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3154 Haematology > IC5 Warfarin > Flashcards

IC5 Warfarin Flashcards

1
Q

Warfarin exists as a racemate

Which enantiomer is the active one?

A

S-enantiomer

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2
Q

What are the metabolic pathways involved in Warfarin?

A

CYP2C9 (S-Warfarin => 7-OH Warfarin)
VKORC1

Others (less significant)

  • CYP4F2
  • CYP2C18
  • NQO1

VS R-Warfarin

  • Metabolised by CYP3A4, CYP2C19, CYP1A2
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3
Q

What are some factors contributing to interindividual differences in Warfarin response?

A
  1. Genetic factors (polymorphisms) [41%]
  2. Clinical and environmental factors (age, height, weight, race, gender, interaction medicine, diet, smoking, alcohol) [10%]
  3. Others: pharmacomicrobiome, pharmacoepigenetic [49%]
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4
Q

Which clotting factor plunges the fastest when Warfarin is dosed?

Which plunges the slowest?

A

Factor VII - half-life of 4-6h

Factor II - half-life of 42-72h

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5
Q

Why might the initial rise in INR be rapid when high doses of Warfarin is used?

A

Because Factor VII plunges fast

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6
Q

When is anticoagulated state achieved?

A

When Factor II declines to a certain level (takes ~3-5 days)

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7
Q

Monitoring parameter if Warfarin is the _____

Does it measure all factors involved?

A

INR

Only measures factors II, VII, X (from common + extrinsic pathway)

Does not measure factor IX

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8
Q

Explain why Warfarin confers an initial hypercoagulable state (thereby requiring 5 days overlap with LMWH when used in VTE)

A

Warfarin reduces natural anticoagulants, Protein C and Protein S as well (Protein C depletes quickly - half-life 9h)

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9
Q

Is loading dose required for Warfarin?

A

No

  • Warfarin has slow onset of action (24-72h), does not improve with loading dose
  • Therapeutic INR achieved within 3-5 days without loading dose

Local setting:
- load when there’s an existing clot, or when pt wants to be discharged asap

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10
Q

Initial and maintenance dose of Warfarin in local context

A
  • Initiate: 5mg => 3/5mg => 3mg
  • Maintenance for chinese/malays: 2-3mg/day
  • Maintenance for indians: 4-5mg/day
  • Also note that elderly/frail/undernourished/hypoalbuminemia/hepatic or renal impairment/acute illness/high bleeding risk/DDIs with CYP inhibitor or inducer => may have increased sensitivity, and hence require lower doses

bc chinese/malays have mutation of VKORC1, more sensitive to Warfarin thus require lower maintenance dose

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11
Q

Warfarin dose adjustments

A

Renal:

  • eGFR <60/ESKD/HD/PD: decrease dose by 10-20% (because uremia suppresses the action of CYP enzymes. Hence downregulation of CYP enzyme causes warfarin accumulation, thus reduce dose)
  • ESKD/HD/PD: decrease dose by 20%
  • CRRT/PIRRT: avoid use
  • CI in severe renal impairment (stage 5 CKD)

Hepatic:

  • NIL
  • CI in severe hepatic impairment (child-pugh C)
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12
Q

What impacts Warfarin maintenance dose?

A
  • body surface area
  • age
  • target INR
  • race (chinese/malays vs indians)
  • current thrombosis
  • current amiodarone use
  • smokers
  • gender
  • coronary artery disease
  • heart failure
  • diabetes
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13
Q

Which of the following factors is a/w INR stability or INR instability:

  • Age >=70y
  • Absence of chronic disease
  • Congestive heart failure
  • Diabetes
  • Target range for INR >= 3
A

INR Stability

  • Age >=70y
  • Absence of chronic disease

INR instability

  • Congestive heart failure
  • Diabetes
  • Target range for INR >= 3
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14
Q

List some common CYP2C9 inhibitors

A
  • Amiodarone
  • Fluconazole (other Azoles have much less interaction)
  • Metronidazole
  • Sulfamethoxazole/Trimethorprim
  • Isoniazid
  • Efavirenz
  • Ceritinib
  • Isoniazid
  • Allopurinol
  • PPIs
  • Salicylates
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15
Q

List some common CYP2C9 inducers

A
  • Rifampicin
  • Ritonavir
  • Carbamazepine
  • Phenobarbital
  • St John’s Wort
  • Barbiturates
  • Corticosteroids (?)
  • Spironolactone (?)
  • Thiazide diuretics (?)
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16
Q

SSRIs + Warfarin

A

SSRIs may incr bleeding risk

17
Q

Amiodarone + Warfarin

A

Amiodarone: CYP3A4 and CYP1A2 inhibitor
Inhibition of CYP2C9 by desetylamiodarone, the active metabolite of amiodarone may play a role in interaction w warfarin as well

Half-life of 105 days (3+ months)
Due to long half-life, reversal of INR increase following discontinuation of amiodarone may take several weeks

=> Preemptively reduce dose of Warfarin by 30-50%

*When amiodarone is stopped, warfarin dose must be increased

18
Q

Pharmacomicrobiomic factors on Warfarin

A

High microbiome load => require larger dose of Warfarin

19
Q

How might antimicrobials affect Warfarin dosing?

A

Antibiotics can disrupt gut bacteria, cause less menadione (Vit K) from gut

Increases INR

20
Q

Which antimicrobials require preemptive dose adjustment?

