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Warfarin

Application in Ischemic Stroke Description References
Warfarin
Warfarin structure
CAS No.
81-81-2
Chemical Name:
Warfarin
Synonyms
RAX;D-Con;Ratox;Rosex;Kumadu;Warfin;Co-rax;Ratron;temusw;warf42
CBNumber:
CB0413732
Molecular Formula:
C19H16O4
Formula Weight:
308.33
MOL File:
81-81-2.mol

Warfarin Properties

Melting point:
162-164 °C(lit.)
Boiling point:
356°C
Density 
1.1411 (rough estimate)
vapor pressure 
0.09 at 22 °C (NIOSH, 1997)
refractive index 
1.4434 (estimate)
Flash point:
2℃
storage temp. 
2-8°C
solubility 
Soluble in benzene, 1,4-dioxane (Weast, 1986), and acetone (Sax and Lewis, 1987). Moderately soluble in methanol, ethanol, isopropanol, and some oils (Windholz et al., 1983). Also soluble in toluene.
form 
Crystalline
pka
pKa 4.90±0.01(H2O t = 25±0.5 I = 0.15 (KCl))(Approximate)
color 
Colorless
Water Solubility 
Practically insoluble
Merck 
13,10097
BRN 
8868198
Exposure limits
NIOSH REL: TWA 0.1 mg/m3, IDLH 100 mg/m3; OSHA PEL: 0.1 mg/m3; ACGIH TLV: TWA 0.1 mg/m3.
CAS DataBase Reference
81-81-2(CAS DataBase Reference)
EWG's Food Scores
6
FDA UNII
5Q7ZVV76EI
NCI Dictionary of Cancer Terms
warfarin
NIST Chemistry Reference
3-(Alpha-acetonylbenzyl)-4-hydroxycoumarin(81-81-2)
Proposition 65 List
Warfarin
EPA Substance Registry System
Warfarin (81-81-2)
SAFETY
  • Risk and Safety Statements
Symbol(GHS) 
GHS02,GHS07,GHS06,GHS08
Signal word  Danger
Hazard statements  H300-H312-H360-H372-H412-H225-H302+H312+H332-H319
Precautionary statements  P210-P305+P351+P338-P201-P260-P280-P308+P313
Hazard Codes  T,T+,Xn,F
Risk Statements  61-48/25-52/53-28-21-36-20/21/22-11
Safety Statements  53-45-61-52-36/37-28-26-16
RIDADR  UN 2811 6.1/PG 1
WGK Germany  3
RTECS  GN4550000
HazardClass  6.1(a)
PackingGroup  I
HS Code  29322090
Toxicity EC50 (24-hour) for Daphnia magna 88.8 mg/L (Lilius et al., 1995); acute oral LD50 for rats 186 mg/kg (Hartley and Kidd, 1987), 3 mg/kg (RTECS, 1985)

Warfarin price More Price(5)

Manufacturer Product number Product description CAS number Packaging Price Updated Buy
Sigma-Aldrich 45706 Warfarin? PESTANAL 81-81-2 250mg-r $44 2019-12-02 Buy
Sigma-Aldrich 1719000 Warfarin? United States Pharmacopeia (USP) Reference Standard 81-81-2 200mg $352.8 2019-12-02 Buy
Cayman Chemical 13566 (±)-Warfarin ≥98% 81-81-2 1g $18 2020-06-24 Buy
Sigma-Aldrich W-003 Warfarin solution 1.0mg/mL in acetonitrile, ampule of 1mL, certified reference material 81-81-2 003-1ml $26.9 2019-12-02 Buy
Sigma-Aldrich A2250 Warfarin? analytical standard 81-81-2 10g $112 2019-12-02 Buy

Warfarin Chemical Properties,Uses,Production

Application in Ischemic Stroke

Warfarin is the antithrombotic agent of first choice for secondary prevention in patients with atrial fibrillation and a presumed cardiac source of embolism.

