藥理學(xué)教學(xué)課件：Drugs acting on blood system

DrugsactingonbloodsystemBloodcoagulationistheconversionofliquidbloodintoasolidgel.Coagulationinvolvesbothacellular(platelet)anda

protein(coagulationfactor)component.Primaryhemostasis:

Plateletsimmediatelyformaplugatthesiteofinjury;Secondaryhemostasis:Proteinsinthe

bloodplasma,called

coagulationfactors

or

clotting

factors,respondinacomplexcascadetoform

fibrin

strands,whichstrengthentheplateletplugⅠFibrinogen纖維蛋白原ⅡProthrombin凝血酶原ⅢTissuethromboplastin組織凝血活素ⅣCa2+鈣離子Ⅴproaccelerin加速因子ⅦProconvertin轉(zhuǎn)化因子ⅧAntihemophilicfactor抗血友病因子ⅨPlasmathromboplastinantecedent血漿凝血激酶ⅩStuartfactor斯圖爾特因子ⅪPlasmathromboplastincomponent血漿凝血激酶前質(zhì)ⅫHagemanfactor接觸因子XIIIFibrinstabilizingfactor纖維蛋白穩(wěn)定因子ClottingfactorsinthebloodProcessofcoagulation(Secondaryhemostasis)Threemainsteps:Formationofprothrombin-activatingcomplexConversionofprothrombintothrombinConversionofsolublefibrinogenintoinsolublefibrin.FormationoffibrinclotBothsystemsinvolveacascadeofenzymereactionsthatsequentiallytransformvariousplasmafactors(proenzymes)totheiractive(enzymatic)forms.TheyultimatelyproduceFactorXa,whichconvertsprothrombin(FactorII)tothrombin(FactorIIa)Thenaturallyoccurringanticoagulantslimittheextentofclotformation:AntithrombinⅢ(ATⅢ),whichisactivatedbyheparin,andinactivatesthrombinandotherfactors.AnticoagulantsAnti-plateletdrugsFibrinolyticdrugsⅠ.AnticoagulantsThesearedrugsusedtoreducethecoagulabilityofblood.thrombininhibitors

Heparin

LowmolecularweightheparinVkantagonistWarfarin

Heparin

Heparinisamixtureofsulfatedmucopoly-saccharideswithawiderangeofmolecularweights(3-15kDa).ispresentinalltissues.Richestsourcesarelung,liverandintestinalmucosa.Itiscommerciallyproducedfromoxlungandpigintestinalmucosa.Itcarriesstrongelectronegativechargesandisthestrongestorganicacidpresentinthebody.Itmustbegivenparenterally,eitherinadeep

subcutaneoussiteorintravenously,becausethedrugisnotabsorbedfromthegut.

ActionandMechanism

EnhancetheactionofATⅢ

Heparin'sbiologicactivityisdependentupontheplasmaproteaseinhibitoranti-thrombinⅢ(ATⅢ)AntithrombinⅢ(ATⅢ)inhibitsclottingfactorproteases,especiallythrombin(Ⅱa),Ⅸa,Ⅹa,Ⅺa,Ⅻa,byformingstablecomplexeswiththem,andthoseactivefactorsconvertintoinactivefactors.Intheabsenceofheparin,thesereactionsareslow.HeparinmustbindtobothATⅢandtheclottingfactors(Ⅱa,Ⅸa,Ⅹa,Ⅺa,Ⅻa)andinteractivewitheachother.

HeparininducesconformationalchangeinATⅢtoexposeitsinteractivesitesandacceleratestheinactivationofclottingfactors.

Inthepresenceofheparin,thesereactionsareaccelerated1000-fold.Heparininhibitsplateletaggregationpossiblyasaresultofinhibitingthrombinandprolongsbleedingtimeinhigherdoses.Heparinreleasealipoproteinlipasetoclearsturbidpost-prandiallipomicplasma.Thisactionrequireslowerconcentrationofheparinthanneededforcoagulation.

Characters:

mustbegivenparenterally,eitherinadeep

subcutaneoussiteorintravenously

Directly(actonactiveclottingfactor)

Strongeffectivebothinvivoandinvitroonsetofactionisrapid

Clinicaluse:1.Deepveinthrombosisandpulmonaryembolismisusedprophylacticallytopreventpostoperativevenousthrombosisinpatientsundergoingelectivesurgery(forexample,hipreplacement)andthoseintheacutephaseofmyocardialinfarction.

WhenDeepveinthrombosisandpulmonaryembolism

hasoccurred,3monthsanticoagulanttherapyhasbeenrecommended.2.AnginapectorisCoronaryarteryrethrombosisafterthrombolytictreatmentisreducedwithheparin.3.Thedrugisalsousedinextracorporealdevices(forexample,dialysismachines)topreventthrombosis.4.Diffuseintravascularcoagulation(DIC)

Adverseeffect

HemorrhageThechiefcomplicationduetooverdoses.Elderlywomenandpatientswithrenalfailurearemorepronetohemorrhage.Carefulmonitoringofthebleedingtimeisrequiredtominimizethisproblem.Treatedbywithdrawalofthedrugandadministratingheparinantagonist---

protaminesulfate.2.ThrombocytopeniaTypeⅠ:Generallyitismildandtransient;occursduetoaggregationofplatelets.(withinfirst5days)TypeⅡ:plateletsareactivatedbyanimmunoglobulinwhichcauseplateletaggregationandreleaseofplateletcontents.Thiscanresultinthrombocytopeniaoccurringbetweenthefifthandfourteenthdaysoftreatment.Itisimperativethatheparintherapymustbediscontinuedinsuchpatients.

