Drugs acting on blood

For our beloved student

1. Drugs acting on blood Dr. Haji Bahadar, PharmD, PhD, Assistant Professor, IPMS.KMU

2. Toipics Anticoagulants Fibrinolytics Antiplatelets

3. Blood Components Erythrocytes Leukocytes Platelets Plasma

4. Platelets Platelets, also called thrombocytes . They are component of blood whose function is to stop bleeding by clumping and clotting.  The normal platelet count is 150,000-350,000 per microliter of blood.

5. What is coagulation of blood ? Coagulation is the process by which blood forms clots. Coagulation or clotting is defined as the process in which blood loses its fluidity and becomes a jelly-like mass. Clotting factors and anticoagulants are made in the liver. They have the ability to turn on or turn off as needed.

6. Clotting factors Factor Name I Fibrinogen II Prothrombin III Tissue Factor or thromboplastin IV Ca++ V Proaccelerin VII Proconvertin VIII Antihemophilic A factor IX Antihemophilic B factor or Factor Name X Stuart or Stuart- Prower factor XI Plasma thomboplastin antecedent XII Hageman factor, contact factor XIII Fibrin stabilizing factor

7. Anticoagulants (Heparin, Warfarin ) Substances which prevent or postpone coagulation of blood are called anticoagulants. Anticoagulants are of three types: 1. Anticoagulants used to prevent blood clotting inside the body, i.e. in vivo (In the living organism). 2. Anticoagulants used to prevent clotting of blood that is collected from the body, i.e. in vitro. 3. Anticoagulants used to prevent blood clotting both in vivo and in vitro. Anticoagulants and antiplatelet agents are medicines that reduce blood clotting in an artery, a vein or the heart. In vitro anticoagulants: those that remove calcium ions from the blood to prevent coagulation, such as  citrate ,  oxalate , fluoride, and  ethylene diamine tetra acetic acid  ( EDTA )

8. Stages of blood coagulation

9. HEPARIN Heparin is a naturally produced anticoagulant in the body. It is produced by mast cells. Mechanism of Action of Heparin Heparin: It prevents blood clotting by its antithrombin activity. It directly suppresses the activity of thrombin (Combines with antithrombin III (a protease inhibitor present in circulation) and removes thrombin from circulation). Heparin inhibits the coagulation process by enhancing the activity of the endogenous inhibitor, antithrombin by 1000 x.

10. Heparin—Clinical Applications Prophylaxis( action taken to prevent disease) and treatment of Venous thrombosis (DVT) Pulmonary Embolism(PE) Peripheral arterial embolism Prevention of post-op DVT/PE Diagnosis and treatment of DIC?? Prevention of clotting in surgery Anticoagulant in blood transfusions and dialysis

11. Clinical uses of heparin Heparin is used to treat and prevent deep vein thrombosis, pulmonary embolism, and arterial thromboembolism . It is also used in the treatment of heart attacks and unstable angina. It is given by injection into a vein. Other uses include inside test tubes and kidney dialysis machine.

12. Side Effect Of Heparin easy bleeding and bruising; pain, redness, warmth, irritation, or skin changes where the medicine was injected; itching of your feet; or bluish-colored skin.

13. One  unit  of  heparin (the "Howell  unit ") is an amount approximately equivalent to 0.002 mg of pure heparin. Antidote of heparin: Protamine sulfate

14. Warfarin (self study) Warfarin, sold under the brand name Coumadin among other, is a medication that is used as a blood thinner. It is commonly used to treat blood clots such as deep vein thrombosis and pulmonary embolism and to prevent stroke in people who have atrial fibrillation, valvular heart disease or artificial heart valves. Less commonly it is used following ST-segment elevation myocardial infarction (STEMI) and orthopedic surgery.[4] It is generally taken by mouth but may also be used by injection into a vein.

15. Contraindication Warfarin is contraindicated in pregnancy, as it passes through the placental barrier and may cause bleeding in the fetus; warfarin use during pregnancy is commonly associated with spontaneous abortion, stillbirth, neonatal death, and preterm birth.[25] Coumarins (such as warfarin) are also teratogens, that is, they cause birth defects; the incidence of birth defects in infants exposed to warfarin in utero appears to be around 5%, although higher figures (up to 30%) have been reported in some studies.[26] Depending on when exposure occurs during pregnancy, two distinct combinations of congenital abnormalities can arise

16. Side Effect Of Warfarin Severe bleeding, including heavier than normal menstrual bleeding Red or brown urine Black or bloody stool Severe headache or stomach pain Joint pain, discomfort or swelling, especially after an injury Vomiting of blood or material that looks like coffee grounds Bruising that develops without an injury you remember Dizziness or weakness

17. Blood clot Blood clot is defined as the mass of coagulated blood which contains RBCs, WBCs and platelets entrapped in fibrin meshwork. RBCs and WBCs are not necessary for clotting process. However, when clot is formed, these cells are trapped in it along with platelets. The trapped RBCs are responsible for the red color of the clot. Fibrinolysis: Lysis of blood clot inside the blood vessel is called fibrinolysis . It helps to remove the clot from lumen of the blood vessel.

