وارفارين

حبوب الوارفارين الألوان تعكس التركيز الدوائي

الوارفارين' (بالإنجليزية: Warfarin ) ويعرف أيضا بأسماء أخرى (Coumadin, Jantoven, Marevan, Lawarin, and Waran) وهو دواء مضاد تخثر، ظهر لأول مرة عام 1948، تم تسويقه أصلاً كمبيد للقوارض. وبعد بضعة سنوات من تسويقه تبين أنه فعال في اتقاء خثار والانصمام في حالات مرضية عديدة (مثل الوقاية من جلطات الأوعية الدموية سواء شرايين أو أوردة). تم إقرار استخدام الوارفارين كدواء في بداية الخمسينات، ولا يزال أكثر الأدوية المضادة للتخثر/التجلط إستخداماً في العصر الحالي.

إشكالية منع التجلط في المسنين

إشكالية منع التجلط في المسنين وإشكالية قرار منع التجلط وإشكالية أدوية منع التجلط

آلية العمل

الطريقة التي يعمل بها هذا الدواء تقوم على منع تكوين ڤيتامين K ووهو ڤيتامين ضروري لتصنيع لعدد من عوامل التجلط وهيالعوامل رقم ٢، ٧، ٩، و١٠.وكذلك ضرورى لتصنيع عوامل طبيعية أخرى لمنع التجلط بروتين s وبروتين c لذا، فآن عدم توافر ڤيتامين K يحد من فاعلية عوامل التخثر مما يجعل الدم قليل اللزوجة.

وبالتالي يمكن عكس تأثير الوارفارين عن طريق إعطاء فيتامين ك K لتصنيع عوامل تجلط جديدة ولكن هذا الأثر يأخذ ايام عديدة (من يومان لأسبوع) لظهور هذا الأثر. وباتالي عكس أثر الوارفارين أو أثر زيادة جرعته يأخذ نفس الوقت. يقوم فيتامين ك بتنشيط انزيم الكربوكسيليز ليقوم بإضافة مجموعة كربوكسيل إلى حمض الجلوتاميك في عوامل التجلط وذلك ضروري لعمل رابطة مع طبقة الفوسفولبيد في الأوعية الدموية

قضايا وإشكاليات

إشكالية التداخلات الدوائية

على الرغم من فعالية الوارفارين في منع الجلطات إلا أنه عليه بعض الإشكاليات. مثلاً التداخلات الدوائية والتداخلات الغذائية والحاجة لمتابعة نشاطه بتحليل دوري لسيولة الدم للتأكد من سلامة أداء الدواء وفعالية الجرعة المتناولة.

الإستخدامات الطبية (الاستطبابات)

إستخدام الورفارين غالباً وقائي وليس علاجي. مثلاً في الحالات المرضية التي تتسبب في تكوين خثرات دم بشكل متواصل. من أشهر هذه الحالات الرجفان الأذيني. يستخدم الوارفارين لتقليل القابلية لحدوث جلطات الدم thrombosis أو للوقاية الثانوية (منع تكرار نوبات ثانية) في حالات حدوث الجلطات. الوارفارين بإمكانه منع تكون الجلطات مستقبلاً وتقليل فرصة حدوث السدة الدموية embolism (هجرة جزء من جلطة بالدم إلى مكان أخر في الأوعية الدموية وسد الدورة الدموية).

أفضل نتائجه

أفضل نتائج الوارفارين تحدث عند إستخدامه لمنع الجلطات في الأماكن بطيئة سريان الدم (مثل الأوردة veins والدم المتجمع خلف الصمامات الطبيعية أو الصناعية والدم المتجمع في أذينات القلب المتضخمة. وبالتالي من الأسباب المشهورة لإستعمال الوارفارين حدوث:

• الرجفان الأذيني atrial fibrillation
• صمامات القلب الصناعية artificial heart valves
• جلطة الأوردة العميقة deep venous thrombosis
• السدة الرئوية الدموية pulmonary embolism

كما يستخدم في حالات زيادة تثر الدم المرضية Hypercoagulable state مثل متلازمة مضادات اللبيدات الفوسفورية antiphospholipid syndrome.

كما قد يستخدم أحياناً في منع الجلطات الشريانية مثل جلطات الشريان التاجي ولكن الأهم منه هو إستخدام مضادات الصفائح antiplatelets مثل الأسبرين.

من موقع ميدلاين بلس [1]

IMPORTANT WARNING: Warfarin may cause severe bleeding that can be life-threatening and even cause death. Tell your doctor if you have or have ever had a blood or bleeding disorder; bleeding problems, especially in your stomach or your esophagus (tube from the throat to the stomach), intestines, urinary tract or bladder, or lungs; high blood pressure; heart attack; angina (chest pain or pressure); heart disease; pericarditis (swelling of the lining (sac) around the heart); endocarditis (infection of one or more heart valves); a stroke or ministroke; aneurysm (weakening or tearing of an artery or vein); anemia (low number of red blood cells in the blood); cancer; chronic diarrhea; or kidney, or liver disease. Also tell your doctor if you fall often or have had a recent serious injury or surgery. Bleeding is more likely during warfarin treatment for people over 65 years of age, and it is also more likely during the first month of warfarin treatment. Bleeding is also more likely to occur for people who take high doses of warfarin, or take this medication for a long time. The risk for bleeding while taking warfarin is also higher for people participating in an activity or sport that may result in serious injury. Tell your doctor and pharmacist if you are taking or plan to take any prescription or nonprescription medications, vitamins, nutritional supplements, and herbal or botanical products (See SPECIAL PRECAUTIONS), as some of these products may increase the risk for bleeding while you are taking warfarin. If you experience any of the following symptoms, call your doctor immediately: pain, swelling, or discomfort, bleeding from a cut that does not stop in the usual amount of time, nosebleeds or bleeding from your gums, coughing up or vomiting blood or material that looks like coffee grounds, unusual bleeding or bruising, increased menstrual flow or vaginal bleeding, pink, red, or dark brown urine, red or tarry black bowel movements, headache, dizziness, or weakness.

Some people may respond differently to warfarin based on their heredity or genetic make-up. Your doctor may order a blood test to help find the dose of warfarin that is best for you.

Warfarin prevents blood from clotting so it may take longer than usual for you to stop bleeding if you are cut or injured. Avoid activities or sports that have a high risk of causing injury. Call your doctor if bleeding is unusual or if you fall and get hurt, especially if you hit your head.

Keep all appointments with your doctor and the laboratory. Your doctor will order a blood test (PT [prothrombin test] reported as INR [international normalized ratio] value) regularly to check your body's response to warfarin.

If your doctor tells you to stop taking warfarin, the effects of this medication may last for 2 to 5 days after you stop taking it.

Your doctor or pharmacist will give you the manufacturer's patient information sheet (Medication Guide) when you begin treatment with warfarin and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088578.pdf) or the manufacturer's website to obtain the Medication Guide.

Talk to your doctor about the risk(s) of taking warfarin.

