Warfarin Mode of Action
Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors. Vitamin K promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins that are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K1 epoxide
Brands of Warfarin in Kenya
Warexx-5® , Metro Pharmaceuticals Limited
Warfarin is indicated for:
- Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE).
- Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement.
- Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction.
Limitations of Use
Warfarin has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. Once a thrombus has occurred, however, the goals of anticoagulant treatment are to prevent further extension of the formed clot and to prevent secondary thromboembolic complications that may result in serious and possibly fatal sequelae.
Warfarin sodium is contraindicated in:
Warfarin sodium is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism . Warfarin sodium can cause fetal harm when administered to a pregnant woman. Warfarin sodium exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If warfarin sodium is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus
Warfarin sodium is contraindicated in patients with:
- Hemorrhagic tendencies or blood dyscrasias
- Recent or contemplated surgery of the central nervous system or eye, or traumatic surgery resulting in large open surfaces
- Bleeding tendencies associated with:
− Active ulceration or overt bleeding of the gastrointestinal, genitourinary, or respiratory tract
− Central nervous system hemorrhage
− Cerebral aneurysms, dissecting aorta
− Pericarditis and pericardial effusions
− Bacterial endocarditis
- Threatened abortion, eclampsia, and preeclampsia
- Unsupervised patients with conditions associated with potential high level of non-compliance
- Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding
- Hypersensitivity to warfarin or to any other components of this product (e.g., anaphylaxis)
- Major regional or lumbar block anesthesia
- Malignant hypertension
ADVERSE DRUG REACTIONS:
The following serious adverse reactions to warfarin sodium have been noted:
- Tissue Necrosis
- Acute Kidney Injury
- Systemic Atheroemboli and Cholesterol Microemboli
- Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS
- Other Clinical Settings with Increased Risks
Other adverse reactions to warfarin sodium include:
Immune system disorders: hypersensitivity/allergic reactions (including urticaria and anaphylactic reactions)
Vascular disorders: vasculitis
Hepatobiliary disorders: hepatitis, elevated liver enzymes. Cholestatic hepatitis has been associated with concomitant administration of warfarin sodium and ticlopidine.
Gastrointestinal disorders: nausea, vomiting, diarrhea, taste perversion, abdominal pain, flatulence, bloating
Skin disorders: rash, dermatitis (including bullous eruptions), pruritus, alopecia
Respiratory disorders: tracheal or tracheobronchial calcification
General disorders: chills
Drugs which are contraindicated
Concomitant use of drugs used in the treatment or prophylaxis of thrombosis, or other drugs with adverse effects on haemostasis may increase the pharmacological effect of warfarin, increasing the risk of bleeding.
Fibrinolytic drugs such as streptokinase and alteplase are contraindicated in patients receiving warfarin.
Drugs which should be avoided if possible
The following examples should be avoided, or administered with caution with increased clinical and laboratory monitoring:
• NSAIDs (including aspirin and cox-2 specific NSAIDS)
• Thrombin inhibitors such as bivalirudin, dabigatran
• Unfractionated heparins and heparin derivatives, low molecular weight heparins
• Fondaparinux, rivaroxaban
• Glycoprotein IIb/IIIa receptor antagonists such as eptifibatide, tirofiban and abciximab
• SSRI and SNRI antidepressants
• Other drugs which inhibit haemostasis, clotting or platelet action
Low-dose aspirin with warfarin may have a role in some patients but the risk of gastrointestinal bleeding is increased. Warfarin may initially be given with a heparin in the initial treatment of thrombosis, until the INR is in the correct range.
Warfarin is a mixture of enantiomers which are metabolised by different CYPP450 cytochromes. R-warfarin is metabolised primarily by CYP1A2 and CYP3A4. S-warfarin is metabolised primarily by CYP2C9. The efficacy of warfarin is affected primarily when the metabolism of S-warfarin is altered.
Drugs that compete as substrates for these cytochromes or inhibit their activity may increase warfarin plasma concentrations and INR, potentially increasing the risk of bleeding. When these drugs are co-administered, warfarin dosage may need to be reduced and the level of monitoring increased.
Conversely, drugs which induce these metabolic pathways may decrease warfarin plasma concentrations and INR, potentially leading to reduced efficacy. When these drugs are co-administered, warfarin dosage may need to be increased and the level of monitoring increased.
