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Warfarin

Warfarin. By Kirsteen Houston. 1920’s cattle were fed clover instead of corn Cattles died from bleeding Found to be due to the coumarin in the spoilt sweet clover Coumarin was used as rat poison Then developed into clinical use. History.

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Warfarin

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  1. Warfarin By Kirsteen Houston

  2. 1920’s cattle were fed clover instead of corn • Cattles died from bleeding • Found to be due to the coumarin in the spoilt sweet clover • Coumarin was used as rat poison • Then developed into clinical use History

  3. Oral anticoagulation is monitored via the prothrombin time (PT) • Time taken for citrated plasma to clot with the addition of tissue factor • To make it standardised an INR is used • INR = [ PT of the patient/ PT of normal plasma] X k (constant of reagents used) INR

  4. Warfarin only exerts its effect in vivo • Interferes with the post-transciptional y-carboxylation of glutamic acid residues on clotting factors II, VII, IX and X • This renders the clotting factors functionless, which are called proteins induced by vitamin K absence Mechanism

  5. The half life of each factor • VII = 6 hours • II = 60 hours • Hence it is impossible to achieve anticoagulation in less than 48 hours • The INR during the first 2-3 days does NOT reflect the degree of anticoagulation • Heparin is administered for immediate affect • Most helpful time to judge the effect is 3-4 days after initiation IMPORTANT CLINCIAL NUGGET

  6. Extrinsic System Intrinsic System Substances released from damage tissue Vascular endothelial damage Inhibition Warfarin Factors VII Factors IX and X Coagulation cascade – made easy Prothrombin IIA Thrombin II Fibrinogen Fibrin

  7. Brain – extract used as the tissue factor stimulus for extrinsic system activation in prothrombin time test • S VII seven: main factor inhibited by warfarin • W warfarin • E extrinsic system • P prothrombin • T time Brain SWEPT

  8. Indications for anticoagulation

  9. Only given orally • Absorbed rapidly and completely from the GI tract • Takes 1 hour to reach max plasma concentration • In addition it is heavily protein bound (99%) • Metabolised by the liver Administration

  10. Mouth Gut Blood attached to albumin Liver-reduces activation of vitamin K-dependent clotting factors II, VII, IX, X Metabolised by cytochrome p450 enzyme complex How it is metabolised

  11. Before loading dose need baseline tests: PT, APTT, platelets, LFT’s and FBC • This will dictate whether a full or reduced loading dose will be used • Use the Fennerty’s regime – see hospital guidelines • Check warfarin on day 4, as this predicts the maintenance dose that will be given Loading and maintenance

  12. Interactions

  13. CLOT BLEED Mouth Antibiotics- destroy vit K producing bacteria; avoid co-trimoxazole. Care with metronidazole, erythromycin, amoxycillin and trimethoprim; check INR Cholestyramine- can bind warfarin in gut reducing its absorption Gut Blood attached to albumin Aspirin and NSAIDs- damage gut mucosa and displace warfarin Liver-reduces activation of vitamin K-dependent clotting factors II, VII, IX, X. 10, 9, 7, 2 (“1972”) OCP- slightly increases clotting factors Steroids- liver disease and also reduces “1972” Metabolised by cytochrome p450 enzyme complex Enzyme inducers- anti-epileptic drugs eg phenytoin, carbamazepine, rifampicin, griseofulvin, chronic alcohol Enzyme inhibitors- cimetidine, omeprazole, acute binge OR stopping chronic alcohol

  14. Haemorrhage: bruising, nosebleeds, gum bleeds and haematuria • Skin rashes, alopecia and purple toes?! • Phenindione is an alternative if sensitivity is a problem • S/E seen especially in elderly • Anticoagulations shouldn’t be used in pregnancy or women trying to conceive. Warfarin is teratogenic in early pregnancy and towards the end of pregnancy may cause neonatal haemorrhage Adverse Effects

  15. If INR >5 reversal protocol needs to be observed • Use of vit K done with knowledge that the control of INR will be erratic over the following few weeks • Try to avoid or use in very small doses • 10mg of vit K is for alcoholics and should not normally be given in its entirety; try 2 mg to begin with and titrate from there Reversing warfarin

  16. 47 year old female suffers a DVT after undergoing a cholecystectomy 2/52 ago, being discharged after an uneventful recovery 1/52 ago • Do you admit this patient to hospital? A cheeky AMK style question

  17. This patient MUST be admitted: life-threatening risk of PE

  18. 47 year old female suffers a DVT after undergoing a cholecystectomy 2/52 ago, being discharged after an uneventful recovery 1/52 ago • What drugs would you prescribe, provided there are no contraindications?

  19. Heparin, LMWH is preferred as doesn’t need constant monitoring.

  20. 47 year old female suffers a DVT after undergoing a cholecystectomy 2/52 ago, being discharged after an uneventful recovery 1/52 ago • What is the long-term treatment? Including length of treatment and any target ranges to aim for

  21. Warfarin treatment, continued for 6/52 and the target range should be an INR 2-3

  22. Questions? I will also send you a few AMK style questions regarding anticoagulation

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