Organophosphates (Organophosphorus Compounds) - Insecticides

INSECTICIDES

These are compounds which kill or repel insects and related species. For example, organophosphates, carbamates, organo-chlorines, pyrethrum and its derivatives (pyrethroids).

Organophosphates (Organophosphorus Compounds)

It is true that calling these compounds “organophosphates” is not correct, and they should be referred to as “organophos-phorus compounds”. But, “organophosphates” is such an irre-sistibly compact expression.

Organophosphates are among the most popular and most widely used insecticides in India. Table 28.1 lists common varieties along with respective brand names.

Physical Appearance

These compounds are available as dusts, granules, or liquids. Some products need to be diluted with water before use, and some are burnt to make smoke that kills insects.

Usual Fatal Dose

Toxicity Rating*:

The following compounds are extremely toxic (LD50: 1 to 50 mg/kg), or highly toxic (LD50: 51 to 500 mg/kg)—

Chlorfenvinphos, Chlorpyriphos, Demeton, Diazinon, Dichlorvos, Dimethoate, Disulfoton, Ediphenphos, Ethion, Fenitrothion, Fensulfothion, Fenthion, Fonophos, Formothion, Methyl Parathion, Mevinphos, Monocrotophos, Oxydemeton Methyl, Phenthoate, Phorate, Phosphamidon, Quinalphos, TEPP, and Thiometon.

The following compounds are moderately toxic (LD50:501 to 5000 mg/kg), or slightly toxic (LD50: more than 5000 mg/kg)—

Abate, Acephate, Coumaphos, Crufomate, Famphur, Glyphosate, Malathion, Phenthoate, Primiphos Methyl, Ronnel, Temephos, Triazophos, and Trichlorphon.

Even in cases where treatment was begun early with atropine and oximes, mortality in organophosphate poisoning is gener-ally to the extent of 7 to 12%.

Mode of Action

·     Organophosphates are powerful inhibitors of acetylcho-linesterase which is responsible for hydrolysing acetyl-choline to choline and acetic acid after its release and completion of function (i.e. propagation of action poten-tial). As a result, there is accumulation of acetylcholine with continued stimulation of local receptors and eventual paralysis of nerve or muscle.

·     Although organophosphates differ structurally from acetylcholine, they can bind to the acetylcholinesterase molecule at the active site and phosphorylate the serine moiety. When this occurs, the resultant conjugate is infinitely more stable than the acetylcholine -acetylcho-linesterase conjugate, although endogenous hydrolysis does occur. Depending on the amount of stability and charge distribution, the time to hydrolysis is increased. Phosphorylated enzymes degrade very slowly over days to weeks, making the acetylcholinesterase essentially inactive.

·              Once the acetylcholinesterase is phosphorylated, over the next 24 to 48 hours an alkyl group is eventually lost from the conjugate, further exacerbating the situation. As this occurs, the enzyme can no longer spontaneously hydrolyse and becomes permanently inactivated.

·              Apart from acetylcholinesterase, organophosphates exert powerful inhibitory action over other carboxylic ester hydrolases such as chymotrypsin, butyrlcholinesterase (pseudocholinesterase), plasma and hepatic carboxyles- terases, paraoxonases, and other non-specific proteases.

·              It has been proposed that delayed peripheral neuropathy caused by organophosphates is due to phosphorylation of some esterase(s) other than acetylcholinesterase, such as neurotoxic esterase, also known as neuropathy target esterase (NTE). Neuropathy caused by inhibition of NTE may develop 2 to 5 weeks after an acute poisoning.

Toxicokinetics

·              Organophosphates can be absorbed by any route including transdermal, transconjunctival, inhalational, across the GI and GU mucosa, and through direct injection.

·              hours, but may be delayed upto 12 hours or more in the case of certain compounds (e.g. fenthion, parathion).

