1. Fibrinolytics, anticoagulants and antiplatelets

2. Anticoagulants
Drugs that interfere with blood coagulation cascade are called anticoagulant

3. Key Clotting Factor is THROMBIN
COAGULATION CASCADE
Key Clotting Factor is THROMBIN

4. COAGULATION CASCADE

6. ANTICOAGULANTS & COAGULATION CASCADE

7. Classification of anticoagulants
1. Parenteral anticoagulants
2. Oral anticoagulants

8. Parenteral Anticoagulants (THROMBIN INHIBITORS)
Indirect thrombin inhibitors
High molecular weight (HMW) heparin or unfractionated (UFH) heparin.
Low molecular weight (LMW) heparin.
Direct thrombin inhibitors

9. Indirect Thrombin Inhibitors
are antithrombin III –dependent thrombin inhibitors
High molecular weight (HMW) heparin or unfractionated (UFH) heparin.
Low molecular weight (LMW) heparin.

10. unfractionated (UFH) heparin.
Heterogeneous mixture of sulfated
mucopolysaccharides (glycosaminoglycan).
Strongly acidic nature.

11. Extraction of unfractionated (UFH) heparin.
Extracted from porcine intestinal mucosa &
bovine lung. 11

12. Mechanism of Action of UFH
Has anticoagulant effect that depends upon antithrombin III
Antithrombin III: is a natural anticoagulant that inhibits activated clotting factors especially (IIa, IXa, Xa, XIa).
This inhibition is slow but increased 1000 fold in presence of heparin.

13. Heparin  inhibits activated clotting factors in blood by  activity of antithrombin III against activated clotting factors as (IIa, IXa, Xa, XIIa)  inhibits blood clotting.
LMWH acts via increasing activity of antithrombin III against activated clotting factor Xa .

14. MECHANISM OF ACTION OF UFH

15. MECHANISM OF ACTION OF UFH & LMWH
Heparin
Free
Heparin

16. Pharmacokinetics of UFH
Given only parenerally (S.C. or I.V) Not I.M (hematoma).
Immediate anticoagulant effect (t ½ = min).
Metabolized in the liver (80 %) - 20 % excreted unchanged in urine (not by microsomes).
Does not cross placenta & not excreted in milk.

17. Low Molecular Weight Heparin (LMWH)
Enoxaparin – Dalteparin -Danaproid.
prepared by chemical or enzymatic depolymerization of UFH
LMWHs are antithrombin III-dependent
Administration: S.C. in- & out-hospital

18. LMW heparins
Increased bioavailability
Longer biological half life.
Less frequent dosing requirements
Doses are specified in milligrams
Favorable pharmacokinetic characters.
predictable anticoagulant effect
No dose adjustment or monitoring
Less incidence of bleeding and thrombocytopenia.

19. Pharmacological Actions
1. Heparin& LMWH have anticoagulant activity in vivo & in vitro.

20. Control of Therapy
Unfractionated heparin (UFH)
1. Activated partial thromboplastin time (aPTT) times that of the normal value (30 sec).
Whole blood clotting time (WBCT):
2 - 3 times the normal value (5 - 7 min).
LMWH estimation of plasma factor Xa.

21. Side Effects of Heparin
Bleeding
Thrombocytopenia & Thrombosis
Hypersensitivity reactions: (Antigenicity due to animal source) rarely occurring reactions include urticaria, rash, rhinitis.
Reversible alopecia & osteoporosis (long term, for 6 months or longer).

22. Heparin-induced thrombocytopenia (HIT)
is an immune reaction that occurs in up to 3% of patients on heparin therapy for 5-14 days due to formation of IgM & IgG against heparin-PF4 complex
Platelet count is required.
Lower risk with LMWH
Treated by
Heparin discontinuation
Direct thrombin inhibitor is used

23. Heparin antidote Protamine sulphate Basic peptide
Given I.V. slowly (1 mg / 100 U heparin).
Excess protamine should be avoided since
it has anticoagulant effect.

