造血系统药物英文

Drug Affecting hematopoiesis system,Department of Pharmacology,When your finger is stuck by a needle.,Overview,Anticoagulants and coagulants maintain the normal blood flow.,Coagulation,Coagulation is a complex process by which blood forms clots. A damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel. Disorders of coagulation can lead to an increased risk of bleeding (hemorrhage) or clotting (thrombosis).,Coagulation involves both a platelet and a coagulation factor component.Platelets immediately form a plug at the site of injury; coagulation factors respond in a complex cascade to form fibrin strands, which strengthen the platelet plug,The Classic Coagulation Pathway,Some additional information,Factors II, VII, IX, and X are vitamin K dependent.,Anticoagulants,Heparin,Heparin 1,Heparin is a polymerised glucose. It is a strong acidic molecule because of its high content of anionic sulfate and carboxylic acid.,History of Heparin,Heparin was originally isolated from liver in 1916 by McLean, a graduate student of William Henry Howell (1860-1945). Howell named the substance heparin. Howell was the first chair of the Department of Physiology at Johns Hopkins and wrote a popular textbook of medical physiology that was continued under the names of other authors until the 1990s. Charles H. Best (who also co-discovered insulin) was the first physician to introduce heparin into clinical medicine. This was done at the University of Toronto in 1935.,Heparin Source and function,Heparin is produced by mast cells.When released from mast cells, it is rapidly destroyed by macrophagesTherefore, heparin is not detected in the blood.,Heparin Action,Heparin acts by accelerating the antithrombin III reaction. Recall: antithrombin III inhibits serine proteases including factors IIa , VIIa , IXa , Xa, XIIa by forming equimolar stable complexes with them.The above reaction goes 1000 to 3000 times faster with heparin.,Heparin Action,It acts (with antithrombin III) most effectively on IIa, and to a lesser extent, on Xa, IXa, VIIa, and possibly others. The above reaction provides anticoagulant effect within minutes.,Heparin Action,Other effects: reduce the plasma CM,VLDL.anti-inflammationinhibit the proliferation of smooth muscle cells,Heparin Administration, Absorption, and Antidote,Poor oral absorption at physiological pH. Does not cross GI membrane Administered IV or SCEffect can be terminated by protamine sulfate (a basic protein isolated from Salmon sperm) that combines with heparin.,Heparin Elimination,Eliminated by mononuclear phagocyte system (RE system). Much of this clearance occurs in the liver, so clearance is reduced in cirrhosis or hepatitis. A small amount (probably LMW heparin) is eliminated by the kidney.,Heparin Uses -1,Treatment of deep venous thrombosis.Prophylactic prevention of postoperative venous thrombosis.Initial prophylactic prevention of thrombosis following a myocardial infarct.,Heparin Uses -2,In IV dialysis to prevent thrombosis in the pumps.DIC (disseminated intravascular coagulation) to prevent coagulation and consequent depletion of clotting factors in some disorders.,Heparin Toxicity - Hemorrhage,Hemorrhage can be reversed by protamine sulfate Monitoring : APTT or PTTProtamine sulfate is also an anticoagulant because it interacts with platelets, fibrinogen, and other clotting factors so it can make hemorrhage worse if more is given than is necessary.,Heparin-induced Thrombocytopenia,2nd most common side effect after bleedingOccurs in 3-5% of patients 5 to 10 days after initiation of therapy of standard heparinLower incidence in low molecular wt heparin. Can be life-threatening.,1,Heparin-induced Thrombocytopenia,Due to production of IgG against complexes of heparin with platelet factor 4. The antigen-antibody complexes will bind to adjacent platelets,causing aggregation and