Why is this medication prescribed? Warfarin is used to prevent blood clots from forming or growing larger in your blood and blood vessels. It is prescribed for people with certain types of irregular heartbeat, people with prosthetic (replacement or mechanical) heart valves, and people who have suffered a heart attack. Warfarin is also used to treat or prevent venous thrombosis (swelling and blood clot in a vein) and pulmonary embolism (a blood clot in the lung). Warfarin is in a class of medications called anticoagulants ('blood thinners'). It works by decreasing the clotting ability of the blood.

How should this medicine be used? Warfarin comes as a tablet to take by mouth. It is usually taken once a day with or without food. Take warfarin at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take warfarin exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. Call your doctor immediately if you take more than your prescribed dose of warfarin.

Your doctor will probably start you on a low dose of warfarin and gradually increase or decrease your dose based on the results of your blood tests. Make sure you understand any new dosing instructions from your doctor.

Continue to take warfarin even if you feel well. Do not stop taking warfarin without talking to your doctor.

Other uses for this medicineReturn to top This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?Return to top Before taking warfarin, tell your doctor and pharmacist if you are allergic to warfarin, any other medications, or any of the ingredients in warfarin tablets. Ask your pharmacist or check the Medication Guide for a list of the ingredients. do not take two or more medications that contain warfarin at the same time. Be sure to check with your doctor or pharmacist if you are uncertain if a medication contains warfarin or warfarin sodium. tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take, especially acyclovir (Zovirax); allopurinol (Zyloprim); alprazolam (Xanax); antibiotics such as ciprofloxacin (Cipro), clarithromycin (Biaxin, in Prevpac), erythromycin (E.E.S., Eryc, Ery-Tab), nafcillin, norfloxacin (Noroxin), sulfinpyrazone, telithromycin (Ketek), and tigecycline (Tygacil); anticoagulants such as argatroban (Acova), dabigatran (Pradaxa), bivalirudin (Angiomax), desirudin (Iprivask), heparin, and lepirudin (Refludan); antifungals such as fluconazole (Diflucan), itraconazole (Onmel, Sporanox), ketoconazole (Nizoral), miconazole (Monistat), posaconazole (Noxafil), terbinafine (Lamisil), voriconazole (Vfend); antiplatelet medications such as cilostazol (Pletal), clopidogrel (Plavix), dipyridamole (Persantine, in Aggrenox), prasugrel (Effient), and ticlopidine (Ticlid); aprepitant (Emend); aspirin or aspirin-containing products and other nonsteroidal anti-inflammatory drugs such as celecoxib (Celebrex), diclofenac (Flector, Voltaren, in Arthrotec), diflunisal, fenoprofen (Nalfon), ibuprofen (Advil, Motrin), indomethacin (Indocin), ketoprofen, ketorolac, mefenamic acid (Ponstel), naproxen (Aleve, Naprosyn), oxaprozin (Daypro), piroxicam (Feldene), and sulindac (Clinoril); bicalutamide; bosentan; certain antiarrhythmic medications such as amiodarone (Cordarone, Nexterone, Pacerone), mexiletine, and propafenone (Rythmol); certain calcium channel blocking medications such as amlodipine (Norvasc, in Azor, Caduet, Exforge, Lotrel, Twynsta), diltiazem (Cardizem, Cartia XT, Dilacor XR, Tiazac) and verapamil (Calan, Isoptin, Verelan, in Tarka); certain medications for asthma such as montelukast (Singulair), zafirlukast (Accolate), and zileuton (Zyflo); certain medications used to treat cancer such as capecitabine (Xeloda), imatinib (Gleevec), and nilotinib (Tasigna); certain medications for cholesterol such as atorvastatin (Lipitor, in Caduet) and fluvastatin (Lescol); certain medications for digestive disorders such as cimetidine (Tagamet), famotidine (Pepcid), and ranitidine (Zantac); certain medications for human immunodeficiency virus (HIV) infection such as amprenavir, atazanavir (Reyataz), efavirenz (Sustiva), etravirine (Intelence), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir, nelfinavir (Viracept), ritonavir (Norvir), saquinavir (Invirase), and tipranavir (Aptivus); certain medications for narcolepsy such as armodafinil (Nuvigil) and modafinil (Provigil); certain medications for seizures such as carbamazepine (Carbatrol, Equetro, Tegretol), phenobarbital, phenytoin (Dilantin, Phenytek), and rufinamide (Banzel); certain medications to treat tuberculosis such as isoniazid (in Rifamate, Rifater) and rifampin (Rifadin, in Rifamate, Rifater); certain selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) such as citalopram (Celexa), desvenlafaxine (Pristiq), duloxetine (Cymbalta), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem, in Symbyax), fluvoxamine (Luvox), milnacipran (Savella), paroxetine (Paxil, Pexeva), sertraline (Zoloft), venlafaxine (Effexor) corticosteroids such as prednisone; cyclosporine (Neoral, Sandimmune); disulfiram (Antabuse); methoxsalen (Oxsoralen, Uvadex); metronidazole (Flagyl); nefazodone (Serzone), oral contraceptives (birth control pills); oxandrolone (Oxandrin); pioglitazone (Actos, in Actoplus Met, Duetact, Oseni); propranolol (Inderal) or vilazodone (Viibryd). Many other medications may also interact with warfarin, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list. Do not take any new medications or stop taking any medication without talking to your doctor. tell your doctor and pharmacist what herbal or botanical products you are taking, especially coenzyme Q10 (Ubidecarenone), Echinacea, garlic, Ginkgo biloba, ginseng, goldenseal, and St. John's wort. There are many other herbal or botanical products which might affect your body's response to warfarin. Do not start or stop taking any herbal products without talking to your doctor. tell your doctor if you have or have ever had diabetes. Also tell your doctor if you have an infection, a gastrointestinal illness such as diarrhea, or sprue (an allergic reaction to protein found in grains that causes diarrhea), or an indwelling catheter (a flexible plastic tube that is placed into the bladder to allow the urine to drain out). Tell your doctor if you are pregnant, think you might be pregnant, or plan to become pregnant while taking warfarin. Pregnant women should not take warfarin unless they have a mechanical heart valve. Talk to your doctor about the use of effective birth control while taking warfarin. If you become pregnant while taking warfarin, call your doctor immediately. Warfarin may harm the fetus. tell your doctor if you are breast-feeding. if you are having surgery, including dental surgery, or any type of medical or dental procedure, tell the doctor or dentist that you are taking warfarin. Your doctor may tell you to stop taking warfarin before the surgery or procedure or change your dosage of warfarin before the surgery or procedure. Follow your doctor's directions carefully and keep all appointments with the laboratory if your doctor orders blood tests to find the best dose of warfarin for you. ask your doctor about the safe use of alcoholic beverages while you are taking warfarin. tell your doctor if you use tobacco products. Cigarette smoking may decrease the effectiveness of this medication. What special dietary instructions should I follow?Return to top Eat a normal, healthy diet. Some foods and beverages, particularly those that contain vitamin K, can affect how warfarin works for you. Ask your doctor or pharmacist for a list of foods that contain vitamin K. Eat consistent amounts of vitamin K-containing food on a week-to-week basis. Do not eat large amounts of leafy, green vegetables or certain vegetable oils that contain large amounts of vitamin K. Be sure to talk to your doctor before you make any changes in your diet. Talk to your doctor about eating grapefruit and drinking grapefruit juice while taking this medication.

