药理学教学课件：Chapter 22 Antipyretic-analgesic and anti-inflammatory drugs

Chapter22

Antipyretic-analgesicandanti-inflammatorydrugsAntipyretic-analgesicandanti-inflammatorydrugsalsocallednon-steroidalanti-inflammatorydrugs（NSAIDs,非甾体抗炎药）Isaclassofdrugswithantipyreticandanalgesicaction,exceptPhenylamines苯胺类,thevastmajorityofdrugshavetheanti-inflammatoryandanti-rheumatism.Introduction

广义的抗炎药物1.解热镇痛抗炎药物（非甾体抗炎药，NSAIDs)）2.Glucocorticoids糖皮质激素类（甾体抗炎药）3.Antirheumaticdrugs抗风湿药4.Antigoutdrugs抗痛风药5.H1-receptorantagonistAutacoids自体活性物质(localhormones)Histamine组胺Serotonin，5-HTProstaglandins,前列腺素（PGs）leukotrienes,白三烯（LTs）Vascularactivesubstances:

Psubstance,angiotensin,EndothelinNOAdenosine

hormonesLocalhormonesProstaglandinsProstaglandins(PGs)playtherolesasalocalhormones.ManyoftheNSAIDsactbyinhibitingthesynthesisofPGs,i.e.inhibitionofthecyclooxygenase.1.SynthesisofPGs

Arachidonate(AA,花生四稀酸)istheprimaryprecursorofPGsandrelatedcompounds.FreeAAisreleasedfromtissuephospholipidsbytheactionofphospholipaseA2andotheracylhydrolases

(酰基水解酶).

Twomajorpathways(1)Cyclooxygenase(COX)

pathway:Alleicosanoids类花生酸类物质suchasprostaglandins,thromboxanesA2(TXA2,血栓素),andprostacyclin(PGI2,前列环素),aresynthesizedviatheCOXpathway.(2)Lipoxygenase(LOX)pathway:LOXcanactonarachidonatetoformtheunstableperoxidatedderivatives:

5-hydroperoxyeicosatetraenoicacid(5-HPETE,5-氢过氧化二十碳四烯酸),whichareconvertedtoleukotrienes(LTs,白三烯).2.ActionsofPGs:PGsareoneofthechemicalmediatorsthatarereleasedinallergicandinflammatoryprocesses.TheiractionsaremediatedbybindingtothevarietyofmembranereceptorsthatoperateviaGproteins,whichsubsequentlyactivateorinhibitadenylylcyclase(AC)orstimulatephospholipaseC(PLC).Thiscausesanenhancedformationofdiacylglycerol(DAG,二酰基甘油)andinositol-1,4,5-trisphosphate(IP3).PGF2α,LTs,andTXA2mediatecertainactionsbyactivatingphosphatidylinositolmetabolismandcauseanincreaseofintracellularCa2+.13

Section1.Antipyretic-analgesicandanti-inflammatorydrugsDifferentclassesaccordingtotheirchemicalstructures

Sharesimilarpharmacologicaleffects,mechanismsofactionandadversereactionsTheyallinhibitthebiosynthesisofPGs.

ClassificationofNSAIDsTheNSAIDsaredividedintothevariousgroupsontheirchemicalstructuresasfollow.(1)Salicylates水杨酸类:acetylsalicylicacid(aspirin)andsodiumsalicylate.(2)Phenylamines(苯胺类):acetaminophen(对乙酰氨基酚)(3)Pyrazolidones(吡唑酮类):phenylbutazone(保泰松),

metamizole(安乃近)(4)Indolylaceticacids(吲哚乙酸类):Indomethacin(吲哚美辛),sulindac(舒林酸)(5)Anthranilicacids(邻氨基苯甲酸类):diclofenac(双氯芬酸)，

aceclofenac(醋氯芬酸),(6)Arylalkylacids(芳基烷酸类):Ibuprofen(布洛芬),naproxen(萘普生)(7)Xicam(昔康类):piroxicam(吡罗昔康),meloxicam(美洛昔康),lornoxicam(氯诺昔康)17MembranephospholipidsArachidonicacidPGG2PGH2

PGI2

PGF2

PGE2

TXA2(vascular(bronchial(vasculardilation;(vasculardilation;constriction)GIprotection;constriction;plateletpain,fever)thrombosis)disaggregate;pain)

PLA2LTsLTC4/D4/E4LTB4chemotaxisBronchialconstriction;AlterationofvascularpermeabilityCOXlipoxygenaseglucocorticoidNSAIDs18TheDifferentbiologicalActivitiesoftheProductsofAAPGI2:vasodilationhyperalgesiainhibitplateletaggregationTXA2:plateletaggregationandvasoconstriction.PGE2:induceinflammation,feverandpainvasodilationandhyperalgesiaPGF2α:bronchialconstrictionandvasoconstriction.

