Pesticide poisoning is a severe issue among developing country populations, specially in rural agricultural regions, where pesticides usage percentage is high & where access to pesticides is poorly controlled. 2
Pesticide poisoning is usually based on organophosphate exposure. The toxicity of organophosphate is mainly due to their inhibition of acetyl cholinesterase. These compounds are absorbed in to the human body through all accessible routes, including the skin, lungs, gastrointestinal tract, and conjunctiva; it may also trespass the skin by injection, although this is a rare occurrence. Out of organophosphate insecticides, parathion & malathion are mostly used. Some of them are used medically for the treatment of glaucoma & (rarely) myasthenia gravis.Parathion ( O,O-diethyl-O-p-nitrophenyl phosphorothiotase ) is one of the most toxic, and most organophosphate poisoning have been caused by this compound. Malathion ( diethyl mercaptosuccinate S-ester with O,O-dimethyl phosphorodithioate ) is one of the less toxic organophosphate insecticides. 3
Organophosphate compounds are powerful inhibitors of carboxylic ester hydrolases, including acetyl cholinesterase ( acetylcholine acetyl-hydrolase, 188.8.131.52 ) which we find in human erythrocytes, nerves, synapses, & skeletal muscle; & cholinesterase ( acetylcholine acyl-hydrolase, 184.108.40.206 ), present in human plasma ( serum ) & liver. These esterases are categorized as following.
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Substrate specificity ( acetyl cholinesterase hydrolyses acetyl-Î²-methylcholine but very little benzoylcholine, propinoylcholine, or butyrylcholine,meantime the opposite occurs with cholinesterase )
Substrate inhibition ( acetyl cholinesterase is inhibited by acetylcholine concentrations equal to or greater than 4mM or higher and cholinesterase by concentrations higher than 100 mM )
Organophosphate generally inhibits those two enzymes. 3
Non-synaptic acetyl cholinesterase ( AchE ) is postulated to maintain excitability & to initiate and propagate action potential in nerve and muscle by regulating active and passive transport of electrolytes.patients with paroxysmal nocturnal haemoglobinuria, erythrocyte acetyl cholinesterase activity is decrease, particularly in erythrocytes that are readily lysed upon the addition of complement ( Kunstling & Rasse, 1969 ). However symptoms are detected in familial reduction of erythrocyte acetyl cholinesterase ( Johns, 1962 ). Cholinesterase is considered to excite cardiac & smooth muscles locally, & to provide free choline in acetylcholine synthesis by hydrolyzing butyrylcholine ( Clitherow et al, 1963 ) or by dissociating conjugated choline ( Funnel & Oliver, 1965 ). However, there was no clinical manifestation in two family members who had a complete lack of plasma ChE ( Hodgkin et al., 1965 ).
Plasma ChE is synthesized in liver, and its activity is a sensitive indicator of liver function. The syndrome of genetically inherited qualitative adaptation of plasma ChE produces hypersensitivity to succinylcholine, a cholinesterase inhibiter used as a muscle relaxant in anesthesia, but patients with this syndrome don't appear to be having any other symptoms. Therefore, the effect of organophosphorus compound is primarily, if not entirely, illusrtated by the inhibition of AChE cholinergic synapses.
At the cholinergic synapses, acetylcholine is released from nerve endings as the neurohumoral transmitter in response to the nerve impulse, and initiates excitation by reacting with the receptor. Acetylcholine is then hydrolyzed, as follows:
(1) the acetylcholine is bound to AChE, the quaternary nitrogen to the anionic site and the carboxyl group to the esteratic site, forming a substrate-enzyme complex;
(2) choline is split off, leaving acetylated AChE;
(3)And then reacts with water, dissociating into acetic acid and active AChE. This reaction completes rapidly and the synapse becomes ready for the next impulse.
In cases of poisoning, AChE is bound with organophosphorus compound, its organic residue dissociates, leaving the phosphate group bound with the esteratic site of AChE. Since the rate at which this phosphorylated AChE dissociates is slow as to be practically negligible, organophosphorus compounds are said to be Ì’ Ì’irreversible Ì“ Ì“ inhibitors. As the result of AChE inhibition, acetylcholine molecules accumulate at the synapse, initially causing excessive excitation and later leading to the blockage of synaptic transmission. The inhibition of AChE is considered as an extremely slow enzymatic hydrolysis of the organophosphorus compound molecule.
