drugs acting on the blood and blood-forming organs yun-bi lu, phd 卢韵碧 dept. of pharmacology,...

Drugs acting on the blood and Drugs acting on the blood and blood-forming organsblood-forming organs

Yun-Bi Lu, PhDYun-Bi Lu, PhD卢韵碧卢韵碧

Dept. of Pharmacology, Dept. of Pharmacology, School of Medicine, Zhejiang UniversitySchool of Medicine, Zhejiang University

[email protected]@zju.edu.cn

Drugs affecting the blood and blood-Drugs affecting the blood and blood-forming organsforming organsAnticoagulant drugs Anticoagulant drugs (( 抗凝药抗凝药 ))Antiplatelet drugs Antiplatelet drugs (( 抗血小板药抗血小板药 ))Thrombolytic drugs Thrombolytic drugs (( 纤溶药纤溶药 ))Drugs for treatment of bleeding Drugs for treatment of bleeding

(( 止血药止血药 ))

Drugs for treatment of anemia Drugs for treatment of anemia (( 抗贫血药抗贫血药 )) Hematopoietic growth agentsHematopoietic growth agents

Drugs for treatment of hypovolemiaDrugs for treatment of hypovolemia (( 血容量扩充药血容量扩充药 ))

Coagulation Coagulation - bleedingbleeding

Blood cell Blood cell growthgrowth

Blood Blood volumevolume

heparinheparin 肝素肝素

low molecular weight heparinlow molecular weight heparin 低分子量肝素低分子量肝素dermatan sulfate dermatan sulfate 硫酸皮肤素硫酸皮肤素

lepirudinlepirudin 重组水蛭素重组水蛭素

coumarinscoumarins 香豆素类香豆素类

warfarin warfarin 华法林华法林 dicoumarol dicoumarol 双香豆素双香豆素 acenocoumarol acenocoumarol 醋硝香豆素醋硝香豆素

Anticoagulant drugsAnticoagulant drugs

heparinheparin 肝素肝素 (( 凝血酶间接抑制药凝血酶间接抑制药 ))

low molecular weight heparinlow molecular weight heparin 低分子量肝素低分子量肝素dermatan sulfate dermatan sulfate 硫酸皮肤素硫酸皮肤素 (( 凝血酶间接抑制药凝血酶间接抑制药 ))

lepirudinlepirudin 重组水蛭素重组水蛭素 (( 凝血酶直接抑制药凝血酶直接抑制药 ))

coumarinscoumarins 香豆素类香豆素类 (( 维生素维生素 KK 拮抗药拮抗药 ))



Stage IStage I

Stage IIStage II

Stage IIIStage III

II IIa

I Ia

外源性（组织损伤）外源性（组织损伤）内源性（血管壁损伤）内源性（血管壁损伤）

AT III

Major reactions of blood coagulationMajor reactions of blood coagulation

ThrombosisThrombosis injures vital organs injures vital organs

Coumarins


HeparinHeparin 肝素肝素

Molecular weights:Molecular weights: 3~30 kDa; mean 15 kDa3~30 kDa; mean 15 kDa

1. 1. Pharmacological effectsPharmacological effects

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


more more rapidrapid

Example of the effect of heparinExample of the effect of heparin

(2) Anti –atherosclerosis(2) Anti –atherosclerosis blood lipids blood lipids protecting endothelial cellsprotecting endothelial cells inhibiting the hypertrophy of smooth muscle cellsinhibiting the hypertrophy of smooth muscle cells

(3) Other effects: (3) Other effects: Anti-inflammatory, anti-oxidant effects, Anti-inflammatory, anti-oxidant effects, etc. etc.


2. 2. Clinical usesClinical uses(1) Thrombosis:(1) Thrombosis: pulmonary emboli, deep vein thrombopulmonary emboli, deep vein thrombo

sis, cardiac infraction, sis, cardiac infraction, etcetc..

(2) Cardiac ischemia:(2) Cardiac ischemia: high-risk patientshigh-risk patients

(3) Disseminated intravascular coagulation ((3) Disseminated intravascular coagulation ( 弥散性血管内凝血， DIC):DIC): early use.early use.

(4) Prevention of coagulation (4) Prevention of coagulation in vitroin vitro:: cardiovasculcardiovascular surgery, hemodialysis(ar surgery, hemodialysis( 血透血透 ), cardiac canula(), cardiac canula( 心导心导管管 ), ), etc.etc.


