Chapter34AgentsactingonthebloodsystemBloodBloodcellPlasma:RBC:abnormal,anemiaWBCplateletSection1AnticoagulantsBloodcoagulationandfibrinolysis:balanceThrombosis

Hemorrhagicdisease

XXaplasmozymeplasmaseFibrinogenFibrinintrinsicpathwayextrinsicpathwayⅤ.ⅧⅨ.ⅪⅫⅢ,Ⅴ,ⅦCoagulationprocessAntithromboticdrugsInhibitcertainbloodcoagulationfactorofbloodclottingprocess,preventthrombogenesis.Usedforpreventionofthromboembolicdisease.ClassificationofanticoagulantsAnticoagulantsbothinvivoandvitro:HeparinAnticoagulantsinvivo:Coumarins

Anticoagulantsinvitro:Natriumcitricum

A.Heparin1916:discoveredinliverNowextractedfromoxlungandswinemucousmembraneofsmallintestine.Mucoitinsulfate硫酸粘多糖,MW5~30kDa(sulfate40%).Sourceandchemistry(1)largeamountofnegativecharge(2)strongacidityPHARMACOKINETICSAbsorption:oraladministrationsubcutaneoulyinjectionintramuscularinjectionintravenousinjection:YESDistribution:Metabolism:Liverheparinase肝素酶Mononuclearphagocyte

Excretion:Kidney:metabolitesorheparinnegativecharge,isnottransportedthroughbiomembrane,Uptake:endothelialcell

PHARMACOLOGICALACTIONS(1)activateantithrombinⅢ(ATⅢ)，factorsⅡ,Ⅸ,Ⅹ,Ⅺ,andⅫareinactivated.Mechanism:

enhancetheanticoagulativeactivityofATⅢandaccelerateinactivationofclottingfactors.(Ⅱ,Ⅸa,Ⅹa,Ⅺa,Ⅻa)1.Anticoagulativeeffect:bloodcoagulationfactor(Ⅱ,Ⅸ,Ⅹ,Ⅺ,Ⅻ)serineinactivationAT-IIIargininelysineActionofAT-ⅢAT-IIIargininelysineActionofHeparinHeparinbloodcoagulationfactor(Ⅱ,Ⅸ,Ⅹ,Ⅺ,Ⅻ)serAT-IIImaybeexhaustible(2)ActivateHCII(肝素輔助因子II):

inactivatethrombin凝血酶(3)Activatefibrinolysis:releaset-PA,TFPI

t-PA:plasminogen纖溶酶原

activatorTFPI:inhibittissuefactor抑制組織因子2.Antiplateletaggregation3.Lipids↓TG、VLDL,↑HDL

(lipoproteinlipaserelease)4.Others:AntiinflammatoryLowerbloodviscosityInhibitVECproliferation

CLINICALUSES1.

Thromboembolicdisease

myocardialinfarctionpulmonaryembolismcerebralembolismperipheralveinthrombosis.preventthrombogenesisanditsgrowingupcouldnotdissolvethrombosis(hasnothrombolysis)

2.DIC

(disseminatedintravascularcoagulation)

Itshouldbeusedearlytopreventthesecondaryhemorrhageinducedbyexhaustionoffibrinogenandcoagulationfactor.3.

Ischemicheartdisease:

suchasunstableangina4.

AS:

5.

Others:

Anticoagulationinvivoandinvitro,usedforblood-transfusion,extracorporeal體外的circulation,hemodialysis(血透),etc.ADVERSEREACTIONS1.

Spontaneoushemorrhage:mucosalbleeding,(antagonist:protaminesulfate硫酸魚精蛋白2.Plateletreduction

3.

Allergicreaction4.

Otherreactions:Sc.Localnecrosis;alopecia(脫發),bonerarefaction(osteoporosis,骨質疏松).