3.Hypersensitivityandosteoporosis

Heparinisofanimaloriginandshouldbeusedcautiouslyinpatientswithallergy.

Osteoporosismaydeveloponlongtermuseofrelativelyhighdose.

Contraindication

ActivelybleedingHemophiliaSeverehypertensionHypersensitivetotheheparinLowmolecularweightheparin(LMWH)Similartoheparin,buthasaloweraveragemolecularweightlessthan7KDa.SelectivelyinhibitactivatedfactorXawithlesseffectonthrombin(andoncoagulationingeneral)thanheparin.LMWHhasalowerriskofbleedingthanheparin.LMWHcombineswithAT-ⅢonlyandselectivelyinhibitfactorⅩawithlittleeffectonⅡa.AsaresultLMWHhavesmallereffectonaPPTandwholebloodclottingtime.HavelessantiplateletactionBleedingandthrombocytopeniaareless.

Somepropertiesofheparinandlowmolecular-weightheparins(LMWHs)VitaminKAntagonist(Coumarins)

(oralanticoagulants)

Warfarin

Warfarinisgenerallyadministeredasthesodiumsaltandhas100%bioavailability.Over99%ofwarfarinisboundtoplasmaalbumin.Mechanism

Actindirectlybyinterferingwiththesynthesisofvit.Kdependentclottingfactorsinliver

VitaminKantagonistsblockthereductionofinactivevitaminKepoxide

backtoitsactivehydroquinoneform,whichisnecessaryforitsactionasaco-factorinthesynthesisoffactor

Ⅱ,Ⅶ,ⅨandⅩ.

HydroquinoneformofVitaminKisregeneratedfromtheepoxidebyvitaminKepoxidereductasetheenzymethatisinhibitedbywarfarin.

WarfarinbehavesascompetitiveantagonistsofvitKandreducetheplasmalevelsoffunctionalclottingfactorsinadosedependentmanner.vitaminKepoxidereductase

OnsetofactionislongerthanthatofheparinThoughthesynthesisofclottingfactorsdiminisheswithin2-4hoursofwarfarinadministration,anticoagulanteffectdevelopsgraduallyoverthenext1-3daysasthelevelsoftheclottingfactorsalreadyinplasmadeclineprogressively.Thereisalwaysadelaybetweenadministrationofthedrugandtheanticoagulanteffect.Therapeuticeffectoccurswhensynthesisofclottingfactorsisreducedby40-50%.

Characters:

begivenOrally

IndirectlyStrongeffectiveonlyinvivoonsetofactionislongerthanthatofheparinIndications

Itisusedtopreventtheprogressionorrecurrenceofacutedeep-veinthrombosisorpulmonaryembolismafterinitialheparintreatment.Prophylactically,itisusedinpatientswithacutemyocardialinfarction,prostheticheartvalves,orchronicatrialfibrillation.Adverseeffect:

HemorrhageTreatment:MinorbleedingmaybetreatedbywithdrawalofthedrugandadministrationoforalvitaminK1

SeverebleedingrequiresthatgreaterdosesofthevitaminK1begivenintravenously.Wholeblood,frozenplasma,orplasmaconcentratesofthebloodfactorsmayalsobeemployedtoarresthemorrhaging.Adverseeffect:

seriousbirthdefect

Warfarinshouldneverbeusedduringpregnancy,becauseitisteratogenicandcancauseabortionaswellasbirthdefects(abnormalboneformation).necrosisofskinandtissue

Skinlesionsandnecrosisarerarecomplicationsofwarfarintherapyandareobservedprimarilyinwomen.(treatments:withdrawalofwarfarinandadministrationofVk1)

ⅢFibrinolyticdrugsDuringplugformation,thefibrinolyticpathwayislocallyactivated.Plasminogenisenzymaticallyprocessedtoplasmin(fibrinolysin)byplasminogenactivatorsinthetissue.Plasminlimitsthegrowthoftheclotanddissolvesthefibrinnetwork.Streptokinase(SK)isobtainedfromβhaemolyticstreptococcigroupC.Streptokinasehasnoenzymicactivity.Instead,itformsanactiveone-to-onecomplexwithplasminogen.Thisenzymaticallyactivecomplexconvertsuncomplexedplasminogentotheactiveenzymeplasminwhichcatalyzesthedegradationoffibrin.SKisapprovedforuseinacutepulmonaryembolism,deep-veinthrombosis,acutemyocardialinfarction,arterialthrombosis.

SKisnowconsideredafirstlineapproachiffibrinolytictherapycanbeinstitutedwithin12hr.ofsymptomonset.

*Assoonaspossible

SKisantigenic;cancausehypersensitivityreactionsandanaphylaxis,speciallywhenusedsecondtimeinapatient.Feveriscommon.

Urokinase(UK)

isanenzymeisolatedfromhumanurine;nowpreparedfromculturedhumankidneycells.Itdirectlyconvertsplasminogentoactiveplasmin.Itisnonantigenic.Feveroccursduringtreatment,buthypotensionandallergicphenomenaarerare.Evaluation:

Thrombolytictherapyisexpensive,complexrequiresskill,experience,andotherintensivecarefacilities.Haemorrhageisthemaincomplication;itsincidenceisrelatedtodurationofdruginfusion.Thrombolytictherapyis