1、Drug Affecting hematopoiesis systemDepartment of PharmacologyWhen your finger is stuck by a needle.Overview Anticoagulants and coagulants maintain the normal blood flow.CoagulationCoagulation is a complex process by which blood forms clots. A damaged blood vessel wall is covered by a platelet and fi

2、brin-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

3、 of injury; coagulation factors respond in a complex cascade to form fibrin strands, which strengthen the platelet plug Some additional informationFactors II, VII, IX, and X are vitamin K dependent.AnticoagulantsHeparinHistory of HeparinHeparin was originally isolated from liver in 1916 by McLean, a

4、 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. Be

5、st (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 functionHeparin is produced by mast cells.When released from mast cells, it is rapidly destroyed by macrophagesTherefore, he

6、parin is not detected in the blood.Heparin ActionHeparin 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 fas

7、ter with heparin. Heparin ActionIt 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 ActionOther effects: reduce the plasma CM,VLDL.anti-inflammationinhibit the

8、proliferation of smooth muscle cells Heparin EliminationEliminated 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 -1Treatment of

9、 deep venous thrombosis.Prophylactic prevention of postoperative venous thrombosis.Initial prophylactic prevention of thrombosis following a myocardial infarct.Heparin Uses -2In IV dialysis to prevent thrombosis in the pumps.DIC (disseminated intravascular coagulation) to prevent coagulation and con

10、sequent depletion of clotting factors in some disorders. Heparin Toxicity - HemorrhageHemorrhage 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 hemorrha

11、ge worse if more is given than is necessary. Heparin-induced Thrombocytopenia2nd 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.1Heparin-induced Thromboc

12、ytopeniaDue 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.2Other adverse effectsHypersensitive reaction ：Asthma , fever, urticaria.Fracture, osteoporosis(骨質疏松).Contraind

13、icationsPatients who are sensitive to heparinActive bleeding, hemophilia(血友病）, purpura（紫癜）, thrombocytopenia（血小板減少癥）Intracranial（顱內） hemorrhage, gastrointestinal ulcer, infective endocarditis.Advanced hepatic diseasePatients during or after surgeryLow Molecular Weight Heparin - 2Less likely to cause

14、 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.AnticoagulantsCoumarinsWarfarin History1900. Sweet clover was planted in Canada, th

15、e 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

16、 product called Warfarin (from the initials of the foundation + -arin to indicate a coumarin compound). 1Warfarin History1948 -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 a

17、nticoagulant it was.1952. Warfarin introduced into clinical use as an oral anticoagulant.2Coumarins - structureMechanism of actionCourmarin decrease blood coagulation by inhibiting vitamin K epoxide reductase.This enzyme recycles oxidized vitamin K to its reduced form. And then the reduced vitamine

18、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 CoumarinsVitamin KCoumarins are competitive inhibitorsCoumarins - ActionInh

19、ibits the synthesis of (in order of potency)Factor IIFactor XFactor VIIFactor IXCoumarins - 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 Cro

20、sses placenta is teratogenicIs found in breast milk can affect infants developmentClinical uses1. 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

21、embolism caused by surgery, rheumatic heart disease.Adverse EffectsBleeding: gingival（齒齦） 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

22、 interactionInducer 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（抗血小板藥）C

23、yclooxygenase inhibitors Aspirin ADP receptor inhibitorsTiclopidine(噻氯匹定）Phosphodiesterase inhibitors Dipyridamole（雙嘧達莫）Glycoprotein IIB/IIIA inhibitors - Abciximab（阿昔單抗） COX-2 inhibitor Asprin1. Action: Small doses (60-80 mg/d) of aspirin given orally irreversibly inhibit the synthesis of thromboxa

24、ne A2 (TXA2) within the platelets by inhibition of cyclooxygenase producing an inhibitory effect on platelet .Antipyretic and analgesic effects: 0.30.6g 2.UsesPrevention and treatmemt of thromboembolism disease, such as myocardial infarction, reducing the morbidity and mortality of myocardial infarc

25、tion. 誘發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） 環化加氧酶血管壁中PG合成酶花生四烯酸釋放 環內過氧化物（PGG2 、PGH2） PGI2合成生理性拮抗 TXA2TXA2合成酶TXA2對血小板聚集有 強大的促進作用 血小板聚集 血小板釋放ADP阿司匹林抑制血小板聚集的原理Fibrinolytic drugs（纖維蛋白溶解藥）Streptokinase（鏈激酶）An extracellular protein purified from culture broths of Group C-hemolytic streptococciStreptoki

26、nase has no enzymic activity, instead it forms an active 1:1complex with plasminogen（纖溶酶原）, which then converts uncomplexed plasminogen to the active enzyme plasmin.Adverse effects: bleeding,hypersensitivity.Antidote: PAMBAUrokinase（尿激酶）An enzyme capable of directly degrading both fibrin and fribrin

27、ogen.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-PAIt has low affinity for free plasminogen,but it rapidly activates plasminogen bound

28、to fribrin in a thrombus or a hemostatic plug.Therapeutic uses: myocardial infarction, massive pulmonary emolism Short t1/2 (5 min)CoagulantsVitamin K1. 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 absorptio

29、n from intestinal tract.2. Synthetic form: Vit K3 and K4 are water-soluble.Clinical usesBleeding 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 newbornAdverse effectLarge doses have been shown to cause a

30、llergic reactions, hemolytic anemia and cytotoxicity in liver cells.Antianemic drugsAnemias1. Microcytic anemia ：Iron insufficiency 2. Macrocytic anemia ： Vitamine B12 insufficiency Folic acid insufficiency3.aplastic anemia IronAbsorption: duodenum and proximal jejunumTransport: transferrinStorage:

31、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 w

32、omen 15 mg/day Preparations (1) ferrous sulfate （硫酸亞鐵） (2) ferric ammonium citrate (枸櫞酸鐵胺）(3) iron dextran(右旋糖酐鐵） Adverse Effects be related to the amount of soluble iron in the upper gastrointestinal tract. nausea, heartburn , diarrhea and constipation （便秘） Antidote: deferoxamineFolic acid（葉酸） Its

33、active form is tetrahydrofolate （四氫葉酸）which plays a role in transportation of one-carbon units to synthesize some important substances.Clinical usesMegaloblastic anemia caused by increase demand ,poor absorption of folic acid and treatment with drugs that are dihydrofolate reductase （二氫葉酸還原酶）inhibit

34、ors.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

35、 with megaloblastic anemia need to be tested for vitamin B12 deficiency before folate treatment .Vitamin B12Vitamin 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 Usespernicious anemia and megaloblastic anemia ErythropoietinEPO is synthesized in the kidneyAction:acts upon the bone marrow to stimulate stem cells to divide, to produce cells of the red cell li