Heparin-inducedthrombocytopenia(血小板減少癥HIT):

3%,2～10days,maycausethromboticcomplicationsCONTRAINDICATIONSrenalfailure,ulcer,hypertension,pregnantwomen.DRUGINTERACTION1.Incompatibility配伍禁忌:alkalinousdrugswithstrongacidicheparin2.Synergism:withotheranticoagulants,↑bleedrisk3.Aspirin:

↑bleedriskofheparinOthersLMWHS(lowmolecularweightheparins):

Enoxaparin(依諾肝素)Tedelparin（替地肝素）Antithrombosis>anticoagulationInhibitionofⅩa>ⅡaLittleinfluenceonplateletLongert1/2，couldbeScinjection,bioavailability>90%Bonerarefactionisseldom.ATⅢ:aplasmaproteaseinhibitorHirudin(水蛭素)Specificpotentplasmase(factorII)inhibitor---noeffectonATIIIInhibitactivationofⅤ、Ⅷ、Ⅻ;inhibitplateletactivationmediatedbyplasmase(II);promotethethrombolysisinducedbyplasminogenactivator.Others:rivaroxaban利伐沙班，effectonⅩ，noeffectonplateletaggregation.B.

Dicoumarol雙香豆素

Coumarinsanticoagulants:

---Oralanticoagulants

Acenocoumarol（醋硝香豆素，新抗凝）,

Warfarin（華法林,芐丙酮香豆素）,

Phenprocoumon(苯丙香豆素).PHARMACOKINETICSAbsorption:

po.slow,warfarin:fastDistribution:

highplasmaproteinbindingratio(99%)；liver,lung,spleenandkidney.Metabolism:hepaticmicrosomalenzymeExcretion:urinePHARMACOLOGICALACTIONSonlyeffectiveinvivo,slow,longaction.Mechanism:

inhibitVKepoxidereductase

(VK環氧化物還原酶)1.Spontaneoushemorrhage：Vk,10mg,iv2.Liverdamage:cholestasis(膽汁淤積)

3.AbnormalembryoCLINICALUSESADVERSEREACTIONThromboembolicdiseaseOnebyonetherapy:firstheparin,thendicoumarolDRUGINTERACTIONLiverdrugenzymeinducers:↓action:(phenobarbital)Liverdrugenzymeinhibitors:↑action:

(metronidazole甲硝唑，cimetidine西米替丁);

plasmaproteinbinding：↑action:

butazone(保泰松)，sulfonylureas(磺脲類)Antiplateletdrugs:synergisticeffect

Antibioticsinhibitintestinaltractmicrobialpopulation→↓synthesisofVk,↑actionC.Sodiumcitrate枸櫞酸鈉AnticoagulantsinvitroMechanism：Sodiumcitrate＋Ca2+→comolescompound絡合物→↓[Ca2+]b→anticoagulation--UsedforAnticoagulantinvitro.Section2AntiplateletdrugsCyclooxygenaseinhibitors:Aspirin;TXA2synthetaseinhibitors:ridogrel(利多格雷)ACactivator:Epoprostenol(依前列醇/PGI2)PDEinhibitors:Dipyridamole(雙嘧達莫);Inhibitorsofplateletmetabolismenzyme

ADPantagonist:

Ticlopidine噻氯匹定inhibitP2Y21receptor

Clopidogrel氯吡格雷:inhibitP2Y12receptor

GPIIb/IIIareceptorantagonist:abciximab(阿昔單抗)cellmembranelipoxidaseLTsAAPGI2CycloxygenaseTXA2PGG,PGHAAPLA2TXA2synthetasePlateletaggregationinhibitADPpromotethrombosis

AATXA2PGI2

(－)(＋)ACAC

cAMP↓cAMP↑↓PDE

↑aggregation↓aggregation(PLT)(endothelium)plasminogen

inhibitors－

+activatorsplasmin

＋

＋DegrationfibrinsplitsproductsfibrinogenfibrinproductsSection3Fibrinolyticdrugs1.Streptokinase(SK)(鏈激酶)Proteingeneratedbyβ-streptococcusLoadingdoseatfirst:uselargedoseonpatientswithstreptococcalinfection(because

ofantistreptokinaseantibody)Streptokinase(SK)(鏈激酶)

1.1mechanism:SK-plasminogencomplex→activatedplasmin→dissolvethrombusNote:Beeffectivefornewfibrin,noeffectonorganizedthrombus.1.2clinicaluses:

Acutethromboembolicdisease:

acutepulmonaryembolism,deeppartvenousembolism(earlytreatment).couldnotbeusedforalongtime.1.3adversereactions:bleeding,allergicreaction2.Urokinase(UK)尿激酶

mechanism:activatingplasminogendirectlyclinicaluses:SameuseasSK,especiallycerebralembolismadversereactions:bleeding,butnoantigenicity

(抗原性)

