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Organophosphorus and carbamate pesticides 

Michael Eddleston

South Asian Clinical Toxicology Research Collaboration
Centre for Tropical Medicine
Nuffield Department of Clinical Medicine
University of Oxford 

Introduction

  • Organophosphorus (OP) or carbamate poisoning cannot be considered as homogenous single entities since there are significant intra-class differences between pesticides.

    • Result in highly variable clinical syndromes, response to therapy, and outcome.

    • Important to determine which of the 100-200 OP or carbamate pesticides has caused the poisoning.

  • Many OP pesticides have a sulphur atom attached to the phosphorus atom (P=S) and are termed ‘thions’. This sulphur must be replaced with an oxygen (P=O) to make the active ‘oxon’. OP pesticides already in the oxon form (eg. monocrotophos) are active as soon as they are absorbed; thion OPs must be activated by enzymes in the gut wall or liver. The speed of onset of poisoning therefore depends upon whether the OP is an oxon or, if not, how quickly the thion is converted to an oxon. For some thion OPs (eg. methylparathion), this is extremely quick with symptoms occurring within minutes; for others (such as dimethoate) it can be relatively slow and take hours.

  • Carbamates do not need activating and therefore cause symptoms relatively quickly.

  • Most OPs can be divided into two groups based on their chemical structure:

    • those with two [-O-CH3] groups (dimethyl OPs)

    • those with two [-O-C2H5] groups (diethyl OPs) attached to the phosphorus

    • a few have atypical side groups (eg [-S-C3H7] in profenofos).

    • classification is important for determining responsiveness to oximes.

  • Marked variation in fat solubility of the OPs.

    • Some are very soluble (log Kow of 4.0-5.0; eg. fenthion)

      • rapidly distributed into fat and leach out slowly over days. This can result in mild or absent acute cholinergic features on admission with subsequent cholinergic crises as OP comes out of the fat

    • Others relatively insoluble (log Kow <1.0; eg. dimethoate)

      • small volumes of distribution producing high blood OP concentrations. These will reduce the effectiveness of oximes (see below).

Mechanism of action

  • Bind to and inhibit acetylcholinesterase (AChE) at synapses in the autonomic nervous system, neuromuscular junction (NMJ), and central nervous system (CNS).

  • Clinical features appear to result from this AChE inhibition (table 1). However, the pesticides also inhibit other esterases – the clinical significance of this inhibition is not yet known.

  • When OPs inhibit AChE, they leave the phosphate attached together with its oxygen and two alkyl groups. Oximes speed up the removal of this group and allow further function of the AChE.

  • Carbamates deposit a carbamyl group on the AChE which is believed to spontaneously reactivate rapidly, so that oximes are not normally recommended for treatment.

  • Reactivation of OP-inhibited AChE by oximes is limited by:

    • quantity of OP in the blood. After large self-poisoning ingestions, the blood OP concentration may be so high that all reactivated AChE is simply re-inhibited as soon as it is generated. Oximes will not be effective until the blood OP concentration drops below a certain level.

    • whether ageing has occurred

      • Ageing involves the loss of one of the two methyl or ethyl groups by the phosphate bound to the AChE. Once this has occurred, oximes no longer work and recovery must wait for elimination of the OP from the body and generation of new AChE at synapses.

      • Occurs slowly for diethyl OPs, with a half life of around 33 hours. Oximes will therefore offer some benefit for up to 130 hrs (4 half lives). Ageing occurs more quickly with dimethyl OPs (half life 3 hrs), thereby reducing the opportunity for oximes to work to less than 12 hrs. Ageing occurs very rapidly in patients poisoned with atypical OPs (eg profenofos or edifenphos) such that oximes are probably not effective after the first hour.

Table 1.

Receptor type

Location

Effect

Muscarinic  (stimulation)

Pupils

Miosis

 

Ciliary body

Blurred vision

 

Exocrine glands

Increased secretions

 

Heart

Decreased heart rate

 

Bronchial smooth muscle

Bronchoconstriction

 

GI smooth muscle

Nausea, vomiting, abdominal cramps, diarrhea

 

Bladder

Incontinence, frequency

 

Sphincter of Oddi

Pancreatitis

 

CNS

Variable

Nicotinic (stimulation then depression )

Skeletal muscle

Weakness, cramps, fasciculation, paralysis

 

Sympathetic ganglia

Increased HR and BP then decreased BP

 

CNS

Variable symptoms from anxiety & restlessness to confusion, obtundation, coma & fits

Clinical features

  • The time to onset of symptoms will vary according to the pesticide ingested (see above). Patients can be unconscious 20-30 minutes after ingestion of parathion. Inhalation may produce even quicker onset of poisoning. Some fat soluble OPs may produce only very mild - falsely reassuring - symptoms for the first few days before a subsequent crisis.

  • If onset of significant poisoning occurs before presentation to medical care, patients may suffer the consequences of respiratory arrest (anoxia, aspiration) and die before hospital admission. If patients survive to hospital admission, they may die from such complications only after several days or weeks.

  • The acute cholinergic crisis may last several days, particularly with fat soluble OPs. These features respond to atropine treatment.

  • Metabolic abnormalities may occur, especially of electrolytes if enthusiastic gastric lavage or forced emesis has been carried out in a transferring hospital or the emergency department.

  • Fits are uncommon in pesticide poisoning and probably relate more to hypoxia than to a direct effect of the OP.

  • Respiratory failure may occur on admission or after several days when the cholinergic features are controlled. In both cases, the respiratory failure can last many days.

Investigations

  • In addition to routine blood tests, two inhibited esterases are routinely assayed: plasma butyrylcholinesterase (BuChE; plasma/pseudocholinesterase) and red cell AChE. The relative affinity for these two enzymes varies between OPs.

