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

Chapter 36Chapter 36

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

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

Anticoagulant drugsAnticoagulant drugsAntiplatelet drugsAntiplatelet drugsThrombolytic drugsThrombolytic drugsDrugs for treatment of bleeding Drugs for treatment of bleeding

Drugs for treatment of anemiaDrugs for treatment of anemia Hematopoietic growth agentsHematopoietic growth agents

Drugs for treatment of hypovolemiaDrugs for treatment of hypovolemia

Coagulation Coagulation - bleeding- bleeding

Blood cell Blood cell growthgrowth

Blood Blood volumevolume

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 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

A.A. Anticoagulant drugs Anticoagulant drugs

Thrombosis:Thrombosis: injury in vital organs injury in vital organs

Coumarins

Stage IStage I

Stage IIStage II

Stage IIIStage III

A.A. Anticoagulant drugs Anticoagulant drugs

HeparinHeparin 肝素肝素

A.A. Anticoagulant drugs Anticoagulant drugs1. 1. Pharmacological effectsPharmacological effects (1) Anticoagulation(1) Anticoagulation Increasing the activity of AT III:Increasing the activity of AT III: The AT III inhibiting t The AT III inhibiting t

he activity of the activated XIIa, XI, Xa, IXa,he activity of the activated XIIa, XI, Xa, IXa,ⅦⅦa, IIa, a, IIa, 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 (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: Antiinflammatory, antioxydant effects, Antiinflammatory, antioxydant effects, etc. etc.

Effect of heparinEffect of heparin

A.A. Anticoagulant drugs Anticoagulant drugs

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: high-risk patientshigh-risk patients

(3) Prevention of coagulation (3) Prevention of coagulation in vitroin vitro:: cardiovascular sucardiovascular surgery, hemodialysis, cardiac canula, rgery, hemodialysis, cardiac canula, etc.etc.

(4) Disseminsted intravascular coagulation (DIC):(4) Disseminsted intravascular coagulation (DIC): eaearly use.rly use.

A.A. Anticoagulant drugs Anticoagulant drugs

3. 3. Adverse effectsAdverse effects

(1) (1) Bleeding (at higher doses)Bleeding (at higher 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 shoulwarfarin should be substituted if the platelet count fallsd be substituted if the platelet count falls

(3) Others:(3) Others: allergy, local necrosis, long-term use: alpallergy, local necrosis, long-term use: alp

ecia (ecia ( 脱发脱发 ), osteoporosis (), osteoporosis ( 骨质疏松骨质疏松 ), ), etc.etc.

A.A. Anticoagulant drugs Anticoagulant drugs

Low molecular weight heparinLow molecular weight heparin

Mean MW = 1Mean MW = 1 ～～ 12 kD12 kD Features:Features: Stronger effects on Xa, XIIa than on IIaStronger effects on Xa, XIIa than on IIa Stronger anticoagulantsStronger anticoagulants Longer half -lifeLonger half -life Weak bleeding effectsWeak bleeding effects

A.A. Anticoagulant drugs Anticoagulant drugs

WarfarinWarfarin 华法林华法林

A.A. Anticoagulant drugs Anticoagulant drugs

1. 1. Pharmacological effectsPharmacological effects

(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 induc , and inducing the activated II, VII, IX, X ing 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

Sites of warfariSites of warfarin actionn action

A.A. Anticoagulant drugs Anticoagulant drugs

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

3. 3. Adverse effectsAdverse effects (1) Bleeding:(1) Bleeding: vvitamine K may antagonite the reitamine K may antagonite the re

action; Interrelaction with other agentsaction; Interrelaction 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. Drug interactionsDrug interactions

Plasma protein binding Plasma protein binding replacementreplacement

Hepatic metabolism:Hepatic metabolism:

inhibitioninhibition

stimulationstimulation

B.B. Antiplatelet drugs Antiplatelet drugsInhibition 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: aspirin aspirin 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

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))

B.B. Antiplatelet drugs Antiplatelet 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

O

Aspirin Aspirin

阿司匹林阿司匹林

B.B. Antiplatelet drugs Antiplatelet drugs

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

nthesis, preventing thrombosis.nthesis, 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

(( 血小板解聚血小板解聚 ).).

