Here are some key drug and food interactions to consider with warfarin: - Thyroid medications, metronidazole, fluconazole/azoles can increase INR. Monitor more closely. - Certain antibiotics like 2nd/3rd gen cephalosporins, broad spectrum antibiotics can interact. Monitor INR. - Alcohol in excess and amiodarone can potentiate warfarin's effects. Limit intake. - Azithromycin, some statins, and omeprazole have been associated with interactions. Monitor INR. - Phenytoin can decrease warfarin's effects. May require warfarin dose adjustment. - Grapefruit juice

1. Pharmacology of
ANTICOAGULANT

2. An anticoagulant is a substance that prevents coagulation;
that is, which stops blood from clotting
Anticoagulants reduce blood clotting.
This prevents
Deep vein thrombosis,
Pulmonary embolism,
Myocardial infarction
Stroke.

3. Prothrombin time (PT) evaluates the ability of blood
to clot properly, it can be used to help diagnose
bleeding.
When used in this instance, it is often used in
conjunction with the PTT to evaluate the function of
all coagulation factors. the test may be used to screen
patients for any previously undetected bleeding
problems prior to surgical procedures.

4. • Historically, a most reliable and “relied upon”
clinical test
However:
– Proliferation of thromboplastin reagents with widely
varying sensitivities to reduced levels of vitamin K-
dependent clotting factors has occurred
– Concept of correct “intensity” of anticoagulant therapy
has changed significantly (low intensity)
– Problem addressed by use of INR (International
Normalized Ratio)

5. • A mathematical “correction” (of the PT ratio) for
differences in the sensitivity of thromboplastin
reagents
• Relies upon “reference” thromboplastins with known
sensitivity to antithrombotic effects of oral
anticoagulants
• INR is the PT ratio one would have obtained if the
“reference” thromboplastin had been used
• Allows for comparison of results between labs and
standardizes reporting of the prothrombin time

6. Patient’s PT in Seconds
Mean Normal PT in Seconds
INR =( )ISI
INR = International Normalized Ratio
ISI = International Sensitivity Index

7. The International Normalized Ratio (INR) is used
to monitor the effectiveness of blood thinning drugs
such as warfarin (Coumadin).
These anti-coagulant drugs help inhibit the formation
of blood clots. They are prescribed on a long-term
basis to patients who have experienced recurrent
inappropriate blood clotting.

8. The test result for PT depends on the method used, with
results measured in seconds and compared to the average
value in healthy people.
Most laboratories report PT results that have been adjusted to
the International Normalized Ratio (INR) for patients on anti-
coagulant drugs.
These patients should have an INR of 2.0 to 3.0 for basic
"blood-thinning" needs. For some patients who have a high risk
of clot formation, the INR needs to be higher - about 2.5 to 3.5.

9. Prothrombin Time Blood Test-PT:
This test is done to evaluate the blood for its ability to
clot.
It is often done before surgery to evaluate how likely
the patient is to have a bleeding or clotting problem
during or after surgery.
Normal PT Values:
10-12 seconds

10. Partial Thromboplastin Time Blood Test-PTT
This test is performed primarily to determine if heparin
(blood thinning) therapy is effective. It can also be used
to detect the presence of a clotting disorder. It does not
show the effects of drugs called “low molecular weight
heparin”
Normal PTT Values: 30 to 45 seconds
Extended PTT times can be a result of anticoagulation
therapy, liver problems, lupus and other diseases that
result in poor clotting.

11. International Normalized Ratio Blood Test-INR
Normal INR Values: 1 to 2
The INR is used to make sure the results from a PT test
is the same at one lab as it is at another lab.

