Overview of Anticoagulant Drugs and Their Effects

1. Drugs affecting blood and blood-forming organs (作用于血液和造血系统药物) Tang Huifang (汤慧芳) Email: tanghuifang@zju.edu.cn

2. General concept Anticoagulant drugs(抗凝血药) Antiplatelet drugs(抗血小板药) Fibrinolytic drugs(纤维蛋白溶解药) Hemostatic drugs(止血药) Drugs affecting the blood and blood-forming organs Coagulation- bleeding • Antianemic drugs(抗贫血药) Hematopoietic growth agents agents (促白细胞生长药) Blood cell growth Blood volume • Drugs for treatment of • hypovolemia (血容量扩充剂)

3. Part 1.Anticoagulants 抗凝血药 • 凝血酶间接抑制剂： • Heparin（肝素） • Low molecular weight heparin （低分子量肝素） • Fondaparinux (磺达肝癸钠) • Oral direct Factor X inhibitors：Apixaban （阿派沙班）、Rivaroxaban(利伐沙班) • 凝血酶直接抑制剂（direct thrombin inhibitors，DTIs)： • ORAL DTIs: Dabigatran (达比加群) • Factor II inhibitor: Lepirudin（重组水蛭素/来匹卢定）、desirudin （地西卢定）、bivalirudin(比伐卢定)、Argatroban（阿加曲班） • Vitamin K antagonists: Coumarins 香豆素类 • Warfarin（华法林）、dicoumarol（双香豆素）、 acenocoumarol（醋硝香豆素）

4. Anticoagulant drugs Heparin（肝素） MW of 5～30 kD(mean12 kD). 化学：强酸性，具强负电荷（抗凝作用基础） 特效解毒剂：鱼精蛋白（碱性，强正电荷）

5. Ⅺa、Ⅸa、Ⅹa、Ⅻa Heparin accelerates inactivation of coagulation factors by antithrombin.

6. Anticoagulant drugs 1. Pharmacological effects (1)Anticoagulation: 1)Heparin increase the activity of AT Ⅲ The AT Ⅲ may inhibit the activity of the activated Ⅱa、Ⅺa、Ⅸa、Ⅹa、Ⅻa, to cause anticoagulation. 2)Characteristics of anticoagulation ①It is effective in vitro and in vivo; ②Its effects are rapid(iv) (<10min)and short(3～4 h): activated partial thromboplastin time(APTT) ↑

7. Anticoagulant drugs (2)Anti-atherosclerosis: 1)Regulating blood lipids: VLDL 2)Protecting endothelial cells; 3)Inhibiting the proliferation of smooth muscle cells. 4)Inhibits platelet aggregation (3)Other effects: Anti-complement,anti-inflammation, and blood viscosity（血液粘度）.

8. Anticoagulant drugs 2. Pharmacokinetics (1)Heparin is not absorbed by GI. It need iv. or sc. (2)plasma protein binding rate: 80% (3)t1/2: 1～2 hr. It’s metabolised in liver, and partially degraded heparin appears in the urine.

9. 3. Clinical uses (1)Anticoagulation Such as: pulmonary emboli; deep vein thrombosis; cardiac infarction, etc. (2)Heart ischemia Prevent emboli in coronary artery—— early use. (3)DIC(disseminated intravascular coagulation, 弥散性血管内凝血) Such as: certain surgical procedures, hemodialysis, cardiac catheterization, etc. (4)Prevent coagulation in vitro Anticoagulant drugs

10. Anticoagulant drugs 4. Adverse effects (1)Bleeding(5%～10%) Protamine sulfate（硫酸鱼精蛋白）is the antagonist of heparin.1mg protamine=100U heparin. (2) Heparin-induced thrombocytopenia(血小板减少症)(HIT) 5%～6%,Warfarin should be substi-tuted if the platelet count falls. (3)Others Allergy(过敏反应); Local necrosis(局部坏死), when sc; Increased loss of hair and reversible alopecia(脱发); Osteoporosis(骨质疏松). (4) Contraindicated in patients with bleeding risk

