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Transcript
Clinical Toxicology Case Presentation Dr.K.Go UCH 16/2/2005 A Bleeding Case F/73 Known CRHD with valvular replacement/AF On warfarin 4mg/4.5mg alt day History of GIB a month ago OGD – gastritis / Colonoscopy - NAD c/o PRB once P/E Proctoscopy – piles, no active bleeding, no melena Bruise over L scapula A Bleeding Case – Con’t BP 123/68, Pulse 79 Hb 9.8 g/dl, similar to CBP a month ago INR 5.9 Haemodynamically stable during AED stay and no evidence of further PRB What is your management ? The consideration Indications for anticoagulants Presence of severe/life threatening bleeding INR +/- causes of over-anticoagulation. Mx in the AED Withhold Warfarin Consider Vit K 1-2.5mg orally if bleeding . If con’t bleeding , consider FFP & Vit K 10mg SC Admit Medical Progress All along – no more PRB Hb - stable 30/12 FFP Vit K1 31/12 1/1 2/1 3/1 4/1 5/1 6/1 7/1 on on on on on on off 4u 10mg IV 10mg IV Heparin Warfarin 3mg 3mg 3mg 3mg 3mg APTT INR 5.9 35.9 43.6 61.2 51.1 40.2 55.5 69.3 65.8 1.3 1.2 1.3 1.2 1.2 1.4 1.6 1.9 Warfarin An anticoagulant . A racemic mixture of S and R enantiomers. S racemer is 1.5-2X more potent than R racemer But faster clearance. How warfarin works ? Action of warfarin Metabolism by 2C9, 1A2, 3A4, 2C19 High Protein Bound Inactive Factor 2,7,9,10 Protein C,S Vitamin K Quinol Active Factor 2,7,9,10 Protein C,S Vitamin K 2,3 epoxide Vitamin K Quinone Vitamin K supply Warfarin inhibition Pharmacokinetics of warfarin. Absorption: completely absorbed orally Distribution: Metabolism: P450 to inactive hydroxylated metabolites Reductase to warfarin alcohols (minimal anticoagulant activity). Excretion : Vd 0.14L/kg 99% protein bound. Most metabolite excreted into urine . Some into the bile. Little excreted unchanged in the urine. Effective t½ =20-60 hrs (mean 40 hrs) Onset of action :delayed , At least 15 hrs. % of clotting factor loss Shortest T1/2 –Factor VII ~ 5 hrs About 3 T1/2 to see effect of ↓INR 100% 75% 50% 25% 1 5 10 15 INR Why our patient got supra-therapeutic INR ? Major causes Overdose Drug interaction: Inhibition of warfarin metabolism (P450) in the liver. Displacement of warfarin from protein binding. Vit K deficiency : Malnutrition Malabsorption (recent diarrhea) Change in gut flora (e.g antibiotic uses) Other causes Hypoalbuminaemia Concomitant disease Increase free fraction of drug. Malignancy ,CHF, etc. Hepatic dysfunction Aging Synergistic drug combination NSAID + Warfarin 13x increase in hemorrhagic ulcer disease. Shorr R I. Arch Intern.Med, 1993 ;153 (14) Over-warfarinisation Known Cx of warfarin therapy Rate of major bleeding in elderly (age >80) discharged with OAT = 2.4 per 1000 patients month. Risk factors : Insufficent patient education (OR= 8.83) Polypharmacy (OR=6.14) Use of INR above therapeutic range (OR=1.08) Kagansky N Arch. Intern.Med ,2004 Oct;164(18) In a surveillance of outpatient adverse drug events treated in hospital ED Warfarin and insulin Most common drugs encountered (16% and 33% respectively) in patients of age >50. Budnitz DS. Annals of Emerg Med ,Feb 2005 ;45 Management of warfarin overdose Stop warfarin If life threatening hemorrhage FFP 10ml/kg IVI Vit K 10mg SC/slow IV Switch to heparin if necessary For non-life threatening hemorrhage No need for long term anticoagulation Vit K1 Need for chronic anticoagulation: Stop warfarin and observe. Try avoid giving Vit K ( complete reversal will occur, difficult to reanticoagulate in future). If vit K is to be given, give a low dose e.g 2.5mg orally. If significant bleeding, give FFP. Management of supra-therapeutic INR 6th ACCP Consensus Conference on Antithrombotic Therapy; CHEST 2001:119:22S-38S INR Bleeding Recommendations <5 No Omit 1 dose Resume at lower dose 5-9 No Omit 1 to 2 dose, monitor INR more frequently Consider Vit K1 1-2.5mg PO Resume a lower dose. 9-20 No Withhold, frequent INR monitoring Consider Vit K1 3-5mg PO Resume a lower dose . >20 Severe Withhold Vit K1 10mg slow IV +/- FFP Any Abnormal INR Life Threatening Withhold. Give FFP Vitamin K1 10mg slow IV Summary/Learning Points Warfarin PK & PD Supra-therapeutic INR is common Causes of over-warfarinisation Management options for over-warfarinisation Aware the drug interactions of warfarin and try to avoid it Thank you