The mechanism of The mechanism of aspirin:aspirin:

Target enzymes Target enzymes acetylatedacetylated

C.C. Thrombolytic Thrombolytic drugsdrugs

C.C. Thrombolytic drugs Thrombolytic 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-PA )Tissue plasminogen activator ( t-PA ) i.v.i.v. T T1/21/2 = 3~8 min = 3~8 min

Action of thrombolytic drugsAction of thrombolytic drugs

C.C. Thrombolytic drugs Thrombolytic drugsCommon adverse effectsCommon adverse effects bleedingbleeding antidotes:antidotes: antifibrinolytic drugsantifibrinolytic drugs

BleedingBleeding

ThrombolysisThrombolysis

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

Vitamine KVitamine K

Carboxylation of the glutamic acid residues of factoCarboxylation of the glutamic acid residues of factors II, IIV, IX, X, protein C.rs II, IIV, IX, X, protein C.

Preventing bleeding with vitamine K deficiency or Preventing bleeding with vitamine K deficiency or warfarin-induced bleedingwarfarin-induced bleeding

Vitamin KVitamin K Vitamin KVitamin K

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

Thrombin-like agentsThrombin-like agents

thrombin,thrombin, prothrombin complex,prothrombin complex, used for various bleedingused for various bleeding

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

Drugs preventing activation of antifibrinolytDrugs preventing activation of antifibrinolyticsics

aprotinin, aprotinin, tranexamic acid tranexamic acid (AMCHA, (AMCHA, 氨甲环酸氨甲环酸 )) p-aminomethylbenzoic acidep-aminomethylbenzoic acide (PAMBA, (PAMBA, 氨氨甲苯酸）甲苯酸）

used forused for preventing the activation fibrinolpreventing the activation fibrinolysis and resultant bleedingysis and resultant bleeding

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

Anemia may result from the excess destruction of eAnemia may result from the excess destruction of erythrocytes, and nutritional deficiencies (iron, minerythrocytes, and nutritional deficiencies (iron, minerals, cobalt, vitamin Brals, cobalt, vitamin B1212, folic acid, ascorbic acid, ri, folic acid, ascorbic acid, ri

boflavin, copper, zinc, etc.boflavin, 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

Erythropoietin (EPO)Erythropoietin (EPO) promoting red cell proliferation and differetiationpromoting red cell proliferation and differetiation

E.E. Drugs for treatment of anemia Drugs for treatment of anemiaIronIron

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 tInteraction with other drugs or diet in the GI tractract

2. Used for anemia due to loss of erythrocytes an2. Used for anemia due to loss of erythrocytes and iron deficiency d iron deficiency

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

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

Folic acid and vitamin BFolic acid and vitamin B1212

1. 1. Pharmacological effectsPharmacological effectsRegulating nucleic acid, amino acid metabolismRegulating nucleic acid, amino acid metabolism 2. 2. Clinical usesClinical usesMegaloblastic anemiaMegaloblastic anemia 3. 3. Adverse effectsAdverse effectsRare reportsRare reports

Folic acid metabolism Folic acid metabolism and the effect of and the effect of vitamin Bvitamin B1212

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

Erythropoietin (EPO)Erythropoietin (EPO) rhEPOrhEPO 1. 1. Pharmacological effectsPharmacological effects promoting red cell proliferation and differetiationpromoting red cell proliferation and differetiation 2. 2. Clinical usesClinical usesAnemia due to Anemia due to chronic renal failure with hemodialysichronic renal failure with hemodialysi

s,s, radiotherapy, chemotherapy, AIDS, radiotherapy, chemotherapy, AIDS, etc.etc. 3. 3. Adverse effectsAdverse effectsHypertension, 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 growth agents Hematopoietic growth agents

Granulaocyte 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 (chemotheapy or radiotherapy), (chemotheapy or radiotherapy), autologous bone marrow transplantation, myelodyspautologous bone marrow transplantation, myelodysplasia, aplastic anemia, AIDS-associated neutropenialasia, aplastic anemia, AIDS-associated neutropenia

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

G.G. Drugs for treatment of hypovolemia Drugs 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 volumeIncreasing blood volume Inhibiting platelet aggregation (~ MW 40,000)Inhibiting platelet aggregation (~ MW 40,000)Osmotic diuretic effectsOsmotic diuretic effects