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Brodifacoum is a highly lethal
4-hydroxycoumarin 4-Hydroxycoumarin is a coumarin derivative with a hydroxy group at the 4-position. Occurrence 4-Hydroxycoumarin is an important fungal metabolite from the precursor coumarin, and its production leads to further fermentative production of the na ...
vitamin K antagonist Vitamin K antagonists (VKA) are a group of substances that reduce blood clotting by reducing the action of vitamin K. The term "vitamin K antagonist" is technically a misnomer, as the drugs do not directly antagonise the action of vitamin K in t ...
anticoagulant Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where the ...
poison Poison is a chemical substance that has a detrimental effect to life. The term is used in a wide range of scientific fields and industries, where it is often specifically defined. It may also be applied colloquially or figuratively, with a broa ...
. In recent years, it has become one of the world's most widely used
pesticides Pesticides are substances that are meant to control pests. This includes herbicide, insecticide, nematicide, molluscicide, piscicide, avicide, rodenticide, bactericide, insect repellent, animal repellent, microbicide, fungicide, and la ...
. It is typically used as a
rodenticide Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to as "rat poison", rodenticides are also used to kill mice, squirrels, woodchucks, chipmunks, porcupines, nutria, beavers, and voles. Despite ...
, but is also used to control larger pests such as possum.Eason, C.T. and Wickstrom, M. ''Vertebrate pesticide toxicology manual'',
New Zealand Department of Conservation The Department of Conservation (DOC; Māori: ''Te Papa Atawhai'') is the public service department of New Zealand charged with the conservation of New Zealand's natural and historical heritage. An advisory body, the New Zealand Conservation Au ...
Brodifacoum has an especially long half-life in the body, which ranges up to nine months, requiring prolonged treatment with antidotal
vitamin K Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...
for both human and pet poisonings. It has one of the highest risks of
secondary poisoning Secondary poisoning, or relay toxicity, is the poisoning that results when one organism comes into contact with or ingests another organism that has poison in its system. It typically occurs when a predator eats an animal, such as a mouse, rat ...
to both mammals and birds.Rodenticides: Topic Fact Sheet
National Pesticide Information Center The National Pesticide Information Center (NPIC) is a collaboration between Oregon State University and the United States Environmental Protection Agency to provide objective, science-based information about pesticides, the recognition and managem ...
Significant experience in brodifacoum poisonings has been gained in many human cases where it has been used in attempted suicides, necessitating long periods of vitamin K treatment. In March 2018, cases of severe coagulopathy and bleeding associated with
synthetic cannabinoid Synthetic cannabinoids are a class of designer drug molecules that bind to the same receptors to which cannabinoids (THC, CBD and many others) in cannabis plants attach. These novel psychoactive substances should not be confused with syntheti ...
use contaminated with brodifacoum were reported in five states of the US.


Chemical synthesis

Brodifacoum is a derivative of the 4-hydroxy-coumarin group. Compounds numbers are found next to their respective compounds in the image below. Compound 1 is the starting ester needed to synthesize brodifacoum. To obtain this starting Compound 1, a simple Wittig condensation of ethyl chloroacetate with 4’-bromobiphenylcarboxaldehyde is accomplished. Compound 1 is transformed into Compound 2 by consecutive
hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis i ...
,
halogenation In chemistry, halogenation is a chemical reaction that entails the introduction of one or more halogens into a compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, ...
to form an acid chloride, and then reacted with the required
lithium Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid e ...
anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...
. This is done using KOH and EtOH for hydrolysis, and then adding SOCl2 for chlorination to form the acid chloride which reacts with the addition of lithium anion. Compound 2 is then transformed using
organocopper Organocopper compounds is the chemistry of organometallic compounds containing a carbon to copper chemical bond. Organocopper chemistry is the study of organocopper compounds describing their physical properties, synthesis and reactions. They a ...
chemistry to yield Compound 3 with good
stereoselectivity In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non- stereospecific creation of a new stereocenter or during a non-stereospecific transformation of ...
of about 98%. Typically, a Friedel-Crafts type cyclization would then be used to obtain the two-ring system portion of Compound 4, but this results in low yield. Instead,
trifluoromethanesulfonic acid Triflic acid, the short name for trifluoromethanesulfonic acid, TFMS, TFSA, HOTf or TfOH, is a sulfonic acid with the chemical formula CF3SO3H. It is one of the strongest known acids. Triflic acid is mainly used in research as a catalyst for es ...
in dry
benzene Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms ...
catalyzes the cyclization with good yield. The
ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
is then reduced with
sodium borohydride Sodium borohydride, also known as sodium tetrahydridoborate and sodium tetrahydroborate, is an inorganic compound with the formula Na BH4. This white solid, usually encountered as an aqueous basic solution, is a reducing agent that finds applica ...
yielding a
benzyl alcohol Benzyl alcohol is an aromatic alcohol with the formula C6H5CH2OH. The benzyl group is often abbreviated "Bn" (not to be confused with "Bz" which is used for benzoyl), thus benzyl alcohol is denoted as BnOH. Benzyl alcohol is a colorless liquid ...
. Condensation with 4-hydroxycoumarin under HCl yields Compound 5, brodifacoum.


