Warfarin is an anticoagulant which is used to prevent blood clotting in patients who are at high risk of developing blood clots. Such as people who are likely to suffer from/ or have: DVT, Pulmonary embolism (PE), AF, MI, patients who have had a stroke.

Mechanism of action

• Vitamin K antagonist
• Inhibit with the post translational γ-carboxylation of glutamic acid residues in clotting factors II, VI,IX and X (coagulating factors)
• They do this via inhibiting Vit K epoxide reductase component 1 (VKORC1), therefore preventing Vit K epoxide being converted to its active hydroquinone form
• Therefore, there is a decrease in the level of prothrombin and thrombin. Reduces thrombogenicity of clots

WARFARIN METABOLISED IN LIVER VIA CYP450.

Remember CYP450 SYSTEM (Inducers and Inhibitors!!)

Indications and doses

Prophylaxis of embolization in rheumatic heart disease and AF/ Prophylaxis after insertion of prosthetic heart valve/ Prophylaxis in treatment of venous thrombosis and PE/ TIA

• Orally
• Baseline prothrombin should be determined, but initial dose should not be delayed whilst awaiting results
• Rapid anticoagulation: initially 5-10mg on Day1 (elderly should receive a lower induction dose), subsequent doses depending on the INR scores.
• Non rapid anticoagulation: lower loading dose can be used over 3-4 weeks.
• Daily maintenance dose, 3-9mg (SAME TIME EACH DAY!!!!)

Pregnancy

• Avoid in 1^st trimester, as warfarin can cross the placenta and may cause congenital malformations, foetal/neonatal haemorrhage. Notably in the last few weeks of gestation and at time of deliver. TERATOGENIC
• If possible should generally be avoided in pregnancy. If this is not possible then avoid at 1^st and 3^rd trimester
• Stopping warfarin before the 6^th week of gestation will increase the chance of avoiding any foetal abnormalities.

Babies of mothers taking warfarin at the time of delivery will need to be offered immediate prophylaxis with IM Vit K₁ (Phytomenadione)

Women of child bearing age should be warned beforehand about the teratogenic effects of warfarin.

Cautions

• Bacterial endocarditis
• Conditions where there is an increased risk of bleeding
• History of GI bleeds
• Peptic ulcers
• Postpartum (delay until risk of bleeding is low, 5-7 days after delivery)
• Recent ischaemic stroke
• Recent surgery
• Uncontrolled hypertension

Side Effects

Alopecia, diarrhoea, haemorrhage hepatic dysfunction, jaundice, nausea, pancreatitis, purpura, pyrexia, skin necrosis (protein C, or protein S deficiency, increased risk), vomiting, purple toes

Ask patients if they have had any abnormal bruising, or bleeding such as epistaxis.

Monitoring Requirements

• Baseline prothrombin
• INR
• Changes in patients clinical condition

Breast feeding

• Risk of haemorrhage increase with Vit K deficiency
• Warfarin not present in significant concentrations, therefore, appears safe.

Hepatic Impairment

• Avoid in severe
• Notably if prothrombin time is prolonged

Renal impairment

• Caution with mild-mod impairment
• Severe impairment, monitor INR frequently

Interactions

• Alcohol
• Anabolic steroids
• Analgesics: NSAIDS, Diclofenac, Ketorolac, Tramadol, Aspirin
• Anthelmintics: Levamisole
• Anti-arrythmics: Amiodarone, Dronedarone, Propafenone
• Anitbacterials: CHECK WITH ALL ANTIBACTERIALS
• Anitcoagulants: Apixaba, Dabigatran, Rivaroxaban
• Antidepressants: Venlafaxine, SSRI’s, St John’s wort, Tricyclics
• Antidiabetics: Sulfonylureas
• Antiepileptic’s: Carbamazepine, Phenobarbital, Primidone, Fosphenytoin, Phenytoin
• Antifungals: Fluconazole, Itraconazole, Ketoconazole, Miconazole, Griseofluvin
• Antivirals: Nevirapine, Ritonavir, Efavirenz, Telaprevir
• Azathioprine
• Clopiodogrel
• Corticosteroids
• Cranberry Juice
• Cytotoxics: Etoposide, Ifosfamide, Sorafenib, Capecitabine, Fluorouracil, Tegafur, Geftinib, Vemurafenib, Mercaptopurine, Mitotane, Erlotinib, Regorafenib
• Dipyridamole
• Disulifram
• Dopaminergics: Entacapone
• Enteral foods
• Glucosamine
• Hormone antagonists: Toremifene, Danazol, Enzalutamide, Flutamide, Tamoxifen
• Lipid Regulating Drugs: Colestyramine, Fibrates, Fluvastatin, Rosuvastatin
• Retinoids: Acitretnin
• Sulfinpyrazone
• Sympathomimetics: Methyphenidate
• Testolactone
• Thyroids Hormones
• Ulcer healing drugs: Cimetidine, Omeprazole, Esomeprazole, Sucralfate
• Vitamins: Vit E, VIT K

Interaction Mnemonics

O-DEVICES – is a mnemonic you can use to remember drugs that inhibit the cytocrhome p450 enzyme system and thus increase the effects of warfarin:

O –           Omperazole

D –           Disulfiram

E –            Erythromycin

V –           Valproate

I –             Isoniazid

C –            Cimetidine + Ciprofloxacin

E –            Ethanol (Acutely)

S –            Sulphonamides

PC BRAS – is a mnemonic you can use to remember drugs that induce the cytocrhome p450 enzyme system and thus decrease the effects of warfarin:

P –            Phenytoin

C –            Carbamazepine

B –            Barbituates

R –            Rifampicin

A –           Alcohol (chronic use)

S –            Sulphonylureas

Advice for patients and carers

• Recognise signs of bleeding such as: epistaxis, bruising, blood in faeces, black faeces, hematemesis, bleeding gums, unusual headaches and heavy bleeding during period/ any other bleeding during period
• If patient is seen to have any of these signs they need to seek URGENT MEDICAL ATTENTION

References

BNF 70, Joint Formulary Committee (2015) British National Formulary. 70th Ed., London: British Medical Association and Royal Pharmaceutical Society of Great Britain.

NHS Choices. (2014). Side effects of warfarin. Available: http://www.nhs.uk/Conditions/Anticoagulants-warfarin-/Pages/Side-effects.aspx. Last accessed 28/01/2016

Rang, HP and Dale, M (2012). Rang and Dales Pharmacology. 7th ed. London: Churchill Livingstone, Elsevier. 301-302.

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