Anticoagulant therapy

Haemostasis

1. AnticoagulantsAnticoagulants
Dr. Ibrahim Khider Ibrahim

2. AnticoagulantsAnticoagulants: prevent thrombus formation and : prevent thrombus formation and
extension by inhibiting extension by inhibiting clotting factors clotting factors e.g. heparin, low e.g. heparin, low
molecular weight heparin, coumarins/ warfarin.molecular weight heparin, coumarins/ warfarin.
Antiplatelet drugsAntiplatelet drugs: reduce risk of clot formation by : reduce risk of clot formation by
inhibiting inhibiting platelet functions platelet functions e.g. aspirin. e.g. aspirin.
Fibrinolytic agentsFibrinolytic agents: dissolve thrombi: dissolve thrombi already formedalready formed
e.g. streptokinase.e.g. streptokinase.
Drugs and coagulationDrugs and coagulation

3. ParenteralParenteral
AnticoagulantsAnticoagulants
OralOral
AnticoagulantsAnticoagulants
ANTICOAGULANTSANTICOAGULANTS
Thrombin inhibitorsThrombin inhibitors
Indirect
Direct
Vitamin K antagonistsVitamin K antagonists
Warfarin

4. Indication of anti-coagulantsIndication of anti-coagulants
Anticoagulants are indicated:Anticoagulants are indicated:
In myocardial infarction (MI) In myocardial infarction (MI)
Deep venous thrombosis (DVT)Deep venous thrombosis (DVT)
Pulmonary embolism (PE) and many other conditions Pulmonary embolism (PE) and many other conditions
Anticoagulants are also used in blood transfusions, and Anticoagulants are also used in blood transfusions, and
dialysis procedures dialysis procedures

5. Indirect Thrombin inhibitorsIndirect Thrombin inhibitors
Heparin and
heparin- related agents
Parenteral AnticoagulantsParenteral Anticoagulants

6. Heparin and related H- agentsHeparin and related H- agents
Heparin is an Heparin is an injectable injectable rapidlyrapidly acting acting
anticoagulantanticoagulant
Active in Active in vitro and in vivovitro and in vivo
Low–molecular–weight forms (LMWHs), 1/3 Low–molecular–weight forms (LMWHs), 1/3
the size of UFH are used as well and have the size of UFH are used as well and have
many advantages over UFHmany advantages over UFH

7. Heparin: Mechanism of actionHeparin: Mechanism of action
IndirectIndirect Thrombin Inhibitor Thrombin Inhibitor
It acts indirectly by increasing the activity of It acts indirectly by increasing the activity of
the endogenous anticoagulant “the endogenous anticoagulant “antithrombinantithrombin
IIIIII”” (1000 folds) which inhibits (1000 folds) which inhibits activatedactivated clotting clotting
factors factors mainly thrombin mainly thrombin (factor IIa) and Xa(factor IIa) and Xa
When Heparin binds to antithrombin III, it causes When Heparin binds to antithrombin III, it causes
conformational changes that accelerates its rate of conformational changes that accelerates its rate of
action 1000 foldaction 1000 fold

8. Heparin: Mechanism of actionHeparin: Mechanism of action
Heparin
Antithrombin IIIAntithrombin III
ThrombinThrombin
Heparin binds to both
antithrombin III and
thrombin to form a
ternary complex
Heparin
ThrombinThrombinAntithrombin IIIAntithrombin III

9. Heparin: Mechanism of actionHeparin: Mechanism of action

Heparin dissociates Heparin dissociates leaving the thrombin bound to its
inhibitor
Once dissociated, Heparin is free Once dissociated, Heparin is free to bind to another to bind to another
antithrombin molecule and subsequently inhibits more antithrombin molecule and subsequently inhibits more
thrombinthrombin
Heparin
ThrombinThrombin
Antithrombin IIIAntithrombin III
Antithrombin IIIAntithrombin III
ThrombinThrombin

10. UFH : PharmacokineticsUFH : Pharmacokinetics
Heparin is not absorbed from the GITHeparin is not absorbed from the GIT
It should be administered by IV or SC injection. It should be administered by IV or SC injection. NotNot
injected IM as it causes haematomas at injection site injected IM as it causes haematomas at injection site
Once in the blood stream, UFH binds to plasma proteins, Once in the blood stream, UFH binds to plasma proteins,
endothelial cells and macrophagesendothelial cells and macrophages
Heparin does not cross the placenta; Heparin does not cross the placenta; therefore therefore it is the it is the
drug of choice as anticoagulat during pregnancydrug of choice as anticoagulat during pregnancy
Close monitoring of the Close monitoring of the activated partial thromboplastin activated partial thromboplastin
timetime (aPTT)(aPTT) is necessary in patients receiving UFH.is necessary in patients receiving UFH.