What should I do if I forget a dose?Return to top Take the missed dose as soon as you remember it, if it is the same day that you were to take the dose. Do not take a double dose the next day to make up for a missed one. Call your doctor if you miss a dose of warfarin.

What side effects can this medication cause?Return to top Warfarin may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away: gas

abdominal pain

bloating

change in the way things taste

loss of hair

feeling cold or having chills

If you experience any of the following symptoms, or those listed in the IMPORTANT WARNING section, call your doctor immediately: hives

rash

itching

difficulty breathing or swallowing

swelling of the face, throat, tongue, lips, or eyes

hoarseness

chest pain or pressure

swelling of the hands, feet, ankles, or lower legs

fever

infection

nausea

vomiting

diarrhea

extreme tiredness

lack of energy

loss of appetite

pain in the upper right part of the stomach

yellowing of the skin or eyes

flu-like symptoms

You should know that warfarin may cause necrosis or gangrene (death of skin or other body tissues). Call your doctor immediately if you notice a purplish or darkened color to your skin, skin changes, ulcers, or an unusual problem in any area of your skin or body, or if you have a severe pain that occurs suddenly, or color or temperature change in any area of your body. Call your doctor immediately if your toes become painful or become purple or dark in color. You may need medical care right away to prevent amputation (removal) of your affected body part.

Warfarin may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

What should I know about storage and disposal of this medication?Return to top Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat, moisture (not in the bathroom), and light. Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.

In case of emergency/overdoseReturn to top In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following: bloody or red, or tarry bowel movements

spitting or coughing up blood

heavy bleeding with your menstrual period

pink, red, or dark brown urine

coughing up or vomiting material that looks like coffee grounds

small, flat, round red spots under the skin

unusual bruising or bleeding

continued oozing or bleeding from minor cuts

What other information should I know?Return to top Carry an identification card or wear a bracelet stating that you take warfarin. Ask your pharmacist or doctor how to obtain this card or bracelet. List your name, medical problems, medications and dosages, and doctor's name and telephone number on the card.

Tell all your healthcare providers that you take warfarin.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

معلومات هامة عن الوافارين Important information [2]

You should not take warfarin if you have a bleeding disorder, blood in your urine or stools, stomach bleeding, an infection of the lining of your heart, bleeding in your brain, recent or upcoming surgery, or if you need a spinal tap or epidural. Do not take warfarin if you cannot take it on time every day.

HealthQuiz - Basics About Stroke Signs and Symptoms Do not use warfarin if you are pregnant, unless your doctor tells you to.

While using warfarin, you will need frequent "INR" or prothrombin time tests to measure your blood-clotting time.

Warfarin increases your risk of bleeding, which can be severe or life-threatening. Call your doctor or seek emergency medical attention if you have bleeding that will not stop, if you have black or bloody stools, or if you cough up blood or vomit that looks like coffee grounds.

Many drugs can cause serious medical problems when used with warfarin. Tell your doctor about all medicines you have recently used.

قبل تناول الوارفارين Before taking this medicine [3]

You should not take warfarin if you are allergic to it, or if you have:

hemophilia or any bleeding disorder that is inherited or caused by disease; a blood cell disorder (such as low red blood cells or low platelets); blood in your urine or stools, or if you have been coughing up blood; an infection of the lining of your heart (bacterial endocarditis); stomach or intestinal bleeding or ulcer; recent head injury, aneurysm, or bleeding in the brain; or if you undergo a spinal tap or spinal anesthesia (epidural). You should not take warfarin if you cannot be reliable in taking it because of alcoholism, psychiatric problems, dementia, or similar conditions.

Warfarin can make you bleed more easily, especially if you have:

a history of bleeding problems; high blood pressure or severe heart disease; kidney or liver disease; cancer; a disease affecting the blood vessels in your brain; a history of stomach or intestinal bleeding; a surgery or medical emergency, or if you receive any type of injection (shot); if you are 65 or older; or if you are severely ill or debilitated. To make sure warfarin is safe for you, tell your doctor if you have:

celiac sprue (an intestinal disorder); diabetes; congestive heart failure; overactive thyroid; recent or upcoming surgery on your brain, spine, or eye; a connective tissue disorder such as Marfan Syndrome, Sjogren syndrome, scleroderma, rheumatoid arthritis, or lupus; a hereditary clotting deficiency (warfarin may make your symptoms worse at first); if you use a catheter; or if you have ever had low blood platelets after receiving heparin. Do not use warfarin if you are pregnant, unless your doctor tells you to. Warfarin can cause birth defects, but preventing blood clots in certain women may outweigh any risks to the baby. Use effective birth control to prevent pregnancy during treatment. Tell your doctor right away if you become pregnant.

It is not known whether warfarin passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

كيفية تناول الوارفارين How should I take warfarin? [4]

Take warfarin exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take warfarin in larger or smaller amounts or for longer than your doctor tells you to.

Take warfarin at the same time every day, with or without food. Never take a double dose of this medicine.

While using warfarin, you will need frequent "INR" or prothrombin time tests (to measure how long it takes your blood to clot). You may not notice any change in your symptoms, but your blood work will help your doctor determine how long to treat you with warfarin. You must remain under the care of a doctor while using this medicine.

If you have received warfarin in a hospital, call or visit your doctor 3 to 7 days after you leave the hospital. Your INR will need to be tested at that time. Do not miss any follow-up appointments.

Tell your doctor if you are sick with diarrhea, fever, chills, or flu symptoms, or if your body weight changes.

You may need to stop taking warfarin 5 to 7 days before having any surgery or dental work. Call your doctor for instructions. You may also need to stop taking warfarin for a short time if you need to take antibiotics, or if you need to have a spinal tap or spinal anesthesia (epidural).

Wear a medical alert tag or carry an ID card stating that you take warfarin. Any medical care provider who treats you should know that you are using this medicine.

Store at room temperature away from heat, moisture, and light.

معلومات ضبط جرعة الوارفارين Warfarin dosing information

Usual Adult Dose for Congestive Heart Failure:

Initial: 2 to 5 mg orally or intravenously once a day for 1 to 2 days, then adjust dose according to results of the International Normalized Ratio (INR) or prothrombin time (PT).

Maintenance: the usual maintenance dose ranges from 2 to 10 mg orally or intravenously once a day.

Usual Adult Dose for Thromboembolic Stroke Prophylaxis:

Initial: 2 to 5 mg orally or intravenously once a day for 1 to 2 days, then adjust dose according to results of the International Normalized Ratio (INR) or prothrombin time (PT).

