Warfarin MOA, Dosing, Bridging, Target and Toxicity.

1. Prepared by:
Dr. Basheer Abd El Rahman
Pharm.D Degree, BCPS
ICU Clinical Pharmacist
KSMC
Supervised by:
Dr. Sulafa Al Shanawani
MSc.Pharm,BCPS.
ICU Clinical Pharmacist
Head of ICU Pharmacy Services
KSMC

2.  Outlines
 Introduction.
 Indications.
 Mechanism of Action.
 Pharmacodynamics/Pharmacokinetics.
 Drug Interactions.
 Bridging.
 Dosing.
 Over dose treatment.
 References.

3.  Is a synthetic anticoagulant normally used in the
prevention of thrombosis and thromboembolism, and
the formation of blood clots in the blood vessels and
their migration elsewhere in the body respectively.
 It was initially introduced in 1948 as a pesticide against
rats and mice and still used for this purpose.

4.  Is used to treat blood clots and/or to prevent new clots
from forming in the body. And this will helps to
reduce the risk of a stroke or heart attack.
 Warfarin is commonly called a "blood thinner," but it is
more correct term is anticoagulant. It helps to keep
blood flowing smoothly by decreasing the amount of
certain substances (clotting proteins) in the blood.

5.  Prophylaxis and treatment of thromboembolic
disorders (eg, venous, pulmonary).
 Embolic complications arising from atrial fibrillation
or cardiac valve replacement.
 Adjunct to reduce risk of systemic embolism (eg,
recurrent MI, stroke) after myocardial infarction.
 Use - Unlabeled Prevention of recurrent transient
ischemic attacks.

6. Hepatic synthesis of coagulation factors II, VII, IX, and X,
as well as proteins C and S, requires the presence of
vitamin K. These clotting factors are biologically activated
by the addition of carboxyl groups to key glutamic acid
residues within the proteins’ structure. In the process,
“active” vitamin K is oxidatively converted to an
“inactive” form, which is then subsequently reactivated
by vitamin K epoxide reductase complex 1 (VKORC1).
Warfarin competitively inhibits the subunit 1 of the multi-
unit VKOR complex, thus depleting functional vitamin K
reserves and hence reduces synthesis of active clotting
factors.
When this occurs, the coagulation factors are no longer
carboxylated at certain glutamic acid residues, and are
incapable of binding to the endothelial surface of blood vessels,
and are thus biologically inactive.
1972 CS

7. Warfarin
Synthesis of
Non
Functional
Coagulation
Factors
Antagonism
of
Vitamin K
Vitamin K
VII
IX
X
II

8. Warfarin full antithrombotic effect
is not achieved UNTIL adequate
reductions in prothrombin (factor
II) occur and possibly factor
X. Early reductions in factors VII
and IX do NOT represent the full
therapeutic effect of
warfarin. Anticoagulant effects
occur in a minimum of 4-6
days for an initial antithrombotic
effect.
Protein C half life 4-6 hours.
Protein S half life 40-60 hours.

9.  Onset of action: Anticoagulation: Oral: 24-72
hours.
 Peak effect: Full therapeutic effect: 5-7 days;
INR may increase in 36-72 hours.
 Duration: 2-5 days.

10.  Absorption: Oral: Rapid, complete.
 Protein binding: 99%.
 Distribution: 0.14 L/kg, Vd: 8-10 L.
 Metabolism: Hepatic, primarily via CYP2C9.
 Half-life elimination: 20-60 hours; Mean: 40 hours.
 Excretion: Urine (92%).

11.  Decreased warfarin effect (Lower INR)
Carbamazepine Ribavirin Mesalamine
Phenobarbital Rifampin Nafcillin
Phenytoin Cholestyramine Vitamin K

12. Increased warfarin effect
Allopurinol Amiodarone Argatroban Azithromycin Fluconazole
Citalopram Diltiazem Aspirin Clarithromycin Isoniazid
Gemfibrozil Simvastatin Sulfamethoxazole Ciprofloxacin Levofloxacin
Influenza
vaccine
Cimetidine Tamoxifen Erythromycin Metronidazole

13. Category X Interactions:
 Apixaban.
 Rivaroxaban.
 Dabigatran Etexilate.
 Tamoxifen.
 Streptokinase.

14.  Category D Interactions:
 Allopurinol.
 Amiodarone .
 Antithyroid Agents.
 Barbiturates.
 Carbamazepine.
 Clopidogrel.
 Fluconazole.
 Metronidazole.
 Phenytoin.