11. Disadvantages of UFHDisadvantages of UFH
The need for regular monitoring (aPTT)The need for regular monitoring (aPTT)
UFH carries a risk of UFH carries a risk of heparin-induced heparin-induced
thrombocytopenia (HIT)thrombocytopenia (HIT), a fall in the platelet , a fall in the platelet
count and increased risk of thrombosis due count and increased risk of thrombosis due
to binding to plateletsto binding to platelets

12. UFH: Adverse effectsUFH: Adverse effects
The major adverse effect of heparin isThe major adverse effect of heparin is bleedingbleeding
Allergic reactions (chills, fever, urticaria) Allergic reactions (chills, fever, urticaria) as as
heparin is of animal origin and should be used heparin is of animal origin and should be used
cautiously in patients with allergy cautiously in patients with allergy
Long-term heparin therapy is associated with Long-term heparin therapy is associated with
osteoporosisosteoporosis
Heparin-induced thrombocytopenia (HIT )Heparin-induced thrombocytopenia (HIT )

13. Reversal of Heparin ActionReversal of Heparin Action
Discontinuation of the drug Discontinuation of the drug
Heparin is strongly acidic and is neutralized Heparin is strongly acidic and is neutralized
by i.v.by i.v. protamine sulfateprotamine sulfate (a strongly basic (a strongly basic
protein) protein)
It combines with heparin to form a stable It combines with heparin to form a stable
complex devoid of anticoagulant activitycomplex devoid of anticoagulant activity

14. LMWHs are derived from the chemical or enzymatic LMWHs are derived from the chemical or enzymatic
degradation of UFH into fragments approximately one-degradation of UFH into fragments approximately one-
third the size of heparin.third the size of heparin.
Have equal efficacy, Have equal efficacy, without frequent laboratory without frequent laboratory
monitoringmonitoring ( suitable for outpatient therapy) ( suitable for outpatient therapy)
Have a more predictable anticoagulant response Have a more predictable anticoagulant response
( better bioavailability, longer t 1/2)( better bioavailability, longer t 1/2)
Binding Binding to platelets and osteoblasts is reduced to platelets and osteoblasts is reduced with with
LMWH compared with UFH LMWH compared with UFH
Low-Molecular-Weight HeparinsLow-Molecular-Weight Heparins

15. Synthetic Heparin DerivativesSynthetic Heparin Derivatives
FondaparinuxFondaparinux is a synthetic compound that is a synthetic compound that
inhibits factor inhibits factor XaXa by antithrombin by antithrombin but does but does
not inhibit not inhibit thrombinthrombin
Advantages:Advantages:
Fondaparinux can be given once a day at a Fondaparinux can be given once a day at a
fixed dose without coagulation monitoring fixed dose without coagulation monitoring
Less likely than UFH or LMWHs to trigger HIT Less likely than UFH or LMWHs to trigger HIT

16. Drug Drug
characteristiccharacteristic
ss
HeparinHeparin
(UFH) (UFH)
LMWHLMWH
IV ½ lifeIV ½ life 2 hours 4 hours
Bioavailability Bioavailability
after SC after SC
injectioninjection
20% 90%
Anticoagulant
response
variable Predictable
Differences between UFH and LMW HeparinsDifferences between UFH and LMW Heparins

17. Major
adverse
effect
Frequent
bleeding
HIT,
osteoporosis
Less frequent
bleeding
Setting for
therapy
Hospital Hospital and
OPC
Laboratory
monitoring
Needed
aPTT
Not needed

18. Direct thrombin inhibitors (DTIs)Direct thrombin inhibitors (DTIs)
DTIs exert their anticoagulant effect by DTIs exert their anticoagulant effect by
directdirect binding to thrombin binding to thrombin
This direct effect is This direct effect is rapid and potentrapid and potent
DTIs are not associated with the
development of thrombocytopenia

