BIPYRIDYL HERBICIDES

Toxicology

  • Bipyridyl herbicides-diquat and paraquat-exist as divalent cations in association with anions such as bromide and chloride
  • Paraquat has one of the highest acute toxicity among herbicides; its oral LD50 in rat is about 100 mg/kg . In humans as little as 10-15 mL of a 20% solution is toxic (Costa GL 2008; Roberts and Reigart, 2013).
  • The extent of paraquat poisoning depends on the amount, route, and duration of exposure and the victim’s health status at the time of the exposure.
  • Upon ingestion, paraquat is rapidly but incompletely absorbed; it is excreted unchanged in the urine within 12-24 hrs. Renal failure will increase tissue concentration and hence more injury (Costa GL 2008;Roberts and Reigart, 2013)
  • Paraquat is accumulated preferentially against concentration gradient in the lungs (alveolar typeI and II cells) and kidney due to structural similarity of paraquat with the naturally occurring polyamines taken up by these cells leading to pneumonitis and lung fibrosis as well as kidney damage. 
  • Paraquat is actively secreted by the kidney via organic cation transport systems, a process which
    becomes saturated at higher concentrations leading to accumulation in proximal tubular epithelial cells (responsible for renal tubular necrosis.).
  • In the presence of large ingestions, paraquat accumulation in the lung or renal cells results in redox cycling and generation of toxic reactive oxygen species that can overwhelm cellular defence mechanisms and lead to lung damage (acute alveolitis and subsequent pulmonary fibrosis) and renal tubular necrosis. The major cause of death in paraquat poisoning results from respiratory failure due to obliterating fibrosis through lipid peroxidation, hemorrhagic proteinaceous edema fluid and leukocytes infiltratiion of the alveolar spaces. Progressive decline in arterial oxygen tension and carbon dioxide diffusion capacity which causes proliferation of more fibroblasts in the alveoli (Suntres ZE, 2002;Roberts and Reigart, 2013).
  • The molecular mechanisms of paraquat is through redox-cycling, a process involving repetitive enzyme-mediated cycling  between paraquat  and paraquat radicals (2PQ2+↔2PQ+•) that utilizes two molecules of NADPH. The reduced form (PQ.+) rapidly gets re-oxidized back to paraquat (PQ2+ ) intracellularly in a process generating superoxide (O2.−) which can cause direct cellular damage or react further to form other reactive oxygen species such as hydrogen peroxide (from 2 superoxide reacting with each other in the presence of superoxide dismutase+ 2H+), peroxinitrite (ONOO-)and hydroxyl radical. The more potent hydroxyl radical ( formed from hydrogen peroxide via Fenton reaction in the presence of Fe2+) can attack the lipid chains of biological membranes initiating lipid peroxidation (Free radicals of fatty acids) that results in disruption of lipid membrane integrity, degeneration of membranous organelles (e.g. cell membrane, mitochondria, endoplasmic reticulum, lysosomes) and ultimately cell death and multi-organ dysfunction. In addition, depletion of NADPH through redox reactions disrupts essential physiological and biochemical functions  cells more susceptible to lipid peroxidation and other oxidative damage that cause cell death (Teitelbaum DT 2012 ;Suntres ZE 2002;Gawarammana and Buckley, 2011;Roberts and Reigart, 2013).
  • The redox cycling occur in most cells but predominantly in the lungs, liver and kidney. Death within a few hours of ingestion is due to massive depletion of NADPH,one of the cell’s key antioxidant defenses, with consequent disruption of energy generation especially in the liver. In mild poisoning the cellular destruction results from cell membrane destruction by lipid peroxidation.
  • Ingestion of bipyridyls has been reported to cause cerebral edema and brain damage (Roberts and Reigart, 2013)
  • Metabolism of paraquat generates reactive oxygen species and the depletes of NADPH  to cause oxidative stress that cause direct cellular damage via lipid peroxidation, activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitochondrial dysfunction and apoptosis in many organs.
  • Plasma paraquat concentrations assumes a two-compartment model. At first absorption is independent of amount ingested (zero order) but with time absorption increases with increasing amounts probably due to  damage of organs of absorption and elimination ie gut, kidney and liver damage. The organ damage manifests as progressively increasing half-life due to  marked toxicity (Gawarammana and Buckley, 2011)
  • Paraquat is rapidly distributed to other tissues and re-distributes back to the blood relatively slowly. i.e. toxic levels in tissues occur early in the course of the poisoning. This makes enhanced elimination less efficient.
  • Charcoal columns are very efficient at removing paraquat from the blood. Filtratyion of blood through charcoal may help ( if done within 4 hrs of ingestion) reduce the poison burden. A proposed scheme is to use up to 7 haemoperfusion sessions of 6 – 8 hours duration, started within 4 hours of ingestion (Syngenta, 2017).