The toxicity of these compounds in vivo doesn't always match their AChE-inhibiting activity in vitro, owing to differences in their metabolism in the body. The rate at which they are absorbed and transported varies, depends on the nature of the compounds, the vehicle, and the characteristics of the ports accessed. A substantial proportion of the absorbed compound doesn't reach the cholinergic synapse because it is bound with non-synaptic cholinesterase or is detoxified in liver or in other sites. Also certain organophosphorus compounds are converted into more toxic derivatives in vivo.
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Since synaptic AChE activity has been measured only experimentally ( Namba & Grob, 1970), blood cholinesterase activity is used to assess the degree of inhibition of synaptic AChE. Signs and symptoms of poisoning by organophosphorus compounds occur when more than 50% of the plasma ChE or erythrocyte AChE is inhibited, and therefore the threshold level of synaptic AChE inhibition is probably about 50%. Recovery of blood cholinesterase takes about 2 weeks in patients with mild poisoning. However, the recovery of synaptic AChE appears to be rapid, since signs and symptoms disappear within 24 hours in mild or moderately severe poisoned patients. Since inhibition by organophosphorus compound is Ì’ Ì’irreversible'' the recovery of cholinesterase is probably due to replacement and not reactivation. Since the recovery of tissue cholinesterase and detoxifying takes a long time, repeated exposures to organophosphorus compounds, even at levels below the toxic does, decrease these protective mechanisms, resulting in increasingly greater exposure of synaptic AChE to the compounds and finally producing inhibition powerful than the threshold level.
The cholinergic synapses, in which acetylcholine is the transmitter, include the synapses of the central nervous system, neuromuscular junctions, sensory nerve endings, ganaglionic synapses of both sympathetic and parasympathetic nerves, postganglionic sympathetic nerve terminals that innervate the sweat glands and blood vessels, sympathetic nerve terminals (without ganglionic synapses ) in the adrenal medulla, and all postganglionic parasympathetic nerve terminals. Most of the postganglionic sympathetic nerve terminals are adrenergic, nor epinephrine serving as the transmitter. The cholinergic and adrenergic manifestations are generally antagonistic. Most of the manifestations of poisoning by organophosphorus compounds are in agreement with excessive cholinergic action. Exceptions- e.g., tachycardia and increased blood pressure-are explained by overwhelming cholinergic effects on the central nervous system, sympathetic ganglionic synapses, or adrenal medulla ( Paulet, 1954; Dirnhuber & Cullumbine, 1955; De Burgh-Daly & Wright, 1956; Hornykiewicz & Kobinger, 1956; Polet & De Schaepdryver, 1959 ).
SIGNS AND SYMPTOMS OF ACUTE POISONING
The time gap between exposure to organophosphorus insecticides and the onset of signs and symptoms varies from minutes to hours, but in most cases less than 12 hours. Manifestations that occur more than 24 hours after the last exposure usually cannot be attributed directly to the insecticides.
The severity of poisoning is classified by clinical manifestations and the degree of inhibition of plasma ChE. The classification serves as a guide for prognosis and therapy. In mild poisoning, the manifestations are predominantly due to the stimulation of parasympathetic nerve endings. Manifestations resulting from the stimulation of other nerve endings appear in moderate or serve poisoning. Impulse generation at some sensory ending and their synapses in the central nervous system is cholinergic, but the sensory signs are not clearly identified.
The characteristic central nervous system manifestation is the disturbance of consciousness, which occurs in patients with severe poisoning and may appear without circulatory or respiratory disturbance. Mental signs such as anxiety, insomnia, excessive dreaming, and difficulty in concentration may occur as prodromal manifestations or after the disappearance of acute somatic manifestations.
Miosis and muscle fasciculation are valuable objective manifestations, and are found in about 50% of the patients. Muscle fasciculation occur in moderate or severe poisoning, particularly in the early stage, and disappear in later stages either because of improvement, with the disappearance of neuromuscular stimulation, or because of the advance of poisoning, with depolarizing neuromuscular block. Miosis occurs in patients with poisoning of any severity, generally lasts throughout the course of the illness, and is a good indicator of the effectiveness of treatment. However, miosis and muscle fasciculations may not be present even in severe poisoning. The most important manifestation and the usual cause of death is respiratory difficulty caused by weakness of the respiratory muscles, paralysis of the respiratory centre, bronchospasm, and increased bronchial secretion. Cardiac manifestations-including atrial fibrillation, conduction block, and ventricular fibrillation and flutter -may occur, but usually in the terminal stage. Recently there have been more reports of cardiac manifestations in poisoning by organophophorus compounds because of prolonged courses resulting from improved respiratory care ( Namba et al., 1970; Barckow et al., 1969; Harris et al., 1969; Heitmann & Felgenhauer, 1969; Singh et al., 1969). Tachycardia and increased blood pressure occur in the initial stage and bradycardia and decreased blood pressure in the later stages.