12. Common drugs influencing INR values :
INR  / PT decreases
amoxicillin
quinolones
cephalosporins
macrolid antibiotics
paracetamol
salicylate
amiodarone
allopurinol
omeprasole
heparin
NSAID & COX2 inb.
tricyclic antidepressants
INR  /PT increases
rifampin
antihistamine
barbiturates
carbamazepin
digoxin
diuretics
pills
caffeine
pentoxiphylline
Vitamin K

13. • Heparin, Low Molecular Weight Heparin
• Heparinoids– Heparan Sulfates
• Danaparoid
• Lepirudin
• Ancrod

15. • Central to the coagulation cascade is the
generation of thrombin (factor IIa)
• thrombin is generated from prothrombin by the
action of activated factor X (Xa)
• thrombin then acts on fibrinogen to generate fibrin
clot

17. Vitamin K
Synthesis of
Functional
Coagulation Factors
VII
IX
X
II

18. XIIa
XIa
IXa
Intrinsic Pathway
(surface contact)
Xa
Extrinsic Pathway
(tissue factor)
VIIa
Thrombin (IIa)
Thrombin-Fibrin
Clot
aPTT
PT
Heparin / LMWH
(AT-III dependent)
Hirudin/Hirulog
(direct antithrombin)
Courtesy of VTI

19. THROMBOSIS
Collagen   XIa
Tissue Factor   IXa
Platelet Clumping
Thrombus Formation
Thrombus Growth
HEMOSTASIS
Tissue Factor &
Collagen
PlateletAggregation
Platelet-rich
Hemostatic Plug
Xa
HEP
Fluid
Thrombin
HEP & HIR

20. • Only approximately one third of an administered
dose of heparin binds to AT, and this fraction is
responsible for most of its anticoagulant effect.
• The remaining two thirds has minimal anticoagulant
activity at therapeutic concentrations, but at
concentrations greater than those usually obtained
clinically, both high- and low affinity heparin
catalyze the AT effect of a second plasma protein,
heparin cofactorII

21. The heparin-AT complex inactivates a number of
coagulation enzymes, including thrombin factor (IIa) and
factors Xa, IXa, XIa, and XIIa.
Of these, thrombin and factor Xa are the most responsive
to inhibition, and human thrombin is 10-fold more
sensitive to inhibition by the heparin-AT complex than
factor Xa

22. • For inhibition of thrombin, heparin must bind to both
the coagulation enzyme and AT, but binding to the
enzyme is less important for inhibition of activated
factor X (factor Xa )
• Molecules of heparin with fewer than 18 saccharides
• By inactivating thrombin, heparin not only prevents
fibrin formation but also inhibits thrombin-induced
activation of factor V and factor VIII

23. • UH (mw 3k - 30k) is a heterogeneous mixture of
polysacchride chains (glycosaminoglycans)
• LMWH (mw 5k) is obtained by alkaline
degradation of heparin benzyl ester
• LMWH molecules are enriched with short chains
with higher anti-Xa:IIa ratio

24. • Both UH and LMWH exert their anticoagulation
activity by catalyzing antithrombin (AT or AT III)
• catalyzed AT is accelerated in its inactivation of
the coagulation enzymes thrombin (factor IIa) and
factor Xa.
• prolongs aPTT

25. AT
HC II
HF
Thrombin
S C
HF
Thrombin
S C
Heparin has a higher
affinity for AT than for
HC II and there is more
AT in plasma than HC II

26. AT
Free Thrombin
AT alone does not inactivate
free-thrombin
HF
Thrombin
S C

27. Heparin binds to antithrombin and increases the
rate of thrombin inactivation
AT
Heparin
HF
Thrombin
S C

28. AT
Fibrin-Bound Thrombin
The rate at which AT inactivates
fibrin-bound thrombin is reduced 50-fold
HF
Thrombin
S C

29. When thrombin binds to fibrin, it becomes
resistant to inactivation by heparin.
HeparinFibrin
HF
Thrombin
S C

30. • Any size of heparin chain can inhibit the action of factor Xa
by binding to antithrombin (AT)
• In contrast, in order to inactivate thrombin (IIa), the
heparin molecule must be long enough to bind both
antithrombin and thrombin
• < half the chains of LMWH are long enough

31. AT
Unfractionated Heparin
F H
Thrombin (IIa)
S C
AT
LMWH
F H
Thrombin (IIa)
S C
By binding to AT, most UH and LMWH can inhibit Xa activity.
Fewer than half the chains of LMWH are of sufficient length to
also bind factor IIa, therefore has decreased anti-IIa activity.