Description

Warfarin is tasteless and colorless. It is a widely used as anticoagulant (which stops the blood clotting) in the treatment and prevention of thrombosis, in the treatment for chronic atrial fibrillation, mechanical valves, pulmonary embolism, and dilated cardiomyopathy. Warfarin is metabolized primarily via oxidation in the liver by CYP2C9, and exerts its anticoagulant effect by inhibiting the protein vitamin K epoxide reductase complex, subunit 1 (VKORC1). Warfarin therapy can be associated with significant bleeding complications. Achieving a safe therapeutic response can be difficult because of warfarin’s narrow therapeutic index and great individual variability in the dose required, which is mostly a consequence of individual genetic variants: it is influenced by ageing, co-prescribed drugs, diet, alcohol consumption, and comorbid conditions. To maintain a therapeutic level of anti-thrombosis and to minimize the risk of bleeding complications, warfarin therapy requires intensive monitoring via the INR to guide its dosing. It is also used as the first generation of anticoagulant rodenticides.

References

[1] Simon Sanderson, Jon Emery, Julian Higgins (2005) CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: A HuGEnetTM systematic review and meta-analysis, 7, 97-104
[2] http://npic.orst.edu/factsheets/rodenticides.html
[3] http://emedicine.medscape.com/article/1733331-overview

Description

Warfarin was the first of the synthetic anticoagulant rodenticides with structural features inspired by a natural product (88). This prototype coumarin derivative was developed in the 1940s by systematically altering the structure of dicumarol (46), recognized earlier as the causative agent of the sweet clover disease causing severe bleeding in grazing cattle (89). These rodenticides act by inhibiting the oxidoreductive recycling of vitamin K, a cofactor necessary for prothrombin synthesis involved in blood coagulation.

Chemical Properties

Colorless crystals; odorless; tasteless. Soluble in acetone, dioxane; slightly soluble in methanol, ethanol; very soluble in alkaline aqueous solution; insoluble in water and benzene.

Chemical Properties

Warfarin is a colorless, odorless crystalline solid.

Uses

Pesticide and rodenticide

Uses

Anticoagulant.

Uses

Coumadin is widely used as an anticoagulant for various systemic diseases such as venous thromboembolism, cardiac arrhythmia, following myocardial infarction, and hematologic abnormalities, among others. However, the efficacy of coumadin for CRVO is not established. It was reported that 13 of 354 patients taking warfarin developed CRVO despite maintaining therapeutic levels of the anticoagulant.

Application

Warfarin is an anti-coagulant used to prevent heart attacks, strokes, and the formation of blood clots. It interferes with the use of vitamin K in the required carboxylation of several vitamin K-dependent proteins in the clotting cascade, preventing the initiating of clotting. (±)-Warfarin is a racemic mixture of 2 optically active isomers. (±)-Warfarin has a half-life of 36-42 hours in circulation, bound to plasma proteins, and accumulates in the liver, where the two isomers are metabolized by different pathways. 

brand name

Athrombin- K (Purdue Frederick);Coumadine;Marevan;Mervan;Sofarin;Waran;Warfilone.

World Health Organization (WHO)

Warfarin, a coumarin anticoagulant, was introduced into medicine in 1950 for the prevention and managementof thrombo-embolic disorders. Its use during the first trimester of pregnancy has been associated with birth malformations, particularly in relation to cranial and limb development, and there have been reports of foetal death due to haemorrhage following administration of the drug during the late stages of pregnancy. The decision of the Egyptian agency to requrie a warning regarding teratogenicity to be included in the approved information of products containing warfarin beings the text of the package insert in line with those approved in other countries. Warfarin is included in the WHO Model List of Essential Drugs.

Reactivity Profile

Warfarin is incompatible with the following: Strong oxidizers .

Health Hazard

Warfarin is classified as very toxic. Probable oral lethal dose in humans is 50-500 mg/kg, between 1 teaspoon and 1 ounce for a 150 lb. person. Material is an anticoagulant. Toxic effects other than hemorrhage are rarely seen in humans. Material is believed to be teratogenic in humans. Persons with a history of blood disorders with bleeding tendencies would be expected to be at increased risk from exposure.