19TheDifferentbiologicalActivitiesoftheProductsofAALTs:allergy,bronch-constrictionleukocytotaxisincreasevascularpermeabilityinduceinflammation

Thedifferentanti-inflammatorymechanismGlucocorticoids:inhibitPLA2NSAIDs:inhibitCOXandreducetheproductionofPGs20

COX-1COX-2

ProductionConstitutiveInducibleFunctionPhysiologicalfunction

PathologicalfunctiongastricprotectionfacilitateinflammationplateletaggregationcausefeverandpainperipheralvesselregulationrenalblooddistributionNASIDseffectsunwantedsideeffectstherapeuticeffects21【ThreemajoractionsofNSAIDs】

AntipyreticeffectAnalgesiceffectAnti-inflammatoryeffect22

mechanismscharacteristicsclinicalapplications

1.Antipyreticeffect:23Mechanism

heatproductionheatdissipationpathogenandtoxinsneutrophilsendogenouspyrogens(IL-1,IL-6,TNF)setpointbodytemperatureCOX

NSAIDsPGE2

(hypothalamus)24Characteristics

①Central②“Elevated”temperature----reduced

“Normal”temperature----noinfluence ③TowhatextenttheCOXinhibitedisconsistentwiththeintensityofNSAIDs’spharmacologicaleffects.Clinical

applications

symptomatictreatment.

25attentionAsfeverisadefensereactionofthebodyandheatpatternisanimportantevidenceindiagnosis,weshouldnothurrytouseantipyreticdrugsformildfever;butforhighfeverandchronicfever,antipyreticdrugsshouldbeusedintimetoreducebodytemperature,avoidoralleviatethecomplications.26

WhatisthedifferencebetweenNSAIDsandchlorpromazineinbodytemperatureregulation

?Question127Comparisonbetween

NSAIDsandChlorpromazine

NSAIDsChlorpromazineMechanism

inhibitCOXin

inhibit

thermoregulatorCNS→

PGE2↓makeitoutoffunction

Effect

setpoint

↓BTalterswiththeBT↓environmentaltemperatureClinicalusesfeverartificialhibernation

rheumaticfeverBT:bodytemperature28

mechanism characteristic clinicalapplication

2.Analgesiceffect:29Mechanism

injuryPGspainOtheralgesiogenicsubstance(BK,histamineetc.)nociceptivenerveendings

+NSAIDs30Bradykinin（BK):causepainthroughstimulatingthealgesireceptorsdirectly.PGs:(1)hyperalgesia(2)PG(E1E2F2α)alsohavealgesiogeniceffect31Characteristics①Peripheral②mildtomoderatepain.③NoaddictionorrespiratoryinhibitionNon-narcoticandnoeuphoria.32Clinicalapplications

①havegoodeffectsonchronicdullpain—headache,toothache,neuralgia,musclepain,arthralgia关节痛,dysmenorrhea痛经.②arenoteffectivefortraumaticpain,severevisceralpain—myocardialinfarctionorrenalorbiliarycolic33WhatisthedifferencebetweenNSAIDsandanalgesicsinanalgesiceffectQuestion2?34

Drug

location

mechanism

characteristics

representative

Analgesics

NSAIDs

CNSperipheryCNS(？)(+)opiumreceptor(-)COX,PGsynthesismorphinedolantinaspirinpowerful；sharppain；causeeuphoriaandaddiction;respiratoryinhibitionmoderate；chronicdullpain；notaddictive

no

respiratoryinhibition35

mechanismcharacteristic3.Anti-inflammatoryeffect:363.Anti-inflammatoryeffect

Mechanismofinflammation:

phospholipidsinjuryfactorPLA2

neutrophilicarachidonicacidgranulocyte

cytokinesinduceCOX-2

(IL-1,6,8TNF)

PGs,BK,celladhesionmolecules

inflammation(redness,swelling,heatandpain)37TheroleofPGsininflammation1.causevasodilationandtissueedema2.coordinatewithbradykinintocauseinflammationMechanismofanti-inflammatoryeffect(1)ReducingbiosynthesisofprostaglandinsbyinhibitingCOX.(2)inhibitionoftheexpressionofsomecelladhesionmolecules38Characteristics