  • BuChE can be used to confirm poisoning with OPs or carbamates. However, it cannot be used to assess severity unless the precise pesticide ingested is known. Some OPs (eg. chlorpyrifos) completely inhibit BuChE while only mildly inhibiting AChE. Others (eg. dimethoate) only poorly inhibit BuChE. Unless the precise OP was known, a low-middle range BuChE could mean a very mild poisoning (chlorpyrifos) or a potentially severe poisoning (dimethoate).

  • Recent studies suggest that red cell AChE activity accurately correlates with AChE activity at the synapse and can often be used as a marker of severity. Major muscarinic features and NMJ dysfunction occur with AChE less than 10% of normal; NMJ abnormalities can be detected at AChE activity <40%.

  • AChE activity in the presence of OP and/or oximes will change within minutes at body or room temperature. It is therefore essential for accurate longitudinal measurement of AChE activity that enzyme activity in the blood sample is stopped immediately after venepuncture by diluting the sample 1:20 or 1:100 in ice cold water or saline. This sample must then be rapidly frozen to -20C until analysis. Variable periods of incubation at room temperature after venepuncture will result in highly variable results. Results should also be standardized against Hb content of the blood sample

Clinical course

  • The majority of pre-hospital deaths and deaths in resource poor locations are due to respiratory failure. However, once effectively ventilated, further deaths may occur due to cardiovascular collapse with certain OPs (eg dimethoate).

  • Some muscarinic causes of cardio-respiratory failure (bronchorrhoea, bronchospasm, bradycardia, hypotension) generally respond well to atropine. Rapid atropinisation of patients on admission should reduce the number of early deaths.

  • Atropine is not effective with nicotinic causes (muscle weakness due to neuromuscular junction dysfunction) and probably central causes (central respiratory depression) of respiratory failure. Therefore atropine alone will not reverse respiratory failure and intubation/ ventilation will be required for severe cases.

  • Respiratory failure may occur due to NMJ dysfunction at any point during the admission. If it occurs after a few days in conscious patients (suggesting no central respiratory depression), it is termed the intermediate syndrome. Sudden respiratory arrest may be fatal in insufficiently observed patients.

  • Fat soluble OPs may cause recurrent cholinergic crises for days after hospital admission.

Management

  • Immediate resuscitation (ABC) with careful attention to the airway and provision of oxygen.

  • Turn the person into the left lateral position to reduce the risk of aspiration of vomitus and secretions.

  • Determine whether atropine is required. Most severe cases of OP/carbamate poisoning can be relatively easily identified since they are typically unconscious, covered with sweat, and have pinpoint pupils.

  • Give atropine: 1.2-3mg IV by fast push initially for significant poisoning. Check for increase in heart rate and blood pressure, reduction in wheeze and crepitations in the chest, and reduced sweating.

  • Set up fluid – give 500-1000ml over 20-30 min. The patient is normally intravascularly fluid depleted.

  • If there is no response to atropine within 5 minutes, repeat the atropine doubling the dose. Repeat this process until the above parameters improve.

  • Tachycardia is not a contra-indication for atropine since it can be caused by nicotinic effects of the OPs as well as pneumonia, hypovolemia, alcohol withdrawal, atropine toxicity, and agitation.

  • Give pralidoxime chloride 30mg/kg bolus IV over 20-30 min, then 8-10mg/kg/hr infusion. Alternatively, give obidoxime 250mg bolus over 20-30 min, then 750mg/24hr infusion. Attempt to stop the infusion after seven days or after atropine has not been required for 24hrs. If the patient deteriorates after stopping the infusion, or requires atropine again at any timepoint, restart the infusion.

  • Give diazepam 10-40mg for seizures.

  • If facilities permit, consider early intubation and ventilation since this will reduce the risk of sudden respiratory arrest. Avoid suxamethonium since it is normally metabolized by the BuChE which has been inhibited by the OP.

  • Once the patient is stable and atropinised, consider careful brief gastric lavage using a NG tube. Never perform lavage until the patient is stable/atropinised. The majority of OP is absorbed in the first one hour; there is no point doing exhaustive lavage after 2 hours except perhaps if the patient has taken a solid formulation.

  • Dermal exposure of the patient to OP in most severe poisoning cases, which are predominantly from oral exposure, is likely to be insignificant. Decontamination of patient’s body and clothes should only occur after the patient is stable.

There is little evidence of risk to healthcare workers from managing OP poisoned patients as long as universal precautions are followed – see refs 5, 6 below

Prognosis

Varies markedly. Above all, it will depend on the specific OP and amount ingested. The availability and proximity of healthcare will determine how many patients survive to hospital admission and therefore the severity of their condition on admission.

Further reading

  1. Johnson MK et al. Evaluation of antidotes for poisoning by organophosphorus pesticides. Emergency Medicine (Fremantle) 2000;12:22–37.

  2. Eddleston M et al. Oximes in acute organophosphorus pesticide poisoning: a systematic review of clinical trials. Q J Med 2002;95:275–283.

  3. Eyer P. The role of oximes in the management of organophosphorus pesticide poisoning. Toxicol Rev 2003;22:165–190.

  4. Eddleston M et al. Early management after self-poisoning with an organophosphate or carbamate pesticide - a treatment protocol for junior doctors. Critical Care 2004; 8:R391-397 

  5. Little M, Murray L. Consensus statement: risk of nosocomial organophosphate poisoning in emergency departments. Emergency Medicine Australasia 2004; 16:456-458

  6. Roberts D, Senarathna L. Secondary contamination in organophosphate poisoning. Q J Med 2004; 97:697-8


 ©Michael Eddleston April 2005


©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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