11. Anticoagulant drugs Low molecular weight heparin (LMWH, 低分子肝素) • 常用LMWH： • enoxaparin (依诺肝素) • Tedelparin (替地肝素) • Fraxiparin （弗希肝素） • Logiparin（洛吉肝素） • Lomoparin （洛莫肝素） FatcorⅩa Mean MW = 1～12 kD Stronger Effects on Ⅹa, Ⅻa than on Ⅱa

12. FatcorⅩa

13. Anticoagulantdrugs Coumarins(香豆素类) Warfarin(华法林); Dicoumarol(双香豆素);Acenocoumarol(醋硝香豆素) 双香豆素 华法林 苯茚二酮

14. Anticoagulant drugs 1. Pharmacological effects (1)Properties: Slowly and longer duration: Theeffect appears after p.o. 1~3 days, and lasts for 4 days Effective only in vivo. (2)Mechanisms of action: Antagonizes vitamin K. It inhibits carboxylation of the gluta-mic acid residues of thefactorsⅡ、Ⅶ、Ⅸ、Ⅹ,to decrease the activation of factorsⅡ、Ⅶ、Ⅸ、Ⅹ.

15. Mechanism ofCoumarins

16. Anticoagulant drugs 2. Clinical uses Anti-coagulation in vivo(such as deep vein thrombosis, pulmonary emboli, and cardiac infarction, etc). 3. Adverse effects (1)Bleeding(9%～10%) Can affect all organs in body. Vitamin K1may antagonist this reaction. can treat with fresh blood or plasma and prothrombin complex(凝血酶原复合物). (2)Necrosis of skin and parenchyma(皮肤和软组织坏死). (3)Liver injury(warfarin).

17. 4. Drug interactions (1)Plasma protein binding replacement (2)Hepatic metabolism: enzyme inhibition enzyme induction

18. Part 2. Antiplatelet drugs(抗血小板药) → PGI2 PGI2 受体 GPⅡb/Ⅲa 受体 TXA2 受体 ADP 受体 Thrombus formation at the site of the damaged vascular wall (EC, endothelials cell) and the role of platelets and clotting factors. Platelet membrane receptors include the glycoprotein (GP) Ia receptor, binding to collagen (C); GP Ib receptor, binding von Willebrand factor (vWF); and GP IIb/IIIa, which binds fibrinogen and other macromolecules. Antiplatelet prostacyclin (PGI2) is released from the endothelium. Aggregating substances released from the degranulating platelet include adenosine diphosphate (ADP), thromboxane A2 (TXA2), and serotonin (5-HT).

19. Antiplatelet drugs(抗血小板药)

20. The class of antiplatelet drugs • Inhibition of AA metabolism in platelets • Irreversible cyclooxygenase inhibitors(COX inhibitor)： Aspirin (阿司匹林) 、 Triflusal (三氟柳) • Thromboxane synthase inhibitors and Thromboxane receptor antagonists： Ridogrel(利多格雷), picotamide(匹可托安) 、Ozagrel、Seratrodast （塞曲司特） • Increase intracellular cAMP • Phosphodiesterase inhibitors(PDE inhibitor)： Cilostazol (西洛他唑) • Adenosine reuptake inhibitors： Dipyridamole (双嘧达莫, 潘生丁) • Activators of adenosine cyclase: epoprostenol（依前列醇）

21. Platelet activation inhibitor • Adenosine diphosphate (ADP) receptor inhibitors(P2Y12 inhibitor)： • Clopidogrel (氯吡格雷) 、Prasugrel (普拉格雷) 、Ticagrelor (替卡格雷) • Ticlopidine (噻氯匹定) • Protease-activated receptor-1 (PAR-1) antagonists: Vorapaxar (沃拉帕沙) • Glycoprotein IIB/IIIA inhibitors ： • Intravenous use only: Abciximab (阿昔单抗)、Eptifibatide (依替巴肽)、 • Tirofiban (替罗非班)、 • Oral use: Xemilofiban（珍米洛非班）、Fradafiban（夫雷非班）、西拉非班（sibrafiban）

22. Anti-platelet drugs Aspirin(阿司匹林) Acetylsalicylic acid(乙酰水杨酸) Itis a cyclooxygenase inhibitor, inhibit-ing TXA2 synthesis.