①

Peripheral②Theyhavecertaineffectonthecontrolofrheumatoidarthritis.③can’teffectaradicalcure根治.Theycanneitheralterthecoursenorpreventcomplications.39AccordingtoselectivityforCOX:

①Non-selectiveCOXinhibitorsNaproxen萘普生、diclofenac双氯酚酸

②SelectiveCOX-1inhibitors--acetaminophen，ibuprofen（lowselective）--aspirin，indomethacin（highselective）

③SelectiveCOX-2inhibitors:

celecoxib塞来昔布,nimesulide尼美舒利【NSAIDsclassifications】40

Aspirin

(Acetylsalicylic

acid)

Section241【Pharmacokinetics】

Absorption:stomach，uppersmallintestineaspirinaceticacid＋salicylate

Distribution:intheformofsalicylate

articularcavity,CSFandplacentaPPBR=80~90%CSF:cerebrospinalfluidPPBR：plasmaproteinbindingrate血浆蛋白结合率42Metabolism:＜1g，first-orderkinetics，t1/2=3~5h;≥1g，zero-orderkinetics，t1/2=15~30h;

Stilllargerdosage→intoxicationExcretion:renalthepHofurine:alkaline→85%;acidic→5%

Insalicylateacuteintoxication,

wecanincreasetheexcretionoffreesalicylatesbyalkalizingtheurine!43

【pharmacologicalactionsandclinicaluses】

(1)Antipyretic-analgesiceffect(2)Anti-inflammatoryandantirheumaticeffects(3)Plateleteffect-thrombosisinhibition44

(1)Antipyretic-analgesiceffects:

mosteffectiveforfeverandmildtomoderatepain

fever—profusesweating,enoughwatersupplement45

(2)Anti-inflammatoryand

antirheumaticeffects:①usedintherapyanddifferentialdiagnosisofacuterheumaticfever②thepreferreddrugforrheumatoidarthritis③adult:3~5g/d④Inrheumatismtreatment,weshouldmonitortheblooddruglevel46(3)Plateleteffect--thrombosisinhibition

AATXA2PGI2

(-)plateletaggregation；vasculardilation(+)platelet

aggregation；vascularconstrictionplateletbloodvesselendothelium

47

AspirinirreversiblyacetylatesandblocksplateletCOX→TXA2biosynthesis(-)→plateletaggregation(-)→thrombosis(-).(8-10d)TXA2↓LowdosethrombosisisinhibitedPGI2notaffected

TXA2↓HighdoseunbeneficialforthrombosisinhibitionPGI2↓48Clinicaluses:

①lowaspirindose(75~150mg/d)isrecommended;

②preventthrombosis:cardiacorbrainischemicdiseases.angioplasty,coronaryarterybypassgrafting.49Others(1)Alzheimer,sdisease(AD):ADisrelatedtotheover-expressionofCOX-2inbrain.Aspirin100mgp.o.dailyhasrepressioneffectonAD(2)Pregnancy-inducedhypertension（PIH)syndromeandpreeclampsia先兆子痫:

isrelatedtotheincreaseoftheratioofTXA2toPGI2inbloodAspirin40-100mgp.o.dailycanreducetheincidenceofPIHandthedangerofpreeclamapsiaOthers(3)lowdose--decreasethedangerofcarcinomaofcolon(4)treatdiarrheainducedbyradiation,getridofbiliaryascariasis蛔虫.5051【Adverseeffects】GastrointestinalsideeffectsDisturbanceofbloodcoagulationSalicylismreactionHypersensitivityreactionsaspirinasthmaReye’ssyndromeNephrotoxicity521.Gastrointestinalsideeffectsgastricupset，gastriculcer，gastrichemorrhageDueto：①directirritationofthegastricmucosa

②highconcentration→irritateCTZ:nauseaandvomiting③inhibitionofproductionofprotectivePGs(PGE2andPGI2)Countermeasures:①takeaftermeals,chewupthetablet,antacids

②enteric-coatedaspirinContraindications:patientswithpepticulcer532.Disturbanceofbloodcoagulationlowdose---prolongbleedingtime;highdoseorlong-termuse---inhibitprothrombinbiosynthesis(VKcanprevent)Contraindications:hemophilia血友病,pregnancy,severhepaticinsufficiency,hypoprothrombinemia,VKdeficiencybestopped1weekpriortosurgery54

3.SalicylismreactionLargedosage(>5g/d)headache,vertigo眩晕,nausea,vomiting,tinnitus耳鸣,decreasedvisionandhearing；hyperpnea,acid-basedisturbance,insanity精神错乱.Therapy:

①aspirinbestoppedatonce,

②sodiumbicarbonateinfusions.(fluidreplacement)

55

4.Hypersensitivityreactionsurticaria，angioneuroedema，allergicshock5.aspirinasthma“aspirinasthma”:relatedtoPGbiosynthesisinhibition

56WhenCOXpathwayisinhibited,LOXpathwayisstrengthened,LTsincreaseaccordingly.PGsAALTsCOXLOXNSAIDsaspirinasthma

Aspirinasthma

①mechanism:AA:→PG↓ →LTs↑→bronchospasm→asthma

②therapy:

adrenaline()antihistaminic,glucocorticoid()

contraindications:

asthma,chronicurticaria,nasalpolyps鼻息肉586.Reye’ssyndromeSeverehepaticdysfunctionwithcomplicationofencephalopathy脑病Substituteaspirinwithacetaminophen对乙酰氨基酚

7.NephrotoxicityAlsohasbeenobserved.Concomitantadministrationofsalicylateswithmanyclassesofdrugmayproduceundesirablesideeffects.plasmaproteinbound:Drugssuchasdicoumarol(双香豆素),tolbutamide(甲磺丁脲),glucocorticoids(糖皮质激素)Renaltubulesecretion:methotrexate(甲氨蝶呤),furosemide(呋塞米)DruginteractionsSection3.PhenylaminesIncludingacetaminophen(对乙酰氨基酚,paracetamol,扑热息痛)andphenacetin(非那西丁)TheyactbyinhibitingprostaglandinssynthesisintheCNS.Thisexplainstheirantipyreticandanalgesicproperties.61Similarantipyreticandanalgesiceffectstoaspirin,nosignificantanti-inflammatoryeffect.ItinhibitssynthesisofPGsinCNSmoreeffectivelythaninperiphery.

Lessfrequentgastrointestinal

irritation.donotaffectplateletfunctionorincreasebloodclottingtime.PhenylaminesSection4.PyrazolidonesIncludingphenylbutazone(保泰松),metamizole安乃近，oxyphenbutazone(羟基保泰松)haspowerfulanti-inflammatoryeffectsbutweakanalgesicandantipyreticactivities.Itisnotafirstlinedrug.shorttermtherapy:acutegoutandacuterheumatoidarthritis.Themostseriousadverseeffectsareagranulocytosisandaplasticanemia(再障).indomethacin,(吲哚美辛)sulindac(舒林酸)Allhaveanti-inflammatory,analgesicandantipyreticactivity.Theyactbyreversiblyinhibitingcyclooxygenase.Theyaregenerallynotusedtolowerfever.Section5.

IndoleaceticAcids1.Indomethacin

(1)PharmacokineticsIndomethacinisrapidlyandalmostcompletelyabsorbedfromtheupperGItractafteroraladministration.Itismetabolizedbytheliver.Unchangeddrugandmetabolitesareexcretedinbileandurine.2.PharmacologicalActions

Indomethacinismorepotentthanaspirinasananti-inflammatoryagent,inferior(劣于)tothesalicylatesatdosestoleratedbyrheumatoidarthriticpatients.Inacutegoutyarthritis,ankylosingspondylitis(强直性脊椎炎),andosteoarthritisofhip(髋部),itismoreeffectiveinrelievinginflammationthanaspirinorotherNSAIDs.(3)Therapeuticusesrheumatoidarthritis,patentductusarteriosus(动脉导管未闭).Itisalsobeneficialinthecontrolofpainassociatedwithuveitis(眼色素层炎)andpostoperativeophthalmic(眼炎)procedures,Andasanantipyreticwhenthefeverisrefractorytootheragents.2.Sulindac舒林酸

NoeffectsofthisdrugMetabolismbyhepaticmicrosomalenzymesproducestheactiveform(asulfide,硫化物),whichhasalongdurationofaction.Althoughthedrugislesspotentthanindomethacin,itisusefulinthetreatmentofrheumatoidarthritis,ankylosingspondylitis(强直性脊椎炎),osteoarthritis,andacutegout.Theadversereactionsaresimilartobutlessseverethanindomethacin.Section6.FenamatesMefenamicacid(甲芬那酸)andmeclofenamate(甲氯芬那酸)havenoadvantagesovertheNSAIDsasanti-inflammatoryagents.Theirsideeffects,suchasdiarrhea,canbesevereandassociatedwithinflammationofthebowel.Casesofhemolyticanemiahavebeenreported.Diclofenac(双氯芬酸)