Clinical (Toxic) Features

Acute Poisoning:

·              Cholinergic Excess—

– Musscarinic Effects (hollow organ parasympathetic manifestations): Common manifestations include bronchoconstriction with wheezing and dyspnoea, cough, pulmonary oedema, vomiting, diarrhoea,abdominal cramps, increased salivation, lacrima-tion, and sweating, bradycardia, hypotension, miosis, and urinary incontinence. Some of these can be remembered by the acronym SLUDGE

—Salivation, Lacrimation, U rination, Diarrhoea, Gastrointestinal distress and Emesis. Excessivesalivation, nausea, vomiting, abdominal cramps, and diarrhoea are common muscarinic effects, and have been reported even following the cutaneous absorption of organophosphate. Bradycardia and hypotension occur following moderate to severe poisoning.

Nicotinic Effects (autonomic ganglionic and somatic motor effects): Fasciculations, weakness, hypertension, tachycardia, and paralysis. Muscle weakness, fatiguability, and fasciculations are very common. Hypertension can occur in up to 20 per cent of patients. Tachycardia is also common. Cardiac arrhythmias and conduction defects have been reported in severely poisoned patients. ECG abnormalities may include sinus bradycardia or tachycardia, atrioventricular and/or intraven-tricular conduction delays, idioventricular rhythm, multiform premature ventricular extrasystoles, ventricular tachycardia or fibrillations, torsades de pointes, prolongation of the PR, QRS, and/or QT intervals, ST-T wave changes, and atrial fibrillation.

·              CNS Effects—Restlessness, headache, tremor, drowsi-ness, delirium, slurred speech, ataxia, and convulsions. Coma supervenes in the later stages. In a review of 16 cases of paediatric organophosphate poisoning, all 16 children developed stupor and/or coma. Death usually results from respiratory failure due to weakness of respiratory muscles, as well as depression of central respiratory drive. Acute lung injury (non-cardiogenic pulmonary oedema) is a common manifestation of severe poisoning. Acute respiratory insufficiency, due to any combination of CNS depression, respiratory paralysis, bronchospasm, ARDS, or increased bronchial secretions, is the main cause of death in acute organo-phosphate poisonings.Metabolic acidosis has occurred in severe poisonings. A characteristic kerosene-like odour is often perceptible in the vicinity of the patient since the solvent used in many organophosphate insec-ticides is some petroleum derivative such as aromax.

·      Other points of importance—

––  The Peradeniya Organophosphorus Poisoning (POP) Scale is predictive of death, necessity for mechanical ventilation, and the required total atro-pine dose over the first 24 hours. This scale rates 5 clinical variables, each on a 0 to 2 scale: miosis, muscle fasciculations, respirations, bradycardia, and level of consciousness.

–– In a given case, there may be either tachy- or brady-cardia; hypo- or hypertension.

––  Miosis while being a characteristic feature, may not be apparent in the early stages. In fact mydriasis is very often present, and hence treatment should not be delayed if there is absence of pupillary constric-tion. Blurred vision may persist for several months.

–– Ocular exposure can result in systemic toxicity. It can cause persistent miosis in spite of appropriate systemic therapy, and may necessitate topical atro-pine (or scopolamine) instillation.

–– Exposure to organophosphate vapours rapidly produces symptoms of mucous membrane and upper airway irritation and bronchospasm, followed by systemic symptoms if patients are exposed to significant concentrations.

–– While respiratory failure is the commonest cause of death, other causes may contribute including hypoxia due to seizures, hyperthermia, renal failure, and hepatic failure.

–– Patients with OP poisoning and QTc prolongation are more likely to develop respiratory failure and have a worse prognosis than patients with normal QTc intervals. Patients with OP poisoning who develop PVCs (premature ventricular contractions) are more likely to develop respiratory failure and have a higher mortality rate than patients without PVCs.

–– Aspiration of preparations containing hydrocarbon solvents may cause potentially fatal lipoid pneu-monitis.