Toxicology

Brodifacoum is a
4-hydroxycoumarin 4-Hydroxycoumarin is a coumarin derivative with a hydroxy group at the 4-position. Occurrence 4-Hydroxycoumarin is an important fungal metabolite from the precursor coumarin, and its production leads to further fermentative production of the na ...
anticoagulant, with a similar mode of action to its historical predecessors
dicoumarol Dicoumarol ( INN) or dicumarol ( USAN) is a naturally occurring anticoagulant drug that depletes stores of vitamin K (similar to warfarin, a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductases ...
and
warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent ...
. However, due to very high potency and long duration of action (elimination
half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...
of 20 – 130 days), it is characterised as a "second-generation" or " superwarfarin" anticoagulant. Brodifacoum inhibits the
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...
vitamin K epoxide reductase Vitamin K epoxide reductase (VKOR) is an enzyme () that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid residues in blood coagulation enzymes. VKOR is a member of a large family of predicted enzymes that are pre ...
, which is needed for the reconstitution of the vitamin K in its cycle from vitamin K-epoxide, so brodifacoum steadily decreases the level of active vitamin K in the blood. Vitamin K is required for the synthesis of important substances including
prothrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
, which is involved in
blood clotting Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
. This disruption becomes increasingly severe until the blood effectively loses any ability to clot. In addition, brodifacoum (as with other anticoagulants in toxic doses) increases permeability of blood capillaries; the blood plasma and blood itself begin to leak from the smallest blood vessels. A poisoned animal suffers progressively worsening internal bleeding, leading to shock, loss of consciousness, and eventually
death Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...
. Brodifacoum is highly lethal to mammals and birds, and extremely lethal to fish. It is a highly cumulative poison, due to its high
lipophilicity Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...
and extremely slow
elimination Elimination may refer to: Science and medicine *Elimination reaction, an organic reaction in which two functional groups split to form an organic product *Bodily waste elimination, discharging feces, urine, or foreign substances from the body ...
. Following are acute values for a variety of animals:


Brand names

Brodifacoum is marketed under many trade names, including Arakus (Advansia), Biosnap,
d-CON d-CON is an American brand of rodent control products owned and distributed in the United States by the UK-based consumer goods company Reckitt. The d-CON product line includes traps and baits for use around the home for trapping and killing ra ...
, Finale, Fologorat, Havoc, Jaguar, Klerat, Matikus, Mouser, Pestoff, Rakan, Ratak+, Rataquill Colombia, Ratshot Red, Rattex, Rodend, Rodenthor, Ratsak, Talon, Volak, Vertox, and Volid.