Maintenance: the usual maintenance dose ranges from 2 to 10 mg orally or intravenously once a day.

Usual Adult Dose for Myocardial Infarction:

Initial: 2 to 5 mg orally or intravenously once a day for 1 to 2 days, then adjust dose according to results of the International Normalized Ratio (INR) or prothrombin time (PT).

Maintenance: the usual maintenance dose ranges from 2 to 10 mg orally or intravenously once a day.

The duration of therapy is usually three months following acute myocardial infarction.

Usual Adult Dose for Prevention of Thromboembolism in Atrial Fibrillation:

Initial: 2 to 5 mg orally or intravenously once a day for 1 to 2 days, then adjust dose according to results of the International Normalized Ratio (INR) or prothrombin time (PT).

Maintenance: the usual maintenance dose ranges from 2 to 10 mg orally or intravenously once a day.

If cardioversion is planned, anticoagulant therapy is usually initiated two to four weeks prior to cardioversion and is continued for two to four weeks following successful cardioversion. If cardioversion is not planned and this patient has complicated atrial fibrillation (atrial fibrillation associated with underlying heart disease) the duration of therapy is typically lifelong.

Usual Adult Dose for Deep Vein Thrombosis Prophylaxis after Hip Replacement Surgery:

Initial: 2 to 5 mg orally or intravenously once a day for 1 to 2 days, then adjust dose according to results of the International Normalized Ratio (INR) or prothrombin time (PT).

Maintenance: the usual maintenance dose ranges from 2 to 10 mg orally or intravenously once a day.

The duration of anticoagulant therapy for a first-time deep venous thrombosis is usually 3 to 12 months, depending on the reversibility of the condition which may have predisposed this patient to thrombosis. For patients with a first episode of DVT secondary to a reversible risk factor, 3 months of warfarin therapy is recommended. For patients with a first episode of idiopathic DVT, at least 6 to 12 months of treatment is recommended. For patients with two or more episodes of documented DVT, indefinite treatment with warfarin is recommended. For patients with a first episode of DVT who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions, treatment for 12 months is recommended and indefinite therapy is suggested. For patients with a first episode of DVT who have documented deficiency of Protein C or Protein S, deficiency of antithrombin, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels, treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis.

Usual Adult Dose for Deep Vein Thrombosis -- First Event:

Initial: 2 to 5 mg orally or intravenously once a day for 1 to 2 days, then adjust dose according to results of the International Normalized Ratio (INR) or prothrombin time (PT).

Maintenance: the usual maintenance dose ranges from 2 to 10 mg orally or intravenously once a day.

The duration of anticoagulant therapy for a first-time deep venous thrombosis is usually 3 to 12 months, depending on the reversibility of the condition which may have predisposed this patient to thrombosis. For patients with a first episode of DVT secondary to a reversible risk factor, 3 months of warfarin therapy is recommended. For patients with a first episode of idiopathic DVT, at least 6 to 12 months of treatment is recommended. For patients with two or more episodes of documented DVT, indefinite treatment with warfarin is recommended. For patients with a first episode of DVT who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions, treatment for 12 months is recommended and indefinite therapy is suggested. For patients with a first episode of DVT who have documented deficiency of Protein C or Protein S, deficiency of antithrombin, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels, treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis.

Usual Adult Dose for Deep Vein Thrombosis -- Recurrent Event:

Initial: 2 to 5 mg orally or intravenously once a day for 1 to 2 days, then adjust dose according to results of the International Normalized Ratio (INR) or prothrombin time (PT).

Maintenance: the usual maintenance dose ranges from 2 to 10 mg orally or intravenously once a day.

The duration of anticoagulant therapy for a first-time deep venous thrombosis is usually 3 to 12 months, depending on the reversibility of the condition which may have predisposed this patient to thrombosis. For patients with a first episode of DVT secondary to a reversible risk factor, 3 months of warfarin therapy is recommended. For patients with a first episode of idiopathic DVT, at least 6 to 12 months of treatment is recommended. For patients with two or more episodes of documented DVT, indefinite treatment with warfarin is recommended. For patients with a first episode of DVT who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions, treatment for 12 months is recommended and indefinite therapy is suggested. For patients with a first episode of DVT who have documented deficiency of Protein C or Protein S, deficiency of antithrombin, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels, treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis.

Usual Adult Dose for Deep Vein Thrombosis Prophylaxis after Knee Replacement Surgery:

Initial: 2 to 5 mg orally or intravenously once a day for 1 to 2 days, then adjust dose according to results of the International Normalized Ratio (INR) or prothrombin time (PT).

Maintenance: the usual maintenance dose ranges from 2 to 10 mg orally or intravenously once a day.

The duration of anticoagulant therapy for a first-time deep venous thrombosis is usually 3 to 12 months, depending on the reversibility of the condition which may have predisposed this patient to thrombosis. For patients with a first episode of DVT secondary to a reversible risk factor, 3 months of warfarin therapy is recommended. For patients with a first episode of idiopathic DVT, at least 6 to 12 months of treatment is recommended. For patients with two or more episodes of documented DVT, indefinite treatment with warfarin is recommended. For patients with a first episode of DVT who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions, treatment for 12 months is recommended and indefinite therapy is suggested. For patients with a first episode of DVT who have documented deficiency of Protein C or Protein S, deficiency of antithrombin, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels, treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis.

Usual Adult Dose for Prosthetic Heart Valves -- Tissue Valves:

Initial: 2 to 5 mg orally or intravenously once a day for 1 to 2 days, then adjust dose according to results of the International Normalized Ratio (INR) or prothrombin time (PT).

Maintenance: the usual maintenance dose ranges from 2 to 10 mg orally or intravenously once a day.

The duration of anticoagulant therapy following tissue heart valve replacement surgery is usually 6 to 12 weeks. The duration of therapy may be longer in patients with a tissue valve in the mitral location, particularly in the presence of a large left atrium and/or atrial fibrillation. In patients who receive a mechanical heart valve, lifelong anticoagulant therapy is usually needed and low dose aspirin (80 to 100 mg/day) may be added in higher risk patients.

Usual Adult Dose for Prosthetic Heart Valves -- Mechanical Valves:

Initial: 2 to 5 mg orally or intravenously once a day for 1 to 2 days, then adjust dose according to results of the International Normalized Ratio (INR) or prothrombin time (PT).

Maintenance: the usual maintenance dose ranges from 2 to 10 mg orally or intravenously once a day.

The duration of anticoagulant therapy following tissue heart valve replacement surgery is usually 6 to 12 weeks. The duration of therapy may be longer in patients with a tissue valve in the mitral location, particularly in the presence of a large left atrium and/or atrial fibrillation. In patients who receive a mechanical heart valve, lifelong anticoagulant therapy is usually needed and low dose aspirin (80 to 100 mg/day) may be added in higher risk patients.

