| Identification | More | [Name]
Warfarin | [CAS]
81-81-2 | [Synonyms]
3-(1-PHENYL-2-ACETYL)ETHYL-4-HYDROXYCOUMARIN
3-(A-ACETONLYLBENZYL)-4-HYDROXY-COUMARIN
3(A-ACETONYLBENZYL)-4-HYDROXYCOUMARIN
3-(ALPHA-ACETONYLBENZYL)-4-HYDROXYCOUMARIN
3-A-PHENYL-B-ACETYLETHYL-4-HYDROXYCOUMARIN
4-HYDROXY-3-(3-OXO-1-PHENYLBUTYL)COUMARIN
ATHROMBINE-K(R)
COMPOUND 42(R)
COUMADIN(R)
COUMAFEN
COUMAFENE
COUMAFENE(R)
COUMAPHENE(R)
DETHMOR(R)
DL-3-(ALPHA-ACETONYLBENZYL)-4-HYDROXYCOUMARIN
KYPFARIN(R)
PROLIN(R)
SAKARAT
Warfarat
WARFARIN | [EINECS(EC#)]
201-377-6 | [Molecular Formula]
C19H16O4 | [MDL Number]
MFCD00006854 | [Molecular Weight]
308.33 | [MOL File]
81-81-2.mol |
| Questions And Answer | Back Directory | [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
|
| Chemical Properties | Back Directory | [Appearance]
Colorless crystals; odorless; tasteless.
Soluble in acetone, dioxane;
slightly soluble in methanol, ethanol; very soluble
in alkaline aqueous solution; insoluble in water and
benzene. | [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) | [Fp ]
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 | [Odor]
odorless | [Water Solubility ]
Practically insoluble | [Usage]
Coumarin anticoagulant | [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. | [LogP]
2.600 | [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. | [CAS DataBase Reference]
81-81-2(CAS DataBase Reference) | [NIST Chemistry Reference]
3-(Alpha-acetonylbenzyl)-4-hydroxycoumarin(81-81-2) | [EPA Substance Registry System]
81-81-2(EPA Substance) |
| Safety Data | Back Directory | [Hazard Codes ]
T | [Risk Statements ]
R61:May cause harm to the unborn child.
R48/25:Toxic: danger of serious damage to health by prolonged exposure if swallowed .
R52/53:Harmful to aquatic organisms, may cause long-term adverse effects in the aquatic environment . | [Safety Statements ]
S53:Avoid exposure-obtain special instruction before use .
S45:In case of accident or if you feel unwell, seek medical advice immediately (show label where possible) .
S61:Avoid release to the environment. Refer to special instructions safety data sheet .
S52:Not recommended for interior use on large surface areas . | [OEB]
D | [OEL]
TWA: 0.1 mg/m3 | [RIDADR ]
UN 2811 6.1/PG 1
| [WGK Germany ]
3
| [RTECS ]
GN4550000
| [HazardClass ]
6.1(a) | [PackingGroup ]
I | [HS Code ]
29322090 | [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. | [Hazardous Substances Data]
81-81-2(Hazardous Substances Data) | [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) | [IDLA]
100 mg/m3 |
| Hazard Information | Back Directory | [General Description]
Odorless and colorless solid. Used as a rodenticide for Norway rats and for house mice. | [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. | [Potential Exposure]
Warfarin is used as an oral anticoagulant
and as a rodenticide or rat poison. | [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. | [First aid]
If this chemical gets into the eyes, remove any
contact lenses at once and irrigate immediately for at least
15 minutes, occasionally lifting upper and lower lids. Seek
medical attention immediately. If this chemical contacts the
skin, remove contaminated clothing and wash immediately
with soap and water. Seek medical attention immediately. If
this chemical has been inhaled, remove from exposure, begin
rescue breathing (using universal precautions, including
resuscitation mask) if breathing has stopped and CPR if heart
action has stopped. Transfer promptly to a medical facility.
When this chemical has been swallowed, get medical attention.
Give large quantities of water and induce vomiting. Do
not make an unconscious person vomit. Medical observation
is recommended. | [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. | [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. | [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. | [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. | [Originator]
Coumadin ,Endo,US,1954 | [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.
| [Definition]
ChEBI: 4-hydroxy-3-(3-oxo-1-phenylbutyl)-1-benzopyran-2-one is a member of the class of coumarins that is 4-hydroxycoumarin which is substituted at position 3 by a 1-phenyl-3-oxo-1-butyl group. It is a methyl ketone and a hydroxycoumarin. | [Manufacturing Process]
About 0.1 mol each of 4-hydroxycoumarin and benzalacetone are dissolved, in
any desired order, in about three times their combined weight of pyridine. The
solution is refluxed for about 24 hours, and then allowed to cool; after which
it is poured into about 15 volumes of water, and acidified to about pH 2 by the
addition of hydrochloric acid. An oil separates, and on cooling and standing
overnight solidifies. The solid product is recovered, as by filtration, and
recrystallized from ethanol, according to US Patent 2,427,578.
The base melts at about 161°C. It is a white crystalline solid, soluble in hot
ethyl alcohol and substantially insoluble in cold water; it dissolves in alkali
solutions with formation of the salt. The yield is about 40%.
Then, as described in US Patent 2,777,859, warfarin may be reacted with
NaOH to give a sodium salt solution. Crystalline warfarin sodium may be
prepared as described in US Patent 2,765,321. | [Brand name]
Athrombin-
K (Purdue Frederick);Coumadine;Marevan;Mervan;Sofarin;Waran;Warfilone. | [Therapeutic Function]
Anticoagulant | [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. | [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.
| [Synthesis]
Warfarin, 3-(|á-acetonylbenzyl)-4-hydroxycoumarin (24.1.10), is synthesized
via Michael reaction by attaching 4-hydroxycoumarin (24.1.7) to benzalacetone in the
presence of pyridine.
| [Carcinogenicity]
No data suggest that warfarin is either
mutagenic or carcinogenic. | [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. | [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). |
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