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1、神经系统药理6一、麻醉性镇痛药二、解热镇痛抗炎药一、麻醉性镇痛药General ConsiderationsPain ( (疼痛疼痛疼痛疼痛) )： 躯体痛快痛，慢痛躯体痛快痛，慢痛躯体痛快痛，慢痛躯体痛快痛，慢痛 内内内内脏脏痛痛痛痛 情情情情绪绪反反反反应应Analgesia ( (镇痛镇痛镇痛镇痛) )： 选择选择性抑制疼痛感性抑制疼痛感性抑制疼痛感性抑制疼痛感觉觉， 不影响意不影响意不影响意不影响意识识和其他感和其他感和其他感和其他感觉觉Pain ClassificationHeadacheHeadache(migraine)(migraine)AcuteAcuteChronicChr
2、onicPainPainNociceptiveNociceptiveMixedMixedNeuropathicNeuropathicVisceralVisceralDiabetic neuropathy (DN)Post-herpetic neuralgia (PHN)Radiculopathy 神经根神经根痛痛(RADIC)Cancer painLow back painOsteoarthritisRheumatoid arthritisFibromyalgia纤维肌痛纤维肌痛IBSPancreatitisBladder painNoncardiac chest painAbdominal
3、pain syndromeInjuryInjuryPostoperativePostoperativeFlareFlareAn adverse or unpleasant reactionplus the reactions evoked by itPain generation and reactionsPain generation and reactionsThe perception of somatic pain Drugs for the Relief of Pain Drugs for the Relief of PainClassification of analgesics：
4、Opioid analgesics (centrally acting) opiatesopiates synthetic agentssynthetic agentsAntipyretic, analgesic, and anti-inflammatory drugs (peripherally acting) aspirin, indomethacinaspirin, indomethacinOther drugs (for special types of pain) carbamazepine, atropine, nitroglycerin, carbamazepine, atrop
5、ine, nitroglycerin, etc.etc.General ConsiderationsOpiumOpiumA. Opioid AnalgesicsMorphine 吗啡吗啡吗啡吗啡Morphine Morphine 吗吗 啡啡啡啡Heroin Heroin 海洛因海洛因海洛因海洛因A. Opioid AnalgesicsMorphine: Morphus, the Greek god of dreams1. Pharmacological effects(1) Mechanisms of actions Acting on central opioid receptors rec
6、eptors receptors receptorsA. Opioid AnalgesicsATPcAMPGiACOpioidReceptorsandEndogenousLigands EndorphinEndorphin( (内啡内啡内啡内啡肽肽) )EnkephalinEnkephalin( (脑脑啡啡啡啡肽肽) )DynorphinDynorphin( (强强啡啡啡啡肽肽) )K+abgabgGi=Opioids and opioid receptor ligandsMechanisms of morphine actionsPeripheral mechanisms of morphi
7、ne actionsCentral mechanisms of morphine actionsCentral mechanisms of morphine actionsCentral mechanisms of morphine actionsCentral mechanisms of morphine actions: : Pain inhibitory systemPain inhibitory system(2) Central nervous system effectsA. AnalgesiaAnalgesia：maximal analgesic efficacymaximal
8、analgesic efficacy； relieving unpleasant sensation;relieving unpleasant sensation; euphonia euphonia ( (欣快欣快欣快欣快) ) and potential of dependence; and potential of dependence; sedation sedationB. Depression of respirationDepression of respiration: reducing the sensitivity of respiratory center to redu
9、cing the sensitivity of respiratory center to COCO2 2C. Depression of cough reflexDepression of cough reflexD. Other central effectsOther central effects: miosismiosis（瞳孔（瞳孔（瞳孔（瞳孔缩缩小）小）小）小）, emesis, emesis（呕吐）（呕吐）（呕吐）（呕吐）A. Opioid Analgesics(3) Cardiovascular effectsA. Postural hypotensionPostural h
10、ypotension： Releasing histamine; depressing CVS centersReleasing histamine; depressing CVS centersB. Increase of intracranial pressuresIncrease of intracranial pressures： Respiratory depression Respiratory depression brain CObrain CO2 2 increaseincrease vasodilatation in the brain vasodilatation in
11、the brainA. Opioid Analgesics(4) Effects on smooth musclesA. GI tractA. GI tract： Constipation Constipation ( (便便便便秘秘秘秘): ): increasing increasing resting resting tone tone of of smooth smooth muscles muscles and and sphincters, sphincters, decreasing decreasing propulsive propulsive peristalsis per