(List 5)

A

Bactrim

  • preemptively reduce dose (due to protein binding, reduction in gut flora, CYP2C9 inhibition)

Ciprofloxacin

  • preemptively reduce dose (due to potential inhibition of R-warfarin, protein binding displacement, reduction in gut flora)

^^UTI drugs

Metronidazole

  • preemptively reduce dose (due to CYP2C9 inhibition)

Rifampicin

  • preemptively increase dose (CYP2C9, CYP3A4, CYP1A2 induction)

Fluconazole

  • preemptively reduce dose (due to CYP2C9 and CYP3A4 inhibition)

*Note to always increase monitoring of INR + S&S of bleeding to guide further dose adjustments

21
Q

Which antimicrobials DON’T require preemptive dose adjustment?

(List 3)

A

NO DOSE ADJUSTMENT:

  • Macrolides (possible CYP3A4 inhibition)
  • Amox-Clav
  • Doxycycline
22
Q

Patient on warfarin has H. pylori and requires triple therapy

What should be used? What dose adjustments to make?
What should be monitored?

A

Use Omeprazole + Clarithromycin + Amoxicillin

Either Amox or Metronidazole

DO NOT use Metronidazole - need to preemptively reduce dose due to CYP2C9 inhibition

Monitor INR within 2 weeks

  • TCU is longer because we don’t expect drastic change in INR from the current Abx used in her PUD treatment
  • consider DDI w Warfarin (disruption to gut microbiome, incr in INR)

Monitor PUD, bleeding

23
Q

Warfarin and Paracetamol

A

Paracetamol can enhance anticoagulant effect of Warfarin, causing increase risk of bleeding

Recommend to take max 2g instead of max 4g, and do not exceed long-term therapy (>2 weeks)

24
Q

Warfarin-herb interactions

A

Vit E (>400IU/day: antiplatelet effect)
Omega 3 (>2g/day: antiplatelet effect)
Ginkgo
Ginseng
Garlic
Cranberry juice
Reishi mushrooms

=> incr warfarin effects, incr risk of bleeding

25
Q

[Dietary and lifestyle interaction]

Warfarin and alcohol binge

A

Alcohol binge can cause inhibtion of CYP450
INR blip

26
Q

[Dietary and lifestyle interaction]

Warfarin and chronic alcoholism

A

Chronic alcoholism can cause induction of CYP450
Increase Warfarin metabolism
INR decrease

27
Q

[Dietary and lifestyle interaction]

Warfarin and sudden increase in physical activity

A

Sudden increase in physical activity
Increase Warfarin metabolism
INR decrease

28
Q

[Dietary and lifestyle interaction]

Smoking

A

Smoking induces CYP450
Increase warfarin metabolism
INR decrease

29
Q

[Drug-disease interaction]

Liver impairment

A

Liver impairment causes decrease synthesis of clotting factors
Liver impairment also causes decrease warfarin metabolism
INR increases

30
Q

[Drug-disease interaction]

Fluid retention

A

Oedematous gut causes malabsorption of warfarin from gut => INR decrease

Liver congestion causes decrease warfarin metabolism => INR increase

*Usually acute fluid retention in the liver cause INR blip, malabsorption is a more chronic process

31
Q

[Drug-disease interaction]

Febrile state

In the event antibiotics is started due to infection, comment on when to repeat INR

A

Fever increases turnover of clotting factors (dcr clotting factors) => INR increase

Repeat INR in 3-5 days after starting antibiotic therapy
Consider daily INR if pt is admitted and unstable/septic

32
Q

[Drug-disease interaction]

Hyperthyroidism

A

Hyperthyroidism increases turnover of clotting factors
Increase INR

Hypothyroidism decreases turnover of clotting factor
Decrease INR

33
Q

Warfarin counseling points:

A
  • Do not interchange b/w brands (due to narrow TI)
  • Action of warfarin
  • Indication
  • Compliance, risk of thromboembolic events (TEE)
  • Target range, importance of blood test
  • DDIs - supplements, food, meds, TCM
  • Diet
  • Alcohol (binge, chronic)
  • Illness (fever)
  • Precautions (sports, accidents)
  • Adverse events: bleeding, N/V/D
  • Stop in pregnancy, may use in breastfeeding
  • Storage
34
Q

What are some foods that are high in Vit K?

=> dcr warfarin efficacy

A
  • green leafy vegetables
  • avocado
  • mango
  • beef or pork liver
  • soybean oil
  • green tea
  • chrysanthemum tea
  • cranberry juice
  • grapefruit juice
35
Q

When is Warfarin still needed?

A
  • Left ventricular thrombus
  • Prosthetic/Mechanical heart valve
  • Mod-severe mitral stenosis
  • Antiphospholipid syndrome related VTE
36
Q

When might Warfarin PGx testing be considered?

A
  • Existing clot: left ventricular thrombosis
  • Outpatient commencement/initiation
  • Complex DDIs
  • Questionable adherence
37
Q

PGx might be beneficial for those requiring what doses of Warfarin?

A

Extreme doses

  • =<21mg / week (=<3mg/d)
  • > = 49mg/week (>= 7mg/d)
38
Q

Warfarin discontinuation prior to surgery

A

Discontinue for 5 days (depending on INR and type of procedure) prior to surgery

Reinstitute Warfarin within 24h post-surgery when there is adequate hemostasis at the patient’s usual maintenance dose

Bridging with parenteral LMWH may be needed for pt at high risk for thromboembolism

3154 Haematology (14 decks)

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