PARENTERAL anticoagulants, fibrinolytics

PARENTERAL anticoagulants

1. PARENTERAL ANTICOAGULANTS Dr.M.Karthiga M.D., DNB., Pharmacology

2. Hemostasis - finely regulated dynamic process of maintaining fluidity of the blood , repairing vascular injury, and limiting blood loss while avoiding vessel occlusion (thrombosis) and inadequate perfusion of vital organs.

3. ANTITHROMBOSIS Some factors also oppose clot formation, rather lyse it To check the balance, these anticoagulants are present They operate to maintain blood in fluid state in circulation & allows rapid haemostatis following injury E.g. antithrombin , protein C, protein S, antithromboplastin & fibrinolysin system NOTE – PT is raised in common & extrinsic pathway disturbance & a PTT is raised in common & intrinsic pathway damage Normally, PT=12-14 S, a PTT= 26-32 S units

4. Drugs to reduce coagulability of blood Inhibition of formation of fibrin clots 1) USED IN-VIVO- PARENTERAL (Heparin LMW); ORAL - Coumarins & Indandiones (Warfarin, dicoumarol ) 2) USED IN-VITRO- Heparin CALCIUM COMPLEXES- sodium citrate/ oxalate/ edetate 6

5. Antithrombin

6. HEPARIN

7. HEPARIN UFH Large sulfated polysaccharide polymer obtained from animal sources. Anionic glycosaminoglycans Average molecular weight- 15,000–20,000. Highly acidic and can be neutralized by basic molecules ( eg , protamine). IV/SC- avoid the risk of hematoma associated with intramuscular injection.

8. Low-molecular-weight (LMW) heparin Breakdown by alkalisation of heparin benzyl ester Molecular weights of 2000–6000 Greater bioavailability and longer durations of action than unfractionated heparin SC Fondaparinux is a small pentasaccharide fragment of heparin

9. MOA

10. MOA

11. Binds to clotting factors Xa , IIa , IXa , XIa , XIIa , XIIIa  inactivates intrinsic pathway only Heparin provides anticoagulation immediately after administration because it acts on preformed blood components aPTT LMW heparins and fondaparinux , like unfractionated heparin, bind ATIII. These complexes have the same inhibitory effect on factor Xa as the unfractionated heparin–ATIII complex Provide a more selective action because they fail to affect thrombin

12. systemic hypercoagulable immunological reaction degradation of platelets T/t - argatroban .

13. FONDAPARINUX Synthetically derived pentasaccharide anticoagulant that selectively inhibits factor Xa. DVT and PE and for the prophylaxis of venous thromboembolism in the setting of orthopedic and abdominal surgery. Predictable pharmacokinetic profile Eliminated in the urine mainly as unchanged drug with an elimination half-life of 17 to 21 hours. Bleeding is the major side effect of fondaparinux.

14. Direct Thrombin Inhibitors Based on proteins made by Hirudo medicinalis , the medicinal leech.

15. Lepirudin - recombinant form of the leech protein hirudin , while desirudin and bivalirudin are modified forms of hirudin . Predictable pharmacokinetics, which allows for fixed dosing, as well as a predictable immediate anticoagulant response Lepirudin bind simultaneously to the active site of thrombin and to thrombin substrates. Argatroban binds solely to the thrombin-active site. Inhibit both soluble thrombin and the thrombin enmeshed within developing clots . Bivalirudin also inhibits platelet activation. Bleeding. No reversal agents Prolonged infusion of lepirudin can induce antibodies that form a complex with lepirudin and prolong its action, and it can induce anaphylactic reactions. Dabigatran Prevention of stroke and systemic embolism in nonvalvular atrial fibrillation.

16. Drugs that activates the conversion of plasminogen to plasmin , a serine protease that hydrolyzes fibrin and, thus, dissolves clots Streptokinas e Urokinase Alteplase Tenecteplase Reteplase

17. STREPTOKINASE Extracellular protein purified from culture broths of group C b-hemolytic streptococci. It forms an active one-to-one complex with plasminogen. This enzymatically active complex converts uncomplexed plasminogen to the active enzyme Catalyzes the degradation of clotting factors V and VII Acute myocardial infarction,  acute pulmonary embolism  (PE),  deep vein thrombosis (DVT), reperfusion of occluded peripheral arteries, and venous catheters

18. Urokinase Naturally in the body by the kidneys. Therapeutic urokinase is isolated from cultures of human kidney cells and has low antigenicity. Directly cleaves the arginine—valine bond of plasminogen to yield active plasmin . Lysis of pulmonary emboli..

19. MOA Start early as clots become more resistant to lysis as they age. Administration of antiplatelet drugs, such as aspirin, or antithrombotics , such as heparin

20. THERAPEUTIC USES For MI, intracoronary delivery of the drugs is the most reliable in terms of achieving recanalization. Restoring catheter and shunt function, by lysing clots causing occlusions. To dissolve clots that result in strokes. Alteplase is approved for the treatment of MI, massive PE, and acute ischemic stroke. Tenecteplase is approved only for use in acute MI.

21. Adverse effects Hemorrhage is a major adverse effect. For example, a previously unsuspected lesion, such as a gastric ulcer, may hemorrhage following injection of a thrombolytic agent Contraindicated in pregnancy, and in patients with healing wounds, a history of cerebrovascular accident, brain tumor, head trauma, intracranial bleeding, and metastatic cancer