12、istalsis and secretions; and secretions; Biliary Biliary tracttract：Oddis Oddis sphincter sphincter contraction, contraction, increasing increasing the the pressure in the biliary tractpressure in the biliary tractB. Respiratory tractB. Respiratory tract：bronchoconstrictionbronchoconstrictionC. Urin
13、ary tractC. Urinary tract：increasing vesical sphincter tone increasing vesical sphincter tone urinary urinary retentionretentionD. D. UterusUterus： decreasing uterus smooth muscle tone decreasing uterus smooth muscle tone A. Opioid Analgesics(5) Other effectsA. Immune depressionImmune depressionB. E
14、ndocrine Endocrine effects, increaseeffects, increaseA. Opioid Analgesics2. Clinical uses(1) Analgesia (1) Analgesia the the pain pain of of high high intensity intensity and and the the pain pain of of terminal terminal illnessillnessCautionsCautions: a) obscure the symptoms and the progress of the
15、 disease; a) obscure the symptoms and the progress of the disease; b b) dependence or addiction; not used for long-term if ) dependence or addiction; not used for long-term if no clear indications no clear indications c c) biliary colic: combined with atropine) biliary colic: combined with atropineA
16、. Opioid Analgesics(2) Cardiac asthma (acute left ventricular failure)(2) Cardiac asthma (acute left ventricular failure) As an adjuvant treatmentAs an adjuvant treatment A. VasodilatationA. Vasodilatation: : afterload afterload B. SedationB. Sedation: : anxiety anxiety C. Respiratory depressionC. R
17、espiratory depression: : breathing slowly and deeplybreathing slowly and deeply(3) Diarrhea(3) Diarrhea Mixture containing opiate Mixture containing opiate A. Opioid Analgesics3. Adverse effects(1) Side effects(1) Side effects(2) Tolerance and dependence(2) Tolerance and dependence psychological and
18、 physic dependence: psychological and physic dependence: addictionaddiction withdrawal withdrawal syndromes syndromes or or abstinance abstinance syndromes syndromes ( (戒断症状戒断症状戒断症状戒断症状) )A. Opioid Analgesics药物依赖性与药物成瘾相关的概念药物依赖性与药物成瘾相关的概念1、药物依物依赖性性 是是药物与机体相互作用所造成的一种精神状物与机体相互作用所造成的一种精神状态，有，有时也包括身体状也包
19、括身体状态，它表，它表现出一种出一种强迫要迫要连续或定期使用或定期使用该药的行的行为和其他反和其他反应，为的是要去感受它的精神效的是要去感受它的精神效应，或是，或是为了避了避免由于停免由于停药所引起的不舒适。所引起的不舒适。 包括：精神依包括：精神依赖性和生理依性和生理依赖性性 （ psychological and physic dependencepsychological and physic dependence ）（1）精神依赖性（）精神依赖性（psychological dependence，psychic dependence） 精精神神依依赖性性是是指指使使人人产生生一一种种对
20、药物物欣欣快快感感的的渴渴求求，这种种精精神神上上不不能能自自制制的的强烈烈欲欲望望驱使使滥用者周期性或用者周期性或连续地用地用药。 又被称又被称为情感情感动机依机依赖性性（2）身体依赖性（）身体依赖性（physical dependence） 指指大大多多数数具具有有依依赖性性特特征征的的药物物经过反反复复使使用用所所造造成成的的一一种种适适应状状态，用用药者者一一旦旦停停药，将将发生生一一系系列列生生理理功功能能紊紊乱乱，称称戒戒断断综合征合征（withdrawal syndrome）。）。精精神神依依赖性性与与身身体体依依赖性性的的主主要要不不同同点点是是前者在停前者在停药后不出后不出现
21、严重的戒断症状。重的戒断症状。2、药物成瘾（、药物成瘾（drug addiction） 指指强迫迫性性、失失去去控控制制的的用用药行行为，是是药物物的的精神依精神依赖性和生理依性和生理依赖性共同造成的性共同造成的结果。果。一一些些具具有有生生理理依依赖性性的的药物物，如如某某些些抗抗癫痫药、抗抗高高血血压药、 受受体体阻阻断断药、糖糖皮皮质激激素素等等，突突然然停停药可可引引起起停停药综合合征征，但但不属于不属于药物成物成瘾。3、药物滥用（、药物滥用（drug abuse） 指指与与医医疗目目的的无无关关的的反反复复使使用用能能成成瘾的的药物物，用用药者者采采用用自自身身给药的的方方式式，是是
22、药物物成成瘾的后果。的后果。成成瘾药物物表表表表11-111-1，美国精神病学会，美国精神病学会，美国精神病学会，美国精神病学会对对物物物物质质依依依依赖赖和物和物和物和物质滥质滥用的用的用的用的评评判判判判标标准准准准 应与与药物物误用用（misuse）区区别，如如不不合合理理应用抗菌用抗菌药、激素等。、激素等。(3) Acute intoxication(3) Acute intoxication coma, respiratory depression, coma, respiratory depression, hypotension, pinpoint pupils hypotens