thromboembolism.,2,Heparin-induced Thrombocytopenia,Heparin from beef lung is more likely to cause this than heparin from porcine intestinal mucosa.Once thrombocytopenia is determined, heparin must be stopped.Platelets must NOT be given because they will react with antibody already being produced against them, causing greater chance of thrombosis.,3,Other adverse effects,Hypersensitive reaction ：Asthma , fever, urticaria.Fracture, osteoporosis(骨质疏松).,Contraindications,Patients who are sensitive to heparinActive bleeding, hemophilia(血友病）, purpura（紫癜）, thrombocytopenia（血小板减少症）Intracranial（颅内） hemorrhage, gastrointestinal ulcer, infective endocarditis.Advanced hepatic diseasePatients during or after surgery,Low Molecular Weight Heparin -1,Has an average mol. wt of 4,500 daltons Is isolated from standard heparin Is absorbed more uniformlyHigher bioavailablity (greater than 90%)Has a longer biological half-life,Low Molecular Weight Heparin - 2,Less likely to cause thrombocytopeniaCan be given SC once or twice daily without monitoring.Is cleared unchanged by kidney (do not use in renal failure!) rather than by mononuclear phagocyte system (RE system) as is for standard heparin.,Anticoagulants,Coumarins,Warfarin History,1900. Sweet clover was planted in Canada, the Dakotas, and Wisconsin because it would flourish in poor soil.improperly cured silage of sweet clover fed to cattle would kill them.1939. Campbell and Link isolated the substance as bishydroxycoumarin (dicumerol), a coumarin compound1948. Wisconsin Alumni Research Foundation developed a patentable product called Warfarin (from the initials of the foundation + -arin to indicate a coumarin compound).,1,Warfarin History,1948 -51. Warfarin becomes a common rodenticide (it still is).1951. Army inductee tried to commit suicide with Warfarin. He was saved, but the physicians remarked at how good an anticoagulant it was.1952. Warfarin introduced into clinical use as an oral anticoagulant.,2,Coumarins - structure,Mechanism of action,Courmarin decrease blood coagulation by inhibiting vitamin K epoxide reductase.This enzyme recycles oxidized vitamin K to its reduced form. And then the reduced vitamine K will go back to the recycle and participate in the carboxylation (羧化作用）of several blood coagulation proteins, factor II,VII,VI,X. For this reason, drugs in this class are also referred to as vitamin K antagonists.,Action of Coumarins,Vitamin K,Coumarins are competitive inhibitors,Coumarins - Action,Inhibits the synthesis of (in order of potency)Factor IIFactor XFactor VIIFactor IX,Coumarins - Effect,The activity of anticoagulation is delayed about 8-12 hrs until the clotting factors exhaust.,Administered orallyBiotransformed by the liverCompletely absorbed crosses all membranesCrosses GI mucosa Crosses placenta is teratogenicIs found in breast milk can affect infants development,Clinical uses,1. Prevention and treatment of thromboembolism disease, such as artrial fibrillation, myocardial infarction. And use with antiplatelet drugs (e.g. aspirin) may prevent venous thrombosis.2. Decrease venous embolism caused by surgery, rheumatic heart disease.,Adverse Effects,Bleeding: gingival（齿龈） bleeding, nose bleeding, antagonised by vitamine K1 .Cutaneous necrosis (0.01%0.1% )It can cross the placenta and causes hemorrhagic disorder in fetus.Serious birth abnormal bone formation and development .,Drug interaction,Inducer of CYP enzymes such as rifampin, phenobarbital and phenytoin sodium accelerates the metabolism of warfarin. Courmarins enhance the effects of asprin and butazolidin(保泰松）.Lack of vitamine K and large doses of antibiotics enhance the effect of courmarins.,Antiplatelet agents（抗血小板药）,Cyclooxygenase inhibitors Aspirin ADP receptor inhibitorsTiclopidine(噻氯匹定）Phosphodiesterase inhibitors Dipyridamole（双嘧达莫）Glycoprotein IIB/IIIA inhibitors - Abciximab（阿昔单抗）,COX-2 inhibitor