––  An Intermediate Syndrome sometimes occurs one to four days after poisoning due to long-lasting cholin-esterase inhibition and muscle necrosis. It is more common with chlorpyrifos, dimethoate, monocro-tophos, parathion, sumithion, fenthion, fenitrothion, ethyl parathion, methyl parathion, diazinon, mala-thion, and trichlorfon. Main features include muscle weakness and paralysis characterised by motor cranial nerve palsies, weakness of neck flexor and proximal limb muscles, and acute respiratory paresis. Paralytic signs include inability to lift the neck or sit up, ophthalmoparesis, slow eye movements, facial weakness, difficulty swallowing, limb weakness (primarily proximal), areflexia, respiratory paralysis, and death. It may be due to inadequate treatment of the acute episode especially involving subtherapeutic administration of oximes or inadequate assisted ventilation. Several investigators have proposed that intermediate syndrome may develop as a result of several factors: inadequate oxime therapy, the dose and route of exposure, the chemical structure of the organophosphates, the time to initiation of therapy, and possibly efforts to decrease absorption or enhance elimination of the organophosphates. Once it sets in, the intermediate syndrome will have to be managed by supportive measures, since it does not respond to oximes or atropine.

–– A Delayed Syndrome sometimes occurs 1 to 4 weeks after poisoning due to nerve demyelination, and is characterised by flaccid weakness and atrophy of distal limb muscles, or spasticity and ataxia. A mixed sensory-motor neuropathy usually begins in the legs, causing burning or tingling, then weakness. This syndrome also does not respond to either oximes or atropine. Severe cases progress to complete paralysis, impaired respiration and death. The nerve damage of organophosphate-induced delayed neuropathy is frequently permanent. The mechanism appears to involve phosphorylation of esterases in peripheral nervous tissue and results in a “dying back” pattern of axonal degeneration. Organophosphates that have been associated with delayed neuropathy in humans include chlorophos, chlorpyrifos, dichlorvos, dipterex, ethyl para-thion, fenthion, isofenphos, leptophos, malathion, mecarbam, merphos, methamidophos, mipafox, trichlorofon, trichloronate, and TOCP (tri-ortho-cresyl phosphate).

––  Parathion ingestion is sometimes associated with haemorrhagic pancreatitis which can termi-nate fatally. Diazinon has also been implicated.

Haemoperfusion is said to be beneficial if this occurs.

–– Patients poisoned with highly lipid soluble OPs such as fenthion have rarely developed extrapy-ramidal effects including dystonia, resting tremor, cog-wheel rigidity, and choreoathetosis. These effects began 4 to 40 days after acute OP poisoning and spontaneously resolved over 1 to 4 weeks in survivors.

––  It is important to note that children may have different predominant signs of organophosphate poisoning than adults. In one study of children poisoned by organophosphate or carbamate compounds, the major signs and symptoms were CNS depression, stupor, flaccidity, dyspnoea, and coma. Other classical signs of organophosphate poisoning such as miosis, fasciculations, brady-cardia, excessive salivation and lacrimation, and gastrointestinal symptoms were infrequent.

–– Bradypnoea sometimes occurs. Respiratory rates of less than 8/minute are not unusual. Snoring prior to fatal overdose has been reported and is likely due to a failure to maintain the patency of the upper airway. Gurgling may occur due to accumulation of pulmonary oedema fluid. Non-cardiogenic pulmonary oedema is an infrequent, but severe, complication of overdose and is generally abrupt in onset (immediate-2 hours). Manifestations include rales, pink frothy sputum, significant hypoxia, and bilateral fluffy infiltrates on chest X-ray. Some patients require mechanical ventilation. Resolution of symptoms usually occurs rapidly with supportive care alone, within hours to 1 to 2 days.

Chronic Poisoning:

·              It usually occurs as an occupational hazard in agriculturists, especially those who are engaged in pesticide spraying of crops. Route of exposure is usually inhalation or contamination of skin. The following are the main features—

·              Polyneuropathy: paraesthesias, muscle cramps, weak-ness, gait disorders.

·              CNS Effects : drowsiness, confusion, irritability, anxiety.

·              Sheep Farmer’s Disease : psychiatric manifestationsencountered in sheep farmers involved in long-term sheep-dip operations.

·              Organophosphate poisoning has been associated with a variety of subacute or delayed onset chronic neuro-logical, neurobehavioural, or psychiatric syndromes. One author has termed these “chronic organophos-phate-induced neuropsychiatric disorder; (COPND) and noted that the standard hen neurotoxic esterase test is not sufficient to detect which OPs can cause this condition.

