Drugsaffectingbloodandbloodformingorgans作用于血液【可編輯的文檔】

Drugsaffectingbloodandblood-formingorgans(作用于血液和造血系統(tǒng)藥物)TangHuifang(湯慧芳)Email:tanghuifang@Drugsaffectingthebloodandblood-formingorgansCoagulation-bleedingAnticoagulantdrugs(抗凝血藥)Antiplateletdrugs(抗血小板藥)Fibrinolyticdrugs(纖維蛋白溶解藥)Hemostaticdrugs(止血藥)BloodcellgrowthBloodvolumeAntianemicdrugs(抗貧血藥)Hematopoieticgrowthagentsagents(促白細(xì)胞生長(zhǎng)藥)Drugsfortreatmentofhypovolemia(血容量擴(kuò)充劑)Generalconcept凝血酶間接抑制劑：Heparin（肝素）Lowmolecularweightheparin（低分子量肝素）Fondaparinux(磺達(dá)肝癸鈉)OraldirectFactorXinhibitors：Apixaban（阿派沙班）、Rivaroxaban(利伐沙班)凝血酶直接抑制劑（directthrombininhibitors，DTIs)：ORALDTIs:Dabigatran(達(dá)比加群)FactorIIinhibitor:Lepirudin（重組水蛭素/來(lái)匹盧定）、desirudin（地西盧定）、bivalirudin(比伐盧定)、Argatroban（阿加曲班）VitaminKantagonists:Coumarins香豆素類

Warfarin（華法林）、dicoumarol（雙香豆素）、acenocoumarol（醋硝香豆素）Part1.

Anticoagulants抗凝血藥AnticoagulantdrugsMWof5～30kD(mean

12kD).Heparin（肝素）

化學(xué)：強(qiáng)酸性，具強(qiáng)負(fù)電荷（抗凝作用基礎(chǔ)）特效解毒劑：魚精蛋白（堿性，強(qiáng)正電荷）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,彌散性血管內(nèi)凝血)

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

4.Adverseeffects(1)Bleeding(5%～10%)

Protaminesulfate（硫酸魚精蛋白）istheantagonistofheparin.

1mgprotamine=100Uheparin.(2)Heparin-inducedthrombocytopenia(血小板減少癥)

(HIT)

5%～6%,

Warfarinshouldbesubsti-tutediftheplateletcountfalls.(3)Others

Allergy(過(guò)敏反應(yīng));Localnecrosis(局部壞死),whensc;Increasedlossofhairandreversiblealopecia(脫發(fā));Osteoporosis(骨質(zhì)疏松).(4)ContraindicatedinpatientswithbleedingriskAnticoagulantdrugsLowmolecularweightheparin(LMWH,低分子肝素)

AnticoagulantdrugsMeanMW=1～12kDStrongerEffectsonⅩa,ⅫathanonⅡa常用LMWH：

enoxaparin(依諾肝素)Tedelparin(替地肝素)Fraxiparin（弗希肝素）Logiparin（洛吉肝素）

Lomoparin（洛莫肝素）FatcorⅩa

FatcorⅩaCoumarins(香豆素類)Warfarin(華法林);Dicoumarol(雙香豆素);

Acenocoumarol(醋硝香豆素)

Anticoagulant

drugs苯茚二酮雙香豆素華法林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(凝血酶原復(fù)合物).

(2)Necrosisofskinandparenchyma(皮膚和軟組織壞死).(3)Liverinjury(warfarin).Anticoagulantdrugs4.Druginteractions(1)Plasmaproteinbindingreplacement(2)Hepaticmetabolism:enzymeinhibitionenzymeinductionPart2.Antiplateletdrugs(抗血小板藥)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受體TXA2受體GPⅡb/Ⅲa受體ADP受體→PGI2Antiplateletdrugs(抗血小板藥)TypesDrugsRemarks1.PlateletmetabolisminhibitorAspirin(阿司匹林)Cyclooxygenaseinhibitor,TXA2

Clinicaluse:Angina,infarctionDipyridmole(雙嘧達(dá)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阿昔單抗)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

(雙嘧達(dá)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

(阿昔單抗)、Eptifibatide

(依替巴肽)、Tirofiban

(替羅非班)、Oraluse:Xemilofiban（珍米洛非班）、Fradafiban（夫雷非班）、西拉非班（sibrafiban）Anti-plateletdrugsAspirin(阿司匹林)Acetylsalicylicacid(乙酰水楊酸)

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(雙嘧達(dá)莫,

Persantin,潘生丁)

Reversiblyinhibitsphosphadiesterase(PDE)ofplatelet,

cAMP

,

plateletreactivity

,t1/212hr.

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

Clinicaluses:Preventcerebralapoplexy(中風(fēng))andcardiacinfarction,etc.Part3.Fibrinolyticdrugs纖維蛋白溶解藥阿尼普酶阿替普酶尿激酶鏈激酶纖溶酶纖溶酶原凝血酶纖維蛋白原++-Alteplase(Tissueplasminogenactivator

t-PA,組織型纖溶酶原激活劑)

1.Effect:

Localactiononthethromboticfibrin(血栓纖維蛋白)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(鏈激酶,SK)1.Pharmacologicaleffect:

plasminogen(纖溶酶原)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氨甲環(huán)酸)Part4.Hemostaticdrugs(Haemostats,促凝血藥,止血藥)VitaminK1.Carboxylationof

theglutamicacidresidues

of

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

vitaminK

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

Thrombin(凝血酶,factorⅡ)Prothrombincomplex(凝血酶原復(fù)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,氨甲環(huán)酸)

p-aminomethylbenzoicacide(PAMBA,氨甲苯酸）

usedfor

preventingtheactivationfibrinolysisandresultantbleeding

HaemostatsInhibitingplasminogenactivationPart5.Antianemicdrugs

抗貧血藥1.Causeofanemia:

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

2.Drugsfortreatmentofanemia:

Ironpreparations;

FolicacidandvitaminB12;

Erythropoietin(EPO),andrhEPO(ReconbananthumanEPO)Ironpreparations(鐵制劑)

Ferroussulfate(硫酸亞鐵),

Ferric

ammonium

citrate(枸櫞酸鐵銨)Irondextran(右旋糖酐鐵),Ironsorbitex(山梨醇鐵)1.ClinicalUsesIrondeficiencyanemia.2.ADRsGIreactions:nausea,vomiting,anddiarrhea.

Acuteintoxication:severeCNSsymptomsandGIreactions.Inthistime,treatmentwithdeferoxamine(去鐵胺).AntianemicdrugsFolicacid(葉酸)&VitaminB12

BothFolicacid(葉酸)andVitaminB12

areessentialforthesynthesisofDNA,thisprocessisimpairedinpatientswithmegaloblasticanemia(巨幼紅細(xì)胞貧血).1.Pharmacologicaleffects

Regulatingnucleicacid&aminoacidmetabolism.2.Clinicaluses

Megaloblasticanemia.3.Adversereaction

RarereportsAntianemicdrugsErythropoietin(EPO,紅細(xì)胞生成素)

rhEPO(重組人紅細(xì)胞生成素)1.Pharmacologicaleffectspromotingredcellproliferationanddifferentiation2.Clinicaluses

anemiadueto

chronicrenalfailurewith

hemodialysis,

radiotherapy,

chemo-therapy,AIDS,etc.3.AdverseeffectsHypertensi