Organophosphate poisoning is an important cause of poisonings. Organophosphate compounds are commonly used as agricultural insecticides. Thus, acute organophosphate pesticide poisoning is widespread in the developing countries. Organophosphate compounds inhibit acetylcholinesterase irreversibly and lead to accumulation of acetylcholine at synapses and plasma. The clinical effects are secondary to acetylcholine excess at cholinergic junctions, in the central nervous system, at nerve-muscle junctions, and at autonomic ganglia. Intermediate syndrome and acute cholinergic crisis are important complications of organophosphate poisonings, and these are the main causes of morbidity and mortality. The diagnosis is based on clinical and laboratory findings including cholinesterase levels. Treatment of organophosphate poisonings consists of supportive care, especially aimed at respiratory complications, and specific antidotal therapy including atropine (as an anti-cholinergic agent) and oximes (as cholinesterase reactivators), such as pralidoxime and obidoxime, but they have failed to improve outcomes in some cases. Recently, some other agents, such as clonidine, magnesium, fluoride and human plasma/plasmapheresis has been investigated in management of organophosphate poisonings.
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KEY WORDS: Organophosphorus, poisoning, insecticide, atropine, oxime.
Currently, hundreds of organophosphate (OP) compounds are produced. These compounds are used extensively for the agricultural medication and as insecticides. These compounds are also applied in chemical warfare. It is an important health problem. They are very toxic and their mortality is high. The use of organophosphate insecticides is responsible for about 100.000 poisoning victims per year world-wide. Mortality rate is 30% in suicidal attempts. Suicidal attempt with these easily accessible agents is a major problem in developing countries, such as Turkey, India, and Sri Lanka. Poisonings are common in children and agricultural workers [1, 2, 3, 4].
Organophosphates are derivatives of phosphoric and phosphothioic acids [3, 4].
THE WAY OF EXPOSURE
These insecticides can be absorbed rapidly via all routes including skin, eyes, respiratory and gastrointestinal systems. The onset of symptoms is quickest after inhalation. Dermal absorption is slower but can results in severe symptoms. Gastrointestinal system is the primary entrance when ingested for a suicidal purpose. The parenteral route is very rare. However, the intravenous intoxications may result in severe symptoms. Organophosphate compounds are lipophilic, and accumulate in fat, liver and kidney [4, 5, 6, 7].
MODE OF ACTION
Organophosphate compounds are powerful inhibitors of carboxylic esterase enzymes such as acetylcholinesterase (AChE) and butyrylcholinesterase (pseudocholinesterase, BuCHe). AChE and BuChE are present in a wide variety of tissues. Acetylcholine (ACh) is a neurotransmitter and mainly has functions at the cholinergic synapses. The cholinergic synapses are postganglionic parasympathetic nerve endings, myoneural junction and both parasympathetic and sympathetic ganglia. Organophosphates strongly inhibit AChE and leads to accumulation of ACh. As a result, muscarinic, nicotinic and central nervous system symptoms appear. Death is generally due to central nervous system depression, ventricular arrhythmias, respiratory failure or paralysis of respiratory muscles [1, 4, 5, 7, 8].
These agents are divided into subcategories based on the type of leaving group present. True phosphates have four oxygen atoms arranged around the phosphorus atom. Phosphorothioates refer to OP compounds containing sulfur. In Phosphonates, the phosphorus bonds directly to carbon. Compounds with phosphorus binding directly to carbon and sulfur called as Phosphonothioates. Phosphoramides have phosphorus bonded to a nitrogen atom. The phosphorothioates (P=S) are more lipophilic than phosphates (P=O) and are stored in fat. The phosphothioates are transformed to active phosphates (P=O) by oxidative desulfuration. Therefore, the onset of symptoms is delayed [4, 5, 6, 7].
The toxicity of compounds with each class varies and toxicity mechanism differs between classes. Elimination occurs chiefly by hydrolysis in the liver; rates of this reaction vary widely from one compound to another. In the case of certain organophosphates whose breakdown is relatively slow, significant temporary storage in body fat may occur. Some organophosphates such as diazinon have significant lipid solubility, lead to delayed toxicity due to late release. Many thiophosphates readily undergo conversion from thions (P=S) to oxons (P=O). Conversion occurs in the environment under the influence of oxygen and light, and in the body, mainly by the action of liver microsomes. Oxons are much more toxic than thions, but oxons breakdown more readily [3, 4, 5, 8].