Diagnosis

1. Depression of cholinesterase activity:

If the RBC cholinesterase level is less than 50% of normal, it indicates organophosphate toxicity. RBC cholinesterase levels are more reliable in diagnosing organophosphate poisoning than serum cholinesterase. –– Disadvantages—

-- Normal cholinesterase level is based on popula-tion estimates and there is a wide distribution in the definition of normal. A person with a “high normal” level may become symptomatic with a “low normal” activity.

--Several individuals do not seem to possess a known baseline level.

--A very low cholinesterase level does not always correlate with clinical illness.

--False depression of RBC cholinesterase level is seen in pernicious anaemia, haemoglobinopathies, anti-malarial treatment, and blood collected in oxalate tubes. Elevated levels may be seen with reticulocytosis due to anaemias, haemorrhage, or treatment of megaloblastic or pernicious anaemias.

Depression of plasma cholinesterase level (to less than 50%) is a less reliable indicator of organophosphate toxicity, but is easier to assay and more commonly done. Depressions in excess of 90% may occur in severe poisonings, and is usually associated with mortality.

–– Because it is a liver protein, plasma cholinesterase activity is depressed in cirrhosis, neoplasia, malnu-trition, and infections, some anaemias, myocardial infarction, and chronic debilitating conditions.

–– Certain drugs such as sucinyl choline, lignocaine, codeine, and morphine, thiamine, ether, and chlo-roquine can also depress its activity.

–– Studies have demonstrated that RBC cholinesterase levels may be significantly higher in pregnant women than in nonpregnant controls, while plasma cholinesterase levels are generally lower during pregnancy. These levels revert to normal by six weeks postpartum.

–– The organophosphates phosdrin and chlorpyrifos may selectively inhibit plasma pseudocholines-terase, while phosmet and dimethoate may selec-tively inhibit red blood cell cholinesterase.

For the purpose of estimation of cholinesterase level, blood should be collected only in heparinised tubes. Alternatively, samples can be frozen. Plasma cholin-esterase usually recovers in a few days or weeks; red blood cell cholinesterase recovers in several days to 4 months depending on severity of depression.

2. P-Nitrophenol Test: P-nitrophenol is a metabolite of someorganophosphates (e.g. parathion, ethion), and is excreted in the urine. Steam distill 10 ml of urine and collect the distillate. Add sodium hydroxide (2 pellets) and heat on

water bath for 10 minutes. Production of yellow colour indicates the presence of p-nitrophenol. The test can also be done on vomitus or stomach contents.

3. Thin Layer Chromatography (TLC): The presence of anorganophosphate in a lavage, or vomit, or gastric aspirate sample can also be determined by TLC. The sample is extracted twice with 5 ml of petroleum ether, and the extract is washed with distilled water. It is then dried in steam compressed air, reconstituted in methanol, and spotted on silica gel-coated TLC plate along with the standard and run in a mixture of petroleum ether and methanol (25 : 1). After the solvent has travelled a considerable distance, the plate is dried and exposed to iodine vapour. The RF is compared with that of the standard.

4. Ancillary Investigations:

·              There may be evidence of leukocytosis (with relatively normal differential count), high haematocrit, anion gap acidosis, hyperglycaemia.

·              In every case, monitor electrolytes, ECG and serum pancreatic isoamylase levels in patients with significant poisoning. Patients who have increased serum amylase levels and those who develop a prolonged QTc interval or PVCs are more likely to develop respiratory insuf-ficiency and have a worse prognosis. If pancreatitis is suspected, an abdominal CT-scan can be performed to evaluate diffuse pancreatic swelling.

·              If respiratory tract irritation is present, monitor chest X-ray. Many organophosphate compounds are found in solution with a variety of hydrocarbon-based solvents. Aspiration pneumonitis may occur if these products are aspirated into the lungs. Bronchopneumonia may develop as a complication of organophosphate-induced pulmonary oedema.

·              High performance thin layer chromatography (HPLC) technique can be used to identify several organophos-phate compounds in human serum.

Treatment

Determine plasma or red blood cell cholinesterase activities. Depression in excess of 50 per cent of baseline is generally associated with severe symptoms (vide supra).

Acute Poisoning:

a.  Decontamination:

–– If skin spillage has occurred, it is imperative that the patient be stripped and washed thoroughly with soap and water.