23、ion, pinpoint pupils reversed by naloxone, an opioid receptor antagonistreversed by naloxone, an opioid receptor antagonist(4) Contraindications(4) Contraindications labor and lactation;labor and lactation; bronchial asthma and cor pulmonal( bronchial asthma and cor pulmonal(肺心病肺心病肺心病肺心病); ); increa
24、sed intracranial pressures; increased intracranial pressures; severe hepatic damage severe hepatic damageA. Opioid AnalgesicsPinpointpupilsMorphine toxicity can Morphine toxicity can be reversed by opioid be reversed by opioid receptor antagonistreceptor antagonist (naloxone)(naloxone)Analgesia; cen
25、tral antitussiveCodeine 可待因可待因可待因可待因A. Opioid AnalgesicsPethidine(Pethidine(哌替啶哌替啶哌替啶哌替啶) )1. 1. Pharmacological effectsPharmacological effects Similar Similar to to morphine morphine but but ineffective ineffective for for cough cough and and diarrhea, diarrhea, and and its its metabolite metabolit
26、e normeperidine normeperidine has has central central stimulant stimulant effects.effects.2. Clinical uses2. Clinical uses analgesia;analgesia; cardiac asthma; cardiac asthma; preanesthetic medicationpreanesthetic medication or or artificial hibernationartificial hibernation; ; 3. Adverse effects3.
27、Adverse effects similar to morphine, convulsion (overdose)similar to morphine, convulsion (overdose)B. Synthetic AnalgesicsFentanyl （芬太尼芬太尼芬太尼芬太尼） high efficacyhigh efficacy combined with combined with droperidol droperidol ( (氟氟氟氟哌哌利多利多利多利多): ): 1:50 1:50 neuroleptanalgesia neuroleptanalgesia 神神神神经
28、经安定安定安定安定镇镇痛痛痛痛术术Methadone （美沙（美沙（美沙（美沙酮酮） orally effectiveorally effective long-actinglong-acting also used for displacement in heroin or morphine also used for displacement in heroin or morphine detoxicationdetoxicationB. Synthetic AnalgesicsPentazocine （喷喷他佐辛他佐辛他佐辛他佐辛, , 镇镇痛新痛新痛新痛新） receptor agon
29、ist / receptor agonist / receptor partial agonist; receptor partial agonist; low-narcotic analgesic druglow-narcotic analgesic drug psychotomimetic effects: anxiety, nightmare, psychotomimetic effects: anxiety, nightmare, hallucinationshallucinationsTramadol （曲曲曲曲马朵马朵） Relatively weak efficacy and d
30、ependenceRelatively weak efficacy and dependenceRotundine （l l-tetrahydropalmatine, -tetrahydropalmatine, 罗罗通定通定通定通定）dl-Tetrahydropalmatine （延胡索乙素延胡索乙素延胡索乙素延胡索乙素） chronic chronic pain; sedative effects; no addictionpain; sedative effects; no addictionC. Other AnalgesicsB. Synthetic AnalgesicsSummary
31、 of opioid receptor ligandsNaloxone （纳纳洛洛洛洛酮酮）Naltrexone （纳纳曲曲曲曲酮酮）Antidotes for acute intoxication of opioidsAntidotes for acute intoxication of opioidsTreatment of shock and other diseasesTreatment of shock and other diseasesOpioid receptor antagonists附：癌痛的镇痛治疗附：癌痛的镇痛治疗三级镇痛阶梯治疗：三级镇痛阶梯治疗： 轻轻度：度：度：度
32、：解解解解热热抗炎抗炎抗炎抗炎镇镇痛痛痛痛药药 中度：中度：中度：中度：加用或改用弱阿片加用或改用弱阿片加用或改用弱阿片加用或改用弱阿片药药, , 辅辅助治助治助治助治疗药疗药 重度：重度：重度：重度：强强阿片阿片阿片阿片药药，加非阿片及加非阿片及加非阿片及加非阿片及辅辅助治助治助治助治疗药疗药应用原则：应用原则： 尽可能口服用尽可能口服用尽可能口服用尽可能口服用药药 按按按按时规则时规则用用用用药药，剂剂量个体化量个体化量个体化量个体化 辅辅助措施助措施助措施助措施WHO Analgesic LadderWHO Analgesic Ladder二、解热镇痛抗炎药二、解热镇痛抗炎药Periph
33、eralmechanismsofpainDrugs for the Relief of PainNon-steroidal anti-inflammatory drugs (NSAIDs) are just that - drugs that act to relieve inflammation, but are not structurally related to the corticosteroidsCyclooxygenases: COX 1, COX 2-PGs,mostlybyCOX-1, areconstitutively expressedinalmostalltissues
