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By: Hadeel Al-Kofide MS.c
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Warfarin interactions:
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Drug-drug interactions
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Herb-drug interaction
Bridge therapy:
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Bridge therapy during invasive procedures
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Bridge therapy during dental procedures
Patient education
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CJ is a 48 y.o. male, s/p cadaveric renal transplant,
developed embolic CVA
On chronic anticoagulation for 4 years
Presented to the primary care clinic with painful,
discolored, cracking of great toe
Treated with itraconazole 100 mg po qd
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Presents to AC clinic
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INR 18.5 (repeated and verified)
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Hgb/Hct: 7.5/22
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Guiac: +
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When he was asked why he took it:
Neither my doctor nor the pharmacist that filled the
prescription thought it would be a problem
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Three day admission
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4 units PRBC’s transfused
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Cost to the health care system of $5000-7000
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Cost in lost productivity, work time, etc.??????
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Could this have been avoided?
1. Warfarin + NSAIDs
2. Warfarin + Sulfa drugs
3. Warfarin + Macrolides
4. Warfarin + Quinolones
5. Warfarin + Phenytoin
6. ACE inhibitors + Potassium supplements
7. ACE inhibitors + Spironolactone
8. Digoxin + Amiodarone
9. Digoxin + Verapamil
10. Theophylline + Quinolones
Pharmacokinetic interactions
Alteration in:
Absorption
Pharmacodynamic interactions
Affect tendency for bleeding or
clotting through:
Antiplatelet effects
Protein binding
Hepatic metabolism
Increases
or decreases in vitamin
K catabolism
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Interference with platelet function:
Platelet aggregation is a crucial first step in primary
hemostasis
Drugs that impair platelet function increase the risk of
hemorrhage in patients on warfarin
They do so without elevating the INR
ASA &
clopidogrel
INR = International Normalized Ratio
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Injury to gastrointestinal mucosa:
NSAIDs
NSAIDs cause dose- & duration-dependent
gastrointestinal erosions
The risk of hemorrhage is high by the concomitant use
of warfarin, even in patients whose INR lies within the
desired range
NSAIDs = Non-Steroidal Anti-Inflammatory Drugs
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Reduced synthesis of vitamin K by intestinal flora
Vitamin K is partly dependent on the synthesis of
vitamin K2 by intestinal microflora
Many antibiotics alter the balance of gut flora, thereby
enhancing the effect of warfarin
Some antibiotics also inhibit the hepatic metabolism of
warfarin. These antibiotics include co-trimoxazole,
metronidazole, macrolides & fluoroquinolones
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Interference with warfarin metabolism:
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Warfarin is metabolized through cytochrome P450
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Drugs that inhibit this enzyme (e.g., amiodarone, cotrimoxazole, metronidazole and fluvoxamine)
potentiate the effect of warfarin
Other drugs that induce CYP 2C9 activity (e.g.,
rifampin) will do the converse
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Interruption of the vitamin K cycle:
The most important drug in this category is
acetaminophen
One of acetaminophen metabolites inhibits vitamin Kdependent carboxylase, a key enzyme in the vitamin K
cycle
Some patients may have rapid & dramatic rise in the
INR
Drug
Estrogen
Vitamin K
Risk on hemorrhage
(INR)
Mechanism
↓
Increase synthesis of
clotting factors
Separate dose 2-6 hrs
Cholestyramine
Thyroid Hormones
↓
Reduce absorption of
warfarin
↑
Increase catabolism of
clotting factors
Drug
Nafcillin
Barbiturates
Rifampin
Phenytoin
Macrolides
Co-trimoxazole,
Metronidazole,
Fluoroquinolones
Risk on hemorrhage
(INR)
Mechanism
↓
Induction of warfarin
metabolism
↑
Inhibition of vitamin
K synthesis by
intestinal flora,
inhibition of hepatic
warfarin metabolism,
or both
Drug
Fluconazole,
miconazole
Amiodarone
Acetylsalicylic acid,
Clopidogrel,
Ticlopidine
NSAID
UFH
LMH
Risk on hemorrhage
(INR)
Mechanism
↑
Inhibition of warfarin
metabolism
↑
Interference with
primary hemostasis
↑
Additive
anticoagulant
response
Drug
Chinese wolfberry,
Cranberry
juice, grapefruit juice
Garlic
Ginger
Ginkgo
St. John’s wort
Risk on hemorrhage
(INR)
Mechanism
↑
Inhibition of warfarin
metabolism
↑
Inhibition of platelet
aggregation
↓
Induction of warfarin
metabolism
Drug
Risk on hemorrhage
(INR)
Mechanism
Green tea
↓
Contain vitamin K
Ginseng
↓
Unknown
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Patients taking warfarin are susceptible to numerous
drug interactions
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Can we avoid them??