Human poisoning


Treatment

The primary antidote to brodifacoum poisoning is immediate administration of vitamin K1 (dosage for humans: initially slow intravenous injections of 10–25 mg repeated at 3–6 hours until normalisation of the prothrombin time; then 10 mg orally four times daily as a "maintenance dose"). It is an extremely effective antidote, provided the poisoning is caught before excessive bleeding ensues. As high doses of brodifacoum can affect the body for many months, the antidote must be administered regularly for a long period (several months, in keeping with the substance's half-life) with frequent monitoring of the
prothrombin time The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the ''extrinsic'' pathway and common pathway of coagulation. This blood test is als ...
. If unabsorbed poison is still in the digestive system,
gastric lavage Gastric lavage, also commonly called stomach pumping or gastric irrigation, is the process of cleaning out the contents of the stomach. Since its first recorded use in early 19th century, it has become one of the most routine means of eliminating ...
followed by administration of activated charcoal may be required. Further treatments to be considered include infusion of blood or plasma to counteract
hypovolemic shock Hypovolemic shock is a form of shock caused by severe hypovolemia (insufficient blood volume or extracellular fluid in the body). It could be the result of severe dehydration through a variety of mechanisms or blood loss. Hypovolemic shock i ...
, and in severe cases, infusion of blood clotting factor concentrate.


