Chapter 4 Drugs acting on the blood and blood-forming organs

Transcription

1 Chapter 4 Drugs acting on the blood and blood-forming organs

2 Drugs affecting the blood and blood- Coagulation - bleeding forming organs Anticoagulant drugs( ( 抗凝血药 ) Antiplatelet drugs ( 抗血小板药 ) Thrombolytic drugs ( 溶栓药 ) Drugs for treatment of bleeding ( 止血药 ) Blood cell growth Drugs for treatment of anemia( ( 抗贫血药 ) Hematopoietic growth agents( ( 造血细胞药 ) Blood volume Drugs for treatment of hypovolemia( ( 血容量 扩充药 )

3 A. Anticoagulant drugs

4 A. Anticoagulant drugs Heparin 肝素 Low molecular weight heparin 低分子肝素 Coumarins 香豆素类 warfarin 华法林 dicoumarol 双香豆素 acenocoumarol 醋硝香豆素

5 Thrombosis injures vital organs

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7 外源性 ( 组织损伤 ) 内源性 ( 血管壁损伤 ) Stage I Stage II II IIa Stage III I Ia

8 Major reactions of blood coagulation

9 Coumarins

10 A. Anticoagulant drugs Heparin 肝素 Molecular weights: 3~30 3~30 kda; ; mean 15 kda

11 A. Anticoagulant drugs 1. Pharmacological effects (1) Anticoagulation Increasing the activity of AT III: The AT III inhibiting the activity of the activated IIa, VIIa, IXa, Xa, XIIa, etc. Rapid and short (2~4 h) Effective both in vitro and in vivo.

12 more rapid Example of the effect of heparin

13 A. Anticoagulant drugs (2) Anti atherosclerosis blood lipids protecting endothelial cells inhibiting the hypertrophy of smooth muscle cells (3) Other effects: Antiinflammatory, antioxydant effects, etc.

14 A. Anticoagulant drugs 2. Clinical uses (1) Thrombosis: pulmonary emboli, deep vein thrombosis, cardiac infraction, etc. (2) Cardiac ischemia: high-risk patients (3) Disseminated intravascular coagulation (DIC): early use. (4) Prevention of coagulation in vitro: cardiovascular surgery, hemodialysis,, cardiac canula, etc.

15 A. Anticoagulant drugs 3. Adverse effects (1) Bleeding (at higher doses) Protamine is the inhibitor of heparin. 1 mg (protamine( 鱼精蛋白 ) = 100 U (heparin) (2) Thrombocytopenia ( 血小板减少 ): warfarin should be substituted if the platelet count falls (3) Others: allergy, local necrosis, long-term use: alpecia ( 脱发 ), osteoporosis ( 骨质疏松 ), etc.

16 A. Anticoagulant drugs Low molecular weight heparin Mean MW = 1~ kda Features: Stronger effects on Xa, XIIa than on IIa Stronger in inhibiting thrombosis/coagulation High bioavailability; Longer half -life Weak bleeding effects

17 A. Anticoagulant drugs Warfarin 华法林

18 A. Anticoagulant drugs 1. Pharmacological effects (1) Mechanisms of action: antagonizing vitamine K, inhibiting of carboxylation of the glutamic acid residues of the factors II, VII, IX, X, and reducing the activated II, VII, IX, X (2) Properties: slowly and longer duration: effect appears after p.o. 1~3 days, and lasts for 4 days effective only in vivo

19 Sites of warfarin action

20 Factor II, VII, IX, X warfarin action Activated factor II, VII, IX, X COO - 氢醌型 Vit K 环氧型 Vit K

21 A. Anticoagulant drugs 2. Clinical uses Anticoagulation in vivo 3. Adverse effects (1) Bleeding: vitamine K may antagonize the reaction; interrelaction with other agents (2) Necrosis of skin and parenchyma ( 软组织 ) (3) Liver injury

22 4. Drug interactions Plasma protein binding replacement Hepatic metabolism: inhibition potentiation

23 B. Antiplatelet drugs

24 B. Antiplatelet drugs Inhibition of platelet metabolisms Inhibitors of cyclic nucleotide phosphodiesterase: dipyridamole 双嘧达莫 ( 潘生丁 ) COX inhibitors: aspirin 阿司匹林 TXA 2 receptor antagonists and TXA 2 synthetase inhibitors: ridogrel 利多格雷, picotamide 匹可托安 Activators of adenosine cyclase: epoprostenol 依前列醇 Inhibition of ADP-induced platelet activation ticlopidine 噻氯匹定 Gp IIb/IIIa receptor antagonists abciximab 阿昔单抗 (C7E3Fab)

