全身中毒性毒剂--课件

Chapter 4 Systemic agents(Cyanides)全身中毒性毒剂(氰化物)1ppt课件Chapter 4 Systemic agents(CyAuschwitz campZyklon B2ppt课件Auschwitz camp2ppt课件课件3ppt课件3ppt课件课件1.Introduction2.Representatives3.Physicochemical characteristics4.Toxicity5.Metabolism6.Mechanism of toxicity7.Clinical effects8.Diagnosis and differential diagnosis9.Antidotes and mechanism10.Medical managementContents4ppt课件IntroductionContents4ppt课件课件全身中毒性毒剂(systemic agents)是以氢氰酸(HCN)和氯化氰(ClCN)为代表的一类暂时性毒剂，这类毒剂主要通过呼吸道中毒，破坏机体组织细胞的生理氧化，引起组织细胞不能利用O2，产生组织缺O2，从而导致一系列全身中毒症状的出现。由于其分子结构中含有氰根(CN-)，故亦称为氰类毒剂(cyanides).1.Introduction5ppt课件全身中毒性毒剂全身中毒性毒剂(systemic agents)是以氢氰酸是以氢氰酸(Hydrogen cyanide:first isolated from a blue dye(Prussian blue)in pure form in 1782 by the Swedish chemist Carl W.Scheele,and was eventually given the German name Blausure(literally Blue acid).In English,popularly as Prussic acid.Cyanogen chloride:discovered by Wurtz and first prepared by Berthollet in 1802.1.2 History/Military Relevance6ppt课件Hydrogen cyanide:first isolatAncient Egypt and RomePlayfair(an English)advocated the use in Crimean warNapoleon III proposed use in Franco-Prussian warWWI:French used 4000 tons of cyanide,BritainU.S.maintained a small number of munitions in WWII Japan:against China before and during WWIIIraq used cyanide against the Kurds in the 1980s7ppt课件Ancient Egypt and Rome7ppt课件课件Nazi Germany:Zyklon B in Auschwitz camp In WWII(6,000 each day,totally 6,000,000 claimed)Interior of Majdanek gas chamber,showing Prussian blue residue8ppt课件Nazi Germany:Zyklon B in Ausc1.3 Sources other than military Ubiquitous in nearly all living organismsWidely used in industryCombustion products of many materials9ppt课件1.3 Sources other than milita很多果实与种子(特别是瘢痕中)，例如 樱桃、桃子、杏、利马豆等含有氰类物质(cyanogens)，在酶解之后能够产生自由状态的氰化物。100g almond100250mg HCN Ubiquitous in nearly all living organisms:10ppt课件很多果实与种子很多果实与种子(特别是瘢痕中特别是瘢痕中)，例如，例如 樱桃、桃子、杏、利马豆樱桃、桃子、杏、利马豆东南亚一带的粮食作物之一木薯(cassava)亦可产生氰化物。有一些昆虫(millipedes)可以释放氢氰酸来防卫。有人认为可能跟生命起源有关(最近在太空星云中发现)。Ubiquitous in nearly all living organisms:11ppt课件东南亚一带的粮食作物之一木薯东南亚一带的粮食作物之一木薯(cassava)亦可产生氰化亦可产生氰化Philippines cassava incidentMarch 9,200530 kids died,103 hospitalized12ppt课件Philippines cassava incidentM白色品种氰化物含量可达330360 ppm，黄色品种 3060 ppm.人体最大可耐受量120 ppm13ppt课件白色品种氰化物含量可达白色品种氰化物含量可达330360 ppm，黄色品种，黄色品种 301.3 Sources other than military Ubiquitous in nearly all living organisms Widely used in industry Combustion products of many materials14ppt课件1.3 Sources other than militaIndustrial concerns in the U.S.manufacture thousands of tons of hydrogen cyanide annually.In 2000,732,552 tons were produced in the US.Cyanides find widespread use in chemical synthesis,electroplating,mineral extraction,dyeing,printing,photography,and agriculture,and in the manufacture of paper,textiles,and plastics.15ppt课件Industrial concerns in the U.S1972年联合国裁军委员会将平时是一种化工原料，到战时可很快转入军用生产，作为化学战剂使用的一类化合物，称为“双用途毒剂”。