed) Goodman & Gilman’s The Pharmacological Basis ofTherapeutics 9th Edition. McGraw-Hill, New York 141-145 7. Buck W B, Bratich P M 1986 Activated charcoal: Preventing unnecessary death by poisoning. Veterinary Medicine: Food Animal Practice 81: 73 – 77 8. Chambers J E, Carr R L 2002 Acute toxicities of organophosphates and carbamates.
In Massaro E J (ed) Handbook of Neurotoxicity Humana Press, Totowa (1): 3 –15 9. Clemmons R M, Meyer D J, Sundlof S F, Rappaport J J, Fossler M E, Hubbell J, Dorsey-Lee M R 1984 Correction of organophoshate-induced neuromuscularblockade by diphenhydramine. American Journal of Research 45(10): 2167 – 2169 10. Cordoba D, Cadavid S, Angulo D, Ramos I 1983 Organophoshate poisoning: Modifications in acid base equilibrium and use of sodium bicarbonate as an aid in thetreatment of toxicity in dogs. Veterinary and Human Toxicology 25(1): 1 – 3 11. Desire B, Saint-Andre S 1987 Inactivation of sarin and soman by cyclodextrins in vitro. Experientia 43(4): 395 – 397 12. Dorman D C 1995 Emergency treatment of toxicoses. In Bonagura J D, Kirk R W (ed) Kirk’s Current Veterinary Therapy 12th Edition W B Saunders Co.
Philadelphia 211 – 217 13. Ecobichon D J 2001 Toxic Effects of Pesticides. In Klaasen C D (ed) Casarett and Doulls Toxicology: The Basic Science of Poisons 6th Ed. Mcgraw-Hill, NewYork 763 – 810 14. Fikes F D 1990 Organophosphorous and carbamate insecticides. Veterinary Clinics of North America: Small Animal Practice 20(2): 353-367 15. Haddad L M 1983(a) The organophoshate insecticides. In Haddad L M, Winchester J F Clinical Management of Poisoning and Drug Overdose W BSaunders Company, Philadelphia 704 - 710 16. Hansen S R 1995 Management of organophoshate and carbamate toxicoses. In Bonagura J D, Kirk R W (ed) Kirk’s Current Veterinary Therapy 12th Edition WB Saunders Co, Philadelphia 245 – 248 17. Howland M A, Aaron C K 1994 Pralidoxime. In Goldfrank’s Toxicologic Emergencies 5th Edition Goldfrank L R, Florenbaum N E, Lewin N A, WeismanR S Howland M A, Hoffman R S (ed) Appleton & Lange, Norwalk 1117 - 1118 18. Meerdink G L 1989 Organophosphorus and carbamate insecticide poisoning in large animals. The Veterinary Clinics of North America: Food animal Practice5(2): 375 – 389 19. Mosha R D 1993 The toxicology of organophosphorus insecticides: A review.
Veterinary Bulletin CAB International, Wallingford 63: 1039 – 1050 20. Stevens J T, Breckenridge C B 2001 Crop protection chemicals. In Hayes A W (ed) Principles and Methods of Toxicology 4th Ed. Taylor & Francis, Philadelphia583 – 591 21. Stuart L D, Oehme F W 1982 Organophoshorus delayed neurotoxicity: A neuromyelopathy of animals and man. Veterinary and Human Toxicology 24 (2):107 -118 22. Tecles F, Ceron J J 2001 Determination of whole blood cholinesterase in different animal species using specific substrates. Research in Veterinary Science 70: 233 -238 23. Tecles F, Subiela S, M, Bernal L J, Ceron J J 2000 Use of whole blood for spectrophotometric determination of cholinesterase activity in dogs. The VeterinaryJournal 160: 242 - 249



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