Within one or two days of initial organophosphate binding to AChE, some phosphorylated acetylcholinesterase enzyme can be de-phosphorylated (reactivated) by the oxime antidote pralidoxime. Then, the enzyme- phosphoryl bond is strengthened by loss of one alkyl group from the phosphoryl adduct, a process called aging. Pralidoxime reactivation is therefore no longer possible, although in some cases, improvement has still been seen with pralidoxime administration days after exposure [3, 4, 8, 9]. W.H.O. Classification of Organophosphorus Pesticides is seen at Table 1 [5, 9, 10].
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MECHANISM OF ACTION
Organophosphates are esters, thiol esters or acid anhydride derivatives of phosphorus-containing acids [3, 4, 5]. Organophosphates interact with AChE and some other esterases (ChE- BuChE). This interaction is depends on the structure of the OP compounds and type of enzyme. The OP compound must be in the oxon (P=O) form for inhibition. Thioates (P=S) may be activated in vivo to oxons. The signs of intoxication are closely related with concentration of circulating oxons [3, 4, 5, 9].
Natural course of intoxication
The inhibition of AChE is a progressive reaction. The concentration of circulating oxons increases until reaching to a peak level. Then, this concentration declines depending on metabolic factors and concentration of the compound. However, the inhibition of AChE will continue to increase. For these reasons, there is no significant relationship between the oxon levels and the severity of intoxication. The clearance of oxons is related with their chemical structures [3, 4, 5, 8, 9].
Reactivation of AChE may occur spontaneously. This reaction is important for the outcome of the OP poisoning because only a relatively small amount of neural AChE is required to maintain vital functions. This reaction closely depends on the chemical classes of the compounds. The spontaneous reactivation of dimethyl phosphoryl groups is rapid. However, dietyl phosphoril OPs have a long half-life, and their reactivation is slow [3, 4, 5, 8, 9].
The aging is time dependent and means loss of ability of reactivation of the enzyme by oximes. This depends on pH, temperature and chemical structure of OP compounds [3, 4, 5, 8, 9].
Clinical findings of organophosphate poisoning are attributable to the accumulation of acetylcholine at the cholinergic synapses. The severity of poisoning is determined by the toxicity of the organophosphate and by the rate of AChE inhibition [1, 8, 11].
Muscarinic findings include cough, bronchoconstriction, increased bronchial secretions, increased sweating, hypersalivation, nausea, vomiting, diarrhea, tenesmus, increased lacrimation, bradycardia, hypotension, blurring of vision, miosis and urinary incontinence [1, 3, 11, 12, 13].
Nicotinic features include fasciculation, muscular cramps, weakness, palor, hypertension and tachycardia [1, 3, 5, 11, 12, 13].
Central nervous system (CNS)
Central nervous system features include headache, tremor, anxiety, emotional lability, apathy, depression, drowsiness, confusion, ataxia, weakness, coma, Cheyne-Stokes respiration, convulsion and hypotension [1, 3, 5, 11, 12, 13].
Intermediate syndrome has been defined as delayed development of proximal and diaphragmatic muscle paralysis after resolution of the initial cholinergic signs and symptoms. Intermediate syndrome may result in prolonged requirement of mechanical ventilation. This syndrome occurs in approximately 10-40% of the patients with organophosphate poisoning. This rate was found as 19% of the patients in our study previously published. The causes of this syndrome are still controversial. However, some factors may be responsible [1, 5, 14]:
1.The prolonged effects of oxons
2.The prolonged inhibition
3.The inhibited neuromuscular transmission due to nicotinic stimulation
4.Inadequate oxime treatment? [5, 14, 15].
De Bleeker et al.  concluded that the best explanation was pre- and post-synaptic dysfunction of neuromuscular transmission.
Organophosphate-induced delayed neuropathy (OPIDN) is a rare complication of OP poisoning. This syndrome is manifested by weakness or paralysis and paresthesia of the extremities. Generally, it occurs 1-3 weeks after exposure. Neuropathy target esterase (NTE) may be responsible for this syndrome. This enzyme is a membrane-bound protein with high esterase catalytic activity whose physiological function is not known [4, 5, 16, 17, 18].
OP compounds lead to inhibition of AChE (neurotoxic) or the phosphorylation of NTE (neuropathic). As inhibition of the two different enzymes is followed by distinct neurologic consequences in exposed subjects, it would be useful to distinguish between the neurotoxic and neuropathic OP agents [4, 5, 16, 17, 18].