Usual Adult Dose for Pulmonary Embolism -- First Event:

Initial: 2 to 5 mg orally or intravenously once a day for 1 to 2 days, then adjust dose according to results of the International Normalized Ratio (INR) or prothrombin time (PT).

Maintenance: the usual maintenance dose ranges from 2 to 10 mg orally or intravenously once a day.

The duration of anticoagulant therapy for a first occurrence of pulmonary embolism is 3 to 12 months depending on the reversibility of the condition which may have predisposed this patient to thrombosis. For patients with a first episode of DVT or PE secondary to a reversible risk factor, 3 months of warfarin therapy is recommended. For patients with a first episode of idiopathic DVT or PE, at least 6 to 12 months of treatment is recommended. For patients with two or more episodes of documented DVT or PE, indefinite treatment with warfarin is recommended. For patients with a first episode of DVT or PE who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions, treatment for 12 months is recommended and indefinite therapy is suggested. For patients with a first episode of DVT or PE who have documented deficiency of Protein C or Protein S, deficiency of antithrombin, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels, treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis.

Usual Adult Dose for Pulmonary Embolism -- Recurrent Event:

Initial: 2 to 5 mg orally or intravenously once a day for 1 to 2 days, then adjust dose according to results of the International Normalized Ratio (INR) or prothrombin time (PT).

Maintenance: the usual maintenance dose ranges from 2 to 10 mg orally or intravenously once a day.

The duration of anticoagulant therapy for a first occurrence of pulmonary embolism is 3 to 12 months depending on the reversibility of the condition which may have predisposed this patient to thrombosis. For patients with a first episode of DVT or PE secondary to a reversible risk factor, 3 months of warfarin therapy is recommended. For patients with a first episode of idiopathic DVT or PE, at least 6 to 12 months of treatment is recommended. For patients with two or more episodes of documented DVT or PE, indefinite treatment with warfarin is recommended. For patients with a first episode of DVT or PE who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions, treatment for 12 months is recommended and indefinite therapy is suggested. For patients with a first episode of DVT or PE who have documented deficiency of Protein C or Protein S, deficiency of antithrombin, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels, treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis.

Usual Adult Dose for Chronic Central Venous Catheterization:

1 mg orally or intravenously once a day

Therapy should be initiated three days before insertion of the catheter. No changes in coagulation values are expected with this low dose.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose can cause excessive bleeding.

What should I avoid while taking warfarin?

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth. You may still bleed more easily for several days after you stop taking warfarin.

Ask your doctor before taking any medicine for pain, arthritis, fever, or swelling. This includes acetaminophen (Tylenol), aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib (Celebrex), diclofenac, indomethacin, meloxicam, and others. These medicines may affect blood clotting and may also increase your risk of stomach bleeding.

Avoid making any changes in your diet without first talking to your doctor. Foods that are high in vitamin K (liver, leafy green vegetables, or vegetable oils) can make warfarin less effective. If these foods are part of your diet, eat a consistent amount on a weekly basis.

Grapefruit juice may interact with warfarin and lead to unwanted side effects. Avoid the use of grapefruit products while taking this medicine [5].

الأعراض الجانبية للوارفارين Warfarin side effects

Get emergency medical help if you have any of these signs of an allergic reaction to warfarin: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Warfarin may cause you to bleed more easily, which can be severe or life-threatening. Seek emergency medical attention if you have any unusual bleeding, or bleeding that will not stop. You may also have bleeding on the inside of your body, such as in your stomach or intestines. Call your doctor at once if you have black or bloody stools, or if you cough up blood or vomit that looks like coffee grounds. These could be signs of bleeding in your digestive tract.

Also call your doctor at once if you have:

pain, swelling, hot or cold feeling, skin changes, or discoloration anywhere on your body; sudden and severe leg or foot pain, foot ulcer, purple toes or fingers; sudden headache, dizziness, or weakness; easy bruising, purple or red pinpoint spots under your skin, bleeding from wounds or needle injections; pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating; dark urine, jaundice (yellowing of the skin or eyes); little or no urinating; numbness or muscle weakness; or pain in your stomach, back, or sides. Common warfarin side effects may include:

nausea, vomiting, mild stomach pain; bloating, gas; or altered sense of taste. This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

See also: Side effects (in more detail)

ما هي الأدوية التي تؤثر في الوارفارين What other drugs will affect warfarin?

Many drugs (including some over-the-counter medicines and herbal products) can affect your INR and may increase the risk of bleeding if you take them with warfarin. Not all possible drug interactions are listed in this medication guide. It is very important to ask your doctor before you start or stop using any other medicine, especially:

other medicines to prevent blood clots; medicine to treat any type of infection, including tuberculosis; supplements that contain vitamin K; an antidepressant--citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, vilazodone, and others; seizure medicine--carbamazepine, phenobarbital, phenytoin; herbal (botanical) products--coenzyme Q10, cranberry, echinacea, garlic, ginkgo biloba, ginseng, goldenseal, or St. John's wort. This list is not complete and many other drugs can interact with warfarin. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

As well as its needed effects, warfarin may cause unwanted side effects that require medical attention.

If any of the following side effects occur while taking warfarin, check with your doctor immediately:

Less common Abdominal or stomach pain with cramping bleeding gums blood in the urine bloody stools blurred vision burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings chest pain or discomfort confusion coughing up blood difficulty with breathing or swallowing dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position excessive bruising headache increased menstrual flow or vaginal bleeding nosebleeds paralysis peeling of the skin prolonged bleeding from cuts red or black, tarry stools red or dark brown urine shortness of breath sweating unexplained swelling unusual tiredness or weakness Rare Arm, back, or jaw pain blue-green to black skin discoloration blue or purple toes change in consciousness chest tightness or heaviness chills clay-colored stools diarrhea dizziness fainting or loss of consciousness fast or irregular breathing fast or irregular heartbeat fever itching light-colored stools loss of appetite nausea and vomiting pain in the toes pain, redness, or sloughing of the skin pale skin skin blisters skin rash small red or purple spots on the skin stomach pain swelling of the eyes or eyelids tightness in the chest or wheezing troubled breathing with exertion unpleasant breath odor unusual bleeding or bruising upper right abdominal or stomach pain vomiting of blood yellow eyes and skin Incidence not known Painful or prolonged erection of the penis Some warfarin side effects may not need any medical attention. As your body gets used to the medicine these side effects may disappear. Your health care professional may be able to help you prevent or reduce these side effects, but do check with them if any of the following side effects continue, or if you are concerned about them:

Less common Joint pain muscle pain Rare Bloated change in taste, or bad, unusual, or unpleasant (after) taste cold intolerance excess air or gas in the stomach or intestines full feeling general feeling of discomfort or illness hair loss or thinning of the hair hives or welts lack or loss of strength pain passing gas red, sore, or itching skin sores, welting, or blisters unusual drowsiness, dullness, or feeling of sluggishness [6]

مضادات التجلط الأخرى

توجد بعض الأدوية المضادة للتجلط الأخرى غير الوارفارين.