There is a small subset of drugs for which interactions are known; however the clinical effect on the INR is variable, in these cases increased monitoring on starting and stopping therapy is advised.
Care should also be taken when stopping or reducing the dose of a metabolic inhibitor or inducer, once patients are stable on this combination (offset effect).
Listed below are drugs which are known to interact with warfarin in a clinically significant way.
Examples of drugs which potentiate the effect of warfarin
allopurinol, capecitabine, erlotinib, disulfiram, azole antifungals (ketoconazole, fluconazole etc)
omeprazole, paracetamol (prolonged regular use), propafenone, amiodarone, tamoxifen, methylphenidate
zafirlukast, fibrates, statins (not pravastatin; predominantly associated with fluvastatin)
erythromycin, sulfamethoxazole, metronidazole
Examples of drugs which antagonise the effect of warfarin
Barbiturates, primidone, carbamazepine, griseofulvin, oral contraceptives, rifampicin, azathioprine, phenytoin
Examples of drugs with variable effect
Corticosteroids, nevirapine, ritonavir
Other drug interactions
Broad spectrum antibiotics may potentiate the effect of warfarin by reducing the gut flora which produce vitamin K. Similarly, orlistat may reduce absorption of vitamin K. Cholestyamine and sucralfate potentially decrease absorption of warfarin.
Increased INR has been reported in patients taking glucosamine and warfarin. This combination is not recommended.
Interactions with herbal products
Herbal preparations containing St John’s Wort (Hypericum perforatum) must not be used whilst taking warfarin due to a proven risk of decreased plasma concentrations and reduced clinical effects of warfarin.
Many other herbal products have a theoretical effect on warfarin; however most of these interactions are not proven. Patients should generally avoid taking any herbal medicines or food supplements whilst taking warfarin, and should be told to advise their doctor if they are taking any, as more frequent monitoring is advisable.
Acute ingestion of a large amount of alcohol may inhibit the metabolism of warfarin and increase INR. Conversely, chronic heavy alcohol intake may induce the metabolism of warfarin. Moderate alcohol intake can be permitted.
Interactions with food and food supplements
Individual case reports suggest a possible interaction between warfarin and cranberry juice, in most cases leading to an increase in INR or bleeding event. Patients should be advised to avoid cranberry products. Increased supervision and INR monitoring should be considered for any patient taking warfarin and regular cranberry juice.
Limited evidence suggests that grapefruit juice may cause a modest rise in INR in some patients taking warfarin.
Certain foods such as liver, broccoli, Brussels sprouts and green leafy vegetables contain large amounts of vitamin K. Sudden changes in diet can potentially affect control of anticoagulation. Patients should be informed of the need to seek medical advice before undertaking any major changes in diet.
There are limited data on possible drug interactions with glucosamine, but increments in the INR parameter have been reported with oral vitamin K antagonists. Patients treated with oral vitamin K antagonists should therefore be closely monitored at the time of initiation or termination of glucosamine therapy.
Many other food supplements have a theoretical effect on warfarin; however most of these interactions are not proven. Patients should generally avoid taking any food supplements whilst taking warfarin, and should be told to advise their doctor if they are taking any, as more frequent monitoring is advisable.
Heparins and danaparoid may prolong the prothrombin time, therefore a sufficient time interval should be allowed after administration before performing the test.
Warfarin in Kenya
Brands of warfarin in Kenya
Where to buy warfarin in Kenya
Cost of warfarin in Kenya
Clinical | Pharmacokinetic data
Routes of Administration: By mouth or intravenous
Protein Binding: 99%
Metabolosim: Liver: CYP2C9, 2C19, 2C8, 2C18, 1A2 and 3A4
Onset of Action:
Elimination Half life: 1 week (active half-life is 20-60 hours)
Excretion: Kidney (92%)
Legal Status | Dosage forms & Strengths
Prescription only Medicine (POM) , ℞-only
Narcotic Drugs and Psychotropic Substances (Control ) Act Schedule:
This Drug is not Subject to DDA drugs Act
Dosage Forms | Strengths:
Tablets | Injectable
|CompTox Dashboard (EPA)
- Hamilton R (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 289. ISBN 978-1-284-05756-0.
- Holford NH (December 1986). “Clinical pharmacokinetics and pharmacodynamics of warfarin. Understanding the dose-effect relationship”. Clinical Pharmacokinetics. 11