Other systemic effects of organophosphate compounds
Immunity: It was shown that parathion suppressed IgM and IgG responses to sheep erythrocytes. This is from a direct action of acetylcholine on the immune system or secondary to the toxic chemical stress. Organophosphate poisoning may also lead to influenza-like symptoms. Leukocytosis is another common finding in organophosphate poisoning. We previously reported that a decrease in the leukocyte count to normal levels was paralleled closely by the improvement of clinical signs, and that the time to recovery from intoxication was shorter in patients without leukocytosis [16, 19, 20, 21].
Metabolic and endocrinologic effects: Hyperglycemia is a common finding. Non-ketotic hyperglycemia and glycosuria may be observed. Pancreatitis and hyperkalemia were reported. The changes in the diurnal pattern of plasma adrenocorticotrophic hormone have been reported. Cortisol, ACTH and prolactin may increase during acute intoxication. Similarly, OPs may affect thyroid functions, and euthyroid-sick syndrome may occur. These conditions may be related to the effects of acetylcholine, direct effect of organophosphate compounds and stress caused by intoxication [16, 22].
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Cardiovascular effects: Hypertension, hypotension, arrhythmias and sudden death may occur. Main causes of these complications are probably hypoxia, metabolic acidosis and electrolyte imbalances. High acetylcholine levels may have a negative inotropic effect on muscarinic M2 receptors. ECG changes are not responsive to atropine. Prolonged QT is generally sign of bad prognosis [1, 16, 23, 24].
Reproduction: Organophosphate poisoning may affect FSH levels in humans. We previously showed that FSH levels decreased during OP poisonings . In experimental animals, OP poisoning during pregnancy causes pre- and postnatal death and congenital abnormalities [16, 25].
The diagnosis may be difficult. First step in diagnosis is anamnesis. Patients or their relatives may give some information about compound. The physician must be persistent to learn the name of compound, because not all cholinesterase inhibitors are organophosphates. Clinical and laboratory findings may be helpful.
Cholinergic findings are important. However, amanita muscarina and carbamate insecticides may result in similar findings [1, 4, 11, 12, 26].
If available, the OP insecticides or their metabolites may be detected from body fluids. But, this is a difficult and an expensive analysis, and it is usually performed for investigations. Erythrocyte-acetylcholinesterase confirms the diagnosis, and provides a guide to the severity of poisoning. Plasma cholinesterase also confirms the diagnosis, but does not give information about severity of intoxication. Measurements of plasma and erythrocyte acetylcholinesterase may be used for monitoring of patients. Electrophysiological studies may be important in evaluation of intermediate syndrome [1, 3, 4, 5, 11, 12].
Other laboratory findings
Organophosphate poisonings have very variable laboratory results. Hyperglycemia is a frequent finding, and blood glucose levels may give information about the course of poisoning. Oxidative tissue injury may result in a high level of lactic dehydrogenase. Another frequent finding is leucocytosis, and may give some information about prognosis [1, 11, 12, 13, 21, 26].
The following parameters may be preferred for monitorization;
1-Clinical findings, including muscarinic and nicotinic effects
4-Serum levels of OP compounds and oxons
5-Serum levels of oximes and atropine
Additionally, blood glucose levels and white blood cell counts may be useful [1, 3, 21, 27].
General management and supportive care
The principles of general managements are similar to other acute poisonings;
1. Removing the patients from the contaminated environment, or gastric decontamination,
2. Removal of contaminated clothing,
3. Washing skin and eyes with water and soap,
4. Maintaining respiration, and assess circulation,
5. Symptomatic treatment,
6. Control of convulsions, and agitation,
7. Monitoring [1, 5, 16, 28].
Respiration must be maintained. Intubate the patient and aspirate the secretions if necessary. Mechanical ventilation may be necessary. In cases of oral ingestion, mouth-to-mouth contact should be avoided. If clothes are exposed to OP compound, contaminated clothes should be removed and the skin washed with water and soap [1, 5, 16, 28, 29].
Atropine is a life-saving agent in OP poisonings and may be adequate in mild cases. Atropine blocks the effects of ACh at muscarinic receptors. Toxic reaction to atropine results from its anticholinergic properties. It may have interpersonal variations. Idiosyncrasy may occur at the unusual doses. Allergic reactions were reported. Other systemic findings are tachycardia, tachypnea, hyperthermia, confusion, delirium, psychotic reactions and seizures. The initial dose should be 1-2 mg intravenously, repeated at 5>10 min intervals (or 0.5-2 mg/h infusion) until signs of atropinisation occur. Atropine therapy should be maintained until there is complete recovery [1, 5, 16, 30, 31].
