Drugsaffectingbloodandbloodformingorgans作用于血液【可编辑的文档】

Drugsaffectingbloodandblood-formingorgans(作用于血液和造血系统药物)TangHuifang(汤慧芳)Email:tanghuifang@Drugsaffectingthebloodandblood-formingorgansCoagulation-bleedingAnticoagulantdrugs(抗凝血药)Antiplateletdrugs(抗血小板药)Fibrinolyticdrugs(纤维蛋白溶解药)Hemostaticdrugs(止血药)BloodcellgrowthBloodvolumeAntianemicdrugs(抗贫血药)Hematopoieticgrowthagentsagents(促白细胞生长药)Drugsfortreatmentofhypovolemia(血容量扩充剂)Generalconcept凝血酶间接抑制剂：Heparin（肝素）Lowmolecularweightheparin（低分子量肝素）Fondaparinux(磺达肝癸钠)OraldirectFactorXinhibitors：Apixaban（阿派沙班）、Rivaroxaban(利伐沙班)凝血酶直接抑制剂（directthrombininhibitors，DTIs)：ORALDTIs:Dabigatran(达比加群)FactorIIinhibitor: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）VitaminKantagonists:Coumarins香豆素类

Warfarin（华法林）、dicoumarol（双香豆素）、acenocoumarol（醋硝香豆素）Part1.

Anticoagulants抗凝血药AnticoagulantdrugsMWof5～30kD(mean

12kD).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）Heparinacceleratesinactivationofcoagulationfactorsbyantithrombin.Ⅺa、Ⅸa、Ⅹa、Ⅻa1.Pharmacologicaleffects(1)Anticoagulation:

1)HeparinincreasetheactivityofATⅢTheATⅢmayinhibittheactivityoftheactivatedⅡa、Ⅺa、Ⅸa、Ⅹa、Ⅻa,tocauseanticoagulation.2)Characteristicsofanticoagulation①Itiseffectiveinvitroandinvivo

;②Itseffectsarerapid(iv)(<10min)andshort(3～4h):activatedpartialthromboplastintime(APTT)↑Anticoagulantdrugs(2)Anti-atherosclerosis:

1)Regulatingbloodlipids:VLDL

2)Protectingendothelialcells;3)Inhibitingtheproliferationofsmoothmusclecells.4)Inhibitsplateletaggregation(3)Othereffects:Anti-complement,

anti-inflammation,and

bloodviscosity（血液粘度）.Anticoagulantdrugs2.Pharmacokinetics

(1)HeparinisnotabsorbedbyGI.

Itneediv.orsc.

(2)plasmaproteinbindingrate:80%

(3)t1/2:1～2hr.

It’smetabolisedinliver,andpartiallydegradedheparinappearsintheurine.AnticoagulantdrugsAnticoagulantdrugs3.Clinicaluses(1)Anticoagulation

Suchas:pulmonaryemboli;deepveinthrombosis;cardiacinfarction,etc.(2)HeartischemiaPreventemboliincoronaryartery——earlyuse.(3)DIC(disseminatedintravascularcoagulation,弥散性血管内凝血)

Suchas:certainsurgicalprocedures,hemodialysis,cardiaccatheterization,etc.(4)Preventcoagulationinvitro

4.Adverseeffects(1)Bleeding(5%～10%)

Protaminesulfate（硫酸鱼精蛋白）istheantagonistofheparin.

1mgprotamine=100Uheparin.(2)Heparin-inducedthrombocytopenia(血小板减少症)

(HIT)

5%～6%,

Warfarinshouldbesubsti-tutediftheplateletcountfalls.(3)Others

Allergy(过敏反应);Localnecrosis(局部坏死),whensc;Increasedlossofhairandreversiblealopecia(脱发);Osteoporosis(骨质疏松).(4)ContraindicatedinpatientswithbleedingriskAnticoagulantdrugsLowmolecularweightheparin(LMWH,低分子肝素)

AnticoagulantdrugsMeanMW=1～12kDStrongerEffectsonⅩa,ⅫathanonⅡa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

FatcorⅩaCoumarins(香豆素类)Warfarin(华法林);Dicoumarol(双香豆素);

Acenocoumarol(醋硝香豆素)

Anticoagulant

drugs苯茚二酮双香豆素华法林1.Pharmacologicaleffects

(1)Properties:

Slowlyandlongerduration:

The

effectappearsafterp.o.1~3days,andlastsfor4days

Effectiveonlyinvivo.(2)Mechanismsofaction:

AntagonizesvitaminK.

Itinhibitscarboxylationofthegluta-micacidresiduesofthe

factors

Ⅱ、Ⅶ、Ⅸ、Ⅹ,

todecreasetheactivationoffactors

Ⅱ、Ⅶ、Ⅸ、Ⅹ.AnticoagulantdrugsMechanismof

Coumarins2.Clinicaluses

Anti-coagulationinvivo(suchasdeepveinthrombosis,pulmonaryemboli,andcardiacinfarction,etc).3.Adverseeffects(1)Bleeding(9%～10%)

Canaffectallorgansinbody.