34、;COX-2appearstoonlybeconstitutivelyexpressedinthebrain,kidney,bones,reproductiveorgans,andsomeneoplasms-Undernormalphysiologicconditions,PGsplayanessentialhomeostaticroleincytoprotectionofgastricmucosa,hemostasis(止血止血),renalphysiology,gestation(怀孕孕),andparturition(分娩分娩)-OnlyCOX-1inplateletsconvertsa
35、rachidonicacidtoTXA2-COX-1predominantingastricmucosaisasourceofcytoprotectivePGs-TheproductionofPGs(inducible COX-2 activityCOX-1)atsitesofinflammationpropagatepain,feverCOX-1comparedtoCOX-2COX-1 COX-2ExpressionTissuelocalizationRole“Housekeeping” and maintenanceUbiquitousInflammatory and neoplastic
36、 sites (small amounts in kidney, uterus, ovary, CNS neocortex, hippocampus)Pro-inflammatory and mitogenic functions (? neuronal plasticity)Constitutive (activated by physiologic stimuli)Inducible by pro-inflammatory stimuli (LPS, TNF , IL-2, IFN etc)NSAID TherapyNSAID inhibition of PGs production al
37、leviates most of the pathologic effects associated with inflammation, but it also interferes with the physiologic role of these moleculesConsequently, long-term therapy with nonspecific NSAIDs is frequently limited by their adverse effects, particularly those caused by erosion of gastric mucosal pro
38、tection GI bleedingPharmacodynamic Effects of NSAIDsPositiveanalgesic - referstothereliefofpainbyamechanismotherthanthereductionofinflammation(forexample,headache); - produceamilddegreeofanalgesiawhichismuchlessthantheanalgesiaproducedbyopioidanalgesicssuchasmorphineanti-inflammatory - thesedrugsare
39、usedtotreatinflammatorydiseasesandinjuries,andwithlargerdoses-rheumatoiddisordersantipyretic - reducefever; lowerelevatedbodytemperaturebytheiractiononthehypothalamus;normalbodytemperatureisnotreducedAnti-platelet -inhibitplateletaggregation,prolongbleedingtime;haveanticoagulanteffectsAnalgesic : co
40、mpared with OpioidsNSAIDs OpioidsEffectsClinical usageSide effectsGI reactions，no addictionHeadache, toothache，neuralgia, arthronalgia, courbature(肌肉痛肌肉痛), menalgia(痛经痛经)Various pain including severe painAddictionInhibit PGs and TXA2 synthesis by inhibiting COXStimulate opioid receptorsAnti-inflamma
41、tory: compared with glucocorticoidNSAIDs GlucocorticoidEffectsClinical usageSide effectsGI reactionsRheumatic, rheumatoid, traumaVarious inflammationVarious side effects, such as metabolism disturbance, damage of defense etc.Inhibit PGs and TXA2 synthesis by inhibiting COXVarious effects including i
42、nhibition of PLA2antipyretic : compared with chlorpromazine NSAIDs Chlorpromazine(氯丙丙嗪)EffectsClinical usageSide effectsGI reactions，no addictionLower the abnormal high temperature to normal. Used for various fever.artificial hibernation(人工冬眠人工冬眠), Hypothermic anesthesia Extrapyramidal effects (锥体外体
43、外系反系反应)Inhibit PGs synthesis and enhance thermolysisInhibit thermotaxic center in hypothalamus, induce the body temperature change according to that of environment.Pharmacodynamic Effects of NSAIDsNegative Gastric irritant Decreased renal perfusion Bleeding CNS effectsNSAID-associated dyspepsia(消化不良
44、消化不良) occurs in up to 50% of patients who use these drugsno relationship, however, between NSAID-associated dyspeptic symptoms and the presence of erosions or ulcerationup to 100% of patients taking nonselective NSAIDs， ，subepithelial hemorrhage, 50% have erosions (small, shallow breaks in the GI mu