Glycopyrolate is an anti-cholinergic agent. It is twice as potent as atropine for peripheral effects. However, penetration of glycopyrolate across the blood-brain barrier is lower than atropine. Thus, it is not used for the effects of OP compounds on central nervous system. Glycopyrolate may be used orally, intramuscularly and intravenously. Recommended dose of glycopyrolate is 1 mg bolus every 10-15 minutes until anti-muscarinic effects appear [16, 31].
Scopolamine has central and peripheral anti-muscarinic effects. It crosses the blood-brain barrier. However, administration of this drug during later stages of the intoxication may cause CNS effects, without providing sufficient protection .
Phosphorylated cholinesterases can be reactivated by oximes. Oximes are antidotes against organophosphate compounds. These agents are useful in restoring active AChE and improving the nicotinic effects of acetylcholine are not antagonized by atropine .
The use of oximes in the treatment of OP poisonings is controversial. It may be unnecessary in cases of mild intoxication. However, it is difficult to predict an early stage of intoxication, since clinical findings are not always correlated with severity of intoxication. However, oximes have some important side effects and oximes may be unsuccessful in cases of severe poisoning [1, 5, 30, 32, 33].
Failure of oxime therapy
In some cases, oxime therapy may fail to prevent mortality and morbidity. Possible reasons for failure of oxime therapy are:
1- The dose and the duration of therapy may be inadequate, 2- while oximes are rapidly cleared from the body, the half-lives of organophosphate compounds could have been very long because of a slow release from adipose tissue, 3- treatment with oxime may be started too late (this may be attributed to aging of enzymes), and 4- people with the DG70 mutation (this mutation is carried by 1 in 50 people in North American and European populations) of butyrylcholinesterase may be resistant to re-activation by oximes [5, 34, 35, 36].
Side effects of oximes
Transient hepototoxicity may occur. This is generally related with plasma levels of oximes. In addition, cholinesterase inhibition may be seen due to oximes [30, 32, 36].
Types of oximes
Pralidoxime: Intravenous bolus dose of pralidoxime is 1000 mg. Therapy must be maintained by 200-400 mg (8-10 mg/kg/h infusion) every 6-12 h. Total dose of pralidoxime is not clear.
Obidoxime: Intravenous bolus dose of pralidoxime is 250 mg. The maintenance dose of obidoxime is 0.4 mg/kg/h.
HI-6 dicloride: Intravenous bolus dose of HI-6 dicloride is 500 mg. Upper limit of doses is not known.
HL>-7: One of the most effective oximes is HL>-7. It may be used to treat the patients with organophosphate poisoning.
Efficacy of oximes
The efficacy of obidoxime and pralidoxime are similar in methamidophos poisonings. Obidoxime is most effective oxime in paraoxon poisoning. In cases of diclorvos and malaoxon, the activities of obidoxime and HL>-7 are higher than other oximes [1, 30, 32, 36].
Diazepam has been useful in the management of convulsions after OP poisoning. It may have some anti-cholinergic effects. Diazepam has been shown to increase the effects of atropine and oxime. Diazepam may prevent some of the undesired CNS effects of atropine [5, 11, 12, 16].
De Silva et al. (33) reported that atropine alone seemed to be as effective as atropine plus pralidoxime in the management of acute OP poisonings. However, the dose of pralidoxime may be inadequate in this study. Moreover, plasma oxime and cholinesterase levels were found to be correlated with clinical improvement in some studies. This finding is inconsistent with the report of De Silva et al. But, this issue will remain controversial, since randomized controlled studies are considered unethical in OP poisonings [33, 37].
An uncontrolled animal study showed that bicarbonate administration decreased mortality by 85%. It is reported that a rice of each pH unit resulted in 10-fold increase in hydrolysis of organophosphate compounds. However, clinical data need to be confirmed by future randomized investigations [5,38].
Kiss and Fazekas  reported that the premature ventricular contractions caused by OPs were controlled with magnesium. Magnesium also reverses neurophysiological effects of OP poisonings. These effects may be due to prevention of the direct toxic effects of OP compounds on sodium-potasium-ATPase [16, 40].