• أراص بالفم:
  • دابيجتران dabigatran (لا يحتاج لمتابعة تحليل سيولة الدم) لكن إستعماله لم يوافق عليه في كل الدول بعد.
  • ريفاروكسابان rivaroxaban

ضبط الجرعة الفعالة Dosing

ضبط جرعة الوارفارين عملية معقدة بشدة وتمثل تحدي كبير. وذلك لأن الدواء يتفاعل مع الكثير من الأدوية المستعملة يومياً مع بعض الأغذية. هذه التفاعلات الدوائية والغذائية من الممكن أن تقلل أو تزيد فاعلية الوارفارين. للإستفادة القصوى من الزارفارين دون التعرض للأعراض الجانبية (مثل النزيف) يتم متابعة درجة سيولة الدم بتحليل زمن البروثرومبين prothrombin time في الدم وحساب معدل التطبيع الدولي INR.

خلال المرحلة الأولى من العلاج يتم تحليل زمن البروثرومبين يومياً. ثم بعد الوصول لمعدل التطبيع الدولي INR مستقر على جرعة ثابتة من الدواء فيتم إطالة الفترات بين تكرار تحليل زمن البروثرومبين.

Newer point-of-care testing is available and has increased the ease of INR testing in the outpatient setting. Instead of a blood draw, the point of care test involves a simple finger prick.

When initiating warfarin therapy ("warfarinization"), the doctor will decide how strong the anticoagulant therapy needs to be. The target INR level varies from case to case depending on the clinical indicators, but tends to be 2–3 in most conditions. In particular, target INR may be 2.5–3.5 (or even 3.0–4.5) in patients with one or more mechanical heart valves.

In addition, for the first three days of "warfarinization", the levels of protein C and protein S (anticoagulation factors) drop faster than procoagulation proteins such as factor II, VII, IX, and X. Therefore, bridging anticoagulant therapies (usually heparin) are often used to reverse this temporary hypercoagulable state.

الجرعة المنتظمة Maintenance dose

Vitamine K1-warfarin interaction effects. When warfarin acts above its therapeutic window, patients suffer from bleeding, while high consumption of vitamin K₁-rich diets leads warfarin to act below its therapeutic range, resulting in increased blood clots.

Recommendations by many national bodies, including the American College of Chest Physicians, have been distilled to help manage dose adjustments.

The maintenance dose of warfarin can fluctuate significantly depending on the amount of vitamin K₁ in the diet. Keeping vitamin K₁ intake at a stable level can prevent these fluctuations. Leafy green vegetables tend to contain higher amounts of vitamin K₁. Green parts of members of the family Apiaceae, such as parsley, cilantro, and dill, are extremely rich sources of vitamin K; cruciferous vegetables such as cabbage and broccoli, as well as the darker varieties of lettuces and other leafy greens, are also relatively high in vitamin K₁. Green vegetables such a peas and green beans do not have such high amounts of vitamin K₁ as leafy greens. Certain vegetable oils have high amounts of vitamin K₁. Foods low in vitamin K₁ include roots, bulbs, tubers, and most fruits and fruit juices. Cereals, grains and other milled products are also low in vitamin K₁.

التحليل الذاتي Self-testing

قالب:Main Patients are making increasing use of self-testing and home monitoring of oral anticoagulation. International guidelines on home testing were published in 2005. The guidelines stated: "The consensus agrees that patient self-testing and patient self-management are effective methods of monitoring oral anticoagulation therapy, providing outcomes at least as good as, and possibly better than, those achieved with an anticoagulation clinic.

All patients must be appropriately selected and trained. Currently available self-testing/self-management devices give INR results that are comparable with those obtained in laboratory testing." A 2006 systematic review and meta-analysis of 14 randomized trials showed home testing led to a reduced incidence of complications (thrombosis and major bleeding) and improved the time in the therapeutic range.

موانع الإستعمال Contraindications

• وجود حساسية من أي من مكونات الأقراص.
• الحمل أو إحتمال حدوث الحمل.

الأعراض الجانبية Adverse effects

النزيف Hemorrhage

The only common side effect of warfarin is haemorrhage (bleeding). The risk of severe bleeding is small but definite (a median annual rate of 1 to 3% has been reported) and any benefit needs to outweigh this risk when warfarin is considered as a therapeutic measure. All types of bleeding occur more commonly, but the most catastrophic ones are those involving the brain (intracerebral hemorrhage/hemorrhagic stroke) and the spinal cord. Risk of bleeding is increased if the INR is out of range (due to accidental or deliberate overdose or due to interactions).

A number of risk scores exists to predict bleeding in people using warfarin and similar anticoagulants. A commonly used score (HAS-BLED) includes known predictors of warfarin-related bleeding: uncontrolled high blood pressure (H), abnormal kidney function (A), previous stroke (S), known previous bleeding condition (B), previous labile INR when on anticoagulation (L), elderly as defined by age over 65 (E), and drugs associated with bleeding (e.g. aspirin) or alcohol misuse (D). While their use is recommended in clinical practice guidelines, they are only moderately effective in predicting bleeding risk and don't perform well in predicting hemorrhagic stroke. Bleeding risk may be increased in patients on haemodialysis. Another score used to assess bleeding risk on anticoagulation, specifically Warfarin or Coumadin, is the ATRIA score, which uses a weighted additive scale of clinical findings to determine bleeding risk stratification.

The risks of bleeding are increased further when warfarin is combined with antiplatelet drugs such as clopidogrel, aspirin, or nonsteroidal anti-inflammatory drugs.

موت الأنسجة بسبب الوارفارين Warfarin necrosis

قالب:Main 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. Protein C is an innate anticoagulant that, like the procoagulant factors that warfarin inhibits, requires vitamin K-dependent carboxylation for its activity. Since warfarin initially decreases protein C levels faster than the coagulation factors, it can paradoxically increase the blood's tendency to coagulate when treatment is first begun (many patients when starting on warfarin are given heparin in parallel to combat this), leading to massive thrombosis with skin necrosis and gangrene of limbs. Its natural counterpart, purpura fulminans, occurs in children who are homozygous for certain protein C mutations.

هشاشة العظام Osteoporosis

After initial reports that warfarin could reduce bone mineral density, several studies have demonstrated a link between warfarin use and osteoporosis-related fracture. A 1999 study in 572 women taking warfarin for deep venous thrombosis, risk of vertebral fracture and rib fracture was increased; other fracture types did not occur more commonly. A 2002 study looking at a randomly selected selection of 1523 patients with osteoporotic fracture found no increased exposure to anticoagulants compared to controls, and neither did stratification of the duration of anticoagulation reveal a trend towards fracture.

A 2006 retrospective study of 14,564 Medicare recipients showed that warfarin use for more than one year was linked with a 60% increased risk of osteoporosis-related fracture in men; there was no association in women. The mechanism was thought to be a combination of reduced intake of vitamin K, which is necessary for bone health, and inhibition by warfarin of vitamin K-mediated carboxylation of certain bone proteins, rendering them nonfunctional.