19. Direct thrombin inhibitors (DTIs)Direct thrombin inhibitors (DTIs)
The first DTI to be developed was The first DTI to be developed was hirudin, hirudin,
LepirudinLepirudin is a polypeptide that binds is a polypeptide that binds
directlydirectly to the active site of thrombin to the active site of thrombin
Recombinant hirudin “Lepirudin” Recombinant hirudin “Lepirudin” isis used used
as IV anticoagulant in patients with HITas IV anticoagulant in patients with HIT

20. Oral Anticoagulants Oral Anticoagulants
““Vitamin K antagonists”Vitamin K antagonists”

21. WarfarinWarfarin

22. A brief history of warfarinA brief history of warfarin
The discovery of oral anticoagulants is one of the The discovery of oral anticoagulants is one of the
mostmost important important story in pharmaceutical history. story in pharmaceutical history.
It started with a hemorrhagic disease in cattle It started with a hemorrhagic disease in cattle in in
the 1920sthe 1920s. .
This was due to ingestion of spoiled sweet clover. This was due to ingestion of spoiled sweet clover.
The substance responsible for bleeding was The substance responsible for bleeding was
extracted and identified as a coumarin by extracted and identified as a coumarin by Karl Paul Karl Paul
LinkLink

23. In 1941 it used as a rat and mouse In 1941 it used as a rat and mouse
poison.poison.
Survival of a man suffering from Survival of a man suffering from
thromboembolic disease after an thromboembolic disease after an
attempted suicide by the use of a large attempted suicide by the use of a large
amount of warfarin-based amount of warfarin-based
rodenticide lead to clinical trials of rodenticide lead to clinical trials of
warfarin .warfarin .
Approved for medical use in 1954Approved for medical use in 1954. .
It is used in the prevention and It is used in the prevention and
treatment of thrombotic disorders.treatment of thrombotic disorders.

24. Sweet clover

Systematic name
(RS)-4-hydroxy- 3-(3- oxo- 1-phenylbutyl)- 2H- chromen- 2-one

25. Vitamin KVitamin K
Synthesis of Synthesis of
functional functional
coagulation coagulation
factorsfactors
IIII
VIIVII
IXIX
XX
Vitamin K-Dependent Clotting FactorsVitamin K-Dependent Clotting Factors
Protein Protein CC and and
ProteinProtein S S

26. Warfarin: Mechanism of actionWarfarin: Mechanism of action
Inactive Inactive
clotting factorsclotting factors
( II, VII, IX, X )( II, VII, IX, X )
Active clotting
factors
Vitamin KVitamin K Epoxide form
Epoxide reductase
Warfarin inhibits the synthesis of biologically active forms of Warfarin inhibits the synthesis of biologically active forms of
vitamin K-dependent clotting factors II, VII, IX and Xvitamin K-dependent clotting factors II, VII, IX and X
WarfarinWarfarin
Protein C and
protein S

27. Mechanism of Action of WarfarinMechanism of Action of Warfarin
Inhibits synthesis of Vitamin K-dependent Inhibits synthesis of Vitamin K-dependent
coagulation factors II, VII, IX, & X as well as coagulation factors II, VII, IX, & X as well as
anticoagulant proteins C & Santicoagulant proteins C & S
3-4 days until effect is seen ??3-4 days until effect is seen ??
Does not have any effect on already-synthesized Does not have any effect on already-synthesized
coagulation factors; therefore, the therapeutic coagulation factors; therefore, the therapeutic
effects are not seen until these factors are effects are not seen until these factors are
depleteddepleted

29. Coumarins: Warfarin Coumarins: Warfarin
Act only in vivo
Bioavailability 100%Bioavailability 100%
98% bound to plasma proteins (albumin)98% bound to plasma proteins (albumin)
Monitoring anticoagulant effect of warfarin Monitoring anticoagulant effect of warfarin
by measuring PT, which is expressed as an by measuring PT, which is expressed as an
International Normalized Ratio International Normalized Ratio ((INRINR) )

