WARFARIN :- [IMRAN BHAI ]

Generic Name : - warfarin (WAR far in) Dosage Form : - Tablets

INTRODUCTION : Warfarin is an anticoagulant (blood thinner). Warfarin reduces the formation of blood clots by blocking the formation of certain clotting factors. Warfarin is used to prevent heart attacks, strokes, and blood clots in veins and arteries. Warfarin may also be used for purposes other than those listed in this medication guide. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood. Instead, it acts on the liver to decrease the quantity of a few key proteins in blood that allow blood to clot. It was initially marketed as a pesticide against rats and mice and is still popular for this purpose, although more potent poisons such as brodifacoum have since been developed. A few years after its introduction, warfarin was found to be effective and relatively safe for preventing thrombosis and embolism (abnormal formation and migration of blood clots) in many disorders. It was approved for use as a medication in the early 1950s and has remained popular ever since; warfarin is the most widely prescribed oral anticoagulant drug in North America.

CHEMISTRY :-

IUPAC name :- (RS)-4-hydroxy- 3-(3- oxo- 1-phenylbutyl)- 2H- chromen- 2-one Formula :C19H16O4 Mol. mass :308.33 g/mol Melting point :- fffC Warfarin is a synthetic derivative of dicoumarol, a 4-hydroxycoumarin-derived mycotoxin anticoagulant. Dicoumarol, in turn, is derived from coumarin, a sweet-smelling but coagulationinactive chemical.

MECHANISM OF ACTION : Warfarin inhibits the vitamin K-dependent synthesis of biologically active forms of the calciumdependent clotting factors II, VII, IX and X, as well as the regulatory factors protein C, protein S, and protein Z. The precursors of these factors require carboxylation of their glutamic acid residues to allow the coagulation factors to bind to phospholipid surfaces inside blood vessels, on the vascular endothelium. The enzyme that carries out the carboxylation of glutamic acid is gamma-glutamyl carboxylase. The carboxylation reaction will proceed only if the carboxylase enzyme is able to convert a reduced form of vitamin K (vitamin K hydroquinone) to vitamin K epoxide at the same time. The vitamin K epoxide is in turn recycled back to vitamin K and vitamin K hydroquinone by another enzyme, the vitamin K epoxide reductase (VKOR). Warfarin inhibits epoxide reductase[44] (specifically the VKORC1 subunit), thereby diminishing available vitamin K and vitamin K hydroquinone in the tissues, which inhibits the carboxylation activity of the glutamyl carboxylase. When this occurs, the coagulation factors are no longer carboxylated at certain glutamic acid residues, and are incapable of binding to the endothelial surface of blood vessels, and are thus biologically inactive. As the body's stores of previously-produced active factors degrade (over several days) and are replaced by inactive factors, the anticoagulation effect becomes apparent. The coagulation factors are produced, but have decreased functionality due to undercarboxylation; they are collectively referred to as PIVKAs (proteins induced [by] vitamin K absence/antagonism), and individual coagulation factors as PIVKA-number (e.g. PIVKA-II). The end result of warfarin use, therefore, is to diminish blood clotting in the patient.

PHARMACOKINETICS :
Bioavailability :- Essentially completely absorbed after oral administration. Onset :- Synthesis of vitamin K-dependent coagulation factors is affected soon after absorption (e.g., within 24 hours). Depletion of circulating functional coagulation factors must occur before therapeutic effects of the drug become apparent. Duration :- 25 days after a single dose. Food :- Decreased rate, but not extent, of absorption in the presence of food.

Distribution :- The apparent volume of distribution is about 0.14 L/kg. Crosses the placental
barrier; however, the drug has not been detected in human breast milk. Plasma Protein Binding :- Approximately 99%. Metabolism :- Almost entirely in the liver. Principally by CYP2C9; CYP2C19, 2C8, 2C18, 1A2, and 3A4 involved to a lesser degree. Elimination Route :- Excreted principally in urine as metabolites and to a lesser extent in bile Half-life : - Effective half-life averages 40 hours (range: 2060 hours).

INDICATIONS AND USAGE : Coumadin is used in treating patients with blood clots in the lower extremities to prevent extension of the clot, and to reduce the risk of pulmonary embolism. Patients with pulmonary embolism are treated with Coumadin to prevent further blood clot emboli. Coumadin is also used in patients with atrial fibrillation and artificial heart valves to reduce the risk of strokes. It is also helpful in preventing blood clot formation in certain orthopedic surgeries such as knee or hip replacements. Coumadin is also used in preventing blood clot closure of coronary artery stents.

DOSAGE AND ADMINISTRATION : Coumadin may be taken with or without food. Since Coumadin is metabolized by the liver and excreted by the kidneys, dosages need to be lowered in patients with liver and kidney dysfunction. Frequent blood tests are performed to measure blood clotting time (protime) during Coumadin treatment. Protime results help doctors adjust medication dose to avoid excessive blood thinning and risk of bleeding. Administer orally. Administer by IV injection when a coumarin derivative is indicated and oral therapy is not feasible. IM administration not recommended. Oral Administration : - Administer orally in a single, daily dose.a IV Administration : - For solution and drug compatibility information, Compatibility under Stability. Reconstitution : - Reconstitute powder for injection with 2.7 mL of sterile water for injection to a final concentration of 2 mg/mL. Rate of Administration :- Inject slowly (over 12 minutes) into a peripheral vein.

