Warfarin; Uses, Dosage, Side Effects, Drug Interactions

Warfarin Sodium is the sodium salt form of warfarin, a coumarin and a vitamin K antagonist, with anticoagulant activity. Warfarin sodium inhibits both vitamin K and vitamin K epoxide reductases, thereby interfering with the cyclic interconversion of vitamin K epoxide to its reduced form, vitamin KH2. Vitamin KH2 is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins. As a result, maturation of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited. Without these coagulation factors, thrombogenesis and blood clot formation are prevented.

Warfarin is a medication that is used as an anticoagulant(blood thinner).It is commonly used to treat blood clots such as deep vein thrombosis and pulmonary embolismand to prevent stroke in people who have atrial fibrillation, valvular heart disease or artificial heart valves. Warfarin has since become the most frequently prescribed oral anticoagulant in North America. Warfarin has several properties that should be noted when used medicinally, including its ability to cross the placental barrier during pregnancy which can result in fatal bleeding, spontaneous abortion, preterm birth, stillbirth, and neonatal death. Additional adverse effects such as necrosis, purple toe syndrome, osteoporosis, valve and artery calcification, and drug interactions have also been documented with warfarin use.

Mechanism of Action of Warfarin

Warfarin inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X, and anticoagulant proteins C and S is inhibited. Depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X) results in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.

Indications of Warfarin

Myocardial Infarction
Pulmonary Embolism
Strokes
Antiphospholipid Syndrome
Deep Vein Thrombosis Prophylaxis after Knee Replacement Surgery
Deep Vein Thrombosis, First Event
Chronic Central Venous Catheterization
Deep Vein Thrombosis Prophylaxis after Hip Replacement Surgery
Deep Vein Thrombosis, Recurrent Event
Heart Attack
Heart Failure
Prevention of Thromboembolism in Atrial Fibrillation
Prosthetic Heart Valves – Thrombosis Prophylaxis
Prosthetic Heart Valves, Mechanical Valves – Thrombosis Prophylaxis
Prosthetic Heart Valves, Tissue Valves – Thrombosis Prophylaxis
Protein S Deficiency
Pulmonary Embolism,
Thromboembolic Stroke Prophylaxis
Systemic Embolism
Thromboembolism
Thrombosis, Venous
Transient ischemia attacks

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Therapeutic Indications of Warfarin

For the treatment of retinal vascular occlusion, pulmonary embolism, cardiomyopathy, atrial fibrillation and flutter, cerebral embolism, transient cerebral ischemia, arterial embolism, and thrombosis.
Warfarin and/or aspirin is used to prevent thromboembolism associated with various types of valvular heart disease; the choice of antithrombotic therapy depends on balancing the risk of thromboembolism with the risk of hemorrhagic complications from antithrombotic therapy.
Use of warfarin is recommended to decrease the risk of embolization in patients undergoing pharmacologic or electrical cardioversion of atrial fibrillation/flutter.
Warfarin is used for the prevention of stroke and systemic embolism in patients with atrial fibrillation.
Warfarin also has been used for primary thromboprophylaxis in children with ventricular assist devices or with an arteriovenous fistula undergoing hemodialysis and in children with certain medical conditions associated with a high risk of thrombosis (e.g., moderate or giant coronary aneurysms following Kawasaki disease, primary pulmonary hypertension).
Warfarin has been used in a limited number of patients undergoing percutaneous balloon mitral valvotomy to prevent left atrial embolism.
While warfarin should not be used for initial treatment of heparin-induced thrombocytopenia (HIT), the manufacturers and other clinicians state that therapy with the drug may be considered after platelet counts have normalized.
Warfarin has been used in certain patients with the peripheral arterial occlusive disease. However, ACCP generally recommends the use of antiplatelet agents (aspirin or clopidogrel) rather than anticoagulants for the primary or secondary prevention of cardiovascular events in patients with the peripheral arterial disease.
In the treatment of acute proximal deep-vein thrombosis or pulmonary embolism (i.e., venous thromboembolism) in adults, the American College of Chest Physicians (ACCP) recommends that warfarin therapy is initiated concomitantly with a parenteral anticoagulant (a low molecular weight heparin, unfractionated heparin, or fondaparinux).