Patients with moderate or severe poisoning may have a low-grade fever, not related to infection, for about 1 week. Hyperglycaemia and glycosuria are often present in severe poisoning. Judging from the relatively mild hyperglycaemia accompanied by glycosuria, a lowered renal threshold for glucose excretion is also present. The absence of acetone bodies differentiates the condition from diabetic coma, except for coma in diabetes resulting from hyperosmolarity. Urobilinogen is present in the urine of about 50% of the patients on the first day. In moderate or severe poisoning there is leucocytosis, with a white-cell count of up to 20 000 per mm3 and with an increased number of neutrophils and a decrease in the proportion of lymphocytes and monocytes. In cases of severe poisoning, eosinophils are usually not found on the first day, unless there has been per-existing eosinophilic leucocytosis (usually resulting from parasitic or allergic conditions).
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Local exposure to organophosphorus insecticides produces comparatively severe local manifestations. Exposure of the eye causes severe miosis and lachrymation. Dermal exposure may cause copious sweating. Absorption from the respiratory tract may cause tightness of the chest initially and dyspnoea and bronchial secretions later. The ingestion of organophosphorus compounds is often followed by severe abdominal pain, diarrhoea, and vomiting. Fortunately, the vomiting reduces the amount of the compound that is absorbed.
The signs and symptoms and prognoses listed in the Annex are based on observations of poisonings that occurred following field spraying with parathion and parathion-methyl. The situation is different in patients who have ingested (or injected) a large quantity of an organophosphorus compound; in such patients, the ingested compound in the gastrointestinal tract or other tissues is continuously released, and consequently the course of the poisoning is long, necessitating continuous treatment. The results of studies of extremely toxic organophosphorus compounds (the warfare gases) and of studies on experimental animals may not always be applicable to the poisoning of man by organophosphorus insecticides. For example, only a few minutes after the inhibition of AChE by warfare gases the enzyme can no longer be reactivated by pralidoxime, although it takes hours to reach this condition when AChE is inhibited by organophosphorus insecticides. Man is more sensitive to organophosphorus compounds than are experimental animals and shows signs and symptoms-particularly central nervous system manifestations-earlier than do the latter. Therefore, the quantity of absorbed organophosphorus compound necessary to produce a given effect may be relatively smaller in man.
Prognosis in relation to the severity of poisoning is indicated in the Annex. Untreated parathion poisoning leads to death within 24 hours of the onset of manifestations: if an untreated patient is alive after 24 hours, he will recover. Patients who are under treatment may die from 24 hours to I week after the onset of manifestations.
DIAGNOSIS OF ACUTE POISONING BY ORGANOPHOSPHORUS COMPOUNDS
Diagnosis depends on
(1) history or evidence of exposure to organophosphorus compounds within the previous 24 hours,
(2) signs and symptoms of Poisoning (see the Annex)
(3) inhibition of the cholinesterase activity of the blood or other tissues
(4)And the effectiveness of atropine and pralidoxime.
With most patients, a history or evidence of exposure to organophosphorus compounds within 24 hours before the onset of symptoms can be obtained. The patients may retain a characteristic garlic-like odour for several days. In gastric aspirate or urine and on the skin or clothing organophosphorcs compounds can he identified by means of gas or thin-layer chromatography, or their presence can be demonstrated by the inhibition of cholinesterase activity in vitro. Metabolites of organophosphorus compounds-e.g., p-nitrophenol, a metabolite of parathion, parathion-methyl, Chlorthion, dicapthon, and EPN -may also be detected in urine Excretion of p-nitrophenol in the urine of 4 patients with severe parathion poisoning. However, a history of exposure and the detection of organophmphorus compounds or their metabolites do not always indicate that signs and symptoms are due to poisoning by such compounds. For example, cerebrovascular accidents may develop during the use of organophosphorus insecticides. Although p-nitrophenol was detected in the urine of 75 (83%) of 90 farm workers who had sprayed parathion in fields, none of them had any symptoms, and the p-nitrophenol concentration was not parallel with the degree of inhibition of serum ChE activity (Namba et al., 1971).