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27 B. Antiplatelet drugs Aspirin 阿司匹林 Acetylsalicylic acid 乙酰水杨酸 COOH O O C CH3 Aspirin 阿司匹林

28 B. Antiplatelet drugs small doses (30~100 mg/d): inhibiting TXA 2 synthesis, preventing thrombosis. used to treat ischemic heart disease, reduce the mortality of myocardiac infarction, and prevent cerebral thrombosis. larger doses: inhibiting PGI 2 synthesis, promoting thrombosis. PGI 2 : vasodilation 解聚 ). vasodilation and platelet depolymerization ( 血小板

29 The mechanism of aspirin: Target enzymes acetylated

30 C. Thrombolytic drugs

31 C. Thrombolytic drugs

32 C. Thrombolytic drugs Streptokinase(SK SK)(T Urokinase(UK UK) (T (T 1/2 (T 1/2 1/2 = 23 min; ) 1/2 = 15 min; ) Tissue plasminogen activator ( t-pat PA, 组织 纤溶酶原激活剂 ) i.v. T 1/2 = 3~8 min

33 t-pa (+) Action of thrombolytic drugs

34 C. Thrombolytic drugs Common adverse effects bleeding antidotes: antifibrinolytic drugs

35 Thrombolysis Bleeding

36 D. Drugs for treatment of bleeding

37 D. Drugs for treatment of bleeding Vitamine K Carboxylation of the glutamic acid residues of factors II, IIV, IX, X, protein C. Preventing bleeding with vitamine K deficiency or warfarin-induced induced bleeding

38 Vitamin K Vitamin K

39 D. Drugs for treatment of bleeding Thrombin-like agents thrombin, prothrombin complex, used for various bleeding

40 D. Drugs for treatment of bleeding Drugs preventing activation of antifibrinolytics aprotinin ( 抑肽酶 ) tranexamic acid (AMCHA, p-aminomethylbenzoic acide 苯酸 ) (AMCHA, 氨甲环酸 ) acide (PAMBA, 氨甲 used for preventing the activation fibrinolysis and resultant bleeding

41 Inhibiting plasminogen activation

42 E. Drugs for treatment of anemia

43 E. Drugs for treatment of anemia Anemia may result from the excess destruction of erythrocytes, and nutritional deficiencies (iron, minerals, cobalt, vitamin B 12, folic acid, ascorbic acid, riboflavin, copper, zinc, etc. Iron: anemia due to loss of erythrocytes and iron deficiency Folic acid and vitamin B 12 megaloblastic anemia Erythropoietin (EPO) 12 : promoting red cell proliferation and differentiation

44 E. Drugs for treatment of anemia Iron ferrous sulfate 硫酸亚铁 ferric ammonium citrate 枸橼酸铁铵 1. Interaction with other drugs or diet in the GI tract 2. Used for anemia due to loss of erythrocytes and iron deficiency 3. Adverse effects: GI reactions, hypersensitivity Acute intoxication: severe CVS and GI reactions - treated with deferoxamine( 去铁敏 )

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46 E. Drugs for treatment of anemia Folic acid 1. Pharmacological effects Regulating nucleic acid, amino acid metabolism 2. Clinical uses Megaloblastic anemia; MTX-induced anemia 3. Adverse effects Rarely reported Vitamin B 12 Co-factor of folic acid Important in maintaining neuron myelination

47 E. Drugs for treatment of anemia Erythropoietin (EPO) rhepo 1. Pharmacological effects Promoting red cell proliferation and differetiation 2. Clinical uses Anemia due to chronic renal failure with hemodialysis, radiotherapy, chemotherapy, AIDS, etc. 3. Adverse effects Hypertension, epilepsy, thrombosis, etc.

48 Effect of EPO on red cell proliferation and differentiation

49 F. Hematopoietic growth agents

50 F. Hematopoietic growth agents Granulaocyte colony-stimulating factor G-CSF 粒细胞集落刺激因子 Granulaocyte/macrophage colony-stimulating factor GM-CSF 粒细胞 / 巨噬细胞集落刺激因子 Used for neutropenia (chemotheapy or radiotherapy), autologous bone marrow transplantation, myelodysplasia, aplastic anemia, AIDS-associated neutropenia Allergy, GI and hepatic injuries, local irritation, etc.

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53 G. Drugs for treatment of hypovolemia

54 G. Drugs for treatment of hypovolemia Dextran 右旋糖酐 ( 葡聚糖 ) Hydroxyethyl starch 羟乙基淀粉 Increasing blood volume Inhibiting platelet aggregation (~ MW 40,000) Osmotic diuretic effects

55 hydroxyethyl starch 羟乙基淀粉

56 Enzymatic degradation and excretion of hydroxyethyl starch