如HCN、Phosgene。Dual-use Agents:16ppt课件1972年联合国裁军委员会将平时是一种化工原料，到战时可很快年联合国裁军委员会将平时是一种化工原料，到战时可很快The scenery of Tisa river,branch of Danube(多瑙河).Rescue workers removing dead fish from Tisa.“The river is dead,not even bacteria have survived.”Cyanide can cause great pollution2000,Romania:17ppt课件The scenery of Tisa river,bra2000年10月24日，在龙岩上杭的205国道附近，一辆载有7吨NaCN的卡车倾覆，溪流下游90多人中毒18ppt课件2000年年10月月24日，在龙岩上杭的日，在龙岩上杭的205国道附近，一辆载有国道附近，一辆载有2 Au+4 KCN+O2+H2O 2 KAu(CN)2+2 KOH 2 Ag+4 KCN+O2+H2O 2 KAg(CN)2+2 KOH Ag2S+4 KCN 2 KAg(CN)2+K2S Cyanide mining:19ppt课件2 Au+4 KCN+O2+H2O 2 1.3 Sources other than military Ubiquitous in nearly all living organisms Widely used in industry Combustion products of many materials20ppt课件1.3 Sources other than milita The combustion of many materials containing carbon and nitrogen has the potential to form cyanide.Some plastics(particularly acrylonitriles,丙烯腈)predictably release clinically significant amounts when burned.(1g15mg)Cigarettes burning,vehicle exhaust also produce cyanide.Where there is smoke,there is hydrogen cyanide21ppt课件 The combustion of many mater火灾中可燃物燃烧产生大量烟雾，其中含有：一氧化碳(CO)二氧化碳(CO2)氯化氢(HCl)氮氧化物(NOx)硫化氢(H2S)氰化氢(HCN)光气(COCl2)对人体有麻醉、窒息、刺激等作用，损害呼吸系统、中枢神经系统和血液循环系统等，在火灾中严重影响人们的正常呼吸和逃生，直接危害人的生命安全火灾产生的毒害气体22ppt课件火灾中可燃物燃烧产生大量烟雾，其中含有：火灾产生的毒害气体火灾中可燃物燃烧产生大量烟雾，其中含有：火灾产生的毒害气体223ppt课件23ppt课件课件2015-8-12天津天津24ppt课件2015-8-1224ppt课件课件China19931993年年2 2月月1414日唐山百货大楼发生大火，日唐山百货大楼发生大火，死亡死亡8080人，烧伤人，烧伤5555人，除人，除1 1人摔死外，人摔死外，7979人均为中毒窒息而死人均为中毒窒息而死.20002000年年1212月月2525日，河南省洛阳市东都日，河南省洛阳市东都商厦发生特大火灾事故造成商厦发生特大火灾事故造成309309人死人死亡亡 7 7人受伤人受伤.USACyanide may be a major contributor to the morbidity and mortality observed in approximately 5,000-10,000 deaths occurring each year from smoke inhalation.25ppt课件China25ppt课件课件Suicidal:the chief war crime of WWII,Hermann Gering,committed suicide with KCN;spiesHomicidal:used to murder,in 2000,an evil organization in Uganda killed some of its members Judicial executions:used to execute criminalsTerrorism:US 1993,world trade center;1995 Tokyo1.4 Other uses26ppt课件Suicidal:the chief war crime HCN Hydrogen Cyanide (AC)hydrocyanic acid ClCN Cyanogen Chloride(CK)2.RepresentativesOthers:Others:无机氰化物：无机氰化物：NaCNNaCN、KCNKCN 有机氰化物：丙烯腈、丙酮氰醇有机氰化物：丙烯腈、丙酮氰醇27ppt课件HCN Hydrogen Cyanide (AC)2.