45、cosa) 20% have ulceration (injury extending through the muscular mucosa)unless the ulcer results in symptoms or becomes complicated (e.g., causes bleeding or perforation), it is not clinically relevant. Only 1 - 3% of patients develop serious GI side effects while taking NSAIDs.Gastrointestinal Adve
46、rse Effects associated with NSAIDsForpatientspresentingtohospitalwithuppergastrointestinal(UGI)bleeding-asignificantpercentwereusingNSAIDsNote:Over-the-counter(OTC)useofNSAIDswasmoreprevalentthanwasprescribedNSAIDusage.NSAIDs - Gastric Irritant Effects: Molecular MechanismsPGs reduce H+ secretion an
47、d increase mucous production.Consequently, NSAIDs cause some degree of gastric upset due to inhibition of PG synthesis.- Misoprostol. a synthetic prostaglandin analogue, can also decrease the risk of NSAID-induced ulceration and complications. - PPIs can reduce the risk of peptic ulcer formation. NS
48、AIDs and Platelet FunctionPhysiology:TXA2ismainlyproducedinplatelets:uponplateletactivation;promotesplateletaggregation,vasoconstriction,andvascularproliferationplateletsdonothaveanucleusandcannotsynthesizenewCOXmoleculestoreplacethosethathavebeenirreversiblyinactivated.Pharmacology:-apartfromaspiri
49、n(irreversibleCOXinhibition),allNSAIDsinhibitCOXcompetitively,andinhibitoryeffectsonplateletaggregationdependonthepharmacokineticprofilesoftheagents.Afteradministrationofasingledoseofaspirin,plateletaggregationisimpairedforupto4days,untilnewplateletsenterthecirculationinsufficientnumbers.-asthrombot
50、iceventscanoccuratanytimeandforaprolongedperiodafterruptureofavulnerableplaque,sustainedinhibitionofplateletactivityisneededinordertoprovidecardioprotection. small doses (40small doses (4080 80 mg/d):mg/d): inhibiting TXA inhibiting TXA2 2 synthesis, preventing synthesis, preventing thrombosis.throm
51、bosis. larger doses:larger doses: inhibiting inhibiting PGIPGI2 2 synthesis, promoting synthesis, promoting thrombosis. thrombosis. PGIPGI2 2: : vasodilation and platelet vasodilation and platelet depolymerization (depolymerization (血小板解聚血小板解聚血小板解聚血小板解聚). ).- -Most of these drugs will Most of these
52、drugs will potentiate the action of potentiate the action of oral anticoagulants such as oral anticoagulants such as coumadin, by their effects coumadin, by their effects on platelet aggregation.on platelet aggregation.NSAIDs Effects on Renal FunctionIn healthy hydrated individuals, renal PGs do not
53、 play a major role in sodium and water homeostasisUnder certain conditions of localized circulatory stress associated with elevated levels of angiotensin II and catecholamines resulting in decreased renal perfusion, renal blood flow is dependent upon prostaglandin synthesisNSAID-induced inhibition o
54、f PG synthesis can result in significant decreases in renal blood flow and GFR, leading to acute renal failure in kidney function-compromised individualsPatients at most risk include those with congestive heart failure, volume depletion, chronic renal disease, liver disease and those patients receiv
55、ing diuretics Salicylates(水杨酸类水杨酸类) aspirin(阿司匹林阿司匹林)History - Salicylates Salicylates were first discovered when the observation was made that chewing willow bark could relieve painHippocrates (希波克拉底希波克拉底): Willow bark as a pain killer during childbirthStone (1700) Extract of willow bark to reduce