Health Hazard

Highly toxic substance; exhibits acute,delayed and chronic effects. Ingestion of adose of 3–15 g is thought to be fatal toadult human. It is an anticoagulant causinghemorrhage. The toxic symptoms whichbegin a few days or weeks after ingestioninclude bleeding of nose and gums, pallorand blood in the urine and feces. Anothersymptom may be hematomas around jointsand hip. If the dose is large or lethalthe delayed effects may lead to cerebralhemorrhage, paralysis and death. It exhibitedteratogenic effects in laboratory animals.The LD50 values reported in the literaturewidely vary.

Fire Hazard

Contact with strong oxidizers may cause fires and explosions. Toxic gases and vapors (e.g., carbon monoxide) may be released in heating to decomposition. Avoid strong oxidizers.

Agricultural Uses

Rodenticide: Warfarin and its sodium salt is an anticoagulant rodenticide used for controlling rats and house mice in and around homes, animal and agricultural premises, and commercialand industrial sites. It is effective in very low dosages. About a week is required before a marked reduction in the rodent population is noticeable. Rodents do not become bait-shy after once tasting warfarin; they continue to consume it until its anti-clotting properties have produced death through internal hemorrhaging. It can be used year-after-year wherever a rodent problem exists. Warfarin and its sodium salt are only slightly dangerous to humans and domestic animals when used as directed, but care must be taken with young pigs, which are especially susceptible. The sodium salt is also used to treat people with blood hypercoagulation problems. Registered for use in EU countries . Registered for use in the U.S.

Pharmaceutical Applications

A group of naturally occurring antibiotics chemically related to the coumarin group of anticoagulants. The best known is novobiocin, but a few naturally occurring coumarins and some semisynthetic derivatives have been studied. They share a narrow range of antimicrobial activity largely directed against aerobic Gram-positive organisms. Novobiocin inhibits susceptible strains of Staph. aureus (including β-lactamaseproducing and methicillin-resistant strains), Str. pyogenes and Str. pneumonia at a concentration of 0.1–2 mg/L and it has been considered for the treatment of infection with multiresistant Staph. aureus and other Gram-positive cocci. However, since resistance arises readily and side effects are common, the general consensus is that it no longer has a place in antibacterial therapy.
There has been some revived interest in coumarins as potentiating agents of antineoplastic drugs.

Trade name

ARAB RAT DETH®; ATROMBINE-K®; BRUMIN®; COMPOUND 42®; D-CON®; CO- RAX®; DETHMORE®; EAGLES-7®; EASTERN STATES DUOCIDE®; GROVEX SEWER BAIT®; HOPKINS BAR BAIR®; HOPKINS COV-R-TOX®; HOPKINS RODEX®; KILLGERM SEWARIN P®; KILMOL®; LIQUA-TOX®; MAR-FIN®; MOUSE PAK®; PLUSBAIT®; RAT-A-WAY®; RAT-B-GON®; RAT-O-CIDE®; RAT-GARD®; RAT & MICE BAIT®; RATRON®; RATS-NO-MORE®; RATTUNAL®; RAX®; RCR SQUIRREL KILLER®; RENTOKIL®; RENTOKIL BIOTROL®; RODEX BLOX®; RODENTEX®; RO- DETH®; RODEX®; ROUGH & READY MOUSE MIX®; SAKARAT®; SOLFARIN®; SOREXA PLUS®; SOREX CR1®; SEWARIN®; SPRAY-TROL BRANCH®; TWIN LIGHT RAT AWAY®; RODEN-TROL®; WARFARAT®; WARF COMPOUND®; VAMPIRINIP® Sodium Salt: ATHROMBIN®; LIQUA-TOX®; PANWARFIN®; RATSUL SOLUBLE®; TINTORANE®; VARFINE®; WARAN®; WARCOUMIN®; WARFILONE®