Mice, pretreated with clonidine, were protected from some toxic manifestation of soman. Increased survival rates, reduction in central nervous system symptoms, including tremor and straub tail, were reported. The protective effects of clonidine may be due to blockade of ACh release and of postsynaptic muscarinic receptors, and transient inhibition of AChE. Similarly, pretreatment of mice with atropine and sodium fluoride had a greater antidotal effect than atropine alone against the toxic effects of soman and sarin. The antidotal effect of sodium fluoride is probably due to its antidesensitising action at nicotinic receptors [16, 41, 42]. However, the role of fluoride and clonidine in OP poisonings needs further studies.
The role of plasma cholinesterase in patients with organophosphate poisoning is not clear. BuChE is generally considered to have no natural physiological function. However, it has been shown that exogenously administration of butyrylcholinesterase could be effective therapy for sequestration of OPs in the circulation before they inhibit AChE at physiologically important target sites [43,44,45]. Li et al. showed that BuChE did have a natural physiological function at certain sites and, more generally, serves as a backup to AChE in supporting and regulating cholinergic transmission. The backup role is likely to be important when AChE activity is compromised or absent, as in knockout mice . BuChE in plasma can also bind to OP and inactivate it, thereby protecting the AChE. One molecule of BuChE is required to neutralize one molecule of OP. It has been shown in animal models. When applied to human, a relatively large (stoichiometric) amount of enzyme was required to neutralize OP in vivo. However, a significant improvement in OP/enzyme stoichiometry may be achieved in vitro as well as in vivo by combining enzyme pretreatment with oxime reactivation [47,48,49]. Ashani concluded that well-timed administration of BuChE can prevent initial physiological crisis, development of intermediate syndrome and delayed toxicity following exposure to OPs .
Annealed murine erythrocytes containing a recombinant phosphotriesterase provided striking protection against the lethal effect of paraoxon, an active metabolite of an agricultural pesticide, parathion. Phosphotriesterase hydrolyzes paraoxon to the less-toxic 4-nitrophenol and diethylphosphate. This enzyme was encapsulated into carrier erythrocytes by hypotonic dialysis with subsequent resealing and annealing. When these carrier cells were administered in combination with pralidoxime chloride and atropine, a marked synergism was observed .
Fresh frozen plasma includes many plasma proteins including cholinesterase. Epstein et al. showed that banked bloods and fresh frozen human plasmas have adequate cholinesterase activity during days of storage. Thus, the authors recommended bank blood transfusion in the management of prolonged apnea resulting from a deficiency of plasma cholinesterase. Jenkins et al. found that the apparent half-life of cholinesterase was 10 days in patients who received 460 ml human plasma. In another study, Gary et al. showed that half-life of cholinesterase was 3.4 day after blood transfusion. These results suggest that fresh frozen plasma is a source of cholinesterase, and can be used in the management of patients with low cholinesterase levels. Fresh frozen plasma has been used to replenish cholinesterase in some patients with low cholinesterase levels . Zhong et al. suggested that the transfusion of fresh blood may prove useful in the treatment of OP poisoning.
Plasmapheresis is a non-selective method with a potential to remove harmful or toxic substances from the circulation. Plasmapheresis provides a chance to give active cholinesterase, by rapidly removing undesired inactivated plasma cholinesterase [57,58]. We published a case report showing that plasma exchange therapy may increase plasma cholinesterase levels. This therapy can provide extra time for elimination of organophosphate compounds from human body, reactivation of acetylcholinesterase by oximes, and for restoration decreased plasma cholinesterase levels by liver. However, the clinical importance of this therapy is not clear. The effects of plasma cholinesterase on neuromuscular system and central nervous system needs to be studied further and thus, clinical studies must be organized. In a study, we showed that fresh frozen plasma has significant amount of cholinesterase, and that plasma therapy could increase plasma cholinesterase levels in patients with low plasma cholinesterase levels due to OP poisonings. The administration of plasma may prevent the development of intermediate syndrome and related mortality. Accordingly, plasma (fresh frozen or freshly prepared) therapy may be suggested as an alternative or adjunctive treatment method in patients with organophosphate pesticide poisoning, especially in cases not given pralidoxime. But, further randomized controlled and animal studies are required to inference a definitive result [59, 60].
Organophosphate poisoning is an important health problem and has important mortality. There is a problem in the treatment of OP poisonings. Thus, new treatment methods have been investigated. This is a large area for investigators.