متلازمة إصبع القدم الأرجواني 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 causing embolisms in blood vessels in the skin of the feet, which causes a blueish purple colour 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.

تكلس الصمامات والشرايين Calcification of valves and arteries

Several epidemiological studies have also implicated warfarin use in valvular and vascular calcification. No specific treatment is available, but some modalities are under investigation.

زيادة الجرعة Overdose

The major side effect of warfarin use is bleeding. Risk of bleeding is increased if the INR is out of range (due to accidental or deliberate overdose or due to interactions). Many drug interactions can increase the effect of warfarin, also causing an overdose.

For people who need rapid reversal of warfarin and have serious bleeding or who are having emergency surgery, the effects of warfarin can be reversed with vitamin K with prothrombin complex concentrate or fresh frozen plasma in addition to intravenous vitamin K. Blood products should not be routinely used to reverse warfarin when vitamin K could work alone.

Details on reversing warfarin are provided in clinical practice guidelines from the American College of Chest Physicians. For patients with an international normalized ratio (INR) between 4.5 and 10.0, a small dose (about 1000 mcg = one milligram) of oral vitamin K is sufficient. When warfarin is being given and INR is in therapeutic range, simple discontinuation of the drug for five days is usually enough to reverse the effect and cause INR to drop below 1.5.

حاسبات فرصة حدوث النزيف Online Bleeding Risk Calculators

• ATRIA Bleeding Risk Score from MDCalc
• HAS-BLED Score from MDCalc

التفاعلات الدوائية Interactions

Warfarin interacts with many commonly used drugs, and the metabolism of warfarin varies greatly between patients. Some foods have also been reported to interact with warfarin. Apart from the metabolic interactions, highly protein bound drugs can displace warfarin from serum albumin and cause an increase in the INR. This makes finding the correct dosage difficult, and accentuates the need of monitoring; when initiating a medication that is known to interact with warfarin (e.g. simvastatin), INR checks are increased or dosages adjusted until a new ideal dosage is found.

Many commonly used antibiotics, such as metronidazole or the macrolides, will greatly increase the effect of warfarin by reducing the metabolism of warfarin in the body. Other broad-spectrum antibiotics can reduce the amount of the normal bacterial flora in the bowel, which make significant quantities of vitamin K₁, thus potentiating the effect of warfarin. In addition, food that contains large quantities of vitamin K₁ will reduce the warfarin effect. Thyroid activity also appears to influence warfarin dosing requirements; hypothyroidism (decreased thyroid function) makes people less responsive to warfarin treatment, while hyperthyroidism (overactive thyroid) boosts the anticoagulant effect. Several mechanisms have been proposed for this effect, including changes in the rate of breakdown of clotting factors and changes in the metabolism of warfarin.

Excessive use of alcohol is also known to affect the metabolism of warfarin and can elevate the INR and thus increase the risk of bleeding. The U.S. Food and Drug Administration (FDA) product insert on warfarin states that alcohol should be avoided.

Warfarin also interacts with many herbs and spices, some used in food (such as ginger and garlic) and others used purely for medicinal purposes (such as ginseng and Ginkgo biloba). All may increase bleeding and bruising in people taking warfarin; similar effects have been reported with borage (starflower) oil or fish oils. St. John's Wort, sometimes recommended to help with mild to moderate depression, reduces the effectiveness of a given dose of warfarin; it induces the enzymes that break down warfarin in the body, causing a reduced anticoagulant effect.

Between 2003 and 2004, the UK Committee on Safety of Medicines received several reports of increased INR and risk of haemorrhage in people taking warfarin and cranberry juice. Data establishing a causal relationship is still lacking, and a 2006 review found no cases of this interaction reported to the FDA; nevertheless, several authors have recommended that both doctors and patients be made aware of its possibility. The mechanism behind the interaction is still unclear.

الدوائيات Pharmacology

3 mg (blue), 5 mg (pink) and 1 mg (brown) warfarin tablets (UK colours)

الحركيات الدوائية Pharmacokinetics

Warfarin consists of a racemic mixture of two active enantiomers—R- and S- forms—each of which is cleared by different pathways. S-warfarin is 2-5 times more potent than the R-isomer in producing an anticoagulant response.

Warfarin is slower-acting than the common anticoagulant heparin, though it has a number of advantages. Heparin must be given by injection, whereas warfarin is available orally. Warfarin has a long half-life and need only be given once a day. Heparin can also cause a prothrombotic condition, heparin-induced thrombocytopenia (an antibody-mediated decrease in platelet levels), which increases the risk for thrombosis. It takes several days for warfarin to reach the therapeutic effect since the circulating coagulation factors are not affected by the drug (thrombin has a half-life time of days). Warfarin's long half-life means that it remains effective for several days after it was stopped. Furthermore, if given initially without additional anticoagulant cover, it can increase thrombosis risk (see below). For these main reasons, hospitalised patients are usually given heparin with warfarin initially, the heparin covering the 3–5 day lag period and being withdrawn after a few days.

طريقة العمل Mechanism of action

While warfarin is one of several drugs popularly referred to as a "blood thinner;" this is a misnomer since it does not affect the viscosity of blood.

Warfarin inhibits the vitamin K-dependent synthesis of biologically active forms of the calcium-dependent clotting factors II, VII, IX and X, as well as the regulatory factors protein C, protein S, and protein Z. Other proteins not involved in blood clotting, such as osteocalcin, or matrix Gla protein, may also be affected.

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 (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.

When warfarin is newly started, it may promote clot formation temporarily. This is because the level of protein C and protein S are also dependent on vitamin K activity. Warfarin causes decline in protein C levels in first 36 hours. In addition, reduced levels of protein S lead to a reduction in activity of protein C (for which it is the co-factor) and therefore reduced degradation of factor Va and factor VIIIa. Although loading doses of warfarin over 5 mg also produce a precipitous decline in factor VII, resulting in an initial prolongation of the INR, full antithrombotic effect does not take place until significant reduction in factor II occurs days later. The haemostasis system becomes temporarily biased towards thrombus formation, leading to a prothrombotic state. Thus, when warfarin is loaded rapidly at greater than 5 mg per day, it is beneficial to co-administer heparin, an anticoagulant that acts upon antithrombin and helps reduce the risk of thrombosis, with warfarin therapy for four to five days, in order to have the benefit of anticoagulation from heparin until the full effect of warfarin has been achieved.

الجيندوائية Pharmacogenomics

Warfarin activity is determined partially by genetic factors. Polymorphisms in two genes (VKORC1 and CYP2C9) play a particularly large role in response to warfarin.

