drugs affecting blood and blood-forming organs ( 作用于血液和造血系统药物 ) tang huifang...

Drugs affecting blood Drugs affecting blood and blood-forming and blood-forming

organsorgans

(( 作用于血液和造血系统药作用于血液和造血系统药物物 ))

Tang Huifang (Tang Huifang ( 汤慧芳汤慧芳 ))Email: [email protected]: [email protected]

Drugs affecting the blood Drugs affecting the blood and and

blood-forming organsblood-forming organsCoagulatioCoagulation- bleedingn- bleeding

Anticoagulant drugs( 抗凝血药 )Antiplatelet drugs( 抗血小板药 )Fibrinolytic drugs( 纤维蛋白溶解药 )Hemostatic drugs( 止血药 )

Blood cell Blood cell growthgrowth

Blood Blood volumevolume

Antianemic drugs( 抗贫血药 ) Hematopoietic Hematopoietic growth agentsgrowth agents agents ( 促白细胞生长药 )• Drugs for treatment ofDrugs for treatment of

hypovolemia hypovolemia ( 血容量扩充剂 )

General conceptGeneral concept

凝血酶间接抑制剂： Heparin （肝素） Low molecular weight heparin （低分子量肝素） Fondaparinux ( 磺达肝癸钠 )

Oral direct Factor X inhibitors ： Apixaban （阿派沙班）、 Rivaroxaban( 利伐沙班 )

凝血酶直接抑制剂（ direct thrombin inhibitors ， DTIs) ： ORAL DTIs: Dabigatran ( 达比加群 )

Factor II inhibitor: Lepirudin （重组水蛭素 / 来匹卢定）、 desirudin （地西卢定）、 bivalirudin( 比伐卢定 ) 、 Argatroban （阿加曲班）

Vitamin K antagonists: Coumarins 香豆素类 Warfarin （华法林）、 dicoumarol （双香豆素）、

acenocoumarol （醋硝香豆素）

Part 1. Anticoagulants 抗凝血药

Anticoagulant Anticoagulant drugsdrugs

MW of 5MW of 5 ～～ 30 kD(mean30 kD(mean 12 kD).12 kD).

Heparin （肝素）

化学：强酸性，具强负电荷（抗凝作用基础）

特效解毒剂：鱼精蛋白（碱性，强正电荷）

Heparin accelerates inactivation of coagulation factors by antithrombin.

ⅪⅪaa Ⅸ、Ⅸ、 aa Ⅹ、Ⅹ、 aa Ⅻ、Ⅻ、 aa

1. 1. Pharmacological effectsPharmacological effects

(1)Anticoagulation:(1)Anticoagulation: 1)1)HeparinHeparin increase the activity of AT Ⅲ increase the activity of AT Ⅲ The The AT Ⅲ AT Ⅲ may inhibit the activity of may inhibit the activity of

the activated the activated ⅡaⅡa 、、ⅪⅪ aa Ⅸ、Ⅸ、 aa Ⅹ、Ⅹ、 aa Ⅻ、Ⅻ、 a, a, to cause anticoagulation.to cause anticoagulation.

2)Characteristics of 2)Characteristics of anticoagulationanticoagulation ① ①ItIt is effective is effective in vitroin vitro and and in vivoin vivo ; ; ② ②ItsIts effects are rapid(iv) ( effects are rapid(iv) (<10min<10min)and )and

short(short(33 ～～ 4 h4 h): activated partial ): activated partial thromboplastin time(APTT) ↑thromboplastin time(APTT) ↑


(2)Anti-atherosclerosis:(2)Anti-atherosclerosis: 1)Regulating blood lipids: 1)Regulating blood lipids: VLDLVLDL 2)Protecting endothelial cells;2)Protecting endothelial cells; 3)Inhibiting the proliferation of 3)Inhibiting the proliferation of

smooth muscle cells.smooth muscle cells. 4)Inhibits platelet aggregation4)Inhibits platelet aggregation

(3)Other effects: (3)Other effects: Anti-complement,Anti-complement, anti-anti-

inflammation, and inflammation, and blood blood viscosityviscosity （（血液粘度）） ..