VitaminK1

mayantagonistthisreaction.cantreatwithfreshbloodorplasmaandprothrombincomplex(凝血酶原复合物).

(2)Necrosisofskinandparenchyma(皮肤和软组织坏死).(3)Liverinjury(warfarin).Anticoagulantdrugs4.Druginteractions(1)Plasmaproteinbindingreplacement(2)Hepaticmetabolism:enzymeinhibitionenzymeinductionPart2.Antiplateletdrugs(抗血小板药)Thrombusformationatthesiteofthedamagedvascularwall(EC,endothelialscell)andtheroleofplateletsandclottingfactors.Plateletmembranereceptorsincludetheglycoprotein(GP)Iareceptor,bindingtocollagen(C);GPIbreceptor,bindingvonWillebrandfactor(vWF);andGPIIb/IIIa,whichbindsfibrinogenandothermacromolecules.Antiplateletprostacyclin(PGI2)isreleasedfromtheendothelium.Aggregatingsubstancesreleasedfromthedegranulatingplateletincludeadenosinediphosphate(ADP),thromboxaneA2(TXA2),andserotonin(5-HT).PGI2受体TXA2受体GPⅡb/Ⅲa受体ADP受体→PGI2Antiplateletdrugs(抗血小板药)TypesDrugsRemarks1.PlateletmetabolisminhibitorAspirin(阿司匹林)Cyclooxygenaseinhibitor,TXA2

Clinicaluse:Angina,infarctionDipyridmole(双嘧达莫,潘生丁)ReversiblyinhibitsPDE,

cAMP

,

plateletreactivity

,t1/2:12hr,Clinicaluse:Thrombosis,Ridogrel(利多格雷),picotamide(匹可托安)TXA2synthaseinhibitor

TXA2receptorblocker,Clinicaluse:ThrombosisEpoprostenol(依前列醇)ACactivitor

cAMP

,Clinicaluse:Thrombosis2.PlateletactivationinhibitorTiclopidine(噻氯匹定)

Clopidogrel

(氯吡格雷)SelectivelyinhibitADPinducedactivationofplateletfunctionClinical

use:

substituded

foraspirininischemicheart,braindisorders3.PlateletGpⅡb/ⅢareceptorantigonistAbciximab(C7E3Fab阿昔单抗)CompetitivePlateletGpⅡb/Ⅲare-ceptorantigonistClinicaluse:angina,infarctionInhibitionofAAmetabolisminplateletsIrreversible

cyclooxygenaseinhibitors(COXinhibitor)：Aspirin(阿司匹林)、Triflusal

(三氟柳)ThromboxanesynthaseinhibitorsandThromboxanereceptorantagonists：Ridogrel(利多格雷),picotamide(匹可托安)、Ozagrel、Seratrodast（塞曲司特）IncreaseintracellularcAMP

Phosphodiesteraseinhibitors(PDEinhibitor)：Cilostazol

(西洛他唑)

Adenosinereuptakeinhibitors：Dipyridamole

(双嘧达莫,潘生丁)Activatorsofadenosinecyclase:epoprostenol

（依前列醇）TheclassofantiplateletdrugsPlateletactivationinhibitorAdenosinediphosphate(ADP)receptorinhibitors(P2Y12inhibitor)：

Clopidogrel

(氯吡格雷)、Prasugrel

(普拉格雷)、Ticagrelor

(替卡格雷)Ticlopidine

(噻氯匹定)Protease-activatedreceptor-1(PAR-1)antagonists:Vorapaxar

(沃拉帕沙)GlycoproteinIIB/IIIAinhibitors

：Intravenoususeonly:Abciximab

(阿昔单抗)、Eptifibatide

(依替巴肽)、Tirofiban

(替罗非班)、Oraluse:Xemilofiban（珍米洛非班）、Fradafiban（夫雷非班）、西拉非班（sibrafiban）Anti-plateletdrugsAspirin(阿司匹林)Acetylsalicylicacid(乙酰水杨酸)

It

isacyclooxygenaseinhibitor,inhibit-ingTXA2synthesis.Mechanism:

Targetenzymes(cyclooxygenase)areacetylatedandinactive.Anti-plateletdrugsAspirin

Smalldoses(30～100mg/day):

inhibitingTXA2synthesis,preventingthrombosis.

usedtotreatischemicheartdisease,reducethemortalityofmyocardiacinfar-ction,andpreventcerebralthrombosis.

Largerdoses(

500mg/day):

inhibitingPGI2synthesis,promotingthrombosis.

——

PGI2:

vasodilationandplateletdepolymerization(血小板解聚).Dipyridamole(双嘧达莫,

Persantin,潘生丁)

Reversiblyinhibitsphosphadiesterase(PDE)ofplatelet,

cAMP

,

plateletreactivity

,t1/212hr.

Clinicaluses:Preventthrombosis.Anti-plateletdrugsTiclopidine(噻氯匹定)SelectivelyinterferesADPinducedplateletactivationInhibitsplateletfunction.

