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1、 Chapter 29 Agents affecting blood and hematopoietic organ Thrombosis the formation of an unwanted clot within the blood vessls or heart Bleeding disorders due to failure of hemostasis and include hemophilia and vitamin K deficiency Anemia - caused by nutritional deficiencyDysfunctions of bloodDysfu
2、nctions of blood Anticoagulants Antiplatelet drugs antithrombolic drugs Fibrinolytic drugs Hemostatics Agents Used in Anemia Hematopoietic growth factors Plasma volume expandersClot formation requires platelet activation and aggregation (white clot or platelet clot), followed by formation of a fibri
3、n clot (red clot).aaaaa,a, +Prothrombin()Thrombin(a)Fibrin ( Insoluble)Fibrin (soluble)fibrinogen+IIIIIIa+Fibrin clotprocess of normal blood coagulationprocess of normal blood coagulationextrinsic pathway intrinsic pathway 1 anticoagulantsAnticoagulants are drugs employed in preventing blood coagula
4、tion. They inhibit certain clotting factors in the liver. The function of them is to: 1) prevent the formation of new blood clots. 2) keep existing blood clots from growing larger. Classification of anticoagulantsAnticoagulants both in vivo and vitro:e.g. Heparin Anticoagulants in vivo: dicoumarol A
5、nticoagulants in vitro: Sodium citrate1. Heparinv1.1 source and chemistry(1)large amount of negative charge(2)strong acidity pharmacokineticsAbsorption Administered by i.v or s.c Metabolism Excretion1.2 Pharmacological effects 1. Anticoagulative effect Mechanism: accelerate inactivation of clotting
6、factors.(a, a, a, a, a ) by enhancing the anticoagulative activity of AT ( antithrombin ). aaaaa+Prothrombin()Thrombin(a)Fibrin insolubleFibrin solublefibrinogen+IIIIIIa+Fibrin clotAT: a plasma protease inhibitorMechanism of heparin This reaction This reaction happens in normal happens in normal phy
7、siological state, physiological state, but its very slow and but its very slow and weak. weak. In the presence of In the presence of heparin (which acts heparin (which acts as an catalyst), it will as an catalyst), it will be accelerated by be accelerated by more than 1,000 more than 1,000 timestime
8、sCharacteristics of anticoagulative effect effective both in vivo and in vitro quick onset and potent effects efficacy positively relative to mocular weight 1.2 Pharmacological effects 2.Other effects adjusting blood lipid anti-inflammatory effect anti-proliferative effect on vascularsmooth muscle c
9、ell inhibiting pletelet aggregation.1.3 Clinical uses1) thromboembolic disease:deep venous thrombosis(DVT),pulmonary embolism, unstable angina,acute myocardial infarction, cerebral infarction DIC (Disseminated intravascular coagulation): early stage extracorporal circulation(eg. dialysis machine)1.4
10、 Adverse reactions Spontaneous hemorrhage : monitoring of aPTTantagonist: protamine sulfate(1mg:100u) Heparin-induced thrombocytopenia: (a decrease in circulating platelets)210 days of therapy, 3% , Others : allergic reaction osteoporosis(骨质疏松)1.5 Contraindications: 1. Bleeding tendency: Severe hype
11、rtension Ulcer surgery of the brain ,eye, spinal cord 2. pregnancy 3. Renal and hepatic dysfunctionsLMWHS (low molecular weight heparins) Weaker effect than heparin Low incidence of hemorrage Long-lasting effect Small individual deviation No need to monitor generally Coumarin derivatives-Oral antico
12、agulants These agents are often referred to as oral anticoagulants because they are administered orally, which exists as the main difference from heparin. Warfarin(华法林), Dicoumarin(双香豆素) Acenocoumarin (醋硝香豆素)pharmacokinetics Absorption: rapid and complete (warfarin) Distribution: PPBR90% Elimination
13、: liver Excretion: kindney4.1 pharmacological effects Anticoagulative effect1) mechanism: antagonizing Vit Kinhibiting the synthesis of cloting factor , Vitamin K (reduced)Vitamin K (epoxide)warfarinPrecursors of 、mature 、Vitamin K epo- Xide reductaseMechanism of Oral anticoagulants Several clotting
14、 factors (, , , , , , ) depend on vit K as a coenzyme in their complete synthesis by the liver. Oral anticoagulants antagonize VitK inhibiting the synthesis of clotting factor,inhibiting coagulation2) characteristics (1) oral administration (2) effective in vivo, not in vitro (3) slow onset, long du
15、ration (4) overcome by administration of Vitamin K 4.2 clinical uses: For long use Prevent acute deep vein thrombosis or pulmonary embolism Prevent venous throboembolism in patients undergoing orthopedic or gynecological surgery Prevent systemic embolization in patients with myocardial infarction, prosthetic heart valves or chronic atrial fibrillation4.3 adverse effects 4.3.1 Spontaneous hemorrhage :monitoring of PT (凝血酶原时间) Treatment: withdrawal of the drug; administration of vita
