IC5 Warfarin Flashcards
Warfarin exists as a racemate
Which enantiomer is the active one?
S-enantiomer
What are the metabolic pathways involved in Warfarin?
CYP2C9 (S-Warfarin => 7-OH Warfarin)
VKORC1
Others (less significant)
- CYP4F2
- CYP2C18
- NQO1
VS R-Warfarin
- Metabolised by CYP3A4, CYP2C19, CYP1A2
What are some factors contributing to interindividual differences in Warfarin response?
- Genetic factors (polymorphisms) [41%]
- Clinical and environmental factors (age, height, weight, race, gender, interaction medicine, diet, smoking, alcohol) [10%]
- Others: pharmacomicrobiome, pharmacoepigenetic [49%]
Which clotting factor plunges the fastest when Warfarin is dosed?
Which plunges the slowest?
Factor VII - half-life of 4-6h
Factor II - half-life of 42-72h
Why might the initial rise in INR be rapid when high doses of Warfarin is used?
Because Factor VII plunges fast
When is anticoagulated state achieved?
When Factor II declines to a certain level (takes ~3-5 days)
Monitoring parameter if Warfarin is the _____
Does it measure all factors involved?
INR
Only measures factors II, VII, X (from common + extrinsic pathway)
Does not measure factor IX
Explain why Warfarin confers an initial hypercoagulable state (thereby requiring 5 days overlap with LMWH when used in VTE)
Warfarin reduces natural anticoagulants, Protein C and Protein S as well (Protein C depletes quickly - half-life 9h)
Is loading dose required for Warfarin?
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
Initial and maintenance dose of Warfarin in local context
- 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
Warfarin dose adjustments
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)
What impacts Warfarin maintenance dose?
- body surface area
- age
- target INR
- race (chinese/malays vs indians)
- current thrombosis
- current amiodarone use
- smokers
- gender
- coronary artery disease
- heart failure
- diabetes
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
INR Stability
- Age >=70y
- Absence of chronic disease
INR instability
- Congestive heart failure
- Diabetes
- Target range for INR >= 3
List some common CYP2C9 inhibitors
- Amiodarone
- Fluconazole (other Azoles have much less interaction)
- Metronidazole
- Sulfamethoxazole/Trimethorprim
- Isoniazid
- Efavirenz
- Ceritinib
- Isoniazid
- Allopurinol
- PPIs
- Salicylates
List some common CYP2C9 inducers
- Rifampicin
- Ritonavir
- Carbamazepine
- Phenobarbital
- St John’s Wort
- Barbiturates
- Corticosteroids (?)
- Spironolactone (?)
- Thiazide diuretics (?)
SSRIs + Warfarin
SSRIs may incr bleeding risk
Amiodarone + Warfarin
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
Pharmacomicrobiomic factors on Warfarin
High microbiome load => require larger dose of Warfarin
How might antimicrobials affect Warfarin dosing?
Antibiotics can disrupt gut bacteria, cause less menadione (Vit K) from gut
Increases INR
Which antimicrobials require preemptive dose adjustment?
(List 5)
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
Which antimicrobials DON’T require preemptive dose adjustment?
(List 3)
NO DOSE ADJUSTMENT:
- Macrolides (possible CYP3A4 inhibition)
- Amox-Clav
- Doxycycline
Patient on warfarin has H. pylori and requires triple therapy
What should be used? What dose adjustments to make?
What should be monitored?
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
Warfarin and Paracetamol
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)
Warfarin-herb interactions
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
[Dietary and lifestyle interaction]
Warfarin and alcohol binge
Alcohol binge can cause inhibtion of CYP450
INR blip
[Dietary and lifestyle interaction]
Warfarin and chronic alcoholism
Chronic alcoholism can cause induction of CYP450
Increase Warfarin metabolism
INR decrease
[Dietary and lifestyle interaction]
Warfarin and sudden increase in physical activity
Sudden increase in physical activity
Increase Warfarin metabolism
INR decrease
[Dietary and lifestyle interaction]
Smoking
Smoking induces CYP450
Increase warfarin metabolism
INR decrease
[Drug-disease interaction]
Liver impairment
Liver impairment causes decrease synthesis of clotting factors
Liver impairment also causes decrease warfarin metabolism
INR increases
[Drug-disease interaction]
Fluid retention
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
[Drug-disease interaction]
Febrile state
In the event antibiotics is started due to infection, comment on when to repeat INR
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
[Drug-disease interaction]
Hyperthyroidism
Hyperthyroidism increases turnover of clotting factors
Increase INR
Hypothyroidism decreases turnover of clotting factor
Decrease INR
Warfarin counseling points:
- 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
What are some foods that are high in Vit K?
=> dcr warfarin efficacy
- green leafy vegetables
- avocado
- mango
- beef or pork liver
- soybean oil
- green tea
- chrysanthemum tea
- cranberry juice
- grapefruit juice
When is Warfarin still needed?
- Left ventricular thrombus
- Prosthetic/Mechanical heart valve
- Mod-severe mitral stenosis
- Antiphospholipid syndrome related VTE
When might Warfarin PGx testing be considered?
- Existing clot: left ventricular thrombosis
- Outpatient commencement/initiation
- Complex DDIs
- Questionable adherence
PGx might be beneficial for those requiring what doses of Warfarin?
Extreme doses
- =<21mg / week (=<3mg/d)
- > = 49mg/week (>= 7mg/d)
Warfarin discontinuation prior to surgery
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