2. 2. PharmacokineticsPharmacokinetics (1)(1)HeparinHeparin is not is not

absorbed by GI.absorbed by GI. ItIt need iv. or sc. need iv. or sc.

(2)plasma protein (2)plasma protein binding rate: 80%binding rate: 80%

(3)t(3)t1/21/2: 1: 1 ～～ 2 hr.2 hr. ItIt’s metabolised in ’s metabolised in liver, and partially liver, and partially degraded degraded heparinheparin appears in the urine.appears in the urine.



3. Clinical uses(1)Anticoagulation Such as: pulmonary emboli; deep vein

thrombosis; cardiac infarction, etc.(2)Heart ischemia Prevent emboli in coronary artery——

early use. (3)DIC(disseminated intravascular

coagulation, 弥散性血管内凝血 ) Such as: certain surgical procedures,

hemodialysis, cardiac catheterization, etc.

(4)Prevent coagulation in vitro

4. Adverse effects (1)Bleeding(5% ～ 10%) Protamine sulfate （硫酸鱼精蛋白） is the antagonist of heparin. 1mg protamine=100U heparin.

(2) Heparin-induced thrombocytopenia( 血小板减少症 ) (HIT)

5% ～ 6%, Warfarin should be substi-tuted if the platelet count falls.

(3)Others Allergy( 过敏反应 ); Local necrosis( 局部坏死 ), when sc; Increased loss of hair and reversible alopecia( 脱发 ); Osteoporosis( 骨质疏松 ).(4) Contraindicated in patients with bleeding risk

Anticoagulant Anticoagulant drugdrugss

Low molecular weight heparin(LMWH, 低分子肝素 )


Mean MW = 1 ～ 12 kD

Stronger Effects on Ⅹa, Ⅻa than on Ⅱa

常用 LMWH ： enoxaparin ( 依诺肝素 ) Tedelparin ( 替地肝素 ) Fraxiparin （弗希肝素） Logiparin （洛吉肝素） Lomoparin （洛莫肝素）

FatcorⅩa

FatcorⅩa

Coumarins( 香豆素类 )Warfarin( 华法林 ); Dicoumarol( 双香豆素 ); Acenocoumarol( 醋硝香豆素 )

AnticoagulantAnticoagulant drugsdrugs

苯茚二酮

双香豆素华法林

1. Pharmacological effects (1)Properties: Slowly and longer duration: The effect appears after p.o. 1~3 days, and lasts for 4 days Effective only in vivo. (2)Mechanisms of action: Antagonizes vitamin K. It inhibits carboxylation of the gluta-mic acid residues of the factors Ⅱ、Ⅶ 、Ⅸ、Ⅹ , to decrease the activation of factors Ⅱ、Ⅶ 、Ⅸ、Ⅹ .


Mechanism of Coumarins

2. Clinical uses Anti-coagulation in vivo(such as deep vein thrombosis, pulmonary emboli, and cardiac infarction, etc).

3. Adverse effects (1)Bleeding(9% ～ 10%) Can affect all organs in body. Vitamin K1 may antagonist this reaction, can treat with fresh blood or plasma and prothrombin complex( 凝血酶原复合物 ). (2)Necrosis of skin and parenchyma( 皮肤和软组织坏死 ). (3)Liver injury(warfarin).


4. 4. Drug interactionsDrug interactions

(1)Plasma protein (1)Plasma protein binding replacementbinding replacement

(2)Hepatic metabolism:(2)Hepatic metabolism:

enzyme inhibitionenzyme inhibition

enzyme inductionenzyme induction

Part 2. Antiplatelet drugs(Antiplatelet drugs( 抗血小抗血小板药板药 ))

Thrombus formation at the site of the damaged vascular wall (EC, endothelials cell) and the role of platelets and clotting factors. Platelet membrane receptors include the glycoprotein (GP) Ia receptor, binding to collagen (C); GP Ib receptor, binding von Willebrand factor (vWF); and GP IIb/IIIa, which binds fibrinogen and other macromolecules. Antiplatelet prostacyclin (PGI2) is released from the endothelium. Aggregating substances released from the degranulating platelet include adenosine diphosphate (ADP), thromboxane A2 (TXA2),and serotonin (5-HT).