CONTRAINDICATIONS :Anticoagulation in pregnancy :Warfarin is contraindicated in pregnancy, as it passes through the placental barrier and may cause bleeding in the fetus; warfarin use during pregnancy is commonly associated with spontaneous abortion, stillbirth, neonatal death, and preterm birth. Coumarins (such as warfarin) are also teratogens, that is, they cause birth defects; the incidence of birth defects in infants exposed to warfarin. When warfarin (or another 4-hydroxycoumarin derivative) is given during the first trimester particularly between the sixth and ninth weeks of pregnancya constellation of birth defects known variously as fetal warfarin syndrome (FWS), warfarin embryopathy, or coumarin embryopathy can occur.

Usually, warfarin is avoided in the first trimester, and a low molecular weight heparin such as enoxaparin is substituted. With heparin, risk of maternal hemorrhage and other complications is still increased, but heparins do not cross the placental barrier and therefore do not cause birth defects.

WARNINGS & PRECAUTIONS : Before taking warfarin, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood disorders (such as anemia, hemophilia), bleeding problems (such as bleeding of the stomach/intestines, bleeding in the brain), blood vessel disorders (such as aneurysms), recent major injury/surgery, liver disease, alcohol use, mental/mood disorders (including memory problems), frequent falls/injuries.It is important that all your doctors and dentists know that you take warfarin. Avoid getting injections into the muscles. If you must have an injection into a muscle (for example, a flu shot), it should be given in the arm. This way, it will be easier to check for bleeding and/or apply pressure bandages. This medication may cause stomach bleeding. Daily use of alcohol while using this medicine will increase your risk for stomach bleeding and may also affect how this medication works. Limit or avoid alcoholic beverages. PREGNANCY :- Coumadin should be avoided by pregnant women or women who may become pregnant. Birth defects and fetal bleeding have been reported.

DRUG INTERACTIONS : Many drugs, both prescription and nonprescription (OTC), can affect the anticoagulant action of Coumadin. Some medications can enhance the action of Coumadin and cause excessive blood thinning and lifethreatening bleeding. A few examples of such medications include Aspirin, acetaminophen (Tylenol and others), alcohol, ibuprofen (Motrin), cimetidine (Tagamet), oxandrolone (Oxandrin), certain vitamins, and antibiotics.

ADVERSE REACTIONS :-a) Hemorrhage :- The only common side effect of warfarin is hemorrhage (bleeding). The risk of severe bleeding is small but and may cause hemoptysis (coughing up blood), excessive bruising, bleeding from nose or gums, or blood in urine or stool. The risks of bleeding is increased when warfarin is combined with antiplatelet drugs such as clopidogrel, aspirin, or other nonsteroidal anti-inflammatory drugs. The risk may also be increased in elderly patients and in patients on hemodialysis.

b) Warfarin necrosis :- A rare but serious complication resulting from treatment with warfarin is warfarin necrosis, which occurs more frequently shortly after commencing treatment in patients with a deficiency of protein C. c) Osteoporosis :- After initial reports that warfarin could reduce bone mineral density, several studies have demonstrated a link between warfarin use and osteoporosis-related fracture. d) Purple toe syndrome :- Another rare complication that may occur early during warfarin treatment (usually within 3 to 8 weeks of commencement) is purple toe syndrome. This condition is thought to result from small deposits of cholesterol breaking loose and flowing into the blood vessels in the skin of the feet, which causes a blueish purple color and may be painful. It is typically thought to affect the big toe, but it affects other parts of the feet as well, including the bottom of the foot (plantar surface). The occurrence of purple toe syndrome may require discontinuation of warfarin.

OVERDOSAGE : If overdose is suspected, contact a poison control center or emergency room immediately. Symptoms of overdose may include: bloody/black/tarry stools, pink/dark urine, unusual/prolonged bleeding.

STORAGE : Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets. Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed.

Product information
FORM : - tablet & I.V injections PROTECT FROM LIGHT & Moisture :- yes

MANUFACTURERS :o o Bristol-Myers Squibb Barr, Sandoz, Taro

PRICES : Coumadin 1MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$46.99 or 90/$110.92 Coumadin 10MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$69.99 or 90/$171.97 Coumadin 2MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$50.99 or 90/$126.97 Coumadin 2.5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$52.99 or 90/$130.97 Coumadin 3MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$55.99 or 90/$132.97 Coumadin 4MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$54.99 or 90/$132.97 Coumadin 5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$53.99 or 90/$136.97 Coumadin 6MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$69.99 or 90/$168.97 Coumadin 7.5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$69.99 or 90/$175.97

REFRENCES

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