Drugs acting on the blood and blood-forming organs Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology, School of Medicine, Zhejiang University

Drugs affecting the blood and blood- forming organs §Anticoagulant drugs ( 抗凝药 ) §Antiplatelet drugs ( 抗血小板药 ) §Thrombolytic drugs ( 纤溶药 ) §Drugs for treatment of bleeding ( 止血药 ) §Drugs for treatment of anemia ( 抗贫血药 ) ( 抗贫血药 ) §Hematopoietic growth agents Drugs for treatment of hypovolemia Drugs for treatment of hypovolemia ( 血容量扩充药 ) ( 血容量扩充药 ) Coagulation - bleeding Blood cell growth Blood volume

§heparin 肝素 low molecular weight heparin 低分子量肝素 low molecular weight heparin 低分子量肝素 §dermatan sulfate 硫酸皮肤素 §lepirudin 重组水蛭素 §coumarins 香豆素类 warfarin 华法林 warfarin 华法林 dicoumarol 双香豆素 dicoumarol 双香豆素 acenocoumarol 醋硝香豆素 acenocoumarol 醋硝香豆素 Anticoagulant drugs

§heparin 肝素 ( 凝血酶间接抑制药 ) low molecular weight heparin 低分子量肝素 low molecular weight heparin 低分子量肝素 §dermatan sulfate 硫酸皮肤素 ( 凝血酶间接抑制药 ) §lepirudin 重组水蛭素 ( 凝血酶直接抑制药 ) §coumarins 香豆素类 ( 维生素 K 拮抗药 ) warfarin 华法林 warfarin 华法林 dicoumarol 双香豆素 dicoumarol 双香豆素 acenocoumarol 醋硝香豆素 acenocoumarol 醋硝香豆素 Anticoagulant drugs

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

Major reactions of blood coagulation

Thrombosis injures vital organs

Coumarins

Anticoagulant drugs Heparin 肝素 Molecular weights: 3~30 kDa; mean 15 kDa

1. Pharmacological effects (1) Anticoagulation § Increasing the activity of AT III( 抗凝血酶 III): The AT III inhibiting the activity of the activated IIa, inhibiting the activity of the activated IIa, IXa, Xa, XIa, XIIa. IXa, Xa, XIa, XIIa. Activating HCII( 肝素辅助因子 ) Activating HCII( 肝素辅助因子 ) Enhancing the release of t-PA （组织纤溶酶原激活剂） Enhancing the release of t-PA （组织纤溶酶原激活剂） and TFPI ( 组织因子通路抑制物 ) and TFPI ( 组织因子通路抑制物 ) § Rapid action, short duration (2~4 h) § Effective both in vitro and in vivo. Heparin 肝素

more rapid Example of the effect of heparin

(2) Anti –atherosclerosis § blood lipids  § protecting endothelial cells § inhibiting the hypertrophy of smooth muscle cells (3) Other effects: § Anti-inflammatory, anti-oxidant effects, etc. Heparin 肝素

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. (3) Disseminated intravascular coagulation ( 弥散 性血管内凝血， DIC): early use. (4) Prevention of coagulation in vitro: cardiovascular surgery, hemodialysis( 血透 ), cardiac canula( 心导管 ), etc. Heparin 肝素

3. Adverse effects (1) Bleeding (at larger 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. 4. Contraindication Heparin 肝素

Low molecular weight heparin § MW < 7 kDa § Features:  Stronger effects on Xa than on IIa  Stronger in inhibiting thrombosis/coagulation  High bioavailability; Longer half –life ( min)  Weak bleeding effects Heparin 肝素

Fondaparinux ： 合成肝素衍生物，引起血小板减少症的风险降低。

§heparin 肝素 low molecular weight heparin 低分子量肝素 low molecular weight heparin 低分子量肝素 §dermatan sulfate 硫酸皮肤素（ activate HC II, Heparin-cofactor II ） §lepirudin 重组水蛭素（ thrombin inhibitor ） §coumarins 香豆素类 warfarin 华法林 warfarin 华法林 dicoumarol 双香豆素 dicoumarol 双香豆素 acenocoumarol 醋硝香豆素 acenocoumarol 醋硝香豆素 Anticoagulant drugs

§heparin 肝素 ( 凝血酶间接抑制药 ) low molecular weight heparin 低分子量肝素 low molecular weight heparin 低分子量肝素 §dermatan sulfate 硫酸皮肤素 ( 凝血酶间接抑制药 ) §lepirudin 重组水蛭素 ( 凝血酶直接抑制药 ) §coumarins 香豆素类 ( 维生素 K 拮抗药 ) warfarin 华法林 warfarin 华法林 dicoumarol 双香豆素 dicoumarol 双香豆素 acenocoumarol 醋硝香豆素 acenocoumarol 醋硝香豆素 Anticoagulant drugs