PGI2受体

TXA2受体

GPⅡb/Ⅲa 受体

ADP受体

→ PGI2

Antiplatelet drugs(Antiplatelet drugs( 抗血小板药抗血小板药 ))Types Drugs Remarks

1. Platelet metabolism inhibitor

Aspirin( 阿司匹林 ) Cyclooxygenase inhibitor, TXA2Clinical use: Angina, infarction

Dipyridmole( 双嘧达莫 , 潘生丁 )

Reversibly inhibits PDE, cAMP , platelet reactivity , t1/2: 12 hr, Clinical use: Thrombosis,

Ridogrel( 利多格雷 ), picotamide( 匹可托安 )

TXA2 synthase inhibitor TXA2 receptor blocker, Clinical use: Thrombosis

Epoprostenol( 依前列醇 )

AC activitor cAMP ,Clinical use: Thrombosis

2. Platelet activation inhibitor

Ticlopidine( 噻氯匹定 ) Clopidogrel ( 氯吡格雷 )

Selectively inhibit ADP induced activation of platelet functionClinical use: substituded for aspirin in ischemic heart, brain disorders

3. Platelet GpⅡb/Ⅲa receptor antigonist

Abciximab (C7E3Fab 阿昔单抗 )

Competitive Platelet GpⅡb/Ⅲa re-ceptor antigonistClinical use: angina, infarction

Inhibition of AA metabolism in plateletsIrreversible cyclooxygenase inhibitors(COX inhibitor) ： Aspirin ( 阿司匹林 ) 、 Triflusal ( 三氟柳 )

Thromboxane synthase inhibitors and Thromboxane receptor antagonists ： Ridogrel( 利多格雷 ), picotamide( 匹可托安 ) 、 Ozagrel 、 Seratrodast （塞曲司特）

Increase intracellular cAMP Phosphodiesterase inhibitors(PDE inhibitor) ： Cilostazol ( 西洛他唑 )

Adenosine reuptake inhibitors ： Dipyridamole ( 双嘧达莫 , 潘生丁 )

Activators of adenosine cyclase: epoprostenol （依前列醇）

The class of antiplatelet drugs

Platelet activation inhibitor

Adenosine diphosphate (ADP) receptor inhibitors(P2Y12 inhibitor) ： Clopidogrel ( 氯吡格雷 ) 、 Prasugrel ( 普拉格雷 ) 、 Ticagrelor ( 替卡格雷 )

Ticlopidine ( 噻氯匹定 )

Protease-activated receptor-1 (PAR-1) antagonists: Vorapaxar ( 沃拉帕沙 )

Glycoprotein IIB/IIIA inhibitors ：Intravenous use only: Abciximab ( 阿昔单抗 ) 、 Eptifibatide ( 依替巴肽 ) 、

Tirofiban ( 替罗非班 ) 、Oral use: Xemilofiban （珍米洛非班）、 Fradafiban （夫雷非班）、

Anti-platelet Anti-platelet drugsdrugs

Aspirin(Aspirin( 阿司匹林阿司匹林 ))Acetylsalicylic acid(Acetylsalicylic acid( 乙酰水杨乙酰水杨

酸酸 ))

CH3

COOH

O C

O

ItIt is a cyclooxygenase inhibitor, is a cyclooxygenase inhibitor, inhibit-ing TXAinhibit-ing TXA22 synthesis. synthesis.

MMechanismechanism:: Target Target enzymes enzymes (cyclooxygenas(cyclooxygenase) are e) are acetylated and acetylated and inactive.inactive.


