Warfarin sodium

Chemical Properties

Colorless solid

Originator

Coumadin ,Endo,US,1954

Uses

central stimulant

Uses

Rodenticide.

Uses

Warfarin Sodium (Crystalline Clathrate) is used for pharmaceutical care for patients with chronic heart failure and renal dysfunction.

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 (Purdue Frederick); Coumadin (Bristol-Myers Squibb); Jantoven (USl); Panwarfin (Abbott).

Therapeutic Function

Anticoagulant

General Description

Warfarin sodium, 3-( -acetonylbenzyl)-4-hydroxycoumarin sodium salt (Coumadin,Panwarfin), is a white, odorless, crystalline powder, with aslightly bitter taste; it is slightly soluble in chloroform and solublein alcohol or water. A 1% solution has a pH of 7.2 to 8.5.

General Description

Slightly bitter crystalline powder. An anticoagulant used as a rodenticide.

Reactivity Profile

A coumarin derivative, a lactone. Lactones are similar to esters reactive chemistries.

Health Hazard

Warfarin sodium is highly toxic orally in humans.

Fire Hazard

When heated to decomposition, Warfarin sodium emits toxic fumes of sodium oxide.

Clinical Use

By virtue of its great potency, warfarin sodium at firstwas considered unsafe for use in humans and was used veryeffectively as a rodenticide, especially against rats. At theproper dosage level, however, it can be used in humans, especiallythrough the intravenous route.

Safety Profile

Poison to humans by ingestion. Experimental poison by ingestion and intravenous routes. Human systemic effects by ingestion: dermatitis. Human reproductive effects by ingestion: fetotoxicity, abnormal condition of newborn at birth, other newborn physical effects, and teratogenic effects includmg developmental abnormalities of the eye and ear, craniofacial area, skin and appendages, musculoskeletal system, cardiovascular system, and gastrointestinal system of the fetus. ,4n experimental teratogen. Other experimental reproductive effects. Mutation data reported. An anticoagulant drug. When heated to decomposition it emits toxic fumes of Na2O.

Veterinary Drugs and Treatments

In veterinary medicine, warfarin is used primarily for the oral, long-term treatment (or prevention of recurrence) of thrombotic conditions, primarily in cats, dogs, or horses. Use of warfarin in veterinary species is somewhat controversial and due to unproven benefit in reducing mortality, increased expense associated with monitoring, and potential for serious effects (bleeding), many do not recommend its use.

Drug interactions

Potentially hazardous interactions with other drugs
There are many significant interactions with warfarin.
Prescribe with care with regard to the following:
Anticoagulant effect enhanced by: alcohol, amiodarone, anabolic steroids, aspirin, aztreonam, bicalutamide, cephalosporins, chloramphenicol, cimetidine, ciprofloxacin, clopidogrel, cranberry juice, danazol, danshen, dipyridamole, dronedarone, disulfiram, entacapone, esomeprazole, exenatide, ezetimibe, fibrates, fluconazole, flutamide, fluvastatin, glucosamine, grapefruit juice, itraconazole, ketoconazole, levamisole, levofloxacin, macrolides, methylphenidate, metronidazole, miconazole, mirtazepine, nalidixic acid, neomycin, norfloxacin, NSAIDs, ofloxacin, omeprazole, pantoprazole, paracetamol, penicillins, proguanil, propafenone, ritonavir, rosuvastatin, saquinavir, SSRIs, simvastatin, sulfinpyrazone, sulphonamides, tamoxifen, tegafur, testosterone, tetracyclines, thyroid hormones, tigecycline, toremifene, tramadol, trimethoprim, valproate, venlafaxine, vitamin E and voriconazole.
Anticoagulant effect decreased by: acitretin, atorvastatin, azathioprine, barbiturates, carbamazepine, enteral feeds, eslicarbazepine, enzalutamide, fosphenytoin, ginseng, griseofulvin, oral contraceptives, phenobarbital, phenytoin, primidone, rifamycins, St John’s wort (avoid concomitant use), sucralfate, vitamin K.
Anticoagulant effects enhanced / reduced by: anion exchange resins, atazanavir, corticosteroids, dietary changes, disopyramide, efavirenz, fosamprenavir, nevirapine, ritonavir, telaprevir, tricyclics, trazodone.
Analgesics: increased risk of bleeding with IV diclofenac and ketorolac - avoid concomitant use.
Anticoagulants: increased risk of haemorrhage with apixaban, dabigatran, edoxaban and rivaroxaban - avoid concomitant use.
Antidiabetic agents: enhanced hypoglycaemic effect with sulphonylureas; also possible changes to anticoagulant effect.
Camomile: enhanced anticoagulation.
Ciclosporin: there have been a few reports of altered anticoagulant effect; decreased ciclosporin levels have been seen rarely.
Cytotoxics: increased risk of bleeding with erlotinib, imatinib and regorafenib; enhanced effect with capecitabine, etoposide, fluorouracil, ifosfamide, gefitinib, gemcitabine, sorafenib and vemurafenib; reduced effect with mercaptopurine and mitotane.
Melatonin: possibly enhanced INR.

Metabolism

The R- and S-isomers are both metabolised in the liver. The S-isomer is metabolised more rapidly than the R-isomer, mainly by the cytochrome P450 isoenzyme CYP2C9, which shows genetic polymorphism. Other isoenzymes are also involved in the metabolism of the R-isomer.
The metabolites, which have negligible or no anticoagulant activity, are excreted in the urine following reabsorption from the bile. Dose in renal impairment G