Clinical toxicology case presentation
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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

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Clinical Toxicology Case Presentation

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Clinical toxicology case presentation

Clinical Toxicology Case Presentation

Dr.K.Go UCH 16/2/2005


A bleeding case

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 ?

A Bleeding Case – Con’t


The consideration

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.


Clinical toxicology case presentation

Progress

All along – no more PRBHb - stable


Warfarin

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

How warfarin works ?


Inactive factor 2 7 9 10 protein c s

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


Pharmacokinetics of warfarin

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.


Clinical toxicology case presentation

% 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


Why our patient got supra therapeutic inr

Why our patient got supra-therapeutic INR ?


Major causes

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

Other causes

  • Hypoalbuminaemia

    • Increase free fraction of drug.

  • Concomitant disease

    • Malignancy ,CHF, etc.

    • Hepatic dysfunction

  • Aging


Synergistic drug combination

Synergistic drug combination

  • NSAID + Warfarin

  • 13x increase in hemorrhagic ulcer disease.

    Shorr R I. Arch Intern.Med, 1993 ;153 (14)


Over warfarinisation

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)


Clinical toxicology case presentation

  • 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

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


Clinical toxicology case presentation

  • 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.


Clinical toxicology case presentation

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


Summary learning points

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

Thank you


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