Clinicaluses:Preventcerebralapoplexy(中风)andcardiacinfarction,etc.Part3.Fibrinolyticdrugs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纤维蛋白原++-Alteplase(Tissueplasminogenactivator

t-PA,组织型纤溶酶原激活剂)

1.Effect:

Localactiononthethromboticfibrin(血栓纤维蛋白)toproducefibrinolysis;

iv.t1/2=3～8min,effect1～3hr.Apotentiallyimportantagentintreatingthromboembolicdisease.2.ADR:

bleeding.FibrinolyticdrugsUrokinase(尿激酶,UK)

1.Effect:

Plasminogenactivator,t1/2=15min;2.Clinicaluse:

Severepulmonaryemboli,anddeepveinthrombosis.3.Adversereaction:(1)systemicfibrinolyticstate,(2)bleeding.FibrinolyticdrugsStreptokinase(链激酶,SK)1.Pharmacologicaleffect:

plasminogen(纤溶酶原)activator,t1/2=23min;2.

ClinicalUse:

Severepulmonaryemboli,anddeepveinthrombosis3.Adversereaction:

Systemicfibrinolyticstatewhichcanleadtobleedingproblems(5%);Antigenicity——allergy.FibrinolyticdrugsAnistreplase(阿尼普酶)Itisastreptokinase-plasminogencomplex,inwhichlys-plasminogenisacylatedatitscatalyicsiteserine.Theacylgroupishydrolyzedinvivo,allowingthecomplextobindtofibrinpriortoactivation,andthismodificationconferssomespecificitytowardclotsonthefibrinolyticprocess.Itisusedcoronarythrombolysisalso.FibrinolyticdrugsAdverseeffectsThethrombolyticagentsdonotdistinguishbetweenthefibrinofanunwantedthrombusandthefibrinofabeneficialhemostaticplug.Hemorrhageisamajorsideeffect.Antidotes:fibrinolyticinhibitors(PAMBA氨甲苯酸,AMCHA氨甲环酸)Part4.Hemostaticdrugs(Haemostats,促凝血药,止血药)VitaminK1.Carboxylationof

theglutamicacidresidues

of

II,VII,IX,X,proteinC.2.TopreventbleedingwithvitaminKdeficiency.3.Responseto

vitaminK

isslow,theseverehemostasispatientsshouldbeinfusedwithfreshplasmaimme-diately.Thrombin-likeagents(凝血酶制剂)

Thrombin(凝血酶,factorⅡ)Prothrombincomplex(凝血酶原复合物,factorⅡ、Ⅶ、Ⅸ、Ⅹ)

usedforvariousbleeding.Globulinanti-hemophilia(factorⅧ,抗血友病球蛋白)

usedfor

treatmentforhemophilia.HaemostatsDrugspreventingactivationofantifibrinolyticsaprotinin(抑肽酶）

tranexamicacid(AMCHA,氨甲环酸)

p-aminomethylbenzoicacide(PAMBA,氨甲苯酸）

usedfor

preventingtheactivationfibrinolysisandresultantbleeding

HaemostatsInhibitingplasminogenactivationPart5.Antianemicdrugs

抗贫血药1.Causeofanemia:

(1)Anemiamayresultfromtheexcessdestructionoferythrocytes;(2)Anemiamayresultfromnutritionaldeficiencies,including:iron,minerals,vitamins(B12andfolicacid),ascorbicacid,riboflavin,etc.

2.Drugsfortreatmentofanemia:

Ironpreparations;

FolicacidandvitaminB12;

Erythropoietin(EPO),andrhEPO(ReconbananthumanEPO)Ironpreparations(铁制剂)

Ferroussulfate(硫酸亚铁),

Ferric

ammonium

citrate(枸橼酸铁铵)Irondextran(右旋糖酐铁),Ironsorbitex(山梨醇铁)1.ClinicalUsesIrondeficiencyanemia.2.ADRsGIreactions:nausea,vomiting,anddiarrhea.

Acuteintoxication:severeCNSsymptomsandGIreactions.Inthistime,treatmentwithdeferoxamine(去铁胺).AntianemicdrugsFolicacid(叶酸)&VitaminB12

BothFolicacid(叶酸)andVitaminB12

areessentialforthesynthesisofDNA,thisprocessisimpairedinpatientswithmegaloblasticanemia(巨幼红细胞贫血).1.Pharmacologicaleffects

Regulatingnucleicacid&aminoacidmetabolism.2.Clinicaluses

Megaloblasticanemia.3.Adversereaction

RarereportsAntianemicdrugsErythropoietin(EPO,红细胞生成素)

rhEPO(重组人红细胞生成素)1.Pharmacologicaleffectspromotingredcellproliferationanddifferentiation2.Clinicaluses

anemiadueto

chronicrenalfailurewith

hemodialysis,

radiotherapy,

chemo-therapy,AIDS,etc.3.AdverseeffectsHypertensi