32. Agent Trade Xa:IIa Mol Wt (d)
Enosaparin Lovenox 3.8 : 1 4,200
Dalteparin Fragmin 2.7 : 1 6,000
Ardeparin Normiflo 1.9 : 1 6,000
Nadroparin 3.6 : 1 4,500
Reviparin 3.5 : 1 4,000
Tinzaparin 1.9 : 1 4,500

33. Side Effects :
Hemorrhage:
Hemorrhage is the chief complication that may result
from heparin therapy . An overly prolonged clotting time
or minor bleeding during therapy can usually be
controlled by withdrawing the drug .
Bleeding can occur at any site but certain specific
hemorrhagic complications may be difficult to detect:

34. Adrenal hemorrhage, with resultant acute adrenal insufficiency, has
occurredduring anticoagulant therapy. Therefore, such treatment should be
discontinued in patients who develop signs and symptoms of acute adrenal
hemorrhage and insufficiency.
Ovarian (corpus luteum) hemorrhage developed in a number of women of
reproductive age receiving short- or long-term anticoagulant therapy. This
complication, if unrecognized, may be fatal.
Retroperitoneal hemorrhage.
Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and
Heparin-induced Thrombocytopenia and Thrombosis (HITT) and Delayed
Onset of HIT and HITT

35. Hypersensitivity
Generalized hypersensitivity reactions have been reported,
with chills, fever and urticaria as the most usual manifestations,
and asthma, rhinitis lacrimation ,headache , nausea and
vomiting, and anaphylactoid reactions, including shock,
occurring more rarely.
Itching and burning, especially on the plantar side of the feet,
may occur painful, ischemic and cyanosed limbs
have in the past been attributed to allergic vasospastic
reactions.

36. Local Irritation
Local irritation, erythema, mild pain, hematoma or ulceration may follow
deep subcutaneous injection of heparin sodium. These complications are
much more common after intramuscular use, and such use is not
recommended.
Miscellaneous
Osteoporosis following long-term administration of high doses of heparin,
cutaneous necrosis after systemic administration, suppression of
aldosterone synthesis, delayed transient alopecia, priapism, and rebound
hyperlipemia on discontinuation of heparin sodium have also been
reported.
Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-
ALT]) levels have occurred in a high percentage of patients (and healthy
subjects) who have received heparin.

37. Platelet Inhibitors
Drugs such as acetylsalicylic aci d, dextran,
phenylbutazone, ibuprofen, indomethacin,
dipyridamole, hydroxychloroquine and others that
interfere with platelet- aggregation reactions (the main
hemostatic defense of heparinized patients) may
induce bleeding and should be used with caution in
patients receiving heparin sodium.

38. • No need for laboratory monitoring
– when given on a weight-adjusted basis, the LMWH
anticoagulant response is predictable and reproducible
• Higher bioavailability - 90% vs 30%
• Longer plasma half-life
– 4 to 6 hours vs 0.5 to 1 hour
– renal (slower) vs hepatic clearance

39. • Less inhibition of platelet function
– potentially less bleeding risk, but not shown in clinical use
• Lower incidence of thrombocytopenia and
thrombosis (HIT syndrome)
– less interaction with platelet factor 4
– fewer heparin-dependent IgG antibodies

41. 1. Coumarin Derivatives:
• Bishydroxycoumarin
• Warfarin sod.
• Acenocoumarol
• Ethylbiscoumacetate
2. Indandione derivative :
• Phenindione