(1)Pharmacokinetics

Diclofenacaccumulatesinsynovial(滑膜)fluid.Theurineistheprimaryrouteofexcretionforthedruganditsmetabolites.2.ActionsandusesDiclofenacismorepotentthanindomethacinornaproxen.Itisapprovedforlong-termuseinthetreatmentofrheumatoidarthritis,osteoarthritisandankylosingspondilitis.Anophthalmicpreparationisalsoavailable.(4)Adverseeffects

ItstoxicitiesaresimilartothoseoftheotherNSAIDs,forexample,gastrointestinalproblemsarecommon,andthedrugcanalsogivenrisetoelevatedhepaticenzymelevels.Section7

Propionicacidderivatives

Ibuprofen(布洛芬),naproxen(萘普生),flurbiprofen(氟比洛芬).1.

Pharmacokinetics:

Allarewellabsorbedonoraladministrationandarealmosttotallyboundtoserumalbumin.Theyundergohepaticmetabolismandareexcretedbythekidney.2.PharmacologicalActions

ThesedrugsarereversibleinhibitorsoftheCOXandthus,likeaspirin,inhibitthesynthesisofprostaglandinsbutnotthatofleukotrienes.Theypossessanti-inflammatory,analgesicandantipyreticactivity.3.Therapeuticuse

Thesecompoundswerewidelyusedforthechronictreatmentofrheumatoidandosteoarthritisbecausetheirgastrointestinaleffectsaregenerallylessintensethanthatofaspirin.4.Adverseeffects:Themostcommonadverseeffectisgastrointestinal,rangingfromdyspepsia(消化不良)tobleeding.SideeffectsinvolvingtheCNS,suchasheadache,tinnitus(耳鸣)anddizziness,havealsobeenreported.77

Ibuprofen：LessfrequentgastrointestinalirritationItcanbeslowlyreleasedintosynovialfluid滑液andremainstherewithahighconcentrationWidelyusedinrheumatoidarthritis(RA),andosteoarthritis

Section8.

Oxicamderivatives-PiroxicamPiroxicam(吡罗昔康)isusedtotreatrheumatoidarthritis,ankylosingspondylitis(强直性脊椎炎),andosteoarthritis.Itsmeanhalf-lifeof50hourspermitsadministrationonceaday.GIdisturbancesareencounteredinapproximately20%ofpatients.Thedruganditsmetabolitesareexcretedintheurine.Piroxicamcaninterferewiththerenalexcretionoflithium.Others:meloxicam(美洛昔康)

lornoxicam(氯诺昔康)80

In1998and1999,highlyselectiveCOX-2inhibitors(Celecoxib,nimesulide)havebeendeveloped.Section9

SelectiveCOX-2inhibitors81

CelecoxibahighlyselectiveCOX-2inhibitor，

COX-2:COX-1=375:1gastrointestinaladverseeffectsarelessfrequentnotaffectTXA2biosynthesis,butPGI2synthesiscanbeinhibitedContraindications:patientswiththrombosistendency82

RofecoxibahighlyselectiveCOX-2inhibitordoesnotinhibitplateletaggregationisapprovedmainlyforosteoarthritis六、解热镇痛药的复方配伍常制成复方制剂,如APC、复方扑尔敏片等。目的：增强疗效，减少用量或减轻不良反应。

七、解热镇痛药复方制剂组成成分大致有4类：1.解热镇痛药如阿司匹林、非那西丁、氨基比林和安替比林。2.中枢兴奋药如咖啡因，可减少病人的疲乏感和嗜睡。3.中枢抑制药如苯巴比妥和巴比妥，与小剂量解热镇痛药合用呈现协同作用。4.抗组胺药如氯苯那敏（扑尔敏），可减轻感冒发烧的头痛、鼻塞等。86DrugsusedingoutGoutisametabolicdisordercharacterizedbyhighlevelsofuricacidintheblood.Thishyperuricemiaresultsinthedepositionofcrystalsofsodiumurateintissues,especiallythekidneyandjoints.1.AcutegoutAcutegoutyattackscanresultfromanumberofconditions,includingexcessivealcoholconsumption,adietrichinpurines,orkidneydisease.Acuteattackaretreatedwithcolchicine(秋水仙碱)todecreasemovementofgranulocytesintotheaffectedarea,andwithNSAIDstodecreasepainandinflammation.2.ChronicgoutChronicgoutcanbecausedby(1)ageneticdefect,for