Chapter 4 Drugs acting on the blood and blood-forming organsm-learning.zju.edu.cn/G2S/eWebEditor/uploadfile/... · 2012-03-09 · Drugs affecting the blood and blood- -forming organs

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

Drugs affecting the blood and bloodDrugs affecting the blood and blood-- forming organsforming organs

Anticoagulant drugsAnticoagulant drugs（抗凝血药）（抗凝血药）

AntiplateletAntiplatelet drugsdrugs （抗血小板药）（抗血小板药）

Thrombolytic drugsThrombolytic drugs （溶栓药）（溶栓药）

Drugs for treatment of bleedingDrugs for treatment of bleeding （止血药）（止血药）

Drugs for treatment of anemiaDrugs for treatment of anemia（抗贫血药）（抗贫血药）

Hematopoietic growth agentsHematopoietic growth agents（造血细胞药）（造血细胞药）

Drugs for treatment of Drugs for treatment of hypovolemiahypovolemia（血容量（血容量

扩充药）扩充药）

Coagulation Coagulation -- bleedingbleeding

Blood cell Blood cell growthgrowth

Blood Blood volumevolume

A.A. Anticoagulant drugsAnticoagulant drugs

HeparinHeparin 肝素肝素

Low molecular weight heparinLow molecular weight heparin 低分子肝素低分子肝素

CoumarinsCoumarins 香豆素类香豆素类

warfarinwarfarin 华法林华法林

dicoumaroldicoumarol 双香豆素双香豆素

acenocoumarolacenocoumarol 醋硝香豆素醋硝香豆素


ThrombosisThrombosis injures vital organsinjures vital organs

Stage IStage I

Stage IIStage II

Stage IIIStage III

II IIa

I Ia

外源性外源性

（组织损伤）（组织损伤）内源性内源性

（血管壁损伤）（血管壁损伤）

Major reactions of blood coagulationMajor reactions of blood coagulation

Coumarins


HeparinHeparin 肝素肝素

Molecular weights:Molecular weights: 3~30 3~30 kDakDa; mean 15 ; mean 15 kDakDa


1. 1. Pharmacological effectsPharmacological effects

(1) Anticoagulation(1) Anticoagulation

Increasing the activity of AT III:Increasing the activity of AT III: The AT III The AT III

inhibiting the activity of the activated inhibiting the activity of the activated IIaIIa, , VIIaVIIa, , IXaIXa, , XaXa, , XIIaXIIa, , etc.etc.

Rapid and short (2~4 h)Rapid and short (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 (2) Anti ––atherosclerosisatherosclerosis

blood lipids blood lipids

protecting endothelial cellsprotecting endothelial cells

inhibiting the hypertrophy of smooth muscle inhibiting the hypertrophy of smooth muscle

cellscells

(3) Other effects: (3) Other effects:

AntiinflammatoryAntiinflammatory, , antioxydantantioxydant effects, effects, etc. etc.


2. 2. Clinical usesClinical uses

(1) Thrombosis:(1) Thrombosis: pulmonary emboli, deep vein thrombosis, pulmonary emboli, deep vein thrombosis, cardiac infraction, cardiac infraction, etcetc..

(2) Cardiac ischemia:(2) Cardiac ischemia: highhigh--risk patientsrisk patients

(3) Disseminated intravascular coagulation (DIC):(3) Disseminated intravascular coagulation (DIC): early use.early use.

(4) Prevention of coagulation (4) Prevention of coagulation in vitroin vitro:: cardiovascular cardiovascular surgery, surgery, hemodialysishemodialysis, cardiac , cardiac canulacanula, , etc.etc.


3. 3. Adverse effectsAdverse effects

(1) (1) Bleeding (at higher doses)Bleeding (at higher doses)

ProtamineProtamine is the inhibitor of heparin.is the inhibitor of heparin.