In poisoning by organophosphorus compounds the determination of erythrocyte AChE is theoretically preferable, but the determination of plasma ChE is advantageous in that it is simpler. Following the administration of pralidoxime, the erythrocyte AChE level indicates its effectiveness; plasma ChE indicates the prior presence of cholinesterase inhibition even after the recovery of erythrocyte AChE activity as a result of pralidoxime treatment (Namba & Hiraki, 1958). A finding of normal blood cholinesterase activity excludes systemic poisoning by organophosphorus compounds. In acute poisoning, manifestations generally occur only after more than 50% of the plasma ChE is inhibited, and the severity of manifestations parallels the degree of inhibition. However, this correlation holds true only in the initial stage of acute poisoning, and inhibition of the activity remains even after the patient becomes symptom-free.
PERSISTENT MANIFESTATIONS OF POISONING
Poisoning by organophosphorus insecticides is an acute process, but there have been occasional reports of persistent manifestations.
Polyneuropathy may be a persistent manifestation of organophosphorus insecticides, since some non- insecticide organophosphorus compounds cause this condition. For example, tri-o-tolyl phosphate caused an outbreak of "Ginger Jake" paralysis in the USA in 1930 and 1931 and one of polyneuropathy in Morocco in 1959 in which thousands of people were poisoned by ood contaminated with this compound. The use of mipafox as an insecticide was abandoned after neuropathy occurred among workers in a pilot plant. In animal experiments persistent neuropathy has been caused by triaryl phosphates, S,S,S-tributyl phosphorotrithiote, diisopropyl phorofluoridate, and mipafox, none of which is used as an insecticide, and by the insecticide Dursban, while Chlorthion, dernelon, diazinon, dichlorvos, parathion, paraoxon, and trichlorfon did not produce paralysis (Namba at al., 1971). The development of neuropathy is not related to the inhibition of cholinesterase, and is not prevented by the administration of pralidoxime or atropine. A possible cause may be the inhibition of other as yet unidentified esterases.
The present author has not found neuropathy among patients with acute poisoning by organophosphorus insecticides. One patient with peripheral neuropathy was exposed to non-insecticide organophosphorus compounds and their intermediates, which were synthesized in a research laboratory (Numbs et al., 1971). No neuropathy was found during a 5-year follow-up of 398 workers who were exposed to organophosphorus insecticides, 108 of whom had had acute poisoning (Kovarik & Sercle, 1966). In the literature there are reports of only 7 patients who developed neuropathy that might have been caused by these insecticides: 3 patients had been exposed to trichlorfon, 2 to parathion, 1 to parathion, EPN, and other insecticides, and 1 to malathion (Namba et al., 1971; Humperdinck, 1951; Sutov & Varanhiva, 1969).
Persistent central nervous system manifestations were first reported to include impaired memory, depression, impaired mental concentration, schizophrenic reaction, and instability, lasting far 6-12 months in 16 subjects who had been exposed to organophosphorus insecticides for 18 months to 10 years (Gershon & Shaw, 1961). However, an epidemiological study showed that admissions to mental institutions in areas where organophosphorus insecticides were widely used were no greater than in areas where they were little used (Stoller et al., 1965). There have been many reports of mental or behavioural changes, but most of these symptoms are transitory or are caused by non-insecticide organophosphorus compounds (Namba et al., 1971).
There have been isolated reports of patients with increased serum bilirubin or abnormal liver function, and with histological abnormalities of liver structure with oedema or mild degeneration of parenchymal cells, hyperaemia, fat infiltration, or lymphoid-cell infiltration in liver obtained post-mortem or by biopsy. One month after 70 persons had suffered acute parathion poisoning, jaundice occurred in 4.3% of the patients, liver enlargement in 14.3%, increased urinary urobilinogen in 30%, and a positive serum Takata reaction in 17.1% (Maruyama, 1954). Of 12 patients with acute poisoning by parathion or other organophosphorus insecticides, 8 showed abnormal results of liver function tests (Lutterotti, 1961). However, our patients with acute poisoning showed normal results of liver function tests throughout the period of observation, except for increased urinary urobilinogen limited to the first day of acute poisoning, and persistent liver enlargement in one patient (Namba et al., 1971). A similar finding was reported in 15 patients who had been exposed 5 or more times to organophosphorus compounds during a 2-year period (Kaulla & Holmes, 1961).
