Варфарин

Описание

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.

Химические свойства

Warfarin is a colorless, odorless crystalline solid.

Использование

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.

прикладной

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.

Всемирная организация здравоохранения(ВОЗ)

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.

Профиль реактивности

Warfarin is incompatible with the following: Strong oxidizers .

Угроза здоровью

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.

Пожароопасность

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.

Сельскохозяйственное использование

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.

Фармацевтические приложения

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.

Торговое название

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®

Механизм действия

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.

Фармакокине?тика

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.

Профиль безопасности

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.

Возможный контакт

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

Канцерогенность

No data suggest that warfarin is either mutagenic or carcinogenic.

Экологическая судьба

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)

Метаболизм

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.

Перевозки

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.

Методы очистки

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.

Несовместимости

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.

Утилизация отходов

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.