神经系统药理-吴希美解热镇痛药

神经系统药理—吴希美解热镇痛药第1页/共40页A.GeneralPharmacologicalproperties1.Inhibitionofprostaglandinsynthesisinhibiting

cyclooxygenase(COX，环氧酶),decreasingthesynthesisofPGsandTXA2,resultingantipyretic,analgesic,andanti-inflammatoryeffectsnon-steroidalanti-inflammatorydrugs(NSAIDs,非甾体抗炎药）。第2页/共40页第3页/共40页第4页/共40页2.AntipyreticeffectsInhibitionofPGE2productioninthehypothalamusinducedbyendogenouspyregensafterpathologicalstimulitemperaturenotes:

symptomaticcontrolonly,notbeindicatedinallpatientswithfever.

Theeffectonbodytemperatureisdifferentfromthatofchlorpromazine.A.GeneralPharmacologicalproperties第5页/共40页Comparisonofpropertiesoftwotypesofdrugs第6页/共40页3.AnalgesiceffectsAnalgesiceffectisresultedfrominhibitionofPGE2production.Effectiveonthepainoflowtomoderateintensityrelatedtoinflammatoryresponses.PGE2:apainstimulantandhyperalgesicagentTheanalgesiceffectisdifferentfromopioidanalgesics.A.GeneralPharmacologicalproperties第7页/共40页Comparisonofpropertiesoftwotypesofdrugs第8页/共40页4.Anti-inflammatoryeffects

PGsinduceinflammatoryresponses.InhibitionofPGproductioncanrelieveinflammatoryresponses,suchascongestion,exudation,pain.Theeffectisdifferentfromthatofglucocorticosteroids.A.GeneralPharmacologicalproperties第9页/共40页Comparisonofpropertiesoftwotypesofdrugs第10页/共40页5.COX-1/COX-2andselectivityofthedrugsCOX-1:

constructive;

involvedinphysiologicregulatoryfunctionsinGItract,kidney,etc.;

inhibitionofCOX-1isrelatedtotheadverseeffects.COX-2:

inducible;involvedinpathologicalresponsessuchasinflammation,andpregnancy;

inhibitionofCOX-2isrelatedtothetherapeuticeffects.

A.GeneralPharmacologicalproperties第11页/共40页（－）（＋）（＋）（－）第12页/共40页第13页/共40页第14页/共40页第15页/共40页B.SalicylatesAspirin阿司匹林Acetylsalicylicacid乙酰水杨酸Aspirin阿司匹林Salicylicacid水杨酸Salicylicsodium水杨酸钠第16页/共40页Aspirin阿司匹林1.ADMEtransformedtosalicylicacidforminthebodyhepaticmetabolismisprimarilyconjugation.excretionfromurine,theexcretionofunchangedformsofaspirinisincreasedinthealkalinizedurine.largerdoses(>1g/d):

non-linearelimination,zeroorderkineticprocess,easiertoaccumulationandintoxication.B.Salicylates第17页/共40页第18页/共40页2.Pharmacologicaleffectsandclinicaluses(1)Antipyretic,analgesicandanti-inflammatoryeffects

moderatedoses(0.3～0.6g):antipyreticandanalgesiceffects

largerdoses(3～5g/d):anti-inflammatoryandanti-rheumaticeffects;onlyrelievessymptoms.

totreatacuterheumaticfever(急性风湿热),toabatepainandsymptomsofrheumatic&rheumatoidarthritis(风湿性和类风湿性关节炎).B.Salicylates第19页/共40页(2)Inhibitionofplateletaggregation

smalldoses(30～100mg/d):inhibitingTXA2synthesis,preventingthrombosis.usedtotreatischemicheartdisease,reducethemortalityofmyocardiacinfarction,andpreventcerebralthrombosis.

largerdoses:inhibitingPGI2synthesis,promotingthrombosis.

PGI2:vasodilationandplateletdepolymerization(血小板解聚).

B.Salicylates第20页/共40页Themechanismofaspirin:Targetenzymesacetylated第21页/共40页3.Adverseeffects(1)GIreactions

stimulatinggastricmucosaandCTZ(largerdoses);inhibitingPGsynthesisinGItractirritantsymptoms;gastricbleeding;ulcerousdisordersContraindications:ulcerousdisordersB.Salicylates第22页/共40页(2)Prolongationofbleedingtimesmalldoses:inhibitingplateletaggregationlargerdoses:inhibitingsynthesisofthrombogen

Contraindications:oneweekpriortosurgery;severehepaticdamage;vitaminKdeficiency,;prothrombinopenia(凝血酶原减少症).B.Salicylates第23页/共40页(3)Allergicreactionsurticaria(荨麻疹),angioneuroticedema,aspirin-inducedasthma,occasionallyanaphylacticshock.Contraindications:

bronchialasthmaB.Salicylates第24页/共40页Aspirin-inducedasthma:

Phospholipidsofcellmenbrane

Aspirin

PhospholipaseA2(PLA2)(-)Arachidonicacid

CyclooxygenaseLipoxygenenase

(环氧酶)PGH25-HPETE(脂氧酶)

↓Prostaglandins(PGs)

↑Leukotrienes(LTs)

(前列腺素)

(白三烯)第25页/共40页(4)Salicylism

dose>5g/d:CNSsymptoms,includingmentalconfusion;hyperventilation.i.v.NaHCO3canpromotetheexcretionofaspirin.

(5)Hepaticdamage

Overdose:hepaticdamage

Reye’ssyndrome(瑞夷综合征):inchildren,severehepaticdamage(严重的肝损害)andencephalopathy(脑病)B.Salicylates第26页/共40页Dose-responserelationshipofaspirin:therapeuticeffects;adverseeffects第27页/共40页4.DruginteractionsB.Salicylates第28页/共40页C.Para-aminophenolderivativesAcetaminophen对乙酰氨基酚Paracetamol

扑热息痛第29页/共40页Acetaminophen（对乙酰氨基酚）：

antipyreticandanalgesiceffectsaremildandlasting,butalmostnoanti-inflammatoryeffects,-nota

NSAIDhigherselectivitytoCOXinCNS.

mainlyusedincold,fever,andheadache,etc.

overdosecandamageliverandkidney.C.Para-aminophenolderivatives第30页/共40页DifferencesbetweenNSAIDsandAcetaminophen第31页/共40页Toxicmetabolitesofacetaminophen第32页/共40页D.Otheranti-inflammatorydrugsSalicylates:aspirinPara-aminophenolderivatives:acetaminophenIndoleandindeneaceticacidderivatives:indomethacin,sulindacPropionicacidderivatives:

ibuprofen,naproxen,fenopofen,ketoprofenCOX-2selectiveinhibitors:meloxicam,celecoxide,rofenxidOthers:phenylbutazone,diclofenac第33页/共40页第34页/共