30. Coumarins: Warfarin Coumarins: Warfarin
Their effect takes several days (3-4 ) to develop Their effect takes several days (3-4 ) to develop
because of the time taken for degradation of because of the time taken for degradation of
circulating circulating functional clotting factors functional clotting factors
Therefore the onset of action starts when these Therefore the onset of action starts when these
factors have been eliminated factors have been eliminated
Warfarin has a slow offset of action due to the Warfarin has a slow offset of action due to the
time required for synthesis of new, time required for synthesis of new, functional functional
coagulation factorscoagulation factors

31. Disadvantages of Warfarin therapy
Variable, unpredictable effect necessitating regular
INR monitoring and dose adjustment
Narrow therapeutic window leading to increased risk
of severe bleeding
Slow onset and offset of action
Numerous interactions with foods containing vitamin
K and drugs

32. Drug interactions with oral anticoagulantsDrug interactions with oral anticoagulants
1. Inhibition of Vit. K synthesis by intestinal flora; oral antibiotics
2. Inhibition of Vit K absorption; liquid paraffin
3. Decrease in drug metabolism by microsomal enzyme inhibitors;
chloramphenicol, & cimetidine
4. Displacment of the drug from protein binding sites;
phenylbutazone & salicylates
5. Co-administration of drugs that increase bleeding tendency by;
inhibiting platelet function; NSAIDs
heparin
1. Inhibition of drug absorption from GIT; cholystyramine, colestipol
2. Increase in synthesis of clotting factors; Vit K, oral contraceptives
3. Increase in drug metabolism by microsomal enzyme inducers;
Carbamazepine; barbiturates, rifampicin

33. Green tea and leafy green vegetablesGreen tea and leafy green vegetables
Beverages such as Beverages such as green teagreen tea..
Vegetable oils that include Vegetable oils that include soybean, soybean,
oliveolive..
Peas and green onionsPeas and green onions
Dairy products Dairy products such as yogurtsuch as yogurt
Patients taking warfarin should be Patients taking warfarin should be
advised to avoid advised to avoid garlic garlic supplementssupplements
Note:Note:
Vitamin E may increase warfarin effect.Vitamin E may increase warfarin effect.
Vitamin K ,Foods to Avoid while on WarfarinFood interactions with oral anticoagulantsFood interactions with oral anticoagulants

34. Warfarin is contraindicated during pregnancy as it
can cross the placental barrier and cause abortion, abortion,
hemorrhagic disorder in the fetus and birth defectshemorrhagic disorder in the fetus and birth defects
Oral anticoagulants : Teratogenicity

35. Bleeding due to WarfarinBleeding due to Warfarin
Stop the drug Stop the drug
IV injection of vitamin KIV injection of vitamin K
Fresh frozen bloodFresh frozen blood

36.   Polymorphisms in two genesPolymorphisms in two genes
VKORC1VKORC1    
CYP2C9CYP2C9
Play a particularly large role in response to warfarin.Play a particularly large role in response to warfarin.
PharmacogenomicsPharmacogenomics

37. Explain 30% of the dose variation between patientsExplain 30% of the dose variation between patients
There are two main haplotypes that explain 25% of There are two main haplotypes that explain 25% of
variation: variation:
Low-dose haplotype group (A) Low-dose haplotype group (A)
 High-dose haplotype group (B).High-dose haplotype group (B).
VKORC1 polymorphismsVKORC1 polymorphisms

38. African Americans are relatively resistant to warfarin African Americans are relatively resistant to warfarin
(higher proportion of group B haplotypes)(higher proportion of group B haplotypes)
Asian Americans are generally more sensitive to Asian Americans are generally more sensitive to
warfarin warfarin (higher proportion of group A haplotypes).(higher proportion of group A haplotypes).

39. CYP2C9CYP2C9
Responsible for metabolism of warfarinResponsible for metabolism of warfarin
Two know allelic variants, Two know allelic variants, CYP2C9*2 CYP2C9*2 and and CYP2C9*3CYP2C9*3, ,
differ from wild type by one amino acid each,differ from wild type by one amino acid each,
Associated with impaired hydroxylation of warfarin Associated with impaired hydroxylation of warfarin
in inactivation due to an alteration of the interaction in inactivation due to an alteration of the interaction
with cytochrome p450 oxidoreductase.with cytochrome p450 oxidoreductase.
CYP2C9*2 CYP2C9*2 ~12% efficiency~12% efficiency, CYP2C9*3, CYP2C9*3<5% <5%
efficiency of wild type.efficiency of wild type.

41. Thank
You