18. Fibrinolysis Lysis of blood clot inside the blood vessel is called fibrinolysis . It helps to remove the clot from lumen of the blood vessel. This process requires a substance called plasmin or fibrinolysin . Plasmin is formed from inactivated glycoprotein called plasminogen . Plasminogen is synthesized in liver and it is incorporated with other proteins in the blood clot. Plasminogen is converted into plasmin by tissue plasminogen activator( tPA ). It is a protein involved in the breakdown of blood clots.

19. Formation of Plasmin Plasmin is formed from inactivated glycoprotein called plasminogen . Plasminogen is synthesized in liver and it is incorporated with other proteins in the blood clot. Plasminogen is converted into plasmin by tissue plasminogen activator (t-PA), lysosomal enzymes and thrombin. The t-PA and lysosomal enzymes are released from damaged tissues and damaged endothelium. Thrombin is derived from blood. The t-PA is always inhibited by a substance called t-PA inhibitor. It is also inhibited by factors V and VIII. Besides t-PA, there is another plasminogen activator called urokinase plasminogen activator (u-PA). It is derived from blood.

20. Fibrinolysis

21. Tranexamic acid  is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin

22. Thrombolytic drugs Alteplase Reteplase Tenecteplase Anistreplase Streptokinase Urokinase

23. Side effects Thrombolytic drugs (self study) blood in the urine blood in the stool, or black, tarry stools constipation coughing up blood vomiting blood or material that looks like coffee grounds nosebleeds unexpected or unusually heavy vaginal bleeding dizziness sudden, severe, or constant headaches pain or swelling in the abdomen or stomach back pain or backache severe or constant muscle pain or stiffness stiff, swollen, or painful joints

24. Antiplatelets (aspirin, clopidogrel , and Prasugrel ) Antiplatelets are a group of medicines that stop blood cells (called platelets) from sticking together and forming a blood clot.

25. Basic steps Prothrombin activator --> Prothrombin --> Thrombin --> Fibrinogen --> Fibrin Platelets activation: increase expression of glycoprotein IIb / IIIa  ( GPIIb / IIIa , also known as  integrin α IIb β 3 ) . What increase the above? Answer: Thromboxane A2, ADP (adenosine diphosphate ), and thrombin.

26. Platelet activation stepts

27. Adenosine diphosphate Under normal conditions, platelets circulate in the blood freely and without interaction with one another. ADP is stored in inside platelets and is released upon platelet activation. ADP interacts with a family of ADP receptors found on platelets (P2Y12) which leads to platelet aggregation.

28. What is thromboxane A2? Thromboxane A2 is a type of thromboxane that is produced by activated platelets and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by increasing expression of the glycoprotein complex GPIIb/ IIIa .

29. What is thromboxane? Thromboxane  is a member of the family of lipids known as  eicosanoids (lipids) Thromboxane-A synthase, an enzyme found in platelets, converts the arachidonic acid to thromboxane-A2 which activate aggregation of platelets by increasing the expression of the glycoprotein complex GPIIb/ IIIa .

30. How do Clopidogrel and Aspirin act as antiplatelete ? Clopidogrel acts by inhibiting the ADP receptor on platelet cell membranes. The drug specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, which is important in activation of platelets and cross-linking by the protein fibrin. Aspirin in lower doses(75-150 mg) exert antiplatelet effect by prevent the formation of thromboxane A2 by inhibiting Thromboxane-A synthase.

31. SIDE EFFECTS (SELF STUDY) Side Effect of clopidogrel increased bleeding, nosebleeds, headaches, itching, and bruising.

32. Side Effect of Asprin black, bloody, or tarry stools; coughing up blood or vomit that looks like coffee grounds; severe nausea, vomiting, or stomach pain; fever lasting longer than 3 days; swelling, or pain lasting longer than 10 days; or hearing problems, ringing in your ears. Less serious side effects may include: upset stomach, heartburn; drowsiness; or headache.

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