3. 3. Adverse effectsAdverse effects

(1) (1) Bleeding (at larger doses)Bleeding (at larger doses) Protamine is the inhibitor of heparin.Protamine is the inhibitor of heparin. 1 mg (protamine 1 mg (protamine 鱼精蛋白鱼精蛋白 ) ~ 100 U (heparin)) ~ 100 U (heparin)

(2) Thrombocytopenia(2) Thrombocytopenia (( 血小板减少血小板减少 ):): warfarin should bwarfarin should be substituted if the platelet count fallse substituted if the platelet count falls

(3) Others:(3) Others: allergy, local necrosis, long-term use: alpecallergy, local necrosis, long-term use: alpecia (ia ( 脱发脱发 ), osteoporosis (), osteoporosis ( 骨质疏松骨质疏松 ), ), etc.etc.

4. 4. Contraindication Contraindication


Low molecular weight heparinLow molecular weight heparin

MW < 7 kDaMW < 7 kDa Features:Features: Stronger effects on Xa than on IIaStronger effects on Xa than on IIa Stronger in inhibiting thrombosis/coagulationStronger in inhibiting thrombosis/coagulation High bioavailability; Longer half –life (200-300 min)High bioavailability; Longer half –life (200-300 min) Weak bleeding effectsWeak bleeding effects


Fondaparinux ：合成肝素衍生物，引起血小板减少症的风险降低。

heparinheparin 肝素肝素

low molecular weight heparinlow molecular weight heparin 低分子量肝素低分子量肝素dermatan sulfate dermatan sulfate 硫酸皮肤素（硫酸皮肤素（ activate HC II, Hepaactivate HC II, Hepa

rin-cofactor IIrin-cofactor II ））

lepirudinlepirudin 重组水蛭素（重组水蛭素（ thrombin inhibitorthrombin inhibitor ））

coumarinscoumarins 香豆素类香豆素类



heparinheparin 肝素肝素 (( 凝血酶间接抑制药凝血酶间接抑制药 ))

low molecular weight heparinlow molecular weight heparin 低分子量肝素低分子量肝素dermatan sulfate dermatan sulfate 硫酸皮肤素硫酸皮肤素 (( 凝血酶间接抑制药凝血酶间接抑制药 ))

lepirudinlepirudin 重组水蛭素重组水蛭素 (( 凝血酶直接抑制药凝血酶直接抑制药 ))

coumarinscoumarins 香豆素类香豆素类 (( 维生素维生素 KK 拮抗药拮抗药 ))




WarfarinWarfarin 华法林华法林


(1) Mechanisms of action:(1) Mechanisms of action: antagonizing vitamine K,antagonizing vitamine K, inhibiting of carboxylation of the inhibiting of carboxylation of the

glutamic acid residues of the glutamic acid residues of the factorsfactors II, VII, IX, XII, VII, IX, X , and redu , and reducing the activated II, VII, IX, Xcing the activated II, VII, IX, X


Sites of warfariSites of warfarin actionn action

warfarin actionwarfarin actionFactor II, Factor II, VII, IX, XVII, IX, X

Activated factor Activated factor II, VII, IX, XII, VII, IX, X

氢醌型氢醌型 Vit KVit K 环氧型环氧型 Vit KVit K

COO-


(1) Mechanisms of action:(1) Mechanisms of action: antagonizing vitamine K,antagonizing vitamine K, inhibiting of carboxylation of the inhibiting of carboxylation of the

glutamic acid residues of the glutamic acid residues of the factorsfactors II, VII, IX, XII, VII, IX, X , and redu , and reducing the activated II, VII, IX, Xcing the activated II, VII, IX, X

(2) Properties:(2) Properties: slowly and longer duration:slowly and longer duration: effect appears after effect appears after p.o.p.o. 1~3 d 1~3 d

ays, and lasts for 4 daysays, and lasts for 4 days effective only effective only in vivoin vivo


2. 2. Clinical usesClinical uses Anticoagulation Anticoagulation in vivoin vivo


(1) Bleeding:(1) Bleeding: vvitamine K may antagonize the reacitamine K may antagonize the reaction; interreaction with other agentstion; interreaction with other agents

(2) Necrosis of skin and parenchyma(2) Necrosis of skin and parenchyma (( 软组织软组织 ))(3) Liver injury(3) Liver injury

(4) (4) Serious birth defectSerious birth defect


4. 4. Drug interactionsDrug interactions

• Plasma protein bindinPlasma protein binding replacementg replacement

• Hepatic metabolism:Hepatic metabolism:

inhibitioninhibition

potentiationpotentiation

Antiplatelet drugsAntiplatelet drugs

ticlopidine

Antiplatelet drugsAntiplatelet drugs• Inhibition of platelet metabolismsInhibition of platelet metabolisms

Inhibitors of cyclic nucleotide phosphodiesterase:Inhibitors of cyclic nucleotide phosphodiesterase:

dipyridamoledipyridamole 双嘧达莫双嘧达莫 (( 潘生丁潘生丁 ))

