Paraquat Toxicity

Created on Mon, 12/07/2015 - 13:31
Last updated on Sun, 12/20/2015 - 20:45

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Question 10.1 from the second paper of 2014 and the near-identical Question 14.1 from the first paper of 2008 confront the candidates with an image of a collapsed farmer, issuing green froth from his/her ulcerated mouth. The ABG/biochemistry results associated with this story demonstrate hypoxia and renal failure. Paraquat toxicity presents in this way, as it is green, corrosive, nephrotoxic herbicide which is apparently favoured by clinically depressed farmers.

The LITFL entry on paraquat toxicity is sufficient for the time-poor exam candidate. The candidate whose frenzied lust for herbicide toxicology cannot be satisfied by point-form summaries will find their basic urges well catered for by this 2008 review by Dinis-Oliveria et al.

Pharmacology of paraquat

A few points regarding the unique weirdness of paraquat:

  • It is rapidly absorbed throught the gut, exploiting the carrier-mediated transport system for choline on the brush-border membrane.
  • It is thankfully highly hydrophilic and thus not absorbed through intact skin
  • Aerosolised paraquat granules are large in diameter and thus do not reach the human alveoli when inhaled. Hilariously, some American efforts at Mexican cannabis crop destruction (c.1970s) resulted in a massive harvest of paraquat-contaminated marijuana, as plantation owners hurried to Fortunately for all concerned, it is inactivated by pyrolysis even at modest joint/cone combustion temperatures. 
  • It is beloved by all farm folk as it is rapidly inactivated by the majority of soils, allowing people to plant immediately after spraying for weeds. It destroys plants by contact with their leaves, leaving the roots intact, and hereby preventing soil erosion.
  • Originally the marketed paraquat liquid concentrate used to be dirt-brown, but to pevent confusion with tean and coffee the color is now dark blue-green (see this manufacturer site). If you like, Zhejiang Chemicals will send you a 220L drum of 42% solution for practically peanuts.
  • It is rapidly eliminated unchanged in the urine.
  • It mainly accumulates in the lung (pulmonary concentrations can be 6 to 10 times higher than those in the plasma)
  • Toxicity arises from redox cycling,  a process of alternate reduction and reoxidation steps. It is reduced by local enzymes (many are implicated, eg. xanthine oxidase and nitric oxide synthase)  and then rapidly reoxidised in the presence of ample oxygen (eg in the lung). The process cycles quickly and produces reactive oxygen free radical species with each cycle. The result is free radical-mediated membrane damage.

Clinical features of paraquat toxicity

Mild overdose:

  • Nausea and vomiting
  • Diarrhoea
  • Intestinal hemorrhage
  • Haemoptysis
  • Oliguria
  • Minimal renal dysfunction

Moderate overdose:

  • Renal failure (ATN within 12-24hours)
  • Pulmonary oedema
  • Hepatotoxicity
  • Pulmonary haemorrhage
  • Shock
  • Pulmonary fibrosis

Massive overdose:

  • multi-organ system failure
  • rapidly fatal

The toxicity (at least in moderate doses) emerges in several discrete phases:

  • Phase I: corrosion; mucosal linings ulcerate and swell; there may be haematamesis.This is the first two days.
  • Phase II: organ failure; between the second and fifth days following ingestion, renal failure and hepatocellular necrosis develop. Most patients with severe overdose will die during this phase.
  • Phase III: pulmonary fibrosis; death after many days/weeks of hypoxia.

Acute fulminant toxicity may occur which progresses straight towards the grave over several hours (these are patients who ingest greater than 40 mg/kg).

Management of paraquat toxicity

Decontamination

  • Fuller's Earth: calcium montmorillonite, or bentonite - a absorbent aluminium phyllosilicate, formed from the weathering of volcanic ash.
  • Activated charcoal may have equal efficacy, and is more widely available
  • Cation exchange resins (eg. resonium) may be of use
  • The “window of opportunity”  is very narrow, only a few hours at most. Absorption from the gut is very rapid.
  • Remove contaminated clothes
  • Wash skin with soap and water to prevent transdermal absorption

Enhancement of elimination

  • Charcoal haemoperfusion works very well, but contributes little to the overall prognosis because the drug is rapidly cleared from the plasma anyway, and the pulmonary reserve is trapped there (it is not available for removal).
  • Dialysis is probably going to be useless, as paraquat is rapidly eliminated and by the time you get the circuit set up most of it will have gone already. The alveolar and renal damage will have been done by then, so you have nothing to gain (other than a more rapid control of the acid-base disturbance).

Specific antidotes

  • None exist. Among previously trialled antioxidants, we can find Vitamin E, Vitamin C, desferrioxamine, N-acetylcysteine, methylene blue, etc. Thus far, nothing satisfying has been found.

Supportive management

  • Intubation to protect the rapidly swelling airway after corrosive ingestion
  • Avoidance of hyperoxia:  it has been demonstrated to exacerbate the oxidative toxicity of paraquat.
  • Circulatory support (there will be shock from myocardial necrosis and third space losses
  • Analgesia and sedation which is almost palliative in its intent - many of these people will die in spite of everything you do.
  • Specifically, propofol seems to have some sort of unique scavenging effect.

 

References

Gawarammana, Indika B., and Nicholas A. Buckley. "Medical management of paraquat ingestion." British journal of clinical pharmacology 72.5 (2011): 745-757.

Clark, D. G. "Inhibition of the absorption of paraquat from the gastrointestinal tract by adsorbents." British journal of industrial medicine 28.2 (1971): 186-188.

Kehrer, James P., Wanda M. Haschek, and Hanspeter Witschi. "The influence of hyperoxia on the acute toxicity of paraquat and diquat." Drug and chemical toxicology 2.4 (1979): 397-408.

Dinis-Oliveira, R. J., et al. "Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment." Critical reviews in toxicology 38.1 (2008): 13-71.