Mechanism of action

Warfarin sodium is rapidly and completely absorbed (~100% bioavailability) following oral, intramuscular, intravenous, or rectal administration. Peak plasma concentrations occur at approximately 3 hours. Its anticoagulant effect is not immediately present, however, following initiation of therapy. Instead, a delay in onset of anticoagulation occurs while the clotting factors with normal activity are cleared and those that have not been carboxylated because of the actions of warfarin reach physiologically significant levels. On average, this delay is approximately 5 hours for factor V turnover and 2 to 3 days for factor II (thrombin). Consequently, because of the rapid decline in protein C levels, the anticoagulated state frequently is preceded by a period of hypercoagulability (25).
Warfarin also is highly protein bound (95–99%) and, as a result, has numerous interactions with other drugs. The free drug (i.e., that not bound to plasma proteins) is the active constituent. Therefore, any other substance that displaces bound drug from protein binding sites increases the levels of free drug and, as a result, can cause warfarin toxicity, which usually is manifested by hemorrhage. The volume of distribution(Vd) is quite small (0.1–0.2 L/kg), and the plasma half-life is quite long, both of which presumably result from the high degree of plasma protein binding.

Pharmacokinetics

Warfarin sodium is rapidly and completely absorbed (~100% bioavailability) following oral, intramuscular, intravenous, or rectal administration. Peak plasma concentrations occur at approximately 3 hours. Its anticoagulant effect is not immediately present, however, following initiation of therapy. Instead, a delay in onset of anticoagulation occurs while the clotting factors with normal activity are cleared and those that have not been carboxylated because of the actions of warfarin reach physiologically significant levels. On average, this delay is approximately 5 hours for factor V turnover and 2 to 3 days for factor II (thrombin). Consequently, because of the rapid decline in protein C levels, the anticoagulated state frequently is preceded by a period of hypercoagulability (25).
Warfarin also is highly protein bound (95–99%) and, as a result, has numerous interactions with other drugs. The free drug (i.e., that not bound to plasma proteins) is the active constituent. Therefore, any other substance that displaces bound drug from protein binding sites increases the levels of free drug and, as a result, can cause warfarin toxicity, which usually is manifested by hemorrhage. The volume of distribution(Vd) is quite small (0.1–0.2 L/kg), and the plasma half-life is quite long, both of which presumably result from the high degree of plasma protein binding.

Safety Profile

A human poison by ingestion. Poison by inhalation and intravenous routes. Moderately toxic by skin contact, subcutaneous, and intraperitoneal routes. Human systemic effects by ingestion: hemorrhage, ulceration or bleeding from small intestine, blood clotting factor change. Human reproductive effects by ingestion and intramuscular routes: fetal death and physical abnormalities at birth. Human teratogenic effects include developmental abnormalities of the craniofacial area, musculoskeletal system, and respiratory system. An experimental teratogen. Other experimental reproductive effects. Used as an oral anticoagulant and as a rodenticide. When heated to decomposition it emits acrid smoke and fumes.

Potential Exposure

Warfarin is used as an oral anticoagulant and as a rodenticide or rat poison.

Environmental Fate

Photolytic. Warfarin may undergo direct photolysis since the pesticide showed an absorption maximum of 330 nm (Gore et al., 1971)
Chemical/Physical. The hydrolysis half-lives at 68.0°C and pH values of 3.09, 7.11 and 10.18 were calculated to be 12.9, 57.4 and 23.9 days, respectively. At 25°C and pH 7, the half-life was estimated to be 16 years (Ellington et al., 1986)