COX inhibitors:COX inhibitors: aspirinaspirin 阿司匹林阿司匹林TXATXA22 receptor antagonists and TXA receptor antagonists and TXA2 2 synthetase inhibitors:synthetase inhibitors:

ridogrel ridogrel 利多格雷利多格雷 , , picotamidepicotamide 匹可托安匹可托安 Activators of adenosine cyclase:Activators of adenosine cyclase: epoprostenol epoprostenol 依前列醇依前列醇 ((PGIPGI22))• Inhibition of ADP-induced platelet activation Inhibition of ADP-induced platelet activation

ticlopidineticlopidine 噻氯匹定噻氯匹定• Gp IIb/IIIa receptor antagonistsGp IIb/IIIa receptor antagonists

abciximab abciximab 阿昔单抗阿昔单抗 (c7E3Fab(c7E3Fab))

Major reactions of blood coagulationMajor reactions of blood coagulation

Antiplatelet drugsAntiplatelet drugs

Aspirin Aspirin 阿司匹林阿司匹林Acetylsalicylic acid Acetylsalicylic acid 乙酰水杨酸乙酰水杨酸

CH3

COOH

O C

OAspirin Aspirin

阿司匹林阿司匹林

small doses (40small doses (40 ～～ 80 mg/d):80 mg/d): inhibiting TXA inhibiting TXA22 syn syn

thesis, preventing thrombosis.thesis, preventing thrombosis. used to treat ischemic heart disease, reduce the used to treat ischemic heart disease, reduce the

mortality of myocardiac infarction, and prevent ceremortality of myocardiac infarction, and prevent cerebral thrombosis.bral thrombosis.

larger doses:larger doses: inhibiting PGI inhibiting PGI22 synthesis, promotin synthesis, promotin

g thrombosis.g thrombosis.

PGIPGI22:: vasodilation and platelet depolymerization (vasodilation and platelet depolymerization ( 血小板血小板

解聚解聚 ).).

Aspirin Aspirin 阿司匹林阿司匹林

The mechanism of The mechanism of aspirin:aspirin:

Target enzymes Target enzymes acetylatedacetylated

Thrombolytic drThrombolytic drugsugs

(( 纤溶药纤溶药 ))

Thrombolytic drugsThrombolytic drugs

StreptokinaseStreptokinase （（ SKSK ）） (T(T1/21/2 = 23 min; ) = 23 min; )

UrokinaseUrokinase （（ UKUK ）） (T(T1/21/2 = 15 min; ) = 15 min; )

Tissue plasminogen activator ( t-PATissue plasminogen activator ( t-PA ，，组组织纤溶酶原激活剂织纤溶酶原激活剂 )) i.v. i.v. T T1/21/2 = 3~8 min = 3~8 min

Action of thrombolytic drugsAction of thrombolytic drugs

t-PAt-PA(+)(+)

Thrombolytic drugsThrombolytic drugs

Common adverse effectsCommon adverse effects bleedingbleeding antidotes:antidotes: antifibrinolytic drugsantifibrinolytic drugs

BleedingBleeding

ThrombolysisThrombolysis

Drugs for treatment of bleedingDrugs for treatment of bleeding

Vitamine KVitamine K

Carboxylation of the glutamic acid residueCarboxylation of the glutamic acid residues of factors II, IIV, IX, X, protein C.s of factors II, IIV, IX, X, protein C.

Preventing bleeding with vitamine K deficiPreventing bleeding with vitamine K deficiency or warfarin-induced bleedingency or warfarin-induced bleeding

Vitamin KVitamin K Vitamin KVitamin K


Thrombin-like agentsThrombin-like agents

thrombinthrombin prothrombin complexprothrombin complex

used for various bleedingused for various bleeding


Drugs preventing activation of fibrinolysis Drugs preventing activation of fibrinolysis

(antifibrinolytics)(antifibrinolytics)

aprotinin aprotinin (( 抑肽酶）抑肽酶）

tranexamic acid tranexamic acid (AMCHA, (AMCHA, 氨甲环酸氨甲环酸 ))

p-aminomethylbenzoic acidep-aminomethylbenzoic acide (PAMBA, (PAMBA, 氨甲苯酸）氨甲苯酸）

used forused for preventing the activation fibrinolysis preventing the activation fibrinolysis and resultant bleedingand resultant bleeding

Inhibiting plasminogen activationInhibiting plasminogen activation

Drugs for treatment of anemiaDrugs for treatment of anemiaAnemia may result from the excess destruction of eAnemia may result from the excess destruction of e

rythrocytes, and nutritional deficiencies (iron, minerythrocytes, and nutritional deficiencies (iron, minerals, cobaltrals, cobalt 钴钴 , vitamin B, vitamin B1212, folic acid, ascorbic acid,, folic acid, ascorbic acid,

riboflavin riboflavin 核黄素核黄素 , copper, zinc, etc., copper, zinc, etc. ))

Iron: Iron: anemia due to loss of erythrocytes and iron deficiencyanemia due to loss of erythrocytes and iron deficiency

