Transcript Case 5 - Tripod.com

Clinical Toxicology Case
Presentation
Dr.K.Go UCH 16/2/2005
A Bleeding Case
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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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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
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What is your management ?
The consideration
Indications for anticoagulants
 Presence of severe/life threatening bleeding
 INR
 +/- causes of over-anticoagulation.
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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
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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.
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Absorption: completely absorbed orally
Distribution:
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Metabolism:
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P450 to inactive hydroxylated metabolites
Reductase to warfarin alcohols (minimal anticoagulant activity).
Excretion :
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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:
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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)
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Other causes
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Hypoalbuminaemia
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Concomitant disease
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Increase free fraction of drug.
Malignancy ,CHF, etc.
Hepatic dysfunction
Aging
Synergistic drug combination
NSAID + Warfarin
 13x increase in hemorrhagic ulcer disease.
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Shorr R I. Arch Intern.Med, 1993 ;153 (14)
Over-warfarinisation
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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)
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In a surveillance of outpatient adverse drug events
treated in hospital ED
Warfarin and insulin
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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
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FFP
 10ml/kg IVI
Vit K
 10mg SC/slow IV
Switch to heparin if necessary
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For non-life threatening hemorrhage
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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
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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