AspiriAspirinn Small doses (30Small doses (30 ～～ 100 mg/day):100 mg/day):

inhibiting TXAinhibiting TXA22 synthesis, synthesis, preventing thrombosis.preventing thrombosis. used to treat ischemic heart used to treat ischemic heart disease, reduce the mortality of disease, reduce the mortality of myocardiac infar-ction, and prevent myocardiac infar-ction, and prevent cerebral thrombosis.cerebral thrombosis.

Larger doses ( Larger doses ( 500 mg/day): 500 mg/day):

inhibiting inhibiting PGIPGI22 synthesis, synthesis, promoting thrombosis.promoting thrombosis. ———— PGIPGI22:: vasodilation and vasodilation and platelet depolymerization(platelet depolymerization( 血小板解血小板解聚聚 ).).

Dipyridamole( 双嘧达莫 , Persantin, 潘生丁 )

Reversibly inhibits phosphadiesterase (PDE) of platelet, cAMP , platelet reactivity , t1/2 12 hr. Clinical uses: Prevent thrombosis.


Ticlopidine( 噻氯匹定 )Selectively interferes ADP induc

ed platelet activationInhibits platelet function. Clinical uses: Prevent cerebral

apoplexy ( 中风 ) and cardiac infarction, etc.

Part 3. Fibrinolytic drugs 纤维蛋白溶解药

阿尼普酶

阿替普酶尿激酶链激酶

纤溶酶

纤溶酶原

凝血酶凝血酶

纤维蛋白原

++

++

--

Alteplase(Tissue plasminogen activator

t-PA, 组织型纤溶酶原激活剂 ) 1. Effect: Local action on the thrombotic fibrin

( 血栓纤维蛋白 ) to produce fibrinolysis;

iv. t1/2=3 ～ 8 min, effect 1 ～ 3 hr. A potentially important agent in treating thromboembolic disease.

2. ADR: bleeding.

Fibrinolytic Fibrinolytic drugsdrugs

Urokinase( 尿激酶 , UK) 1. Effect: Plasminogen activator, t1/2=15 min;

2. Clinical use: Severe pulmonary emboli, and

deep vein thrombosis. 3. Adverse reaction: (1)systemic fibrinolytic state, (2)bleeding.


Streptokinase( 链激酶 , SK)1. Pharmacological effect: plasminogen( 纤溶酶原 ) activator, t1/2 = 23 min;2. Clinical Use: Severe pulmonary emboli, and deep vein thrombosis3. Adverse reaction: Systemic fibrinolytic state which can lead to bleeding problems(5%); Antigenicity——allergy.


Anistreplase( 阿尼普酶 ) It is a streptokinase-plasminogen complex, in which lys-plasminogen is acylated at its catalyicsite serine. The acyl group is hydrolyzed in vivo, allowing the complex to bind to fibrin prior to activation, and this modification confers some specificity toward clots on the fibrinolytic process. It is used coronary thrombolysis also.


Adverse effects

The thrombolytic agents do not distinguish between the fibrin of an unwanted thrombus and the fibrin of a beneficial hemostatic plug.

Hemorrhage is a major side effect.Antidotes: fibrinolytic inhibitors (PAMBA

氨甲苯酸氨甲苯酸 , AMCHA 氨甲环酸氨甲环酸 )

Part 4. Hemostatic drugs (Haemostats, 促凝血药 , 止血药 )

Vitamin K1. Carboxylation of the glutamic acid

residues of II, VII, IX, X, protein C.2. To prevent bleeding with vitamin

K deficiency.3. Response to vitamin K is slow, the

severe hemostasis patients should be infused with fresh plasma imme-diately.

Thrombin-like agents( 凝血酶制剂 )

Thrombin( 凝血酶 , factor Ⅱ) Prothrombin complex( 凝血酶原复合物 , factor Ⅱ 、Ⅶ 、Ⅸ、Ⅹ ) used for various bleeding.

Globulin anti-hemophilia(factor Ⅷ, 抗血友病球蛋白 )

used for treatment for hemophilia.