Other possible persistent effects of organophosphorus insecticides included changes in coagulation factors, effects on the fetus, dermatitis, stomatitis, bronchial asthma, and impotence (Namba et al., 1971). The number of reported patients is small, and no relationship between cause and effect has been established.
Cardiac manifestations of acute organophosphate poisoning
Cardiac complications associated with organophosphate poisoning are not fully appreciated by many physicians. Most occur during the first few hours after exposure. Hypoxaemia, acidosis, and electrolyte derangements are major predisposing factors for the development of these complications. Once the condition is recognised, the patient should immediately be transferred to an intensive or coronary care unit where appropriate monitoring and resuscitative facilities are available.
THE CHEMOTHERAPY OF POISONING BY
Oximes (with or without atropine as an adjunct) have recently been used successfully in the treatment of humans poisoned by organophosphate anticholinesterases. The discovery of the nature of the biochemical lesion in organophosphate poisoning has permitted the design of drugs to repair specifically this particular lesion. This paper reviews historically the researches which led to the development of pyridine-2-aldoxime methiodide (PAM) and its corresponding methanesulphonate (P2S), the two most successful oximes yet tried, and summarizes the theoretical background to their rational use. Organophosphates are lethal because they inactivate cholinesterase due to phosphorylation of the enzyme's active centre. Consequently two rational lines of treatment are: (a) To find some compound which could be phosphorylated as rapidly as the enzyme and which, if introduced into the body, would protect the enzyme from inhibition by competing with it for the organophosphate, or (b) to find a compound which would restore the activity of the inhibited enzyme by dephosphorylating it. In both cases essentially the same type of compound is needed, namely one with a high intrinsic reactivity with organophosphoryl compounds, in (a) with the inhibitor itself or in (b) with the phosphorylated enzyme. Types of compounds with either or both of these properties are o-dihydroxybenzene derivatives, metal chelates, hydroxylamine, hydroxamic acids, and oximes. Pyridine-2-aldoxime methiodide and methanesulphonate have been by far the most successful as reactivates and in the treatment of poisoned animals. A brief account is given of the range of compounds for which PAM has been shown to be a successful antidote in intact animals and of the ability of PAM to overcome the signs and symptoms of poisoning both in animals and in man.
In most cases PAM was given without atropine. In all but five of the more severe cases, signs of parathion poisoning almost completely disappeared after the intravenous injection of about 1 g. of PAM. In the other cases further improvement was generally obtained by giving additional PAM. Only one patient died despite being given 2 g. of PAM together with 2 mg. of atropine. This patient had taken a very large amount of parathion with the intention of committing suicide. The most striking effects on the course of poisoning were the disappearance of the signs of neuromuscular block, fasciculations and muscle cramps (which cannot be countered by atropine), and also the complete disappearance of disturbances of consciousness. Some of the muscarinic signs such as salivation and excessive bronchial secretion were also dispersed. The remarkable effect of PAM in clearing consciousness was also noted in a case of suicidal parathion poisoning in Denmark (Karlog, Nimb, and Poulsen, 1958). This effect is difficult to explain if the blood-brain barrier in man is as resistant to the penetration of PAM as it appears to be in animals. The ability of PAM to counteract the nicotinic signs of anticholinesterase poisoning in man has been confirmed (Grob and Johns, 1958) but no corresponding effect was found on muscarinic or central nervous system signs. The discrepancy between these results and those with parathion illustrated above remains unexplained. However there is some evidence that after poisoning with the same anticholinesterase all species don't react equally well to a given reversing agent. So it is impossible to predict human response to PAM treatment solely on the basis of observations on animals. Pyridine-2-aldoxime methiodide (and its corresponding methane sulphonate, P2S) is relatively harmless to animals in therapeutically active doses, and it has reported using animal experiments that at least 30 mg/kg could be given intramuscularly to man with impunity (Davies and Willey, 1958). In ordinary human subjects P2S has been given without ill-effects in doses of over 5 g. orally or, as a 15 % aqueous solution, in doses of over 1 g. intramuscularly (Ladell, 1958). For intramuscular injection P2S is preferable to PAM because of its enormously ascend water solubility.Pyridine-2- aldoxime methiodide itself has been administered intravenously to man quite safely in doses of up to 2g. (Namba and Hiraki 1958; Grob and Johns, 1958).