名名 称称状态状态挥发性及气味挥发性及气味氢氰酸氢氰酸hydrocyanic hydrocyanic acid,acid,hydrogen hydrogen cyanidecyanide无色液体无色液体,极易溶极易溶于水于水,弱酸性弱酸性,轻于轻于空气空气非常易挥发非常易挥发,较明显较明显苦杏仁味苦杏仁味氯化氰氯化氰 cyanogen cyanogen chloridechloride无色液体无色液体,微溶于微溶于水水,重于空气重于空气非常易挥发非常易挥发,苦杏仁苦杏仁味味,强烈刺激味强烈刺激味 全身中毒性毒剂的性状3.Physicochemical characteristics28ppt课件名名 称状态挥发性及气味氢氰酸无色液体称状态挥发性及气味氢氰酸无色液体,极易溶于水极易溶于水,弱酸弱酸水解反应:缓慢,可短期染毒水源，加热可加速水解与碱作用：ClCN可用碱和稀氨溶液消毒与醛、酮作用：无毒氰醇和羟基腈化合物29ppt课件水解反应水解反应:缓慢缓慢,可短期染毒水源，加热可加速水解可短期染毒水源，加热可加速水解29ppt课件课件High affinity for ions of transitional metals cobalt Iron,esp.ferric iron cytochromes:Fe2+,Fe3+heme in methemoglobin(MetHb)(Fe3+)Ability to react enzymatically with sulfanes(S-S-)30ppt课件High affinity for ions of tra4.Toxicity 31ppt课件4.Toxicity 31ppt课件课件hydrocyanic acid(AC):2500-5000 mgmin/m3 cyanogen chloride(CK):11,000 mgmin/m3 LCt50Irritation:ClCNHCNLD50hydrocyanic acid:1.1 mg/kg(i.v.)100 mg/kg(skin)sodium cyanide(NaCN):110 mgpotassium cyanide(KCN):200 mg32ppt课件hydrocyanic acid(AC):2500-50 毒性强:仅次于神经毒HCN大于ClCN，但ClCN刺激性更大Battle capability（强、快、难）（强、快、难）氰化物在弹头中为液态，爆炸后则快速蒸发。蒸气为主要中毒威胁。一般用大的弹头(炸弹或者导弹)，因为小的弹头难以达到杀伤浓度。33ppt课件 毒性强毒性强:仅次于神经毒仅次于神经毒Battle capability（强（强蒸气态蒸气态HCNHCN毒性毒性:0.01mg/m0.01mg/m3 3 居民区允许浓度居民区允许浓度0.3 mg/m0.3 mg/m3 3 生产场所允许浓度生产场所允许浓度50 mg/m50 mg/m3 3 引起中毒引起中毒80 mg/m80 mg/m3 3 中毒程度视时间而定中毒程度视时间而定100 mg/m100 mg/m3 3 15min15min严重中毒，严重中毒，15min15min死亡死亡200 mg/m200 mg/m3 3 10min10min死亡死亡300 mg/m300 mg/m3 3 5min5min死亡死亡 速杀性毒剂作用快:34ppt课件蒸气态蒸气态HCN毒性毒性:0.01mg/m3 居民区允许浓度速居民区允许浓度速防治难防护难、救治难防护难HCN分子量小，挥发度大，蒸气比重轻，不易被防毒炭吸附。过滤式面具滤毒罐可防护沙林致死浓度24h以上，而HCN最多只能防30min，过滤式面具最高允许浓度不超过HCN 1800mg/m3，如超过应改用隔绝式面具。ClCN比HCN更难防，曾被称为“穿透防毒面具的毒剂”。救治难HCN作用快，又是呼吸道中毒，传统急救药需静注，不适合野战条件。35ppt课件防治难防治难防护难、救治难防护难防护难、救治难防护难HCN分子量小，挥发度大，蒸分子量小，挥发度大，蒸5.Metabolism and disposition 36ppt课件5.Metabolism and disposition 5.1 Absorption Rapidly absorbed by the Gl and respiratory tract Liquid and possibly the concentrated vapor:absorbed directly through the intact skin(usu.not clinically significant)37ppt课件5.1 Absorption Rapidly absor5.2 Distribution 可快速全身分布.可进入红细胞，在血液和其他人体正常组织中浓度较低.非致死性暴露后，血氰水平4-8 h后恢复正常，估计血浆后恢复正常，估计血浆半衰期为半衰期为20 min1h.致死性口服中毒后，可在大脑、血液、肾脏、肝脏、胃壁、及尿中检测到氰化物.38ppt课件5.2 Distribution 可快速全身分布可快速全身分布.38ppt5.3 Metabolism 主要代谢途径：在下面两个酶的催化下生成硫氰化物(thiocyanate)rhodanase(thiosulfate sulfurtransferase,硫氰生成酶)-mercaptopyruvate sulfurtransferase(-巯基丙酮酸转硫酶)39ppt课件5.3 Metabolism 主要代谢途径：在下面两个酶的催主要代谢途径：在下面两个酶的催S2O3 2+CNrhodanasethiocyanate oxidaseSCNSO3 2+The thiocyanate is relatively nontoxic.The upper process is the dominant process.