Pesticides Blog Post: Anticoagulants

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Introduction:

Anticoagulants are commonly used in treating thrombosis and blood disorders such as thrombophilia. Oddly enough, its first application was not practiced for therapy or medicinal purposes. The use of anticoagulants was first utilized in pesticides to regulate and control pests in urban environments, agriculture, and the conservation of the native fauna. The expansion of trade and globalization has caused rodents to infringe on foreign ecosystems. This ultimately shapes population health, economic goods, and seasonal harvest. Working as a fast-acting anticoagulant rodenticide and/or pesticide, the mechanism of action is to reduce blood coagulation and as a result, creates a fatal hemorrhage. Consistent consumption of anticoagulants is required to produce a toxic state, a result of anticoagulant pesticides is seen within a week of its application.

Background:

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In the 1920s there were a large number of cattle dying throughout Alberta, Canada to Wisconsin, United States. In 1929 Dr. Frederick Schofield, a Canadian veterinarian, took an interest in why livestock through the north-midwest were exhibiting hemorrhage and fatality. This question was further addressed by a colleague of his named Dr. L.M. Roderick, a veterinarian who found that the cause of the hemorrhage was due to a consumption of sweet clover hay. When the sweet clover hay begins to mold the indigenous chemical substance within the hay, coumarin, is converted into dicoumarol. This substance was responsible for anticoagulation and diminishing prothrombin, the protein active in the coagulation process. Once the by-product dicoumarol was isolated in 1952 Warfarin was coined as the first anticoagulant pesticide permitted for use. Its substance is manipulated to come in liquid, talc, powder, and even water-soluble form. Second-generation anticoagulants were designed to be more potent and to target pests that were resistant to first-generation anticoagulants.

• • First-generation anticoagulants
    • Warfarin
    • Chlorophacinone
    • Coumafuryl
    • Diphacinone
  • Second-generation anticoagulants
    • Difethialone
    • Bromadiolone
    • Difenacoum
    • Brodifacoum

• Biotransformation

  • The Biotransformation of anticoagulants is important in its performance not only from a pharmacokinetic standpoint but pharmacodynamics as well. Here is an article addressing how antacids act on anticoagulants for a more detailed description (Click Here for Article). In summary, the abstract from that article entails:
    

    Vitamin K antagonists (VKAs) such as warfarin are the most commonly prescribed oral anticoagulants worldwide. However, factors affecting the pharmacokinetics of VKAs, such as food and drugs, can cause deviations from their narrow therapeutic window, increasing the bleeding or thrombosis risk and complicating their long-term use. The use of direct oral anticoagulants (DOACs) offers a safer and more convenient alternative to VKAs. However, it is important to be aware that plasma levels of DOACs are affected by drugs that alter the cell efflux transporter P-glycoprotein and/or cytochrome P450. In addition to these pharmacokinetic-based interactions, DOACs have the potential for pharmacodynamic interaction with antiplatelet agents and non-steroidal anti-inflammatory drugs (Vranckx,2018).

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• Toxicokinetics

  • Below is a table that illustrates the half-life (T 1/2) of some anticoagulant’s pesticides. Labeling the toxicity levels from non-toxic, very low, low, moderate, mild, and high. It is important to note that second-generation anticoagulant pesticides are a mix of two diastereoisomeric forms. One diastereoisomeric typically has a shorter half-life than its pairing, this alters its toxicity due to shorter or prolonged exposure. Second-generation anticoagulants are more toxic due to concentration and a longer half-life than first-generation anticoagulants, known to be effective in a single feeding. The addition of phenyl rings has made anticoagulants more hydrophobic, thus increasing toxicity level.

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• Carcinogenicity

  • There are studies conducted to review if anticoagulant pesticides have a carcinogenic effect but no declaration. On the contrary, the use of anticoagulants have been used in oncology treatments to see its effect on reducing malignancy. First-generation anticoagulants such as warfarin is a well-known teratogen, creating spontaneous abortion or stillbirth.