23. Mechanism: Target enzymes (cyclooxygenase) are acetylated and inactive.

24. Anti-platelet drugs Aspirin Small doses (30～100 mg/day): inhibiting TXA2 synthesis, preventing thrombosis. used to treat ischemic heart disease, reduce the mortality of myocardiac infar-ction, and prevent cerebral thrombosis. Larger doses ( 500 mg/day): inhibiting PGI2 synthesis, promoting thrombosis. ——PGI2:vasodilation and platelet depolymerization(血小板解聚).

25. Anti-platelet drugs Dipyridamole(双嘧达莫, Persantin, 潘生丁) Reversibly inhibits phosphadiesterase (PDE) of platelet,  cAMP ,  platelet reactivity , t1/2 12 hr. Clinical uses: Prevent thrombosis.

26. Ticlopidine(噻氯匹定) Selectively interferes ADP induced platelet activation Inhibits platelet function. Clinical uses: Prevent cerebral apoplexy (中风) and cardiac infarction, etc.

27. Part 3. Fibrinolytic drugs 纤维蛋白溶解药 纤溶酶原 阿替普酶 尿激酶 - + 链激酶 + 纤溶酶 阿尼普酶 凝血酶 纤维蛋白原

28. Fibrinolytic drugs Alteplase (Tissue plasminogen activator t-PA, 组织型纤溶酶原激活剂) 1. Effect: Local action on the thrombotic fibrin (血栓纤维蛋白) to produce fibrinolysis; iv. t1/2=3～8 min, effect 1～3 hr. A potentially important agent in treating thromboembolic disease. 2. ADR:bleeding.

29. Fibrinolytic drugs Urokinase(尿激酶, UK) 1. Effect: Plasminogen activator, t1/2=15 min; 2. Clinical use: Severe pulmonary emboli, and deep vein thrombosis. 3. Adverse reaction: (1)systemic fibrinolytic state, (2)bleeding.

30. Fibrinolytic drugs Streptokinase(链激酶, SK) 1. Pharmacological effect: plasminogen(纤溶酶原) activator, t1/2 = 23 min; 2.Clinical Use: Severe pulmonary emboli, and deep vein thrombosis 3. Adverse reaction: Systemic fibrinolytic state which can lead to bleeding problems(5%); Antigenicity——allergy.

31. Fibrinolytic drugs Anistreplase(阿尼普酶) It is a streptokinase-plasminogen complex, in which lys-plasminogen is acylated at its catalyicsite serine. The acyl group is hydrolyzed in vivo, allowing the complex to bind to fibrin prior to activation, and this modification confers some specificity toward clots on the fibrinolytic process. It is used coronary thrombolysis also.

32. Adverse effects • The thrombolytic agents do not distinguish between the fibrin of an unwanted thrombus and the fibrin of a beneficial hemostatic plug. • Hemorrhage is a major side effect. • Antidotes: fibrinolytic inhibitors (PAMBA氨甲苯酸, AMCHA氨甲环酸)

34. Part 4. Hemostatic drugs (Haemostats, 促凝血药, 止血药) Vitamin K 1. Carboxylation ofthe glutamic acid residuesofII, VII, IX, X, protein C. 2. To prevent bleeding with vitamin K deficiency. 3. Response tovitamin Kis slow, the severe hemostasis patients should be infused with fresh plasma imme-diately.