1 mg (1 mg (protamineprotamine 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):): warfarinwarfarin should should be substituted if the platelet count fallsbe substituted if the platelet count falls

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


Low molecular weight heparinLow molecular weight heparin

Mean MW = 1Mean MW = 1～～12 12 kDakDa

Features:Features:

Stronger effects on Stronger effects on XaXa, , XIIaXIIa than on than on IIaIIa

Stronger in inhibiting thrombosis/coagulationStronger in inhibiting thrombosis/coagulation

High bioavailability; Longer half High bioavailability; Longer half --lifelife

Weak bleeding effectsWeak bleeding effects


WarfarinWarfarin 华法林华法林



(1) Mechanisms of action:(1) Mechanisms of action:

antagonizing antagonizing vitaminevitamine K,K, inhibiting of inhibiting of carboxylationcarboxylation of the of the

glutamicglutamic acid residues of the acid residues of the factorsfactors II, VII, IX, XII, VII, IX, X , and , and reducing the activated II, VII, IX, Xreducing 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 1~3

days, and lasts for 4 daysdays, and lasts for 4 days

effective only effective only in vivoin vivo

Sites of Sites of warfarinwarfarin actionaction

warfarinwarfarin actionactionFactor 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VitVit KK 环氧型环氧型VitVit KK

COO-



Anticoagulation Anticoagulation in vivoin vivo


(1) Bleeding:(1) Bleeding: vvitamineitamine K may antagonize the K may antagonize the reaction; reaction; interrelactioninterrelaction with other agentswith 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. Drug interactionsDrug interactions

Plasma protein binding Plasma protein binding replacementreplacement

Hepatic metabolism:Hepatic metabolism:

inhibitioninhibition

potentiationpotentiation

B.B. AntiplateletAntiplatelet drugsdrugs

B.B. AntiplateletAntiplatelet drugsdrugsInhibition of platelet metabolismsInhibition of platelet metabolismsInhibitors of cyclic nucleotide Inhibitors of cyclic nucleotide phosphodiesterasephosphodiesterase::

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 TXAreceptor antagonists and TXA2 2 synthetasesynthetase inhibitors:inhibitors:

ridogrelridogrel 利多格雷利多格雷, , picotamidepicotamide 匹可托安匹可托安

Activators of adenosine Activators of adenosine cyclasecyclase:: epoprostenolepoprostenol 依前列醇依前列醇

Inhibition of ADPInhibition of ADP--induced platelet activation induced platelet activation

ticlopidineticlopidine 噻氯匹定噻氯匹定

GpGp IIb/IIIaIIb/IIIa receptor antagonistsreceptor antagonistsabciximababciximab 阿昔单抗阿昔单抗

(C7E3Fab(C7E3Fab))


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

O

Aspirin Aspirin

阿司匹林阿司匹林


small doses (30small doses (30～～100 mg/d):100 mg/d): inhibiting TXAinhibiting TXA22

synthesis, preventing thrombosis.synthesis, preventing thrombosis.

used to treat ischemic heart disease, reduce the used to treat ischemic heart disease, reduce the

mortality of mortality of myocardiacmyocardiac infarction, and prevent infarction, and prevent cerebral thrombosis.cerebral thrombosis.

larger doses:larger doses: inhibiting PGIinhibiting PGI22 synthesis, synthesis, promoting thrombosis.promoting thrombosis.

PGIPGI22 :: vasodilationvasodilation and platelet and platelet depolymerizationdepolymerization ((血小板血小板

解聚解聚).).

The mechanism of The mechanism of aspirin:aspirin:

Target enzymes Target enzymes acetylatedacetylated

C.C. Thrombolytic drugsThrombolytic drugs

C.C. Thrombolytic Thrombolytic drugsdrugs


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

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

Tissue Tissue plasminogenplasminogen activator ( tactivator ( t--PAPA，，组织组织纤溶酶原激活剂纤溶酶原激活剂

))

i.v.i.v. TT1/21/2 = 3~8 min= 3~8 min

Action of thrombolytic drugsAction of thrombolytic drugs

tt--PAPA(+)(+)


Common adverse effectsCommon adverse effects

bleedingbleeding

antidotes:antidotes: antifibrinolyticantifibrinolytic drugsdrugs

BleedingBleeding

ThrombolysisThrombolysis

D.D. Drugs for treatment Drugs for treatment of bleedingof bleeding

D.D. Drugs for treatment of bleedingDrugs for treatment of bleeding

VitamineVitamine KK

CarboxylationCarboxylation of the of the glutamicglutamic acid acid residues of factors II, IIV, IX, X, protein C.residues of factors II, IIV, IX, X, protein C.