正常人血液中CN-8 mmol/L)plasma lactate suggest the possibility of acute cyanide poisoning.”58ppt课件Diagnosis“Rapid loss of cons诊断依据全身中毒性毒剂神经性毒剂一氧化碳Differential diagnosis起病气味症状皮肤粘膜化验治疗快快一般缓慢苦杏仁味水果、芳香或无无轻度刺激、咳嗽，很快出现严重呼吸困难、眼球突出，瞳孔散大、惊厥、昏迷瞳孔缩小，大汗淋漓，流涎，呼吸困难头痛、头晕、耳鸣、呼吸脉搏加快，昏迷，血压下降鲜红紫绀樱桃红色血CN-及SCN-升高血液胆碱酯酶活性降低血液中可查到碳氧血红蛋白抗氰药物治疗有特效阿托品、氯解磷定等有良效无特殊治疗59ppt课件诊断依据全身中毒性毒剂神经性毒剂一氧化碳诊断依据全身中毒性毒剂神经性毒剂一氧化碳Differenti9.Antidotes and mechanism 60ppt课件9.Antidotes and mechanism 60p9.1 Stratagem What?Whats your stratagem?61ppt课件9.1 Stratagem What?Whats yoE(Fe)3+CN-E(Fe)3+CNprotect the enzymeantagonize the agentsreactivate the enzymesupportive measuresdrug for pretreatmentdrug for first aid 1.Methemoglobin former:protect and reactivate the enzyme 2.Sulphur donor:antagonize the agents 3.Cobalt compounds:antagonize the agents 62ppt课件E(Fe)3+CN-E(Fe)3+CNprotect th9.2 Methemoglobin former Mechanism:Hb(Fe2+)Hb(Fe3+)bind CN-and protect the enzyme compete with the inhibited enzyme for CN-to reactivate the enzyme 63ppt课件9.2 Methemoglobin former MechBloodTissuescytc2+cytc3+cyta3+cyta2+cyta32+cyta33+O2H2OXHCNH+CN-HbO2MHbNO2-CNMHbCN-64ppt课件BloodTissuescytc2+cytc3+cytTypes of methemoglobin formers:Nitrites(亚亚硝硝基基类类化化合合物物):isoamyl nitrite(亚亚硝硝酸酸异异戊戊酯酯)sodium nitrite(NaNO2)Amino-phenols(氨氨基基苯苯酚酚类类化化合合物物):4-DMAP(4-二二甲甲氨氨基基苯酚苯酚)p-aminopropiophenone(PAPP,对氨基苯丙酮对氨基苯丙酮)Methylene blue(美兰美兰,亚甲兰亚甲兰):Small dose(12mg/kg)as reductant(还原剂还原剂)Large dose(10mg/kg)as oxidant(氧化剂氧化剂)65ppt课件Types of methemoglobin formers(1)亚硝酸异戊酯 优点：用药方便，吸入，对争取急救时间有利 缺点：吸入量不准，如呼吸暂停就无法吸入(2)亚硝酸钠 优点：作用快，效价比较高 缺点：不持久，需静注，可使血管扩张，血压下降，休克或出血病人不宜使用 亚硝酸盐类化合物66ppt课件(1)亚硝酸异戊酯亚硝酸异戊酯 亚硝酸盐类化合物亚硝酸盐类化合物66ppt课件课件4-二甲氨基苯酚(4-DMAP)对氨基苯丙酮（PAPP）优点：优点：作用快：形成MHb的半数最高浓度时间 NaNO2 4.99min 4-DMAP 20s3min 可以肌注给药；效价高：单药4-DMAP 抗 34 LD50，伍用Na2S2O3 抗 20 LD50 缺点：缺点：不能清除CN-，抗毒不彻底，严重中毒须与Na2S2O3等合用。67ppt课件4-二甲氨基苯酚二甲氨基苯酚(4-DMAP)对氨基苯丙酮（对氨基苯丙酮（PAMHb(%)510162025LDs11.52.0234MHb antagonizes the LDs of CN-(theoretical)*一般体内形成MHb达到2530%正好，若超过40%就可形成“青紫症”68ppt课件MHb(%)510162025LDs11.52.0239.3 Sulphur donor Sodium thiosulfate(Na2S2O3)S2O3 2+CNrhodanaseSCNSO3 2+优点 破坏毒剂，抗毒彻底，故临床上常与NaNO2伍用，取长补短。缺点 作用慢，需在酶作用下穿透细胞膜；需静注，不利于急救；效价低，用量大。69ppt课件9.3 Sulphur donor Sodium thi9.4 Cobalt compoundsDicobalt EDTA(Co2EDTA,Kelocyanor,依地酸钴)Hydroxycobalamin(vitamin B12a,羟钴胺)优点直接破坏毒剂，抗毒彻底。缺点 重金属盐毒性大；EDTA可螯合Ca2+，引起低血钙；需静注，不利抢救。70ppt课件9.4 Cobalt compoundsDicobalt E Should administration of oxygen be applied as a treatment measure for cyanide poisoning?Why?Question:71ppt课件 Should administration of oxAlthough in theory oxygen should not help,in both experimental studies and in actual patient management normobaric oxygen has provided some benefit.Administration of oxygen has been one of the most useful initial treatments for cyanide poisoning.The mechanism is not yet clear.9.5 Others:O2 72ppt课件Although in theory oxygen shou 提高抗CN-药物效价；阻断CN-对酶的作用，改善由于呼吸中枢兴奋引起喘息反应；改善中毒后期的继发性缺O2；加强黄素酶的氧化作用，加速CN-排出体外。