15. Drug Potential effect Recommendation
Warfarin plus ciproprofloxacin ,
clarithromycin , erythromycin,
metronidazole, fluconazole,
metronidazole or trimethoprim-
sulfamethoxazole
Increased effect of warfarin. Select alternative -antibiotic.
OR decrease 30%
Warfarin plus
Acetaminophen
Increased bleeding, increased INR. Use lowest possible acetaminophen
dosage and monitor INR.
Warfarin plus acetylsalicylic acid
(aspirin)
Increased bleeding, increased INR. Limit aspirin dosage to 100 mg per
dayand monitor INR.
Warfarin plus NSAID Increased bleeding, increased INR. Avoid concomitant use if possible; if
coadministration is necessary, use a
cyclooxygenase-2 inhibitor and monitor
INR.
Warfarin plus Amiodarone Increased bleeding Consider empiric reduction of 30% to
50% in warfarin dose.
Warfarin plus Rifampin Decrease Warfarin Increase dose 50-0%
Warfarin plus Carbamazipine Decrease Warfarin Increase dose 30%

16.  What Is Bridging Anticoagulation?
Bridging anticoagulation refers to giving a short-
acting blood thinner, usually low-molecular-weight
heparin given by subcutaneous injection for 10 to 12
days around the time of the surgery/procedure,
when warfarin is interrupted and its anticoagulant
effect is outside a therapeutic range. Bridging
anticoagulation aims to reduce patients risk for
developing blood clots, such as stroke, but may also
increase patients’ risk for developing potentially
serious bleeding complications after surgery.

17.  Patients on long-term warfarin therapy who
undergo minor invasive procedures and are
taken off their oral anticoagulation for up to 5
days have a less than 1% risk of experiencing a
thromboembolic event.

18.  In patients with a mechanical heart valve or
atrial fibrillation or venous thromboembolism
(VTE):At high risk for thromboembolism,
bridging anticoagulation is recommended with
therapeutic-dose subcutaneous (SC) low-
molecular-weight heparin (LMWH) or
intravenous unfractionated heparin (UFH)
rather than no bridging during temporary
interruption of vitamin K antagonist (VKA)
therapy.

19.  At moderate risk for thromboembolism, it's
proposed to use bridging anticoagulation with
therapeutic-dose SC LMWH, therapeutic-dose
IV UFH, or low-dose SC LMWH over no
bridging during temporary interruption of
VKA therapy.

20.  At low risk for thromboembolism, low-dose
SC LMWH (Prophylaxis) or no bridging over
bridging with therapeutic-dose SC LMWH or
IV UFH is recommended.
 In patients with a bare metal coronary stent
who require surgery within 6 weeks of stent
placement, the ACCP recommends to
continue aspirin and clopidogrel in the
perioperative period.

22. BRIDGE STUDY

23.  Initiation of Warfarin:
 When warfarin is newly started, it may promote clot
formation temporarily. This is because the level
of protein C and protein S are also dependent on
vitamin K activity. Warfarin causes decline in protein C
levels in first 36 hours. In addition, reduced levels of
protein S lead to a reduction in activity of protein C ,
therefore reduced degradation of factor Va and factor
VIIIa.

24.  Initiation of Warfarin:
 Although loading doses of warfarin over 5 mg also
produce a rapid decline in factor VII, resulting in an
initial prolongation of the INR, full antithrombotic effect
does not take place until significant reduction in factor II
occurs days later. The haemostasis system becomes
temporarily biased towards thrombus formation, leading
to a prothrombotic state. Thus, when warfarin is loaded
rapidly at greater than 5 mg per day, it is beneficial to co-
administer heparin, an anticoagulant that acts
upon antithrombin and helps reduce the risk of thrombosis,
with warfarin therapy for four to five days, in order to have
the benefit of anticoagulation from heparin until the full
effect of warfarin has been achieved.