Warfarin 华法林

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 Warfarin 华法林

Sites of warfarin action

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

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 Warfarin 华法林

2. Clinical uses Anticoagulation in vivo § Anticoagulation in vivo 3. Adverse effects (1) Bleeding: v itamine K may antagonize the reaction; interreaction with other agents (2) Necrosis of skin and parenchyma ( 软组织 ) (3) Liver injury (4) Serious birth defect Warfarin 华法林

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

Antiplatelet drugs

ticlopidine

Antiplatelet drugs Inhibition of platelet metabolismsInhibition of platelet metabolisms Inhibitors of cyclic nucleotide phosphodiesterase: dipyridamole 双嘧达莫 ( 潘生丁 ) 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 ridogrel 利多格雷, picotamide 匹可托安 Activators of adenosine cyclase: epoprostenol 依前列醇 ( PGI 2 ) Inhibition of ADP-induced platelet activationInhibition of ADP-induced platelet activation ticlopidine 噻氯匹定 ticlopidine 噻氯匹定 Gp IIb/IIIa receptor antagonistsGp IIb/IIIa receptor antagonists abciximab 阿昔单抗 (c7E3Fab ) abciximab 阿昔单抗 (c7E3Fab )

Major reactions of blood coagulation

Antiplatelet drugs Aspirin 阿司匹林 Acetylsalicylic acid 乙酰水杨酸 Aspirin阿司匹林

§ small doses (40 ～ 80 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 and platelet depolymerization ( 血小板 PGI 2 : vasodilation and platelet depolymerization ( 血小板 解聚 ). 解聚 ). Aspirin 阿司匹林

The mechanism of aspirin: Target enzymes acetylated

Thrombolytic drugs ( 纤溶药 )

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

Action of thrombolytic drugs t-PA (+)

Thrombolytic drugs Common adverse effects § bleeding § antidotes: antifibrinolytic drugs

Bleeding Thrombolysis

Drugs for treatment of bleeding Vitamine K § 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 bleeding

Vitamin K

Drugs for treatment of bleeding Thrombin-like agents thrombin § thrombin § prothrombin complex used for various bleeding used for various bleeding

Drugs for treatment of bleeding Drugs preventing activation of fibrinolysis (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 used for preventing the activation fibrinolysis and resultant bleeding

Inhibiting plasminogen activation

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

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）

Vit B 12

Folic acid 1. Pharmacological effects Regulating nucleic acid, amino acid metabolism Regulating nucleic acid, amino acid metabolism 2. Clinical uses Megaloblastic anemia; MTX( 甲氨蝶呤 )-induced anemia Megaloblastic anemia; MTX( 甲氨蝶呤 )-induced anemia 3. Adverse effects Rarely reported Rarely reported Vitamin B 12  Co-factor of folic acid  Important in maintaining neuron myelination

Effect of EPO on red cell proliferation and differentiation

§Erythropoietin (EPO) rhEPO rhEPO 1. Pharmacological effects Promoting red cell proliferation and differetiation Promoting red cell proliferation and differetiation 2. Clinical uses Anemia due to chronic renal failure with hemodialysis, radiotherapy, chemotherapy, AIDS… Anemia due to chronic renal failure with hemodialysis, radiotherapy, chemotherapy, AIDS… 3. Adverse effects Hypertension, epilepsy, thrombosis, etc. Hypertension, epilepsy, thrombosis, etc.

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 (chemotherapy or radiotherapy), autologous bone marrow transplantation, myelodysplasia( 脊髓发育不良 ), aplastic anemia( 再生障碍性贫血 ), AIDS-associated neutropenia §Allergy, GI and hepatic injuries, local irritation, etc.

Drugs for treatment of hypovolemia §Dextran 右旋糖酐（葡聚糖） §Increasing blood volume (MW 70, 40, 10kD) §Inhibiting platelet aggregation (MW 40,10kD) §Osmotic diuretic effects (MW 40, 10kD)

Drugs for treatment of hypovolemia §Dextran 右旋糖酐（葡聚糖 ） §Hydroxyethyl starch 羟乙基淀粉 §Increasing blood volume (MW 70, 40, 10kD) §Inhibiting platelet aggregation (MW 40,10kD) §Osmotic diuretic effects (MW 40, 10kD)

hydroxyethyl starch 羟乙基淀粉

Enzymatic degradation and excretion of hydroxyethyl starch

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