-- Shower is preferable. Make the patient stand (if he is able to) under the shower, or seated in a chair.

-- Wash with cold water for 5 minutes from head to toe using non-germicidal soap. Rinse hair well.

-- Repeat the wash and rinse procedure with warm water.

-- Repeat the wash and rinse procedure with hot water.

-- Treating personnel should protect themselves with water-impermeable gowns, masks with eye shields, and shoe covers. Latex and vinyl gloves provide inadequate protection, unless a double pair is used.

–– If ocular exposure has occurred, copious eye irriga-tion should be done with normal saline or Ringer’s solution. If these are not immediately available, tap water can be used.

–– In the case of ingestion, stomach wash can be done, though this is often unnecessary because the patient would have usually vomited several times by the time he is brought to hospital. Activated charcoal can be administered in the usual way.

b. Antidotes:

––  Atropine—It is a competitive antagonist of acetyl- choline at the muscarinic postsynaptic membrane and in the CNS, and blocks the muscarinic mani- festations of organophosphate poisoning.

––  Oximes—The commonest is pralidoxime (pyridine- 2-aldoxime methiodide), which is a nucleophilic oxime that helps to regenerate acetylcholinesterase at muscarinic, nicotinic, and CNS sites. Actually, human studies have not conclusively substantiated the benefit of oxime therapy in acute organophos- phate poisoning, but they are widely used. Most authors advocate the continued use of pralidoxime in the clinical setting of severe organophosphate poisoning.

The antidotes for organophosphates have been discussed together in detail in Table 28.2.

c. Supportive Measures:

––  Administer IV fluids to replace losses.

––  Maintain airway patency and oxygenation. Suction secretions. Endotracheal intubation and mechanical ventilation may be necessary. Monitor pulse oxim-etry or arterial blood gases to determine need for supplemental oxygen.

––  Oxygenation/intubation/positive pressure ventila-tion: To minimise barotrauma and other compli- cations, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 ml/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS.

––  The following drugs are contraindicated: parasym- pathomimetics, phenothiazines, antihistamines, and opiates. Do not administer succinylcholine (suxamethonium) or other cholinergic medica-tions. Prolonged neuromuscular blockade may result when succinylcholine is administered after organophosphate exposure.

–– Treat convulsions with benzodiazepines or barbi-turates.

–– Antibiotics are indicated only when there is evidence of infection.

–– Haemoperfusion, haemodialysis, and exchange transfusion have not been shown to affect outcome or duration of toxicity in controlled trials of organo-phosphate poisoning.

d. Prevention of Further Exposure: After the patient hasrecovered, he should not be re-exposed to organophos-phates for at least a few weeks since he is likely to suffer serious harm from a dose that normally would be harmless, owing to alteration of body chemistry. Following acute poisoning, patients should be precluded from further organophosphate exposure until sequential RBC cholinesterase (AChE) levels have been obtained and confirm that AChE activity has reached a plateau.

Plateau has been obtained when sequential determina-tions differ by no more than 10%. This may take 3 to 4 months following severe poisoning.

e. Treatment of Pregnant Victim: Therapeutic choicesduring pregnancy depend upon specific circumstances such as stage of gestation, severity of poisoning, and clinical signs of mother and foetus. The mother must be treated adequately to treat the foetus. A severely poisoned patient with a late gestation viable foetus may be a candidate for emergency Caesarean section. The foetus may require intensive care after birth.

–– Pralidoxime chloride is recommended for use in the pregnant patient to counteract muscle weakness.

–– Glycopyrrolate: Unlike atropine, glycopyrrolate usually does not readily cross the placenta and would not directly affect foetal poisoning. However, the foetus may be best served by treating the mother to retain good respiratory function and foetal oxygen-ation.

Chronic Poisoning:

·              Removal of the patient from the source of exposure.

·              Supportive and symptomatic measures.

Autopsy Features

External—

·              Characteristic odour (garlicky or kerosene-like).

·              Frothing at mouth and nose.

·              Cyanosis of extremities.

·              Constricted pupils.

Internal—

·              Congestion of GI tract; garlicky or kerosene-like odour of contents.

·              Pulmonary and cerebral oedema.

·              Generalised visceral congestion.