• Mechanism of Action

  • Anticoagulant pesticides work as Vitamin K antagonists by inhibiting vitamin k epoxide reductase enzymes (VKORC1). VKORC1 plays an essential role in blood clotting due to its storage and recycling of Vitamin K. The addition of a gamma-carboxylase facilitates this process but without the presence of VKCOR1, the gamma-carboxylase is inactive. When an anticoagulant is introduced the recycle and storage of vitamin K that is stored in the liver is depleted and derivatives that are formed from this storage are unable to initiate clotting. The ingestion of Vitamin K through dietary means is not a sufficient amount to aid in clotting at this point and the organism is prone to hemorrhage.

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• Target Organs

  • The liver is affected due to the lack of Vitamin K storage and its utilization but hemorrhage is continued throughout the thorax, cardiovascular system, cerebral vasculature, pericardium, and muscle tissue. Anticoagulants prove to be quite effective in its design and ultimately disrupt all organ systems due to the inability to process clotting factors.

                                                             

• Signs & Symptoms of Toxicity

  1. Ocular hemorrhage may induce blindness
  2. Vomiting
  3. Convulsions
  4. Ataxia-impaired coordination

• Common Causes of Exposure

  1. Occupational hazard – an example of an occupational hazard sheet of warfarin
  2. Suicidal intent
  3. Infants accidental ingestion
• Anticoagulants are created in many forms, exposure could be from ingestion or as an inhalant but the typical form of exposure is ingestion.
  • Diagnosis: residue of the chemical agent can be found in body fluid and tissue through diagnostics.

• Genetic Susceptibility of Heritable Traits

  • Currently, there is no credible evidence placed forth by regulatory bodies to claim there is genetic susceptibility in anticoagulant pesticides but a study address by Northwestern University touches on the possibility (Click Here for Article).

• Treatments

  • Antidote: The first line of treatment is Vitamin K all anticoagulant rodenticides, given through intravenous.
  • Monitor: repeated determinations of OSPT and red blood cell numbers (e.g., packed cell volume [PCV] or hematocrit [HCT])
  • Severe Treatment: If blood and plasma levels are compromised a transfusion may be required if blood loss is far too great.
• Many anticoagulant pesticide agents resemble pet food and due to it being colorless and odorless to pets they are susceptible to poisoning. Here is a short video provided by Dr. Beck, a wellness veterinarian, who discusses the poisoning and treatment of anticoagulants for household pets.

• Biomarkers

  • Assays to examine proteins, such as prothrombin, in serums will give indications of anticoagulants and its influence on the Vitamin K cycle.  Coagulation. Here is a link that gives a description of assays used in 6 anticoagulants and a case study where the technique was used to examine a 6-month-old female dachshund (Click Here for Article).

Resources:

1. Eason CT, Murphy EC, Wright GR, Spurr EB. Assessment of risks of brodifacoum to non-target birds and mammals in New Zealand. Ecotoxicology. 2002;11(1):35‐48. doi:10.1023/a:1013793029831
2. Seljetun, K. O., Eliassen, E., Karinen, R., Moe, L., & Vindenes, V. (2018). Quantitative method for analysis of six anticoagulant rodenticides in faeces, applied in a case with repeated samples from a dog. Acta veterinaria Scandinavica, 60(1), 3. https://doi.org/10.1186/s13028-018-0357-
3. Watt BE, Proudfoot AT, Bradberry SM, Vale JA. Anticoagulant rodenticides. Toxicol Rev. 2005;24(4):259‐269. doi:10.2165/00139709-200524040-00005
4. Vranckx, P., Valgimigli, M., & Heidbuchel, H. (2018). The Significance of Drug-Drug and Drug-Food Interactions of Oral Anticoagulation. Arrhythmia & electrophysiology review, 7(1), 55–61. https://doi.org/10.15420/aer.2017.50.1
5. Feinstein, D. L., Akpa, B. S., Ayee, M. A., Boullerne, A. I., Braun, D., Brodsky, S. V., Gidalevitz, D., Hauck, Z., Kalinin, S., Kowal, K., Kuzmenko, I., Lis, K., Marangoni, N., Martynowycz, M. W., Rubinstein, I., van Breemen, R., Ware, K., & Weinberg, G. (2016). The emerging threat of superwarfarins: history, detection, mechanisms, and countermeasures. Annals of the New York Academy of Sciences, 1374(1), 111–122. https://doi.org/10.1111/nyas.13085