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.
Description
(±)-Warfarin (Item No. 13566) is a vitamin K antagonist, a coumarin derivative, and a racemic mixture of (+)-warfarin and (–)-warfarin . It is an anticoagulant that interferes with interconversion of vitamin K and vitamin K epoxide and the role of vitamin K in carboxylation of several clotting cascade proteins, inhibiting the initiation of clotting. Formulations containing warfarin have been used to treat and prevent blood clots in atrial fibrillation, heart valve replacement, venous thrombosis, and pulmonary embolism.
Chemical Properties
Warfarin is a colorless, odorless crystalline
solid.
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.
Originator
Coumadin ,Endo,US,1954
History
Warfarin was first discovered by Karl Paul Link in 1948 during his research on coumarin. Initially named compound 42, he later combined the abbreviation WARF with the last few syllables of coumarin to create "warfarin." However, at that time, the drug was only used as a rodenticide. Later, researchers improved it and found that the most potent analogue against rats was also proven to be the safest and most effective drug for preventing thrombosis in humans. A water-soluble form of warfarin sodium can be taken orally or intravenously, requiring only routine follow-up blood tests, unlike the close monitoring required with dicumarin. Warfarin sodium was officially approved by the FDA in 1954 as a treatment for human thrombosis and marketed under the brand name Coumadin.
Uses
Pesticide and rodenticide
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.
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.
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.
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.
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.
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.
Potential Exposure
Warfarin is used as an oral anticoagulant
and as a rodenticide or rat poison.
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 K
1 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.
References
[1] JACK HIRSH. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy.[J]. Circulation, 2003, 107 12: 1692-1711. DOI:
10.1161/01.cir.0000063575.17904.4e[2] UFER M. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol.[J]. Clinical Pharmacokinetics, 2005, 44 12: 1227-1246. DOI:
10.2165/00003088-200544120-00003