3.tissue-typeplasminogenactivator

(t-PA)

Alteplase(阿替普酶),Reteplase(瑞替普酶)Actingontheembolismselectively，↓bleedingUsedforacutemyocardialischemia（AMI）,acutestrokesymptomsincreasingly.4.Anistreplase(阿尼普酶)Anisoylatedplasminogenstreptokinaseactivatorcomplex(APSAC)--茴香酰化纖溶酶原-鏈激酶激活劑復合物acetylated：protecttheactivesitedeacetylated:producetheeffectst1/2:105～120min,asingleintravenousinjectionof30units.Fibrinolyticdrugs-in

allStreptokinase(SK)Urokinase(UK)Alteplase(t-PA)Anistreplase（APSAC,復合纖溶酶鏈激酶）Ahylysantinfarctase(蝮蛇抗栓酶)Ancordarvin(蛇毒抗凝酶),Hirudin（水蛭素）

Section4BloodCoagulantactivatecertainfactorofbloodclotting,preventhemorrhagicdiseaseinducedbydysfunctionofbloodclotting.VitaminKAminomethylbenzoic

acid(氨甲苯酸)

tranexamicacid

(氨甲環酸)VitaminKLipidsoluble:K1,K2

K1:plantsynthesis，

K2:generatedbyentericbacteriaWater-soluble:K3,K

4

synthesized

artificially.PHARMACOKINETICS(1)Absorption:K1,

K2:bile

assistdissolve，

K3、K4:

intestinaltract，im.(2)Distribution:concentratedinliver,thendegrade,(small)saveintissue.(3)Excretion:excreteviabileandurinebyprimaryform.PHARMACOLOGICALACTIONSVkisthecoenzymeofcarboxylase,

participatethecarboxylationofglutamateresidueofbloodcoagulationfactorslikeⅡ,Ⅶ,Ⅸ,X.9~12γ-carboxyglutamicacids

bindtoCa2+，thenbindtomembranephospholipidofplatelet.Factorsactivated---Bloodclot.hydroquinoneepoxideCLINICALUSES(1)VitaminKdeficiencyhemorrhagicdiseaseinducedbyVKinsufficiency.

Forexample:ObstructivejaundiceBiliaryfistula(膽瘺)；Hemorrhageinnewbornandprematureinfant；Broad-spectrumantibioticsinhibitthesynthesisofVKbyentericbacteria.(2)Detoxicationtooverdoseanticoagulantsantagonizebleedinginducedbyoverdosedicoumarolandsalicylicacid.ADVERSEREACTIONS

(1)Prosopo(面部)-flush,sweat,chestdistress,BP↓

(2)GIreaction:po.K3，K4

(3)Hemolyticanemia:patientswholackG-6-PD(glucose6-phosphatedehydrogenase)

(4)newborn:hyperbilirubinemia(高膽紅素血癥),jaundice,hemolyticanemiaAntifibrinolyticsDrugs：Aminomethylbenzoic

(氨甲苯酸),

tranexamicacid(氨甲環酸).

Bindtolysinebindingsites,blocktheactionoffibrinolysin,inhibitfibrindegradation→hematischesis止血.Usedforbleedinducedbyhyperfibrinolysis.Bleedinginducedbysurgery(uterus，thyroidgland，liver,spleen,etc.).Localhaemostasis止血法:nosebleed,oralcavitySection5PlasmavolumeexpandersIncreaseplasmacolloidosmoticpressureRemain

bloodvolumeEliminationisslowAntigenicity：weakDextran

Dextran70(mediummoleculardextran)Dextran40(lowmoleculardextran)Dextran10(smallmoleculardextran)Expandbloodvolume:Dextran70InhibitplateletandRBCaggregation,improvemicrocirculation:Dextran40BloodvolumelossShockDICMyocardialinfarctionCerebralthrombosis，cerebraledemaUsesDextran(右旋糖酐)

70,40,10Action:

1.increasebloodvolume(70＞40＞10)2.↓aggregationofRBCandPLT(40,10)3.osmoticdiuresisIndications:

1.hypovolemicshock2.DIC3.thrombosisAdversereaction:

allergicreaction,coagulationdisorder,CHFNote

cannotadministrationwithVC、VK、VB12，renaltoxicitycombinedwithgentamicin.Chapter35AntianemicandhematopoieticdrugsSection1.AntianemicdrugsAnemia:RBCnumbersorhematoglobinislowerthannormal.Adultmale:Hematoglobin<120g/LRBC<4.5×1012/LAdultfemale:Hematoglobin<110g/LRBC<4.0×1012/LIrondeficiencyanemia:

ironMegaloblasticanemia:

folicacidorVitaminB12Aregenerativeanemia:

---Haematogenesisfunctionofmarrowimpaired.--infection,drugs,radiotherapy,etc.inducedRBC,WBCandplateletnumbers↓TypesofAnemia:FerrousPreparationFerroussulfateFerricammoniumcitrate枸櫞酸鐵銨Ferrousfumarate(富馬酸亞鐵)Irondextran(右旋糖酐鐵,

im)Promoteabsorption(reducingsubstances):

VC,

gastricacid,fructose果糖,improveFe3+turnto

Fe2+;

Inhibitabsorption:gallicum鞣酸,phosphate,antiacid,tetracycline,bindtoferrumorcomplexation.PHARMACOKINETICSFactorsaffectingabsorption:Absorptionsmallintestine,absorptionsaturabilityFe2+Fe3+

+apoferritinferritin

Fe3++transferrin

hemopoietictissue

Fe2+haematogenesisintestinalmucosa

Carrier:transferrin;

Process:Transport:

bloodFerritin

鐵蛋白Ferruginoushaemoglobin（含鐵血色素）.StorageIntestinalmucosaDermepithelialcellBile,urine,sweat………Excretion鐵的吸收、轉運、分布--Fe3++transferrincompoundsbindtothetransferrinreceptorandaretransportedtocellsofhaematogenesisbypinocytosis胞飲作用.--Ferrumisreleased(acidicsurrounding)forhaematogenesisorstorage.Protoporphyrin

原卟啉FerrumHaemoglobin血色素Globin珠蛋白haematoglobinmitochondria（線粒體）PHARMACOLOGICALACTIONSCLINICALUSES(1)ChronicbloodlossanemiaInducedbyHypermenorrhea（月經過多）

DigestivetracthemorrhageHaemorrhoids(痔瘡).(2)IrondeficiencyanemiaInducedbyCacotrophy(營養不良)Cyophoria(妊娠)ChildgrowingperiodADVERSEREACTIONS(1)GIirritation:aftermeals↓.(2)Constipation便秘:

Iron+H2S→ironsulfide，↓irritationofH2Stogastrointestinaltract.(3)Hemosiderosis(含鐵血黃素沉著癥):

longtermusing.

(4)

AcuteintoxicationanddetoxicationAcuteintoxication:>1g(child).Detoxication（解救）:

Gastriclavage(灌洗):

1%-2%NaHCO3Deferoxamine(去鐵胺):

bindtoiron(i.g.).FolicacidComposition:pteridine(蝶啶),

PABA(p-aminobenzoicacid),glutamicacidDistribution:food,esp.yeast,liver,greenleavesvegetable.Feature:nonthermostability.PHARMACOLOGICALACTIONMethyldonor:--Folicacid→N5-methyl-tetrahydrofolicacid.--VitaminB12→methy-B12.--N5-methyl-FH4→FH4.Transferonecarbonunit:

-CH3,-CHO,=CH2.

Coenzymeofonecarbonunittransferase,transferonecarbonunit,synthesizepurineandpyrimidineandnucleotide(includedTMPsynthesisandinterconversionofaminoacid).Whenfolicacidisinsufficient

-Megaloblasticanemia-Gastritis胃炎

andglossitis舌炎:

Epithelialcellsaredamaged.CLINICALAPPLICATIONReplacementtherapyInducedby

Methotrexate(甲氨蝶呤,MTX),Pyrimethamine(乙胺嘧啶),Trimethoprim(甲氧芐氨嘧啶,TMP):--calciumfolinate(FH2reducasewasinhibited).MoreeffectcombinewithVB12;1.Megaloblasticanemia:-InducedbyVB12deficiency.Adjunctivetherapy,largedosefolicacidmayretrievehemogram,notretrievenervoussymptom.Supply

VB12

2.Pernicious惡性的anemiaVitaminB12Cobaltcomplex

existinanimalvisceralorgan,milk,eggyellow;Cyanocobalamin

(氰鈷胺)Hydroxycobalamin（羥鈷胺）

Nitritoco