56、fever Piria (1838) Isolation of salicin(水水杨苷苷) from willow bark Kolbe (1853) Synthesis of salicylate from salicinVon Gerhardt at Beyer Pharmaceutical Co. synthesized acetyl SA (ASA) in 1850Hoffman, at Beyer gave ASA to his rheumatoid fatherBeyer started sales of Aspirin in1899Acetylsalicylic acid (a
57、spirin) was introduced as a pain reliever in 1899, at that time it was used in doses of 650 mg every 4 hoursHistory - SalicylatesAspirin-Mechanism of Action: Covalent Binding to COXASAcovalentlyandirreversiblymodifiesbothCOX-1andCOX-2byacetylatingserine-530intheactivesiteAcetylationresultsinastericb
58、lock,preventingarachidonicacidfrombindingNote:AcetylationofCOX-2retainstheCOXactivityalthoughthereactionproducesadifferentproduct,15-R-HETEAspirinMetabolismPathwaysacetylsalicylicacid(ASA)ASA:t1/220minsalicylatet1/23-5hrsirreversibleacetylationofCOX-Salicylateeliminationis1storderatlowandmoderatedos
59、es;-Whentotalbodysalicylate600mg(3.5g/d),eliminationiszeroorderUses of AspirinDose-DependentEffects:Low:300mgblocksplateletaggregationIntermediate:300-2400mg/dayantipyreticandanalgesiceffectsHigh:2400-4000mg/dayanti-inflammatoryeffectsSalicylism(水杨酸中毒水杨酸中毒)耳耳鸣中枢性中枢性过度度换气气代代谢性酸中毒性酸中毒脱水脱水低凝血低凝血酶原血症原血症
60、Side effects of aspirinGastrointestinal symptomsCNS toxicity / Salicylate reactionAnaphylaxis (asthma) Metabolic acidosis, respiratory alkalosisHepatic damage / Reyes syndromeRenal damageHematologic effectsNSAIDs: Classification by Plasma Elimination Half LivesShort Half Life ( 10 hours):slower onse
61、t of effect and slower clearance Naproxen (萘普生普生，14 2 hrs)Sulindac (舒林酸舒林酸，14 8 hrs), Piroxicam (吡吡罗昔康昔康，57 22 hrs)NSAIDsReversible Non-Selective COX inhibitors (for mild to moderate pain)Ibuprofen400POq4-6hAvailablewithoutprescriptionNaproxen250-500POq12hDelayedeffectsmaybeduetolonghalf-lifeFenopro
62、fen200POq4-6hContraindicatedinrenaldiseaseIndomethacin25-50POq8hGastrointestinalsideeffectscommonKetorolac15-60IMIVq4-6hAvailableforparenteraluse(IM,IV)GenericNamedose(mg)intervalKetorolacisindicatedfortheshort-term(upto5days)managementofmoderatelysevere,acutepain,thatrequiresanalgesiaattheopioidlev
63、el.ItisNOTindicatedforminororchronicpainfulconditions(萘普生普生)(布洛芬布洛芬)(非非诺洛芬洛芬)(吲哚美辛美辛)(酮咯酸咯酸)COX-1 vs COX-2 InhibitionCOX-1comparedtoCOX-2COX-1 COX-2ExpressionTissuelocalizationRole“Housekeeping” and maintenanceUbiquitousInflammatory and neoplastic sites (small amounts in kidney, uterus, ovary, CNS n
64、eocortex, hippocampus)Pro-inflammatory and mitogenic functions (? neuronal plasticity)Constitutive (activated by physiologic stimuliInducible by pro-inflammatory stimuli (LPS, TNF , IL-2, IFN etc)COX-2 selective inhibitors are generally larger molecules than NSAIDs and therefore preferentially inhib
65、it COX-2 compared to COX-1 because the hydrophobic channel of COX-2 is larger. That is, COX-2 selective inhibitors are too bulky to access the binding pocket of the COX-1 enzymeCOX-2 Selective DrugsCOX-2 is also up-regulated in the CNS and plays an essential role in the mediation of pain and the feb
66、rile response(发热反应发热反应)COX-2 is also up-regulated in colorectal polyps(息肉息肉) and adenocarcinomasSleisenger&FordtransGastrointestinalandLiverDisease,8thed.,Copyright2006Saunders,AnImprintofElsevierNSAIDs: Classification by COX selection InvitroassessmentofCOX-1COX-2activity罗非昔布非昔布塞来昔布塞来昔布NSAIDs and P
67、latelets/Endothelial CellsNote: Selective inhibition of COX-2 will inhibit the production of PGI2 but not of thromboxaneA2, which is produced by COX-1. SO ?SO ? After6monthsoftreatment,approximately43%ofthepatientsdiscontinuedthestudyAfter6monthsoftherapy,theannualizedrateofUGIulcercomplicationswas0