Clinical Manifestation

  • Ingestion of diquat causes paralytic ileus which may contribute to hypovolaemic shock via fluid accumulation in distended bowel loops; tubular necrosis; ventricular fibrillation; bronchopneumonia
  • After a large amount of paraquat is ingested,  pain and swelling of the mouth and throat is likely to ensue immediately. The next signs of illness following ingestion are gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, and diarrhea (which may become bloody), sloughing of the oropharyngeal mucosa, perforation of the oesophagus and dysphagia. 
  • The toxic effects of paraquat is dose related
  • 10-20 mls of 20-24% concentrate  (Roberts and Reigart, 2013)
    • Immediate vomiting, abdominal pain and diarrhea (sometimes bloody)
  • Swelling, edema and corrosion of the mucosal lining in the mouth, pharynx, esophagus, stomach and intestine
    • Pancreatitis 

    • Renal failure leading to increased creatinine
    • Cough, dyspnea and tachypnea may occur 2-14 days after ingestion
    • Coughing up of frothy sputum (pulmonary edema) is an early indication of lung injury
    • Massive pulmonary fibrosis manifesting as progressive respiratory distress may cause death in 2-4 wks.
  • ˃20mls of 20-24% concentrate
    • Similar but more severe presentation as ingestion of 10-20 mls   
  • Immediate vomiting, abdominal pain and diarrhea (sometimes bloody)
  • Hepatic necrosis accompanied by elevated bilirubin, AST, ALT, LDH and alkaline phosphatase
  • Kidney injury (proximal renal tubule)is often more reversible than lung injury.
  • Cardiac arrhythmias possibly due to focal necrosis of muscle tissue
  • Lung fibrosis (evolves more quickly than when small to medium amounts have been ingested)
  • Pulmonary edema (fluid in the lungs)
  • Respiratory failure, possibly leading to death
  • Esophageal perforation.
  • Hypotension results from massive fluid loss and dysrhythmias
  • Coma
  • Convulsions
  • Death occurs within 24-48 hrs from multiple organ failure (kidney, liver and lung failure)
  •  >40 – 55 mg paraquat ion/kg body weight leads to death from cardiogenic shock and multi-organ failure occurs within 1-4 days.

Clinical Management

  • The principle aim of treatment is to prevent absorption and enhance elimination.
  •  No proven antidote or cure exists for paraquat poisoning.
  • Initiate supportive treatment quickly and vigorously.
  • Flush skin immediately with copious amounts of soapy water after removing soiled clothes 
  • Rinse mouth with not more than 300ml of water.
  • Administer strong antiemetics such as:
  • 1. 5HT3 antagonists, e.g. Ondansetron 8mg (5mg/m2 in children) by slow i.v. injection or i.v. infusion over 15 minutes, or
    2. Phenothiazine anti-emetics, e.g. prochlorperazine. However the phenothiazines having dopamine antagonist activity such as metoclopramide is contraindicated  as they may impair efficacy of dopamine in renal support
  • Insert nasogastric tube prophylactically as early as possible as swallowing becomes difficult later.
  • Perform nasogastric suction of gastric contents in patients presenting within 1 hour of the ingesting large volumese  using small gauge NG tube followed by a dose activated charcoal (child: 2g/kg, adult upto 100g) with a laxative such as mannitol(1-2l), sorbitol (1g/kg as 70% solution) or magnesium sulphate (30 g for adults and 250 mg/kg in children). Repeat activated charcoal (25g-50g q 1-4 hrs) and laxative until charcoal is seen stools (Teitelbaum DT 2012).
  • Treat hypotension with boluses of fluids (15–20 ml kg−1 over 15–30 min) repeated as necessary.
  • Enhance renal excretion by aggressive intravenous fluid (normal saline, Ringer’s solution or 5DW). Renal failure commonly develops over 24 h, closely monitor fluid balance. Maintenance of renal function is important to reduce plasma paraquat levels and thereby minimise accumulation in lung cells.
  • For large volume ingestion, initiate several sessions of  charcoal hemoperfusion
  • Stop IV fluids if renal failure occurs, and start hemodialysis preferably over cellophane-coated activated charcoal with close monitoring of blood calcium and platelet (Roberts and Reigart, 2013)
  • Administer antoxidants such as (Gawarammana and Buckley, 2011;Teitelbaum DT 2012; Qin et al., 2012; Syngenta 2017):• vitamin E (300 mg twice daily p.o.) or vitamin C to reduce free radical toxicity;
    • N-acetyl cysteine (150 mg/kg over 3h; 300 mg/kg over 24 h for up to 3 weeks)
    to increase intracellular glutathione;
    • desferrioxamine (100 mg/kg over 24 hours) to chelate iron which acts as catalyst in the production of hydroxyl radicals;
    • salicylic acid which can scavenge hydroxyl radicals and inhibit the activation of NF-κB.      • riboflavin and niacin 
  • Administer immunosuppressants such as (Gawarammana and Buckley, 2011;Roberts and Reigart, 2013)  Iv Cyclophosphamide 5mg/kg/day and Dexamethasone 8mg tid for 2 wks
    Or
     Iv Cyclophosphamide 600mg bd for wk + IV 500mg methyl prednisolone/d then tapered off gradually.
    Or                                                                                                                                                                                                                          Iv Infusion Cyclophosphamide 1 gram over 2hrs daily for 2 days and Iv infusion methylprednisolone 1 gram over 2hrs daily for 3 days 
  • Administer strong analgesics for pain associated with deep mucosal erosions, pancreatitis such as morphine sulfate (Roberts and Reigart, 2013):
    • Adults and children over 12 years: 10 -15 mg SC every 4 hours.
    • Children under 12 years: 0.1 – 0.2 mg /kg body wt every 4 hours.
  • Administer stress ulcer prophylaxis such as ranitidine and proton pump inhibitors; antacid suspension; demulcents for soothing mucosal ulceration.
  • Administer antibiotics to prevent secondary infection of mucosal ulcers.
  • Intubate and mechanically support ventilation in cases of respiratory impairment resulting in altered consciousness from hypoxia

