Warfarin poisoning

Treatment for warfarin poisoning includes vitamin K administration and, in severe cases, transfusions of whole blood... 

Warfarin [81-81-2] (6) is prepared by the Michael condensation of benzyHdene acetone with 4-hydroxycoumarin (86). It is used as a rodenticide (see Poisons, commercial) and in anticoagulant therapy. 

The isoprene-derived molecule whose structure is shown here is known alternately as Coumarin and warfarin. By the former name, it is a widely prescribed anticoagulant. By the latter name, it is a component of rodent poisons. How can the same chemical species be used for such disparate purposes The key to both uses lies in its ability to act as an antagonist of vitamin K in the body. 

Coumarin/warfarin, given at a typical dosage of 4 to 5 mg/day, prevents the deleterious formation in the bloodstream of small blood clots and thus reduces the risk of heart attacks and strokes for individuals whose arteries contain sclerotic plaques. Taken in much larger doses, as for example in rodent poisons, Coumarin/warfarin can cause massive hemorrhages and death. 

WARF) (7). The same reaction with p-nitrobenzalacetone (8) affords acenocoumarole (9). It might be mentioned in passing that one of the largest uses of warfarin is in fact as a rat poison animals that ingest the drug in large amounts simply bleed to death. 

Isoniazid Adults S mg/kg (300 mg) Children 1 0-1 S mg/kg (300 mg) Asymptomatic elevation of aminotransferases, clinical hepatitis, fatal hepatitis, peripheral neurotoxicity, CNS system effects, lupus-like syndrome, hypersensitivity, monoamine poisoning, diarrhea LFT monthly in patients who have preexisting liver disease or who develop abnormal liver function that does not require discontinuation of drug Dosage adjustments may be necessary in patients receiving anticonvulsants or warfarin... 

The major adverse effect of warfarin is bleeding. (Ironically, this compound was originally introduced as a very effective ro-denticide. As the active ingredient in rodent poison, it causes death due to internal hemorrhaging.) Furthermore, because it readily crosses the placenta and can cause a hemorrhagic disorder in the fetus, it is contraindicated in pregnant women. 

Warfarin provides us with a slightly incongruous state of affairs it is used as a drug and also as a rat poison. It was developed from a natural product, dicoumarol, and provides us with a nice example of how pyrone chemistry resembles that of conjugated lactones rather than aromatic systems. 

Because rodent populations world-wide were becoming resistant to the widely used Warfarin-type anticoagulant poisons, a search was initiated to find a rodenticide with a different mode of action one that would be effective against these resistant rodents. This search led to the discovery of the toxic nature of a family of diphenyl amines which act as uncouplers of oxidative phosphorylation. A structure-activity relationship (SAR) study was undertaken to choose a derivative that would be both poisonous to rodents but still readily consumed by them. This approach led to the discovery of bromethalin,... 

Very rapidly, a number of other anticoagulants, including the indanediones (4), (Structure 2), were developed as rodenticides. Warfarin first came into wide usage as a rodenticide in 1950 and virtually supplanted all other materials then in use. In the case of all these early materials, multiple bait applications were needed to control rodent populations which, while making the materials safer to use than the available acute poisons, curtailed their use in underdeveloped and less affluent countries because of the large quantities of bait that must be placed to destroy the populations of rodents. 

The only major side-effect of these oral anticoagulants is prolonged bleeding, thus the dosage levels are chosen with care. Dicoumarol was first isolated from spoiled sweet clover hay, as the agent which promoted haemorrhage disease in cattle. Both dicoumarol and warfarin have also been utilized (at high doses) as rat poisons. 

Warfarin, a coumarin anticoagulant, is incorporated into commeal for use as a rat poison. Repeated exposure results in sufficient inhibition of prothrombin synthesis to cause fatal internal hemorrhage. 

Vitamin K antagonists, such as dicoumarol (8.61, a natural product) and warfarin (8.62), are used as anticoagulants in human therapy (thrombosis, atherosclerosis) and as rat poisons that lead to internal bleeding and death in rodents. Heparin, a polysaccharide consisting of 2-0-sulfonated glucuronic acid and 2-N,6-0-disulfonated glucosamine, is also a widely used anticoagulant, but its effect is connected not with Vitamin K but with enzyme inhibition. 

Warfarin (Fig. 10-22c) is a synthetic compound that inhibits the formation of active prothrombin. It is particularly poisonous to rats, causing death by internal bleeding. Ironically, this potent rodenticide is also an invaluable anticoagulant drug for treating humans at risk for excessive blood clotting, such as surgical patients and those with coronary thrombosis. ... 

Vitamin K is also an antagonist of warfarin, which is sometimes used in rodenticides, Pets that have been exposed to warfarin-containing poisons may be saved from death by internal hemorrhaging through the immediate administration of vitamin K,... 

A structural application of 13C nmr, which shows its power in an area where H nmr is indecisive, is shown in Figure 9-48. Here, we see the high-field 13C resonances of a substance known variously as Coumadin, or the sodium salt of warfarin, 14, which is used widely as a blood anticoagulant in the treatment of diseases such as phlebitis. It also has substantial utility as a rat poison because of its anticoagulant action. 

Structural features that promote biological activity are sometimes called biophores. They are divisible into pharmacophores and toxicophores. Pharmacophores impart desirable properties on a molecule (e.g., pharmacological activity or a particular fragrance). Toxicophores are responsible for undesirable effects such as toxicity (e.g., mutagenicity and skin sensitization). The same molecule can have more than one descriptor that can act as both a pharmacophore and a toxicophore in the same or different biological systems. Examples here are the toxic side effects of anti-cancer drugs and the use of Warfarin, a commercially available rat poison, to help reduce the formation of blood clots in human heart disease. 

Warfarin. Warfarin is a popular rodenticide particularly common in rat poison preparations. Because of its toxic nature, assessment of workplace and environmental exposures is of concern. Warfarin can be quickly and easily determined by reverse phase HPLC. Details of the procedure applied in our laboratory are as follows ... 

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