73ppt课件 提高抗提高抗CN-药物效价；药物效价；73ppt课件课件10.Medical management and pretreatment74ppt课件10.Medical management and pr器材防护为主，药物预防为辅抗氰胶囊(4-DMAP 180mg and PAPP 90mg)服药后45分钟进入毒区工作35小时10.1 Pretreatment75ppt课件器材防护为主，药物预防为辅器材防护为主，药物预防为辅10.1 PretreatmenttimeMHb(%)1h152h(max)206h5*Can prevent i.v.HCN 2 LD,inhalation of HCN 4LD50.(dog)76ppt课件timeMHb(%)1h152h(max)206h5*C戴面具脱离毒区，立即吸入亚硝酸异戊酯，间隔2min连续吸入68支，呼吸暂停应人工呼吸(dont use your mouth!).抗毒治疗：3%NaNO2 10ml(慢35ml/min)、25%Na2S2O3 3050ml 或 50%Na2S2O3 1525ml；如10min惊厥不停可重复半量，当收缩压下降至80mmHg应暂停给药.O2吸入.维持呼吸循环功能.对症处理及加强护理.经典抗氰急救法：10.2 First aid and treatmentSpeed!77ppt课件戴面具脱离毒区，立即吸入亚硝酸异戊酯，间隔戴面具脱离毒区，立即吸入亚硝酸异戊酯，间隔2min连续吸入连续吸入6Isoamyl nitrite inhalant(亚硝酸异戊酯吸入剂)78ppt课件Isoamyl nitrite inhalant(亚硝酸异亚硝酸异Auto-injector for cyanide 79ppt课件Auto-injector for cyanide 79pptime MHb(%)510min 8 30min(max)28 19 19 MHb formation after 10%4-DMAP 2ml i.m.*Can rescue(dog)poisoning i.v.HCN 2 LD,inhalation of HCN 4LD50.80ppt课件time MHb(%)510min 8 30min(The combination of sodium nitrite and sodium thiosulfate is the best way against cyanide poisoning.As long as the heart is still beating,the chances of recovery by utilizing this method are very good.-Chen et al.Experience and comment81ppt课件The combination of sodium nitr国家常用抗毒剂美亚硝酸异戊酯（吸入），3%亚硝酸钠10ml，25%硫代硫酸钠 20ml，iv英法 Co2EDTA 300mg溶于20%葡萄糖 20ml，iv俄美蓝1g 溶于25%葡萄糖100ml，iv 50ml德4-DMAP 3.25mg/kg，25%硫代硫酸钠20ml,iv国外常用抗氰救治方法82ppt课件国家常用抗毒剂美亚硝酸异戊酯（吸入），国家常用抗毒剂美亚硝酸异戊酯（吸入），3%亚硝酸钠亚硝酸钠10ml，Management of acute cyanide poisoning(USA):1.Termination of exposure 2.Supportive care 3.Antidotal treatment 83ppt课件Management of acute cyanide po1.Termination of exposure:For inhalation exposure,removal of victim from site of exposure,using appropriate personal protective equipment For exposure by ingestion,gastric lavage and activated charcoal unless contraindicated For dermal exposure,decontamination of skin with soap and water 84ppt课件 Termination of exposure:For 2.Supportive care:Basic Life Support 100%oxygen Cardiopulmonary support or resuscitation Advanced Life Support Sodium bicarbonate(碳酸氢钠)for metabolic acidosis Anticonvulsants for seizures Epinephrine(肾上腺素)for cardiovascular collapse 85ppt课件Supportive care:Basic Life Su3.Antidotal treatment:Cyanide Antidote Kit(amyl nitrite+sodium nitrite+thiosulfate)(*not generally recommended in smoke-inhalation victims)Hydroxocobalamin(proposed antidote in the United States;can be used regardless of suspected cyanide source,including fire smoke)86ppt课件Antidotal treatment:Cyanide A最近进展美国FDA于2006年12月已批准羟钴胺注射液为新的氰化物解毒药物.3-mercaptopyruvate/cyanide sulfurtransferase(3-MPST)的新底物做为抗毒药物的研究.Herbert T.Nagasawa et al.J.Med.Chem.2007,50,6462646487ppt课件最近进展美国最近进展美国FDA于于2006年年12月已批准羟钴胺注射液为新的月已批准羟钴胺注射液为新的88ppt课件Thank you!88ppt课件课件