24. 3. Post-operative venous thrombosis. 4. Stroke.
Uses of heparin
for the prevention of
1. Pulmonary embolism.
2. Deep vein thrombosis.
3. Post-operative venous thrombosis.
4. Stroke.
5. Myocardial infarction.
6. Hemodialysis.
7. Reduction of coronary artery thrombosis after thrombolytic treatment
8. Anticoagulant of choice in pregnant women

25. Hemophilia, thrombocytopenia. Severe hypertension.
Contraindications of heparin
Hemophilia, thrombocytopenia.
Severe hypertension.
Intra cranial hemorrhage.
Threatened abortion
Ulcerative lesions of GIT.
Threatened abortion.
Advanced hepatic or renal disease.
Hypersensitivity to heparin.
Patients who have had surgery of CNS, eye or spinal cord.

26. LMWH
HMWH
Differences
 activity of antithrombin III against Xa
 activity of a antithrombin III against active factor II, IX, X, XI, and XII.
Low
High
Bleeding tendency
thrombocytopenia
Long ( double )
Short
T ½
Bioavailability
Plasma factor Xa
aPTT, WBC.
Control of dose
1 - 2 dose / day
S.C. only
dose / day
( I.V. or S.C )
Administration
Equal
Efficacy MW

27. Direct Thrombin Inhibitor anticoagulants Lepirudin-Bivalirudin
acts via direct binding to active site on
activated factor II (thrombin)
is antithrombin III- independent.
Prepared by recombinant DNA technology
Given I.V.
Has short duration of action (1 hr)
Used for treatment of thrombosis in
HIT patients.

28. Lepirudin
Is accumulated in renal insufficiency.
It is monitored by aPTT
No antagonists are available.

29. ORAL ANTICOAGULANTS
Coumarin anticoagulants
e.g. warfarin

30. Warfarin Mechanism of action
Warfarin is vitamin K antagonist (vitamin K epoxide reductase inhibitor).
Reduced vitamin K is required for γ-carboxylation of glutamate residues in clotting factors.
Warfarin acts by inhibiting the activation of several clotting factors (II, VII, IX, X ) by blocking γ-carboxylation of glutamate residues in clotting factors in the liver.
This results in the production of inactive clotting factors lacking ɣ-carboxyglutamyl residues

31. vitamin K reductase
The reduced vit K is converted into vitamin K epoxide which is reduced back by vitamin K reductase the target enzyme which warfarin inhibits

34. Pharmacokinetics
Taken orally.
Highly bound to plasma protein (low Vd).
Long plasma half life (36 h).
Cross placenta (# pregnancy).
Metabolized in the liver by cytochrome P450
Excreted in urine and stool.
Delayed onset of action (8-12 h).
Acts in vivo only.

35. Side effects slow onset of action Hemorrhage : treated by vitamin K 1
Soft tissue necrosis
Drug interactions
Teratogenicity:
hemorrhagic disorder
abnormal bone formation in the fetus.

36. Warfarin Drug interactions
Warfarin action is increased by:
Broad spectrum antibiotics
Cyt P450 inhibitors: Cimetidine, erythromycin
Aspirin
Diseases Hyperthyroidism & liver disease

37. Warfarin Drug interactions
Warfarin action is decreased by
Cyt P450 inducers:
Phenobarbitone, rifampicin, phenytoin

38. Contraindications Overdose of warfarin Pregnancy
Hypoprothrombinemia (Liver disease).
Overdose of warfarin
Treated by vitamin K

39. Control of warfarin Therapy
Prothrombin time (PT)
Time required for plasma clotting with calcium and thromboplastin (10-12 seconds) 2-4 times expressed as INR
International normalized ratio (INR)
Ratio between patients PT and standard PT (2-4).
Uses for Maintenance of anticoagulant activity.

40. Uses of anticoagulants
for the prevention of
1. Pulmonary embolism recurrence
2. Deep vein thrombosis
3. Post - operative venous thrombosis
4. Stroke
5. Myocardial infarction
During hemodialysis
Unstable angina
Heparin (LMW) for short term action
Warfarin is used for prolonged therapy

41. Hemophilia, thrombocytopenia. Severe hypertension.
Contraindications of anticoagulants
Hemophilia, thrombocytopenia.
Severe hypertension.
Intra cranial hemorrhage.
Threatened abortion
Ulcerative lesions of GIT.
Threatened abortion.
Advanced hepatic or renal disease.
Hypersensitivity to heparin.
Patients who have had surgery of CNS, eye or spinal cord.