1. Anticoagulants 1. Parenteral Anticoagulants e.g. heparin
2. Oral anticoagulants e.g. warfarin

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

3. Heparin Chemistry Heterogeneous mixture of sulfated
mucopolysaccharides (glycosaminoglycan).
Strongly acidic nature.
Extracted from porcine intestinal mucosa &
bovine lung.

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

6. Heparin  inhibits activated clotting factors in blood by  activity of antithrombin III against activated clotting factors as (IIa, IXa, Xa, XIIa)  inhibits blood clotting.

8. Pharmacokinetics
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.

10. Pharmacological Actions
1. Heparin has anticoagulant activity in vivo & in vitro.
2. Increase activity of lipoprotein lipase from tissues   lipemia after fatty meals ( clearing factor).

11. Control of Heparin Therapy
1. Activated partial thromboplastin time (aPTT) times that of the normal value (30 sec).
Whole blood clotting time (WBCT) : times the normal value ( min).

12. Uses of Heparin 1. Pulmonary embolism 2. Deep vein thrombosis
Initiation of anticoagulant therapy
1. Pulmonary embolism
2. Deep vein thrombosis
3. Post - operative venous thrombosis
4. Stroke
5. Myocardial infarction
6. Hemodialysis
7. Pregnancy

13. Side Effects Bleeding Heparin-induced thrombocytopenia (HIT)
Hypersensitivity reactions: (Antigenicity due to animal source) rarely occurring reactions include urticaria, rash, rhinitis.
Reversible alopecia & osteoporosis (long term, for 6 months or longer).

14. Heparin-induced thrombocytopenia (HIT)
is a life-threatening immune reaction that occurs in up to 3% of patients on heparin therapy for 5-14 days
Venous thrombosis or arterial occlusion may develop.
Platelet count is required.
Lower risk with LMWH
Treated by
Heparin discontinuation
Direct thrombin inhibitor is used

15. Heparin antidote Protamine sulphate Basic peptide
Given I.V. slowly (1 mg / 100 U heparin).

16. 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.

17. Low Molecular Weight Heparin
Enoxaparin – Dalteparin -Danaproid.
prepared by controlled chemical or enzymatic depolymerization of standard unfractionated heparin
its action is antithrombin III-dependent
Acts via inhibition of activated blood clotting factor Xa (less effect on IIa) by increasing activity of antithrombin III.
Doses: given at fixed doses once to twice daily by S.C. route, in- & out-hospital
Control of the Doses estimation of plasma factor Xa.

18. LMW heparins Have equal anticoagulant effect to UF heparin
BUT LMW heparins have
Favorable pharmacokinetic characters.
Increased bioavailability
Longer biological half life.
Less frequent dosing requirements
Doses are specified in milligrams
more predictable anticoagulant response
Less incidence of bleeding and thrombocytopenia.

19. Uses of heparin 1. Treatment of pulmonary embolism.
2. Treatment of 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

20. 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

21. 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.

22. Lepirudin
Is accumulated in renal insufficiency.
It is monitored by aPTT

23. Oral anticoagulants Coumarin anticoagulants e.g. warfarin
are vitamin K antagonists (vitamin K epoxide reductase inhibitors).
reduced vitamin K is required for hepatic synthesis of several clotting factors II, VII, IX, X (gamma carboxyglutamic acid residues).
This results in the production of inactive clotting factors lacking ɣ-carboxyglutamyl residues

24. Vitamin K Antagonists Warfarin
The reduced vit K is converted into vitamin K epoxide which is reduced back by vitamin K reductase the target enzyme which warfarin inhibits

26. 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 (12 h).
Acts in vivo only.

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

28. Drug interactions
1.Broad spectrum antibiotics sulfonamides increase warfarin action
2. Hepatic P450 Inhibitors increase warfarin action
Cimetidine, erythromycin
3. Hepatic P450 Inducers decrease warfarin action
rifampicin, phenobarbitone
4. NSAIDs, aspirin
Contraindications
Pregnancy
Hypoprothrombinemia (Liver disease).

29. Prothrombin time (PT) (10-12 seconds) 2-4 times
Control of warfarin Therapy
Prothrombin time (PT) (10-12 seconds) 2-4 times
International normalized ratio (INR)
Ratio between patients PT and normal standard PT (2-3).
Uses for Maintenance of anticoagulant activity in venous thromboembolic disorder.