Case reports

Cases of brodifacoum intoxication have been reported in the human medical literature. In one report, a woman deliberately consumed over 1.5 kg (3 lb) of rat bait, constituting about 75 mg brodifacoum, but made a full recovery after receiving conventional medical treatment. In another case reported in 2013, a 48-year-old female patient reported 4 days of mild
dyspnea Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...
, dry cough, bilateral popliteal fossae pain, and diffuse upper abdominal pain. She had no history of liver disease or alcohol or illicit substance
abuse Abuse is the improper usage or treatment of a thing, often to unfairly or improperly gain benefit. Abuse can come in many forms, such as: physical or verbal maltreatment, injury, assault, violation, rape, unjust practices, crimes, or other t ...
. Initial physical examination was remarkable only for mildly pale conjunctivae and mild abdominal tenderness and pain in the left
popliteal fossa The popliteal fossa (also referred to as hough, .html" ;"title="/sup>">/sup> or kneepit in analogy to the cubital fossa) is a shallow depression located at the back of the knee joint. The bones of the popliteal fossa are the femur and the tib ...
. A complete blood count and complete metabolic panel were normal.
Prothrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
time (PT) was above 100 s, partial thromboplastin time (PTT) was above 200 s and international normalized ratio (INR) was reported as above 12.0. Urinalysis revealed
hematuria Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. “Gross hematuria” occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable w ...
(blood in the urine). Venous
Doppler ultrasound Doppler ultrasonography is medical ultrasonography that employs the Doppler effect to perform imaging of the movement of tissues and body fluids (usually blood), and their relative velocity to the probe. By calculating the frequency shift of a ...
of lower extremities demonstrated left popliteal vein
thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets ...
. Computed tomography scan of the abdomen demonstrated transmural hematoma, and a
fecal occult blood test Fecal occult blood (FOB) refers to blood in the feces that is not visibly apparent (unlike other types of blood in stool such as melena or hematochezia). A fecal occult blood test (FOBT) checks for hidden (occult) blood in the stool (feces). The ...
was positive. A full anticoagulant work-up showed critical reduction of vitamin K-dependent factors II, VII, IX, and X. PT and PTT corrected with mixing studies proving factor deficiency as the cause of the coagulopathy.
Lupus anticoagulant Lupus anticoagulant is an immunoglobulin that binds to phospholipids and proteins associated with the cell membrane. Its name is a partial misnomer, as it is actually a prothrombotic antibody ''in vivo''. Lupus anticoagulant in living systems caus ...
studies were negative. Superwarfarin toxicity was suspected and confirmed with an anticoagulant poison panel positive for brodifacoum. The patient was hospitalized and successfully treated with fresh frozen plasma,
cryoprecipitate Cryoprecipitate, also called cryo for short, is a frozen blood product prepared from blood plasma. To create cryoprecipitate, fresh frozen plasma thawed to 1–6 °C is then centrifuged and the precipitate is collected. The precipitate is r ...
, and vitamin K. In conclusion, paradoxical thrombosis and hemorrhage should raise the suspicion for superwarfarin toxicity in the appropriate clinical setting. Concomitant presentation for thrombosis and hemorrhage with remarkably abnormal PT and PTT should raise the suspicion for brodifacoum poisoning. In another report, a 17-year-old boy presented to the hospital with a severe bleeding disorder. He was found to have habitually smoked a mixture of brodifacoum and
marijuana Cannabis, also known as marijuana among other names, is a psychoactive drug from the cannabis plant. Native to Central or South Asia, the cannabis plant has been used as a drug for both recreational and entheogenic purposes and in various tra ...
. Despite treatment with vitamin K, the bleeding disorder persisted for several months. He eventually recovered. In 2015, 19
inmate A prisoner (also known as an inmate or detainee) is a person who is deprived of liberty against their will. This can be by confinement, captivity, or forcible restraint. The term applies particularly to serving a prison sentence in a priso ...
s in
New York City New York, often called New York City or NYC, is the most populous city in the United States. With a 2020 population of 8,804,190 distributed over , New York City is also the most densely populated major city in the Un ...
's
Rikers Island Rikers Island is a island in the East River between Queens and the Bronx that contains New York City's main jail complex. Named after Abraham Rycken, who took possession of the island in 1664, the island was originally under in size, but ha ...
jail claimed that they had been poisoned with the chemical. The inmates had noticed "what appeared to be blue and green pellets in the
meatloaf Meatloaf is a dish of ground meat that has been combined with other ingredients and formed into the shape of a loaf, then baked or smoked. The final shape is either hand-formed on a baking tray, or pan-formed by cooking it in a loaf pan. ...
" they were eating on March 3, and felt ill afterwards. A sample was analyzed and tested positive for brodifacoum; the NYC Department of Correction stated it was investigating the incident. A 20-year-old female college student presented with abdominal pain and blood in urine. She was tested for
warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent ...
, a common anticoagulant also used in some rodenticides, which returned a negative result. Vitamin K and fresh plasma were administered to treat symptoms. Three weeks later, she returned with bleeding into her calf, and was subsequently tested for superwarfarin chemicals. The test showed that brodifacoum was in her bloodstream. She later admitted to consuming seven packets of
rodenticide Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to as "rat poison", rodenticides are also used to kill mice, squirrels, woodchucks, chipmunks, porcupines, nutria, beavers, and voles. Despite ...
. A 48-year-old businessman was admitted with a severe nosebleed and abnormal coagulation parameters. Standard treatment of vitamin K and fresh plasma was administered to stem the nosebleed. Two weeks later, he presented again with bleeding into the calf. Continual doses of vitamin K were necessary to counteract the brodifacoum. He denied taking any of the brodifacoum found in his home contained within packages of Contrac. As of November 26, 2018, at least eight fatalities and 320 cases of severe coagulopathy and bleeding associated with
synthetic cannabinoid Synthetic cannabinoids are a class of designer drug molecules that bind to the same receptors to which cannabinoids (THC, CBD and many others) in cannabis plants attach. These novel psychoactive substances should not be confused with syntheti ...
use had been reported in Illinois, Wisconsin, Maryland, Missouri, Florida, North Carolina, Indiana, Pennsylvania, Kentucky, Virginia, and West Virginia. The first case occurred in Illinois on March 7, 2018. Brodifacoum was suspected to be present in these products in Illinois. Products named Matrix and Blue Giant from a convenience store in Chicago have tested positive for brodifacoum and
AMB-FUBINACA AMB-FUBINACA (also known as FUB-AMB and MMB-FUBINACA) is an indazole-based synthetic cannabinoid that is a potent agonist for the cannabinoid receptors, with ''K''i values of 10.04 nM at CB1 and 0.786 nM at CB2 and EC50 values of 0. ...
(FUB-AMB).


References


Further reading

* Tasheva, M. (1995). ''Environmental Health Criteria 175: Anticoagulant rodenticides''. World Health Organisation: Geneva. * * {{rodenticides Anticoagulant rodenticides Coumarin drugs Tetralins Bromoarenes Vitamin K antagonists 4-Hydroxycoumarins Biphenyls Rodenticides