VKORC1 polymorphisms explain 30% of the dose variation between patients: particular mutations make VKORC1 less susceptible to suppression by warfarin. There are two main haplotypes that explain 25% of variation: low-dose haplotype group (A) and a high-dose haplotype group (B). VKORC1 polymorphisms explain why African Americans are on average relatively resistant to warfarin (higher proportion of group B haplotypes), while Asian Americans are generally more sensitive (higher proportion of group A haplotypes). Group A VKORC1 polymorphisms lead to a more rapid achievement of a therapeutic INR, but also a shorter time to reach an INR over 4, which is associated with bleeding.

CYP2C9 polymorphisms explain 10% of the dose variation between patients, mainly among Caucasian patients as these variants are rare in African American and most Asian populations. These CYP2C9 polymorphisms do not influence time to effective INR as opposed toVKORC1, but does shorten the time to INR >4.

Despite the promise of pharmacogenomic testing in warfarin dosing, its use in clinical practice is controversial. In August 2009 the Centers for Medicare and Medicaid Services concluded that "the available evidence does not demonstrate that pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness improves health outcomes in Medicare beneficiaries." A 2014 meta-analysis showed that using genotype-based dosing did not confer benefit in terms of time within therapeutic range, excessive anticoagulation (as defined by INR greater than 4), or a reduction in either major bleeding or thromboembolic events.

تاريخ الدواء History

In the early 1920s, there was an outbreak of a previously unrecognised cattle disease in the northern United States and Canada. Cattle were haemorrhaging after minor procedures, and on some occasions, spontaneously. For example, 21 out of 22 cows died after dehorning, and 12 out of 25 bulls died after castration. All of these animals had bled to death.

In 1921, Frank Schofield, a Canadian veterinary pathologist, determined that the cattle were ingesting moldy silage made from sweet clover that functioned as a potent anticoagulant. Only spoiled hay made from sweet clover (grown in northern states of the USA and in Canada since the turn of the century) produced the disease. Schofield separated good clover stalks and damaged clover stalks from the same hay mow, and fed each to a different rabbit. The rabbit that had ingested the good stalks remained well, but the rabbit that had ingested the damaged stalks died from a haemorrhagic illness. A duplicate experiment with a different sample of clover hay produced the same result. In 1929, North Dakota veterinarian Dr L.M. Roderick demonstrated that the condition was due to a lack of functioning prothrombin.

The identity of the anticoagulant substance in spoiled sweet clover remained a mystery until 1940. In 1933 Karl Paul Link and his lab of chemists working at the University of Wisconsin set out to isolate and characterize the haemorrhagic agent from the spoiled hay. It took five years for Link's student Harold A. Campbell to recover 6 mg of crystalline anticoagulant. Next, Link's student Mark A. Stahmann took over the project and initiated a large-scale extraction, isolating 1.8 g of recrystallized anticoagulant in about 4 months. This was enough material for Stahmann and Charles F. Huebner to check their results against Campbell's and to thoroughly characterize the compound. Through degradation experiments they established that the anticoagulant was 3,3'-methylenebis-(4-hydroxycoumarin), which they later named dicoumarol. They confirmed their results by synthesizing dicoumarol and proving in 1940 that it was identical to the naturally occurring agent.

Dicoumarol was a product of the plant molecule coumarin (not to be confused with Coumadin, a later tradename for warfarin). Coumarin is now known to be present in many plants, and produces the notably sweet smell of freshly cut grass or hay and plants like sweet grass; in fact, the plant's high content of coumarin is responsible for the original common name of "sweet clover", which is named for its sweet smell, not its bitter taste. They are present notably in woodruff (Galium odoratum, Rubiaceae), and at lower levels in licorice, lavender, and various other species. However, coumarins themselves do not influence clotting or warfarin-like action, but must first be metabolized by various fungi into compounds such as 4-hydroxycoumarin, then further (in the presence of naturally occurring formaldehyde) into dicoumarol, in order to have any anticoagulant properties. Fungal attack of the damaged and dying clover stalks explained the presence of the anticoagulant only in spoiled clover silages; dicoumarol is considered to be a fermentation product and mycotoxin.

Over the next few years, numerous similar chemicals (specifically 4-hydroxycoumarins with a large aromatic substitutent at the 3 position) were found to have the same anticoagulant properties. The first drug in the class to be widely commercialized was dicoumarol itself, patented in 1941 and later used as a pharmaceutical. Karl Link continued working on developing more potent coumarin-based anticoagulants for use as rodent poisons, resulting in warfarin in 1948. The name "warfarin" stems from the acronym WARF, for Wisconsin Alumni Research Foundation + the ending -arin indicating its link with coumarin. Warfarin was first registered for use as a rodenticide in the US in 1948, and was immediately popular. Although warfarin was developed by Link, the Wisconsin Alumni Research Foundation financially supported the research and was assigned the patent.

After an incident in 1951, where a US Army inductee unsuccessfully attempted suicide with multiple doses of warfarin in rodenticide and recovered fully after presenting to a hospital, and being treated with vitamin K (by then known as a specific antidote), studies began in the use of warfarin as a therapeutic anticoagulant. It was found to be generally superior to dicoumarol, and in 1954 was approved for medical use in humans. An early recipient of warfarin was US president Dwight Eisenhower, who was prescribed the drug after having a heart attack in 1955.

The exact mechanism of action remained unknown until it was demonstrated, in 1978, that warfarin inhibits the enzyme epoxide reductase and hence interferes with vitamin K metabolism.

It has been theorized that Lavrenty Beria, Nikita Khrushchev and others conspired to use warfarin to poison the Soviet leader Joseph Stalin. Warfarin is tasteless and colourless, and produces symptoms similar to those that Stalin exhibited.

إشتقاق الإسم

تم إكتشاف الوارفارين في البرسيم الحلو المعطب spoiled sweet clover أثناء إستخدامه كغذاء حيواني. لفظ وارفارين Warfarin تم إشتقاقه من مختصر الحروف الأولى Acronym للمشروع العلمي الذي إكتشفه. وهو مشروع "وارف" "WARF" مؤسسة أبحاث خريجيي وسكينسن Wisconsin Alumni Research Foundation ثم تم إضافة النهاية "ارين" له"-arin" للدلالة على إنتماءه للمجمعة الأدوية كومارين Coumarin.

إستعمالات أخرى

يستعمل الوارفارين كسم للفئران.

اقرأ أيضًا

• دالتيبارين الصوديوم

مراجع

• https://ar.wikipedia.org/wiki/%D9%88%D8%A7%D8%B1%D9%81%D8%A7%D8%B1%D9%8A%D9%86
• https://en.wikipedia.org/wiki/Warfarin
• http://www.drugs.com/sfx/warfarin-side-effects.html
• http://www.drugs.com/warfarin.html
• http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682277.html

وصلات خارجية

• Historical information on warfarin from the Wisconsin Alumni Research Foundation
• Online sweet clover disease and warfarin historical review
• U.S. National Library of Medicine: Drug Information Portal–Warfarin
• Warfarin bound to proteins in the PDB: R-warfarin,S-warfarin
• CDC - NIOSH Pocket Guide to Chemical Hazards
• Pesticide Properties DataBase (PPDB)

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