Clinical Toxicology Case Presentation

1. Clinical Toxicology Case Presentation Dr.K.Go UCH 16/2/2005

2. 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

3. 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 ? A Bleeding Case – Con’t

4. 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 The consideration • Indications for anticoagulants • Presence of severe/life threatening bleeding • INR • +/- causes of over-anticoagulation.

5. Progress All along – no more PRBHb - stable

6. 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.

7. How warfarin works ?

8. Inactive Factor 2,7,9,10Protein C,S Vitamin K Quinol Vitamin K 2,3 epoxide Action of warfarin Metabolism by 2C9, 1A2, 3A4, 2C19High Protein Bound Active Factor 2,7,9,10Protein C,S Vitamin K Quinone Vitamin K supply Warfarin inhibition

9. Pharmacokinetics of warfarin. • Absorption: completely absorbed orally • Distribution: • Vd 0.14L/kg • 99% protein bound. • Metabolism: • P450 to inactive hydroxylated metabolites • Reductase to warfarin alcohols (minimal anticoagulant activity). • Excretion : • 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.

10. % of clotting factor loss INR 25% Shortest T1/2 –Factor VII ~ 5 hrs About 3 T1/2 to see effect of ↓INR 100% 75% 50% 1 5 10 15

11. Why our patient got supra-therapeutic INR ?

12. 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)

13. Other causes • Hypoalbuminaemia • Increase free fraction of drug. • Concomitant disease • Malignancy ,CHF, etc. • Hepatic dysfunction • Aging

15. Synergistic drug combination • NSAID + Warfarin • 13x increase in hemorrhagic ulcer disease. Shorr R I. Arch Intern.Med, 1993 ;153 (14)

16. 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)

17. 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

18. 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

19. 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.

20. Management of supra-therapeutic INR6th ACCP Consensus Conference on Antithrombotic Therapy; CHEST 2001:119:22S-38S

21. 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

22. Thank you