35. Haemostats Thrombin-like agents (凝血酶制剂) Thrombin(凝血酶, factor Ⅱ) Prothrombin complex(凝血酶原复合物, factor Ⅱ、Ⅶ、Ⅸ、Ⅹ) used for various bleeding. Globulin anti-hemophilia (factor Ⅷ, 抗血友病球蛋白) used fortreatment for hemophilia.

36. Haemostats Drugs preventing activation of antifibrinolytics aprotinin (抑肽酶） tranexamic acid (AMCHA, 氨甲环酸) p-aminomethylbenzoic acide (PAMBA, 氨甲苯酸） used forpreventing the activation fibrinolysis and resultant bleeding

37. Inhibiting plasminogen activation

38. Part 5. Antianemic drugs 抗贫血药 1. Cause of anemia: (1)Anemia may result from the excess destruction of erythrocytes; (2)Anemia may result from nutritional deficiencies, including: iron, minerals, vitamins (B12 and folic acid), ascorbic acid, riboflavin, etc. 2. Drugs for treatment of anemia: Iron preparations; Folic acid and vitamin B12; Erythropoietin(EPO), and rhEPO (Reconbanant human EPO)

39. Antianemic drugs Iron preparations(铁制剂) Ferrous sulfate(硫酸亚铁), Ferricammoniumcitrate(枸橼酸铁铵) Iron dextran(右旋糖酐铁), Iron sorbitex(山梨醇铁) 1. Clinical Uses Iron deficiency anemia. 2. ADRs GI reactions: nausea, vomiting, and diarrhea. Acute intoxication: severe CNS symptoms and GI reactions. In this time, treatment with deferoxamine(去铁胺).

40. Antianemic drugs Folic acid(叶酸) & Vitamin B12 Both Folic acid(叶酸) and Vitamin B12are essential for the synthesis of DNA, this process is impaired in patients with megaloblastic anemia(巨幼红细胞贫血). 1. Pharmacological effects Regulating nucleic acid & amino acid metabolism. 2. Clinical uses Megaloblastic anemia. 3. Adverse reaction Rare reports

41. Antianemic drugs Erythropoietin(EPO, 红细胞生成素) rhEPO(重组人红细胞生成素) 1. Pharmacological effects promoting red cell proliferation and differentiation 2. Clinical uses anemia due tochronic renal failure withhemodialysis,radiotherapy,chemo-therapy, AIDS, etc. 3. Adverse effects Hypertension, epilepsy, thrombosis, etc.

42. Part 6. Haemopoietic growth factors 促白细胞生成药 非格司亭（filgrastim,G-CSF:粒细胞集落刺激因子) 沙格司亭（sargramostim，GM-CSF:粒细胞/巨噬细胞集落刺激因子, 生白能) 1. Effects and mechanism of effects (1)Stimulatestheformationofmacrophage, granulocyte colony; (2)Stimulates proliferation, differentiation and maturity of blood stem cell; (3)Promotesthereleaseofbloodcell from bone marrow (4)Strenghtens the function of granulocyte

43. Haemopoietic growth factors 2. Clinical uses Bone marrow suppression from chemotherapy and radiotherapy of neoplasm. 3. Adverse effects GI reactions, liver injury, fever, myalgia(肌肉痛).

44. Part 7. Agents correcting blood volume(血容量扩充剂) Dextran(右旋糖酐): (C6H10O5)n Dextran-10;Dextran-40; Dextran-70 1. Pharmacological effects: (1)Blood volume , (2)blood viscosity ,platelet binding and aggregation ; (3)osmotic diuretic effects. 2. Clinical Use: Anti-shock, maintain blood volume. 3. ADRs: hypersensitivity, bleeding.

45. Reference Mega JL1, Simon T2. Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments. Lancet. 2015 Mar 11. pii: S0140-6736(15)60243-4. doi: 10.1016/S0140-6736(15)60243-4. [Epub ahead of print]

46. Have a rest!