Chapter27

Antipyretic-AnalgesicandAntiinflammatoryDrugsA.GeneralPharmacologicalproperties1.Inhibitionofprostaglandinsynthesisinhibiting

cyclooxygenase(COX，環(huán)氧酶),decreasingthesynthesisofPGsandTXA2,resultingantipyretic,analgesic,andanti-inflammatoryeffectsnon-steroidalanti-inflammatorydrugs(NSAIDs,非甾體抗炎藥）。2.AntipyreticeffectsInhibitionofPGE2productioninthehypothalamusinducedbyendogenouspyregensafterpathologicalstimulitemperaturenotes:

symptomaticcontrolonly,notbeindicatedinallpatientswithfever.

Theeffectonbodytemperatureisdifferentfromthatofchlorpromazine.A.GeneralPharmacologicalpropertiesComparisonofpropertiesoftwotypesofdrugs3.AnalgesiceffectsAnalgesiceffectisresultedfrominhibitionofPGE2production.Effectiveonthepainoflowtomoderateintensityrelatedtoinflammatoryresponses.PGE2:apainstimulantandhyperalgesicagentTheanalgesiceffectisdifferentfromopioidanalgesics.A.GeneralPharmacologicalpropertiesComparisonofpropertiesoftwotypesofdrugs4.Anti-inflammatoryeffects

PGsinduceinflammatoryresponses.InhibitionofPGproductioncanrelieveinflammatoryresponses,suchascongestion,exudation,pain.Theeffectisdifferentfromthatofglucocorticosteroids.A.GeneralPharmacologicalpropertiesComparisonofpropertiesoftwotypesofdrugs5.COX-1/COX-2andselectivityofthedrugsCOX-1:

constructive;

involvedinphysiologicregulatoryfunctionsinGItract,kidney,etc.;

inhibitionofCOX-1isrelatedtotheadverseeffects.COX-2:

inducible;involvedinpathologicalresponsessuchasinflammation,andpregnancy;

inhibitionofCOX-2isrelatedtothetherapeuticeffects.

A.GeneralPharmacologicalproperties（－）（＋）（＋）（－）B.SalicylatesAspirin阿司匹林Acetylsalicylicacid乙酰水楊酸Aspirin阿司匹林Salicylicacid水楊酸Salicylicsodium水楊酸鈉Aspirin阿司匹林1.ADMEtransformedtosalicylicacidforminthebodyhepaticmetabolismisprimarilyconjugation.excretionfromurine,theexcretionofunchangedformsofaspirinisincreasedinthealkalinizedurine.largerdoses(>1g/d):

non-linearelimination,zeroorderkineticprocess,easiertoaccumulationandintoxication.B.Salicylates2.Pharmacologicaleffectsandclinicaluses(1)Antipyretic,analgesicandanti-inflammatoryeffects

moderatedoses(0.3～0.6g):antipyreticandanalgesiceffects

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

totreatacuterheumaticfever(急性風(fēng)濕熱),toabatepainandsymptomsofrheumatic&rheumatoidarthritis(風(fēng)濕性和類風(fēng)濕性關(guān)節(jié)炎).B.Salicylates(2)Inhibitionofplateletaggregation

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

largerdoses:inhibitingPGI2synthesis,promotingthrombosis.

PGI2:vasodilationandplateletdepolymerization(血小板解聚).

B.SalicylatesThemechanismofaspirin:Targetenzymesacetylated3.Adverseeffects(1)GIreactions

stimulatinggastricmucosaandCTZ(largerdoses);inhibitingPGsynthesisinGItractirritantsymptoms;gastricbleeding;ulcerousdisordersContraindications:ulcerousdisordersB.Salicylates(2)Prolongationofbleedingtimesmalldoses:inhibitingplateletaggregationlargerdoses:inhibitingsynthesisofthrombogen

Contraindications:oneweekpriortosurgery;severehepaticdamage;vitaminKdeficiency,;prothrombinopenia(凝血酶原減少癥).B.Salicylates(3)Allergicreactionsurticaria(蕁麻疹),angioneuroticedema,aspirin-inducedasthma,occasionallyanaphylacticshock.Contraindications:

bronchialasthmaB.SalicylatesAspirin-inducedasthma:

Phospholipidsofcellmenbrane

Aspirin

PhospholipaseA2(PLA2)(-)Arachidonicacid

CyclooxygenaseLipoxygenenase

(環(huán)氧酶)PGH25-HPETE(脂氧酶)

↓Prostaglandins(PGs)

↑Leukotrienes(LTs)

(前列腺素)

(白三烯)(4)Salicylism

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

(5)Hepaticdamage

Overdose:hepaticdamage

Reye’ssyndrome(瑞夷綜合征):inchildren,severehepaticdamage(嚴(yán)重的肝損害)andencephalopathy(腦病)B.SalicylatesDose-responserelationshipofaspirin:therapeuticeffects;adverseeffects4.DruginteractionsB.SalicylatesC.Para-aminophenolderivativesAcetaminophen對(duì)乙酰氨基酚Paracetamol

撲熱息痛Acetaminophen（對(duì)乙酰氨基酚）：

antipyreticandanalgesiceffectsaremildandlasting,butalmostnoanti-inflammatoryeffects,-nota

NSAIDhigherselectivitytoCOXinCNS.

mainlyusedincold,fever,andheadache,etc.

overdosecandamageliverandkidney.C.Para-aminophenolderivativesDifferencesbetweenNSAIDsandAcetaminophenToxicmetabolitesofacetaminophenD.Otheranti-inflammatorydrugsSalicylates:aspirinPara-aminophenolderivatives:acetaminophenIndoleandindeneaceticacidderivatives:indomethacin,sulindacPropionicacidderivatives:

ibuprofen,naproxen,fenopofen,ketoprofenCOX-2selectiveinhibitors:meloxicam,celecoxid