Metabolic pathway

The metabolism of warfarin in rat, man and other species has been studied in depth, mainly because of its use in anti-coagulant therapy to prevent thrombo-embolic disease. Having one chiral centre the molecule exists as R and S enantiomers but it is used in rodent control as the racemate. The S isomer is about six times more effective than the A isomer as judged by a single oral dose to the rat and using prothrombin time (clotting time) as a measure. The interaction of warfarin at its receptor, vitamin K1 epoxide reductase (see Overview), is completely nonstereoselective, suggesting that the 4-hydroxycoumarin ring system binds with the enzyme. Absorption is also non-selective and, therefore, the differential efficacy must be related to metabolism and disposition.
Warfarin is metabolised by aryl hydroxylation, alkyl hydroxylation and keto-reduction. The regioselective hydroxylation is catalysed by different isozymes of cytochrome P450 and warfarin has been used extensively as a probe for these enzymes.
Metabolism studies on soils and plants do not appear to have been reported. This is due to the use pattern of the compound (see Overview). Most aspects of the medical use of warfarin have been reviewed by Sutcliffe et ul. (1987). Mention should also be made of the work of Trager and co-workers (Black et ul., 1996, and earlier papers) on the chemistry and metabolism (particularly in man) of warfarin. This group has also conducted several of the many studies on potential warfarin-drug interactions.

Metabolism

Warfarin and other coumarin derivatives undergo extensive hepatic oxidative metabolism catalyzed by CYP2C9 isozyme to give 6- and 7-hydroxywarfarins as the major inactive metabolites. Warfarin also undergoes, to a lesser extent, reductive metabolism of the ketone on the C-3 side chain to a pair of pharmacologically active, diastereomeric 2-hydroxywarfarins). Almost no unchanged drug is excreted in the urine. As expected, those individuals with compromised hepatic function are at greater risk for warfarin toxicity secondary to diminished clearance. Many of the drug–drug interactions are associated with enhanced or inhibited metabolism of warfarin via CYP2C9 induction or inhibition. Many additional drugs and conditions have profound effects on warfarin therapy. A partial list of these factors is shown in Table 31.2.

Shipping

UN3027 Coumarin derivative pesticides, solid, toxic, Hazard Class: 6.1; Labels: 6.1-Poisonous materials. UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required.

Purification Methods

dl-Warfarin crystallises from EtOH or MeOH. UV: max at 308nm ( 13,610) in H2O. The acetate has m 117-118o, the O-triflate has m 90-91o, and the 2,4-dinitrophenylhydrazone has m 215-216o. It is an effective anticoagulant and rodenticide. [West et al. J Am Chem Soc 83 2676 1961, HPLC: Banfield & Rowland J Pharm Sci 72 921 1983, Beilstein 17 III/IV 6794.] dl-Warfarin is resolved via recrystallisation of the quinidine salt, and the free acids are recrystallised (70g) from 600mL of 80% aqueous Me2CO. Large prismatic crystals of the pure enantiomers are obtained by slow crystallisation from Me2CO or AcOH. The solubilities of the pure enantiomers at 25o are 11.2% in Me2CO and 2.6% in AcOH, whereas the racemate has solubilities of 6.5% in Me2CO and 2% in AcOH. The IR spectra are the same with max (CHCl3) at 2.78 (w), 5.88, 6.16 and 6.38. [West et al. J Am Chem Soc 83 2676 1961, Cbz-proline diastereoisomeric esters were used for HPLC analysis: Banfield & Rowland J Pharm Sci 72 921 1983.] Poisonous, anticoagulant and rodenticide.

Degradation

Warfarin is a very weak acid which forms alkali metal salts when dissolved in base. Studies have indicated that, as well as existing in the open chain form (illustrated above), warfarin may exist as a cyclic hemiketal, particularly in a lipid environment (see Park, 1988).

Incompatibilities

Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides. Dust mixtures with air may cause explosion.

Waste Disposal

Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Generators of waste containing this contaminant (≥100 kg/mo) must conform to EPA regulations governing storage, transportation, treatment, and waste disposal. Incineration.

Warfarin Preparation Products And Raw materials

Raw materials

Preparation Products


Warfarin Suppliers

Global( 186)Suppliers
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View Lastest Price from Warfarin manufacturers

Image Release date Product Price Min. Order Purity Supply Ability Manufacturer
2018-08-07 Warfarin
81-81-2
US $1.00 / KG 1KG 98% 20KG career henan chemical co
2018-08-20 Warfarin
81-81-2
US $1.00 / KG 1G 98% 100KG career henan chemical co

Warfarin Spectrum


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