Contraindications of Warfarin

All anticoagulants are generally contraindicated in situations where the reduction in clotting that they cause might lead to serious and potentially life-threatening bleeds. This includes people with active bleeding conditions (such as gastrointestinal ulcers), or disease states with an increased risk of bleeding e.g. low platelets, severe liver disease, uncontrolled hypertension. For patients undergoing surgery, treatment with anticoagulants is generally suspended. Similarly, spinal or lumbar puncture (e.g. spinal injections, epidurals, etc.) carry increased risk so treatment is suspended prior to these procedures.

Warfarin should not be given to people with heparin-induced thrombocytopenia until platelet count has improved or normalized. Warfarin is usually best avoided in people with protein C or protein S deficiency as these thrombophilic conditions increase the risk of skin necrosis, which is a rare but serious side effect associated with warfarin.

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Dosage of Warfarin

Strengths: 1 mg; 2 mg; 2.5mg ; 3mg ; 4mg; 5 mg; 6 mg 7.5 mg; 10 mg;

Thromboembolism in Atrial Fibrillation

Initial dose: 2 to 5 mg orally once a day
Maintenance dose: 2 to 10 mg orally once a day

Thromboembolic Stroke Prophylaxis

Initial dose: 2 to 5 mg orally once a day
Maintenance dose: 2 to 10 mg orally once a day

Myocardial Infarction

Initial dose: 2 to 5 mg orally once a day
Maintenance dose: 2 to 10 mg orally once a day

Deep Vein Thrombosis

Initial dose: 2 to 5 mg orally once a day
Maintenance dose: 2 to 10 mg orally once a day

Pulmonary Embolism

Initial dose: 2 to 5 mg orally once a day
Maintenance dose: 2 to 10 mg orally once a day

Side Effects of Warfarin

The most common

Common

nusual bruising, such as:
unexplainable bruises
bruises that grow in size
nosebleeds
bleeding gums
bleeding from cuts that takes a long time to stop
heavier than normal menstrual or vaginal bleeding
pink or brown urine
red or black stools
coughing up blood
vomiting blood

Less common

Bleeding gums
blood in the urine
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

Drug Interactions of Warfarin

Warfarin may interact with following drugs, supplements & may change the efficacy of the drug

alcohol
angiotensin receptor blockers (ARBs; e.g., irbesartan, losartan)
anticancer medications (e.g., carboplatin, cyclophosphamide, fluorouracil)
azathioprine
“azole” antifungals (e.g., fluconazole, ketoconazole, voriconazole)
barbiturates (e.g., phenobarbital, secobarbital)
carbamazepine
cephalosporins (e.g., cefazolin, cefoperazone, cefotetan, cefoxitin)
clopidogrel
coenzyme Q10
corticosteroids (e.g., hydrocortisone, prednisone)
COX-II inhibitors (celecoxib, rofecoxib)
estrogen-containing medications (e.g., birth control pills)
glucosamine
heparin
macrolide antibiotics (e.g., azithromycin, clarithromycin,
methyldopa
metronidazole
mirtazapine
multivitamins
nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., diclofenac, ibuprofen, naproxen)
omega-3 fatty acids
penicillins (e.g., ampicillin, cloxacillin, penicillin G, piperacillin, ticarcillin)
pentoxifylline
phenobarbital
phenytoin
progestins (e.g., levonorgestrel, progesterone)
proton pump inhibitors (e.g., lansoprazole, omeprazole)
quinolone antibiotics (e.g., ciprofloxacin, norfloxacin, ofloxacin)
ranitidine
selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine, paroxetine, sertraline)
“statins” (e.g., fluvastatin, lovastatin, simvastatin)
sulfonamide antibiotics (e.g., sulfamethoxazole)
tetracyclines (e.g., doxycycline, minocycline, tetracycline)
tolterodine
tramadol
tricyclic antidepressasnts (e.g., amitriptyline, clomipramine, desipramine, trimipramine)
vitamin A
vitamin E
vitamin K
zafirlukast

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Pregnancy & Lactation of Warfarin

FDA Pregnancy Category D

Pregnancy

Warfarin should not be used during pregnancy. It passes through the placental barrier and may cause bleeding in the unborn baby. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

It is not known if warfarin passes into human breast milk. If you breastfeeding-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.