Preventing bleeding with Preventing bleeding with vitaminevitamine K K deficiency or deficiency or warfarinwarfarin--induced bleedinginduced bleeding

Vitamin KVitamin K Vitamin KVitamin K


ThrombinThrombin--like agentslike agents

thrombin,thrombin,

prothrombinprothrombin complex,complex,

used for various bleedingused for various bleeding


Drugs preventing activation of Drugs preventing activation of antifibrinolyticsantifibrinolytics

aprotininaprotinin ((抑肽酶）抑肽酶）

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

pp--aminomethylbenzoicaminomethylbenzoic acideacide (PAMBA, (PAMBA, 氨甲氨甲

苯酸）苯酸）

used forused for preventing the activation preventing the activation

fibrinolysisfibrinolysis and resultant bleedingand resultant bleeding

Inhibiting Inhibiting plasminogenplasminogen activationactivation

E.E. Drugs for treatment Drugs for treatment of anemiaof anemia

E.E. Drugs for treatment of anemiaDrugs for treatment of anemia

Anemia may result from the excess destruction of Anemia may result from the excess destruction of erythrocytes, and nutritional deficiencies (iron, erythrocytes, and nutritional deficiencies (iron, minerals, cobalt, vitamin Bminerals, cobalt, vitamin B1212 , folic acid, ascorbic , folic acid, ascorbic acid, riboflavin, copper, zinc, etc.acid, riboflavin, 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 : :

megaloblasticmegaloblastic anemiaanemia

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 Interaction with other drugs or diet in the GI tracttract

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

3. Adverse effects:3. Adverse effects: GI reactions, hypersensitivityGI reactions, hypersensitivity

Acute intoxication:Acute intoxication: severe CVS and GI reactionssevere CVS and GI reactions

-- treated with deferoxaminetreated with deferoxamine（（去铁敏）去铁敏）


Folic acidFolic acid


Regulating nucleic acid, amino acid metabolismRegulating nucleic acid, amino acid metabolism


MegaloblasticMegaloblastic anemia; MTXanemia; MTX--induced anemiainduced anemia


Rarely reportedRarely reported

Vitamin BVitamin B1212

CoCo--factor of folic acidfactor of folic acid

Important in maintaining neuron Important in maintaining neuron myelinationmyelination


Erythropoietin (EPO)Erythropoietin (EPO)

rhEPOrhEPO


Promoting red cell proliferation and Promoting red cell proliferation and differetiationdifferetiation


Anemia due to Anemia due to chronic renal failure with chronic renal failure with hemodialysishemodialysis,, radiotherapy, chemotherapy, AIDS, radiotherapy, chemotherapy, AIDS, etc.etc.


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

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

F.F. Hematopoietic Hematopoietic growth agentsgrowth agents

F.F. Hematopoietic growth agentsHematopoietic growth agents

GranulaocyteGranulaocyte colonycolony--stimulating factorstimulating factor GG--CSF CSF 粒细胞集落刺激因子粒细胞集落刺激因子

GranulaocyteGranulaocyte/macrophage colony/macrophage colony--stimulating stimulating factor factor GMGM--CSF 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 ((chemotheapychemotheapy or radiotherapy), or radiotherapy), autologousautologous bone marrow transplantation, bone marrow transplantation, myelodysplasiamyelodysplasia, , aplasticaplastic anemia, AIDSanemia, AIDS--associated associated neutropenianeutropenia

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

G.G. Drugs for treatment Drugs for treatment of of hypovolemiahypovolemia

G.G. Drugs for treatment of Drugs for treatment of hypovolemiahypovolemia

DextranDextran 右旋糖酐（葡聚糖右旋糖酐（葡聚糖））

HydroxyethylHydroxyethyl starchstarch 羟乙基淀粉羟乙基淀粉

Increasing blood volumeIncreasing blood volume

Inhibiting platelet aggregation (~ MW 40,000)Inhibiting platelet aggregation (~ MW 40,000)

Osmotic diuretic effectsOsmotic diuretic effects

hydroxyethylhydroxyethyl starch starch 羟乙基淀粉羟乙基淀粉

Enzymatic degradation and excretion of Enzymatic degradation and excretion of hydroxyethylhydroxyethyl starchstarch

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Chapter 4 Drugs acting on the blood and blood-forming organsm-learning.zju.edu.cn/G2S/eWebEditor/uploadfile/... · 2012-03-09 · Drugs affecting the blood and blood- -forming organs