Chapter 36 Drugs acting on the blood and blood-forming organs

Drugs affecting the blood and blood- forming organs §Anticoagulant drugs §Antiplatelet drugs §Thrombolytic drugs §Drugs for treatment of bleeding §Drugs for treatment of anemia §Hematopoietic growth agents Drugs for treatment of hypovolemia Coagulation - bleeding Blood cell growth Blood volume

§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 A. Anticoagulant drugs

Thrombosis: injury in vital organs

Coumarins Stage I Stage II Stage III

A. Anticoagulant drugs Heparin 肝素

A. Anticoagulant drugs §1. Pharmacological effects §(1) Anticoagulation  Increasing the activity of AT III: The AT III inhibiting the activity of the activated XIIa, XI, Xa, IXa, Ⅶ a, IIa, etc. § Rapid and short (2~4 h) § Effective both in vitro and in vivo §(2) Anti –atherosclerosis § blood lipids  § protecting endothelial cells § inhibiting the hypertrophy of smooth muscle cells §(3) Other effects: § Antiinflammatory, antioxydant effects, etc.

Effect of heparin

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

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.

A. Anticoagulant drugs §Low molecular weight heparin § Mean MW = 1 ～ 12 kD § Features: § Stronger effects on Xa, XIIa than on IIa § Stronger anticoagulants § Longer half -life § Weak bleeding effects

A. Anticoagulant drugs Warfarin 华法林

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 inducing 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

Sites of warfarin action

A. Anticoagulant drugs §2. Clinical uses Anticoagulation in vivo § Anticoagulation in vivo §3. Adverse effects §(1) Bleeding: v itamine K may antagonite the reaction; Interrelaction with other agents  (2) Necrosis of skin and parenchyma ( 软组织 ) §(3) Liver injury

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

B. Antiplatelet drugs Inhibition 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 Inhibition of ADP-induced platelet activation ticlopidine 噻氯匹定 ticlopidine 噻氯匹定 Gp IIb/IIIa receptor antagonists abciximab 阿昔单抗 (C7E3Fab ) abciximab 阿昔单抗 (C7E3Fab )

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

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 and platelet depolymerization ( 血小板解聚 ).

The mechanism of aspirin: Target enzymes acetylated

C. Thrombolytic drugs

§Streptokinase （ SK ） (T 1/2 = 23 min; ) §Urokinase （ UK ） (T 1/2 = 15 min; ) §Tissue plasminogen activator ( t-PA ) § i.v. T 1/2 = 3~8 min

Action of thrombolytic drugs

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

Bleeding Thrombolysis

D. 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

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

D. Drugs for treatment of bleeding §Drugs preventing activation of antifibrinolytics § aprotinin, § 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

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) § promoting red cell proliferation and differetiation

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 CNS, GI reactions §- treated with deferoxamine （去铁敏）

E. Drugs for treatment of anemia §Folic acid and vitamin B 12 §1. Pharmacological effects §Regulating nucleic acid, amino acid metabolism §2. Clinical uses §Megaloblastic anemia §3. Adverse effects §Rare reports

Folic acid metabolism and the effect of vitamin B 12

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.

Effect of EPO on red cell proliferation and differentiation

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.

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