42. • Mechanism ofAction
• Dosing/Target INRs
• Drug/Food Interactions
• Managing Elevated INRs
• Patient Counseling
• Other Considerations

47. • Inhibits Vitamin K-dependent coagulation factors
II, VII, IX, & X as well as anticoagulant proteins
C & S
• Does not have an effect on already-synthesized
coagulation factors; therefore, the therapeutic effects
are not seen until these factors are depleted
• 3-4 days until effect is seen

48. Elimination Half-Lives of Vitamin K-dependent
clotting factors:
• II  42-72 hours
• VII  4-6 hours
• IX 21-30 hours
• X  27-48 hours

50. • Response to warfarin is highly dependent upon the
individual.
• When initiating warfarin in a patient, close PT/INR
monitoring is key.
-PT vs. PTT vs. INR
• Target INRs will vary based on indication, but an INR >
4 typically confers no additional therapeutic benefit to
justify the increased risk of bleeding.

51. • In patients without known enhanced response to
warfarin:
-Various dosing strategies have been outlined, typically
starting with 2-10 mg/day, titrated to the appropriate
INR.
-5 mg PO initially is thought to carry minimal risk of
bleeding and will bring INR to >/= 2 within 4-5 days

52. Level of
Evidence Potentiation
Alcohol (if concomitant liver disease) amiodarone (anabolic steroids, cimetidine,†
clofibrate, cotrimoxazole, erythromycin, fluconazole, isoniazid [600 mg daily]
metronidazole), miconazole, omeprazole, phenylbutazone, piroxicam,
propafenone, propranolol,† sulfinpyrazone (biphasic with later inhibition)
Acetaminophen , chloral hydrate , ciprofloxacin, dextropropoxyphene, disulfiram,
itraconazole, quinidine, phenytoin (biphasic with later inhibition), tamoxifen,
tetracycline, flu vaccine
Acetylsalicylic acid, disopyramide, fluorouracil, ifosflhamide, ketoprofen,
iovastatin, metozalone, moricizine, nalidixic acid, norfloxacin, ofloxacin,
propoxyphene, sulindac, tolmetin, topical salicylates
Cefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole
I
II
III
IV

53. Level of
Evidence Inhibition
Barbiturates, carbamazepine, chlordiazepoxide, cholestyramine, griseofulvin,
nafcillin, rifampin, sucralfate
Dicloxacillin
I
II
III
Azathioprine, cyclosporine, etretinate, trazodone
IV

54. Level of
Evidence No Effect
Alcohol, antacids, atenolol, bumetadine, enoxacin, famotidine, fluoxetine,
ketorolac metoprolol, naproxen, nizatidine, psyllium, ranitidine‡
Ibuprofen, ketoconazole
Diltiazem, tobacco, vancomycin
I
II
III
IV

55. • Thyroid products
• Metronidazole
• Fluconazole/azole
antifungals
• 2nd, 3rd generation cephs
• Broad spectrum antibiotics
• Alcohol*
• Amiodarone*
• Azithromycin
• Statins
• Omeprazole
• Phenytoin
• Bactrim
• Heparin
• Gemfibrozil
• Fluoroquinolones*
• Cimetidine

56. • Estrogens
• Vitamin K (vitamins, etc)
• Alcohol*
• Carbamazepine
• Barbiturates
• Phenytoin
• Rifabutin
• Rifampin
• Ritonavir

57. • Aspirin
• Clopidogrel
• COX 2 inhibitors
• Glycoprotein IIb/IIIa antagonists
• NSAIDs*
• Ticlopidine

58.  Deep Vein Thrombosis
 Pulmonary Embolism
 Myocardial Infarction
 Unstable Angina
 Rheumatic Heart Diseases; Atrial Fibrillation
 Cerebrovascular Diseases
 Defibrination Syndrome
Vascular Surgery, Prosthetic Heart Valves, Retinal Vessel
Thrombosis,
 Extracorporeal Circulation, Haemodialysis

59. END