Asprin,1. Action: Small doses (60-80 mg/d) of aspirin given orally irreversibly inhibit the synthesis of thromboxane A2 (TXA2) within the platelets by inhibition of cyclooxygenase producing an inhibitory effect on platelet .Antipyretic and analgesic effects: 0.30.6g,2.Uses,Prevention and treatmemt of thromboembolism disease, such as myocardial infarction, reducing the morbidity and mortality of myocardial infarction.,诱发聚集的因子,血小板膜磷脂酶被激活,血小板膜磷脂分解,阿司匹林抑制,（PG合成） 环化加氧酶,血管壁中PG合成酶,花生四烯酸释放,环内过氧化物（PGG2 、PGH2）,PGI2合成生理性拮抗 TXA2,TXA2合成酶,TXA2,对血小板聚集有 强大的促进作用,血小板聚集,血小板释放ADP,阿司匹林抑制血小板聚集的原理,Fibrinolytic drugs（纤维蛋白溶解药）,Streptokinase（链激酶）An extracellular protein purified from culture broths of Group C-hemolytic streptococciStreptokinase has no enzymic activity, instead it forms an active 1:1complex with plasminogen（纤溶酶原）, which then converts uncomplexed plasminogen to the active enzyme plasmin.Adverse effects: bleeding,hypersensitivity.Antidote: PAMBA,Urokinase（尿激酶）,An enzyme capable of directly degrading both fibrin and fribrinogen.Originally isolated from human urine, but it is now obtained from cultures of human fetal renal cells.More expensive than streptokinase and is usually employed in patients who are sensitive to streptokinase.,t-PA,It has low affinity for free plasminogen,but it rapidly activates plasminogen bound to fribrin in a thrombus or a hemostatic plug.Therapeutic uses: myocardial infarction, massive pulmonary emolism Short t1/2 (5 min),Coagulants,Vitamin K,1. Nature form: Vit.K1 and K2 are fat-soluble. K1 is found in food and K2 is synthesized by intestinal bacteria, both require bile salts for absorption from intestinal tract.2. Synthetic form: Vit K3 and K4 are water-soluble.,Clinical uses,Bleeding caused by lack of Vit.K:(1) Oral anticoagulants of over dose(2) Long use of broad spectrum antibiotics(3) Obstructive jaundice(4) Hemorrhage of newborn,Adverse effect,Large doses have been shown to cause allergic reactions, hemolytic anemia and cytotoxicity in liver cells.,Antianemic drugs,Anemias,1. Microcytic anemia ：Iron insufficiency 2. Macrocytic anemia ： Vitamine B12 insufficiency Folic acid insufficiency3.aplastic anemia,Iron,Absorption: duodenum and proximal jejunumTransport: transferrinStorage: ferritinExcretion: no more than 1 mg per day.,The Recommended dietary allowance for iron,For Children 0-6 months 6 mg/day 6-12 months 10 mg/day 1-10 years 10 mg/dayMen 11-14 years 12 mg/day 19 years and over 10 mg/dayWomen 11-50 years 15 mg/day 50+ years 10 mg/day Pregnant women 30 mg/day Lactating women 15 mg/day, Preparations (1) ferrous sulfate （硫酸亚铁） (2) ferric ammonium citrate (枸橼酸铁胺）(3) iron dextran(右旋糖酐铁） Adverse Effects be related to the amount of soluble iron in the upper gastrointestinal tract. nausea, heartburn , diarrhea and constipation （便秘） Antidote: deferoxamine,Folic acid（叶酸）,Its active form is tetrahydrofolate （四氢叶酸）which plays a role in transportation of one-carbon units to synthesize some important substances.,Clinical uses,Megaloblastic anemia caused by increase demand ,poor absorption of folic acid and treatment with drugs that are dihydrofolate reductase （二氢叶酸还原酶）inhibitors.Leucovorin is an antidote to effects of certain chemotherapy drugs such as methotrexate.,Folic acid supplements can correct the anemia associated with vitamin B12 deficiency. Unfortunately, folic acid will not correct changes in the nervous system that result from vitamin B12 deficiency.Patients with megaloblastic anemia need to be tested for vitamin B12 deficiency before folate treatment .,Vitamin B12,Vitamin B12 is a water soluble vitamin with a key role in the normal functioning of the brain and nervous system. B12 is also important for the normal metabolic function of folate, and therefore essential for cell growth.,Clinical Uses,pernicious anemia and megaloblastic anemia,Erythropoietin,EPO is synthesized in the kidneyAct