HaemostaHaemostatsts

Drugs preventing activation of Drugs preventing activation of antifibrinolyticsantifibrinolytics

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 preventing the activation fibrinolysis and resultant bleedingfibrinolysis and resultant bleeding

HaemostaHaemostatsts

Inhibiting Inhibiting plasminogen plasminogen

activationactivation

Part 5. Antianemic drugs 抗贫血药

1. Cause of anemia: (1)Anemia may result from the excess destruction of erythrocytes; (2)Anemia may result from nutritional deficiencies, including: iron, minerals, vitamins (B12 and folic acid), ascorbic acid, riboflavin, etc. 2. Drugs for treatment of anemia: Iron preparations; Folic acid and vitamin B12; Erythropoietin(EPO), and rhEPO (Reconbanant human EPO)

Iron preparations( 铁制剂 ) Ferrous sulfate( 硫酸亚铁 ), Ferric ammonium citrate( 枸橼

酸铁铵 ) Iron dextran( 右旋糖酐铁 ), Iron sorbitex( 山梨醇铁 )1. Clinical Uses Iron deficiency anemia. 2. ADRs GI reactions: nausea, vomiting, and diarrhea.

Acute intoxication: severe CNS symptoms and GI reactions.

In this time, treatment with deferoxamine( 去铁胺 ).

Antianemic Antianemic drugsdrugs

Folic acid( 叶酸 ) & Vitamin B12

Both Folic acid( 叶酸 ) and Vitamin B12 are essential for the synthesis of DNA, this process is impaired in patients with megaloblastic anemia( 巨幼红细胞贫血 ).1. Pharmacological effects Regulating nucleic acid & amino acid metabolism.2. Clinical uses Megaloblastic anemia. 3. Adverse reaction Rare reports


Erythropoietin(EPO, Erythropoietin(EPO, 红细胞生成素红细胞生成素 )) rhEPO(rhEPO( 重组人红细胞生成素重组人红细胞生成素 ))

1. Pharmacological effects1. Pharmacological effects promoting red cell proliferation promoting red cell proliferation and differentiationand differentiation

2. Clinical uses2. Clinical uses anemia due toanemia due to chronic renal chronic renal failure withfailure with hemodialysis,hemodialysis,

radiotherapy,radiotherapy, chemo-therapy, AIDS, chemo-therapy, AIDS, etc.etc.

3. Adverse effects3. Adverse effects Hypertension, epilepsy, Hypertension, epilepsy, thrombosis, etc.thrombosis, etc.


Part 6. Haemopoietic growth factors

促白细胞生成药非格司亭（ filgrastim,G-CSF: 粒细胞集落刺激因子 )沙格司亭（ sargramostim ， GM-CSF: 粒细胞 /

巨噬细胞集落刺激因子 , 生白能 )1. Effects and mechanism of effects (1)Stimulates the formation of

macrophage, granulocyte colony; (2)Stimulates proliferation,

differentiation and maturity of blood stem cell;

(3)Promotes the release of blood cell from bone marrow

(4)Strenghtens the function of granulocyte

2. Clinical uses Bone marrow suppression from chemotherapy and radiotherapy of neoplasm.

3. Adverse effects GI reactions, liver injury, fever, myalgia( 肌肉痛 ).

Haemopoietic growth Haemopoietic growth factorsfactors

Part 7. Agents correcting blood volume( 血容量扩充剂 )

Dextran( 右旋糖酐 ): (C6H10O5)n Dextran-10; Dextran-40; Dextran-70

1. Pharmacological effects: (1)Blood volume , (2)blood viscosity , platelet binding and aggregation ;

(3)osmotic diuretic effects.2. Clinical Use: Anti-shock, maintain blood volume.3. ADRs: hypersensitivity, bleeding.

Reference

Mega JL1, Simon T2. Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments. Lancet. 2015 Mar 11. pii: S0140-6736(15)60243-4. doi: 10.1016/S0140-6736(15)60243-4. [Epub ahead of print]

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drugs affecting blood and blood-forming organs ( 作用于血液和造血系统药物 ) tang huifang...

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