25. Initiation of Warfarin:
1) Consider Contraindications

26.  2) Establish baseline INR
 3) Initial Dose: Initial dose of warfarin is typically
5 mg/day in most patients. A starting dose of less
than 5 mg may be considered for patients greater
than 70 years of age, elevated baseline INR greater
than 1.1, hypoalbuminemic patients (e.g.,
malnourished, liver disorders, post-operative),
impaired nutrition (weight < 45 kg), heart failure,
known to take medications that increase sensitivity
of warfarin, or previously documented increased
sensitivity to warfarin.

27. 4) INR Target and Frequency of Monitoring
Two therapeutic ranges are recommended, depending
on the indication for anticoagulation.

28. 5) Dosage Adjustment & Maintenance Therapy
Dosage adjustment is not required for minor
fluctuations of INR as long as the results remain
within the patient’s target range.
The recent trend is to change the total weekly
warfarin dose (TWD). For example, if the patient is
taking 5mg/ day, the weekly dose is 35mg. If the
dose must be decreased by 10%, then the weekly
dose should be (35 mg - 3.5 mg=31.5 mg) and the
daily dose becomes 31.5 mg/7=4.5 mg.

29. 3 3 3333 3
Mon Tue Wed Thu Fri Sat Sun
Total
Weekly
Dose
21 mg
2 3 3323 3 19 mg
2 2 3333 2 18 mg
 10%

15%

30. 3 3 3333 3
Mon Tue Wed Thu Fri Sat Sun
Total
Weekly
Dose
21 mg
4 3 3343 3 23 mg
4 4 3333 4 24 mg
 10%
 15%

34.  Although excessively elevated INR values are
clearly associated with an increased risk of
bleeding, in particular for INR values of > 5.0,
data from a large registry of warfarin-treated
patients suggest that the short-term risk for
major bleeding is low for someone with a
single INR value between 5.0 and 9.0 (0.96% at
1 month).

35.  Reversal Strategies:
1. Interruption of Warfarin treatment.
2. Administration of vitamin K.
3. Fresh frozen plasma
4. Prothrombin complex concentrates
5. Recombinant activated factor VII.

36.  Interruption of Warfarin may be sufficient in
patients who need an elective invasive
procedure or in asymptomatic patients with
an elevated INR value and a low risk for
bleeding. In this latter case, it must be noted
that it takes approximately 2.5 days for an INR
between 6.0 and 10.0 to decline to , 4.0.

37.  How to use Vitamin K as antidote for warfarin?
 Vitamin K is usually needed for a patient with
an INR over 9 or has serious bleeding. It's
usually NOT needed for INRs under 5.
However it is controversial when INR
is between 5 and 9 and when there is no
bleeding. because vitamin K can bring the INR
down faster than just holding warfarin, but it
doesn't seem to decrease bleeding risk.

38.  For most of these patients, the suggestion
is holding warfarin for a dose or two and then
adjusting it to get the INR in the appropriate
range. But for patients with an INR between 5
and 9 on top of a high risk of bleeding, the
suggestion is giving 1 to 2.5 mg vitamin K.
About 1 mg is often enough to lower the INR
into the therapeutic range in these patients.

42. 1. UWHC Guidelines for Inpatient Warfarin Management in Adults.
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College of Chest Physicians. Antithrombotic therapy for venous thromboembolic
disease: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines (8th Edition). Chest. 2008; 133: 454-545.
3. The BRIDGE Study Investigators a Surgery or Procedure? Bridging Anticoagulation: Is
it Needed When Warfarin Is Interrupted Around the Time of Print ISSN: 0009-7322.
Online ISSN: 1524-4539 Copyright © 2012 American Heart Association, Inc. All rights
reserved.
4. American Heart Association/American College of Cardiology Foundation Guide to
Warfarin Therapy.
5. Anticoagulants and the perioperative period Craig Oranmore-Brown MBBCh FRCA
Richard Griffiths MD FRCA.
6. Evidence-Based Clinical Practice Guidelines ed: American College of Chest
Physicians Therapy and Prevention of Thrombosis, 9th Oral Anticoagulant Therapy :
Antithrombotic.
7. Bridging Anticoagulation: Is it Needed When Warfarin Is Interrupted Around the
Time of a Surgery or Procedure?
8. GUIDELINES & PROTOCOLS ADVISORY COMMITTEE Warfarin Therapy
Management Effective Date: October 1, 2010.
9. American College of Chest Physicians, 9th ed: Diagnosis of DVT : Antithrombotic
Therapy.