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Close monitoring of INR
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Adjust warfarin dose according to INR
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Temporary use of intravenous UFH or LMWH for a
patient on long-term anticoagulation who is about to
undergo a surgical procedure is called bridge therapy
Risk of
thromboembolism
Risk of bleeding
1.
Management of anticoagulation around invasive
procedures
2.
Management of anticoagulation around dental
procedures
High Risk of Bleeding
• Cardiac surgery
• Neurosurgery,
• Most cancer surgery
• Bilateral knee
replacement
• Kidney biopsy
GI = Gastro-Intestinal
Low Risk of Bleeding
• Coronary angiography
• GI endoscopy
• Colonoscopy
• Bronchoscopy
• Biopsy (thyroid, breast,
lymph node, pancreas)
Thrombosis
Risk
CrCl
Bridge Therapy
Pre-Procedure
High
Day 5
Day 3
Post-Procedure
Day 1
12-24 hr
12-48 hr
Resume
enoxaparin
Resume
warfarin
 AF
 Stroke
history
Mechanical
valve
 DVT/PE
< 3 mo
> 30
Enoxaparin
Last dose 1 mg/kg q
Last dose
warfarin
12 hr
enoxaparin
Vitamin K
2.5 mg PO
AF = Atrial Fibrillation; DVT = Deep Vein Thrombosis
PE = Pulmonary Embolism
Thrombosis
Risk
CrCl
Bridge Therapy
Pre-Procedure
High
Day 3
Day 2
Day 1
12-24 hr
12-48 hr
Vitamin
K 2.5 mg
PO
Admit;
IV UFH
LD 70 U/kg
MD 15 U/kg
If INR >1.5
give vitamin
K 1 mg IV
Stop UFH 6
hrs preprocedure
Resume
UFH
Resume
warfarin
 AF
 Stroke
history
Mechanical
valve
≤ 30
Last dose
warfarin
 DVT/PE
< 3 mo
UFH = Un-Fractionated Heparin
IV = IntraVenous
Post-Procedure
Thrombosis
Risk
CrCl
Pre-Procedure
Low
 Cardiomegally with
no history of
thrombosis
 DVT/PE
> 3 mo
Bridge Therapy
All
Post-Procedure
Day 4
Day 2
Day 1
12-24 hr
12-48 hr
Last dose
warfarin
Vitamin K
2.5 mg PO
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Resume
warfarin
Bleeding Risk
Low
Procedure
1.
2.
3.
Surgical scalling
Simple restoration
Local anesthetic
injection
Recommendations
1.
2.
Do not interrupt
warfarin treatment
Use local measures to
prevent or control
bleeding
Bleeding Risk
Procedure
1.
2.
Moderate
3.
4.
5.
Subgingival scalling
Restoration with
subgingival
preparations
Standard root canal
therapy
Simple extraction
Regional injection of
local anesthetics
Recommendations
1.
2.
Interruption of warfarin
treatment is not
necessary
Use local measures to
prevent or control
bleeding
Bleeding Risk
Procedure
1.
2.
High
3.
4.
Extensive surgery
Apicoectomy (root
removal)
Alveolar surgery
(bone removal)
Multiple extractions
Recommendations
1.
2.
Need to reduce INR or
even return to normal
hemostasis
Follow bridge therapy
guideline for invasive
procedures based on
risk of
thromboembolism
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Group Discussion