Folic acid and vitamin BFolic acid and vitamin B1212: : megaloblastic anemiamegaloblastic anemia （（巨红细胞性贫血巨红细胞性贫血））Erythropoietin (EPO)Erythropoietin (EPO) promoting red cell proliferation and differentiationpromoting red cell proliferation and differentiation

IronIron ferrous sulfateferrous sulfate 硫酸亚铁硫酸亚铁 ferric ammonium citrateferric ammonium citrate 枸橼酸铁铵枸橼酸铁铵

1.1. Interaction with other drugs or diet in the GI tractInteraction with other drugs or diet in the GI tract

2. Used for anemia due to loss of erythrocytes and iro2. Used for anemia due to loss of erythrocytes and iron deficiency n deficiency

3. Adverse effects:3. Adverse effects: GI reactions, hypersensitivity GI reactions, hypersensitivityAcute intoxication:Acute intoxication: severe CVS and GI reactions severe CVS and GI reactions - treated with deferoxamine- treated with deferoxamine （去铁敏）（去铁敏）

Vit B12

Folic acidFolic acid1. 1. Pharmacological effectsPharmacological effects Regulating nucleic acid, amino acid metabolismRegulating nucleic acid, amino acid metabolism2. 2. Clinical usesClinical uses Megaloblastic anemia; MTX(Megaloblastic anemia; MTX( 甲氨蝶呤甲氨蝶呤 )-induced anemi)-induced anemi

aa3. 3. Adverse effectsAdverse effects Rarely reportedRarely reported

Vitamin BVitamin B1212 Co-factor of folic acidCo-factor of folic acid Important in maintaining neuron myelinationImportant in maintaining neuron myelination

Effect of EPO on red cell proliferation and differentiationEffect of EPO on red cell proliferation and differentiation

Erythropoietin (EPO)Erythropoietin (EPO) rhEPOrhEPO


Promoting red cell proliferation and differetiationPromoting red cell proliferation and differetiation

2. 2. Clinical usesClinical uses

Anemia due to Anemia due to chronic renal failure with hemodialysichronic renal failure with hemodialysis,s, radiotherapy, chemotherapy, AIDS… radiotherapy, chemotherapy, AIDS…


Hypertension, epilepsy, thrombosis, Hypertension, epilepsy, thrombosis, etc.etc.

Hematopoietic growth agentsHematopoietic growth agentsGranulaocyte colony-stimulating factorGranulaocyte colony-stimulating factor G-CSF G-CSF

粒细胞集落刺激因子粒细胞集落刺激因子Granulaocyte/macrophage colony-stimulating Granulaocyte/macrophage colony-stimulating

factor factor GM-CSF GM-CSF 粒细胞粒细胞 // 巨噬细胞集落刺激因子巨噬细胞集落刺激因子

Used for Used for neutropenianeutropenia (chemotherapy or radiotherap (chemotherapy or radiotherapy), autologous bone marrow transplantation, myelody), autologous bone marrow transplantation, myelod

ysplasia(ysplasia( 脊髓发育不良脊髓发育不良 ), aplastic anemia(), aplastic anemia( 再生障碍性贫再生障碍性贫血血 ), AIDS-associated neutropenia), AIDS-associated neutropenia

Allergy, GI and hepatic injuries, local irritation, Allergy, GI and hepatic injuries, local irritation, etc.etc.

Drugs for treatment of hypovolemiaDrugs for treatment of hypovolemia

DextranDextran 右旋糖酐（葡聚糖右旋糖酐（葡聚糖））

Increasing blood volume (MW 70, 40, 10kD)Increasing blood volume (MW 70, 40, 10kD) Inhibiting platelet aggregation (MW 40,10kD)Inhibiting platelet aggregation (MW 40,10kD)Osmotic diuretic effects (MW 40, 10kD)Osmotic diuretic effects (MW 40, 10kD)

Drugs for treatment of hypovolemiaDrugs for treatment of hypovolemia

DextranDextran 右旋糖酐（葡聚糖右旋糖酐（葡聚糖））Hydroxyethyl starchHydroxyethyl starch 羟乙基淀粉羟乙基淀粉

Increasing blood volume (MW 70, 40, 10kD)Increasing blood volume (MW 70, 40, 10kD) Inhibiting platelet aggregation (MW 40,10kD)Inhibiting platelet aggregation (MW 40,10kD)Osmotic diuretic effects (MW 40, 10kD)Osmotic diuretic effects (MW 40, 10kD)

hydroxyethyl starchhydroxyethyl starch 羟乙基淀粉羟乙基淀粉

Enzymatic degradation and excretion of hydroxyethyl starchEnzymatic degradation and excretion of hydroxyethyl starch

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drugs acting on the blood and blood-forming organs yun-bi lu, phd 卢韵碧 dept. of pharmacology,...

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