68、.76%(11events/1441patient-years)amongpatientstreatedwithcelecoxiband1.45%(20events/1384patient-years)amongthosetreatedwithNSAIDsSimilarincidenceoftheprimaryendpointofulcercomplicationsamongpatientstreatedwithcelecoxiborwithnonspecificNSAIDsTheCelecoxibLong-TermArthritisSafetyStudy(CLASS)布洛芬布洛芬双氯芬酸双氯
69、芬酸塞来昔布塞来昔布Patientswithrheumatoidarthritisweretreatedwithcelecoxib(100,200,or400mgtwicedaily),naproxen500mgtwicedaily,oraplacebofor12weeks.Ratesofgastroduodenalulcerationwithnaproxenwerestatisticallyhigher(*,P.01)thanrateswithcelecoxiboraplacebo.(DatafromSimonLS,WeaverAL,GrahamDY,etal:Anti-inflammato
70、ryanduppergastrointestinaleffectsofcelecoxibinrheumatoidarthritis.JAMA282:19211928,1999.)IncidenceofendoscopicgastroduodenalulcerswithaCOX-2specificinhibitorCelecoxibisnowtheonlyselectiveCOX-2inhibitoravailableintheUS-withdrawalofrofecoxib(Vioxx,Merck&Co)Sept2004-suspensionofvaldecoxib(Bextra,Pfizer
71、)Apr2005Note:ThefactthatitnowcarriesexactlythesamewarningforgastrointestinalriskastheoldernonselectiveNSAIDsisquiteremarkable,newdrugsweresupposedlylessriskytothegastrointestinaltractthantheoldernonselectiveagentsCelecoxibincludesaboxedwarning,highlightingthepotentialforincreasedriskofcardiovascular
72、eventsandthewelldescribed,serious,potentiallife-threateninggastrointestinalbleedingassociatedwiththeiruse.Celecoxib: Current StatusA black box warning by FDARisk of Cardiovascular Events in Patients Receiving Celecoxib:A Meta-Analysis of Randomized Clinical Trials7,462 patients exposed to celecoxib
73、200 to 800 mg/day for 1,268 patient-years compared with 4,057 patients treated with placebo for 585 patient-years19,773 patients treated with celecoxib 200 to 800 mg/day for 5,651 patient-years compared with 13,990 patients treated with nonselective NSAIDs (diclofenac, ibuprofen, naproxen, ketoprofe
74、n, and loxoprofen) for 4,386 patient-yearsAm J Cardiol 2007;99:9198Risk of Cardiovascular Events in Patients Receiving Celecoxib:A Meta-Analysis of Randomized Clinical TrialsAm J Cardiol 2007;99:9198Celecoxib: cardiovascular eventsCelecoxibcomparedwithplaceboisnotassociatedwithanincreasedriskforcard
75、iovasculareventsfordurationofusefrom12to52weeks.CelecoxibcomparedwithnonselectiveNSAIDsisnotassociatedwithincreasedcardiovascularendpoints.Celecoxib: cardiovascular eventsTrelle, S, et al, BMJ, 2011From 29 clinical trialsAcetaminophen (对乙乙酰氨基酚氨基酚)-produces analgesia-antipyretic-no significant anti-i
76、nflammatory effects-no gastric irritation-no platelet function interference-half life 2 3 h-weak inhibitor of COX-1, -2; some evidence for COX 3 inhibition-not contraindicated for asthma-not associated with Reyes SyndromePharmacologyequipotentwithaspirininrelievingmildtomoderatepainandreducingfever;
77、(nosignificantanti-inflammatoryeffects)The major concern regarding the use of acetaminophen is the potential for high doses to cause liver toxicityConcurrent use of alcohol can cause toxicity at lower doses of acetaminophen.Also,theuseofmultipleproductsthateachcontainacetaminophencaninadvertentlycauseatoxicdoseofacetaminophenTheFDArecommendationisthatpatientswhoconsumemorethanthreealcoholicdrinksperdayshouldconsulttheirphysicianbeforeusingacetaminophenAcetaminophen (对乙乙酰氨基酚氨基酚)Good Luck!