 Note

  • Do not administer supplemental oxygen until the patient develops severe hypoxemia; oxygen causes accumulation of reactive oxygen species. Partial oxygen greater than 40 but less than 50% is just sufficient to maintain adequate arterial oxygen tension (Teitelbaum DT 2012;Roberts and Reigart, 2013).
  • Hydrogen peroxide is ordinarily detoxified immediately by catalase or glutathione peroxidase; these systems are exhausted in bipyridyl poisoning leading to devastating cellular effects of hydrogen peroxide
  • NADPH is depleted through two ways: Redox cycling of paraquat and detoxification of hydrogen peroxide, lipid hydroperoxides
  • Unlike paraquat, diquat is not accumulated by the lung
  • The alveolar damage may be reversible as seen in some survivors (Roberts and Reigart, 2013)
  • Depletion of NADPH impairs body defenses against oxidative stress through decreased glutathione regeneration (Gawarammana and Buckley, 2011)
  • Lung injury causes decreased gas exchange and respiratory impairment
  • Hypotension and acidosis worsen oxidative stress; should be avoided (Gawarammana and Buckley, 2011)
  • Monitor electrolytes, full hemogram, liver and kidney function tests daily
  • CT scan of the chest may be useful in detecting early lung fibrosis or evaluating long-term damage in survivors
  • Pancreatitis should be suspected if patients develop abdominal pain and a raised blood sugar
  • Hemodialysis and hemoperfusion is not efficient because of the changing elimination kinetics because of fast initial elimination means most paraquat is eliminated rapidly anyway. In addition, paraquat partitions into organs such as lungs and kidney quickly (within 2hrs) implying a small fraction is available in the blood circulation for dialysis.
  • Control trials have not supported benefit from high-dose immunosuppression but suggested potential benefit from dexamethasone. Dexamethasone works through multiple mechanisms i.e. anti-inflammatory, induction of transporters, anti-oxidant (Gawarammana and Buckley, 2011)
  • Antioxidants can donate an electron to free radicals thereby neutralizing them
  • Iron is an important contributor to the generation of reactive oxygen species through the Fenton reaction. thus, deferoxamine may be useful clinically
  • Salicylic acid has shown anti-inflammatory and anti-oxidant activity via scavenging of hydroxyl radicals and suppression of their production through the Fenton reaction (Gawarammana and Buckley, 2011)

Reference

  • Syngenta. Paraquat Poisoning. A practical guide to diagnosis, first aid and medical management. Revision 8. Draft January 17, 2016.  https://www4.syngenta.com/~/media/Files/S/Syngenta/documents/paraquat-booklet.pdf. Accessed 09/11/2018.
  • Qin Zhang Q,  Wu W, Lu Y,  Wang J, Shang A,Yao F, and  Chen Y (2012). Successful treatment of patients with paraquat intoxication: three case reports and review of the literature. J Zhejiang Univ Sci B. 13(5): 413–418. doi:  [10.1631/jzus.B1200008]
  • Centers for Disease Control and Prevention (CDC), National Institute for Occupational Safety and Health (NIOSH), Pocket Guide to Chemical Hazards.  Paraquat. https://emergency.cdc.gov/agent/paraquat/basics/facts.asp. Accessed 8/11/2018
  • Teitelbaum DT (2012). Toxicology:Introduction to Toxicology: Occupational &Environmental in basic and clinical pharmacology, Gartzung BG, Masters SB, Trevor AJ. Ed, Frassetto D and Henriquez RD 12th edition, McGraw-Hill, pg 1001-12
  • Roberts JR and Reigart JR (2013):Recognition and Management of Pesticide poisoning. Gawarammana IB and Buckley NA (2011). Medical management of paraquat ingestion. British Journal of Clinical Pharmacology.Volume 72, Issue 5. Pg 745–757

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