Anticoagulants - Mansoura University PDF

 Anticoagulants Dr. Ibrahim El-Shenbaby MD, PhD Clinical pharmacology Mansoura University Whats: 01007418721 Horus University [email protected] New Mansoura University  Physiology of coagulation Blood clot  Physical trauma to the...

 Anticoagulants Dr. Ibrahim El-Shenbaby MD, PhD Clinical pharmacology Mansoura University Whats: 01007418721 Horus University [email protected] New Mansoura University  Physiology of coagulation Blood clot  Physical trauma to the vascular system (puncture or cut), initiates a complex of interactions between platelets, endothelial cells, and coagulation system.  This results in the formation of a platelet-fibrin plug (clot) at the site of the puncture to stop bleeding. Thrombus  Involves the same steps as normal clot formation, except that the triggering stimulus is a pathologic condition rather than external physical trauma.  Thrombus/ Clot Platelet plug Fibrin Adhesion Activation Aggregation Extrinsic Intrinsic Resting platelets  Healthy endothelial cells secretes prostacyclin (PGl2) → platelet receptor → ↑ cAMP → ↓ Ca2+. This leads to inhibition of platelet activation and of the subsequent release of platelet aggregation agents  In healthy blood vessels circulating levels of thrombin and thromboxane are low, and the intact endothelium covers the collagen in the subendothelial layers  As a result, platelet activation and aggregation are not initiated  Platelet plug formation Damaged or unhealthy endothelial cells → I. ↓ prostacyclin. II. Platelets adhesion to exposed collagen ↑ Ca2+ → platelet activation III. Activated platelet →  secrete adenosine diphosphate (ADP), thromboxane A2, serotonin, platelet activation factor, and thrombin → activation of platelets circulating nearby  Activation of the glycoprotein (GP) llb/llla receptors that bind fibrinogen resulting in platelet cross-linking and platelet aggregation. Platelet Plug is unstable and must reinforced with fibrin Fibrin formation (coagulation)  Anticoagulants 1. Heparin 2. Warfarin (Oral anticoagulant) 3. Synthetic factor Xa inhibitors 4. Direct thrombin inhibitors  Heparin Warfarin Source & Natural Synthetic cuomarin compound chemistry sulfated polysaccharide present in mast cells & carries –ve charge Absorption No because it precipitates by Good gastric HCl. bioavailability is 100% Distribtion Cannot cross BBB or placenta. Can cross BBB & placenta. Mechanism Activate antithrombin III leading Warfarin inhibits vitamin K to inhibition of several clotting epoxide reductase enzyme in factors especially factor X & the liver →↓ synthesis of thrombin (factor II). vitamin K-dependent clotting factors (II, VII, IX, and X).  Heparin Warfarin Onset and Immediate Delayed duration short (2-4 hrs). long (3-7 d) Effects Anticoagulant in vivo & in vitro Anticoagulant in vivo only. Stimulates lipoprotein lipase→↓↓ serum triglycerides Uses Prevention of thrombosis Prevention of thrombosis Monitoring By activated partial thrombo­ By prothrombin time (PT) or of therapy plastin time (APTT). International Normalized Ratio It must be kept 2-3 times as the (INR). It must be kept 2-3 normal value. times as the normal value.  Heparin Warfarin Side effects Hematoma if given IM Hemorrhagic skin necrosis: Thrombocytopenia: immune- Teratogenicity: abnormal fetal mediated reaction due to bone in early pregnancy formation of antibodies that CNS Hemorrhage in the fetus can bind to platelets if given in late pregnancy. Osteoporosis with long use Sudden withdrawal → Alopecia and dermatitis: rare. thrombosis  Bleeding is the most common and dangerous SE.  It could be treated by : (a) Immediate stopping of the drug. (b) Fresh frozen plasma: to provide fresh clotting factors. (c) Protamine sulfate (c) Vitamin K1 - Protamine carries +ve charge that combines with heparin (carries –ve charge) to form stable complex.  Low-molecular-weight heparins (LMWH) (Enoxaparin – Dalteparin)  Standard (unfractionated) heparin is a mixture of different molecular weight fractions (3000-30,000 Da) that can affect more than one coagulation factor and produce thrombocytopenia (↑ risk of bleeding).  LMWH has a MW less than 8000 Da that makes it specific for factor X with minimal effects on platelets and other clotting factors.  Unfractionated LMWH heparin Molecular weight (3000 to 30,000 Da) Less than 8000 Da Anti-factor Xa activity Less specific More specific Endothelium and PP High Low binding Bioavailability after s.c. Low High injection (binding to s.c. tissue) Half-life Short (given 3 times/d) Long (given once/d) Thrombocytopenia Common (10%) Less common (