全身中毒性毒剂-ppt课件.pptx

1、Chapter 4 Systemic agents (Cyanides)1ppt课件Auschwitz campZyklon B2ppt课件3ppt课件1.Introduction2.Representatives3.Physicochemical characteristics4.Toxicity5.Metabolism6.Mechanism of toxicity7.Clinical effects8.Diagnosis and differential diagnosis9.Antidotes and mechanism10. Medical managementContents4ppt

2、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uHydrogen cyanide: first isolated from a blue dye (Prussian blue) in pure form in 1782 by the Swedish chemist Carl W.

3、 Scheele, and was eventually given the German name Blausure (literally Blue acid). In English, popularly as Prussic acid.uCyanogen chloride: discovered by Wurtz and first prepared by Berthollet in 1802. 1.2 History/Military Relevance6ppt课件uAncient Egypt and RomeuPlayfair (an English) advocated the u

4、se in Crimean waruNapoleon III proposed use in Franco-Prussian waruWWI: French used 4000 tons of cyanide, BritainuU.S. maintained a small number of munitions in WWII uJapan: against China before and during WWIIuIraq used cyanide against the Kurds in the 1980s7ppt课件uNazi Germany: Zyklon B in Auschwit

5、z camp In WWII (6,000 each day, totally 6,000,000 claimed)Interior of Majdanek gas chamber, showing Prussian blue residue8ppt课件1.3 Sources other than military uUbiquitous in nearly all living organismsuWidely used in industryuCombustion products of many materials9ppt课件很多果实与种子(特别是瘢痕中)，例如 樱桃、桃子、杏、利马豆等

6、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 HCNu Ubiquitous in nearly all living organisms:10ppt课件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)。u Ubiquitous in nearly all living organisms:11ppt课件Philippines cassava incidentMarch 9, 200530 kids d

7、ied,103 hospitalized12ppt课件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1.3 Sources other than military u Ubiquitous in nearly all living organismsu Widely used in industryu Combustion products of many materials14ppt课件uIndustrial concerns in the U.S. manufacture thousands of tons of hy

8、drogen cyanide annually. uIn 2000, 732,552 tons were produced in the US. uCyanides 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Dual-use Agents:16ppt课件The

9、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2000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2 Au + 4 KCN + O2 + H2O 2 KAu(CN)2 + 2 KOH

10、 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1.3 Sources other than military u Ubiquitous in nearly all living organismsu Widely used in industryu Combustion products of many materials20ppt课件u The combustion of many materials containing carbon and n

11、itrogen 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u火灾中可燃物燃烧产生大量烟雾，其中含有：一氧化

12、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)u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23ppt课件2015-8-12天津天津24ppt课件uChinauUSACyanide may be a major contributor to the morbidity and mortality observed in approximately 5,000-10,000 deaths occurring e

13、ach year from smoke inhalation. 25ppt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 c

14、enter; 1995 Tokyo1.4 Other uses26ppt课件HCN Hydrogen Cyanide (AC) hydrocyanic acid ClCN Cyanogen Chloride (CK)2. Representatives27ppt课件 全身中毒性毒剂的性状3. Physicochemical characteristics28ppt课件u水解反应:缓慢,可短期染毒水源，加热可加速水解u与碱作用：ClCN可用碱和稀氨溶液消毒u与醛、酮作用：无毒氰醇和羟基腈化合物29ppt课件uHigh affinity for ions of transitional metal

15、s cobalt Iron, esp. ferric iron cytochromes: Fe2+, Fe3+ heme in methemoglobin (MetHb)(Fe3+)uAbility to react enzymatically with sulfanes (S-S-)30ppt课件4. Toxicity 31ppt课件hydrocyanic acid (AC): 2500-5000 mgmin/m3 cyanogen chloride (CK): 11,000 mgmin/m3 LCt50Irritation: ClCNHCNLD50hydrocyanic acid: 1.1

16、 mg/kg (i.v.) 100 mg/kg (skin)sodium cyanide (NaCN): 110 mgpotassium cyanide (KCN): 200 mg32ppt课件u 毒性强:Battle capability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课件速杀性毒剂u作用快:34ppt课件u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H

17、CN 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5. Metabolism and disposition 36ppt课件5.1 Absorption u Rapidly absorbed by the Gl and respiratory tractu Liquid and possibly the concentrated vapor: absorbed directly through the intact skin (usu. not clin

18、ically significant) 37ppt课件5.2 Distribution u可快速全身分布.u可进入红细胞，在血液和其他人体正常组织中浓度较低.u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.u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5.3 Metabolism 主要代谢途径：在下面两个酶的催化下生成硫氰化物(thiocyanate)urhodanase (thiosulfate sulfurtransferase, 硫氰生成酶)u-mercaptopyruvate sul

19、furtransferase (-巯基丙酮酸转硫酶)39ppt课件S2O3 2+ CNrhodanasethiocyanate oxidaseSCNSO3 2+The thiocyanate is relatively nontoxic. The upper process is the dominant process. u正常人血液中CN- 8 mmol/L) plasma lactate suggest the possibility of acute cyanide poisoning.”58ppt课件诊断依据全身中毒性毒剂神经性毒剂一氧化碳Differential diagnosis

20、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9. Antidotes and mechanism 60ppt课件9.1 Stratagem Whats your stratagem? 61ppt课件protect the enzymeantagonize the agentsreac

21、tivate 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9.2 Methemoglobin former Mechanism: Hb(Fe2+) Hb(Fe3+) u bind CN- and protec

22、t the enzymeu compete with the inhibited enzyme for CN- to reactivate the enzyme 63ppt课件BloodTissuescytc2+cytc3+cyta3+cyta2+cyta32+cyta33+O2H2OXHCNH+CN-HbO2MHbNO2-CNMHbCN-64ppt课件Types of methemoglobin formers: u Nitrites (亚硝基类化合物亚硝基类化合物): isoamyl nitrite (亚硝酸异戊酯亚硝酸异戊酯) sodium nitrite (NaNO2)u Amino-

23、phenols (氨基苯酚类化合物氨基苯酚类化合物): 4-DMAP (4-二甲氨基二甲氨基苯酚苯酚)u p-aminopropiophenone (PAPP, 对氨基苯丙酮对氨基苯丙酮 )u 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(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

24、注，可使血管扩张，血压下降，休克或出血病人不宜使用u 亚硝酸盐类化合物66ppt课件u4-二甲氨基苯酚(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MHb(%)510162025LDs11.52.0234MHb antagonizes the LDs of CN- (theoretical) *一般

25、体内形成MHb达到2530%正好，若超过40%就可形成“青紫症”68ppt课件9.3 Sulphur donor Sodium thiosulfate (Na2S2O3) S2O3 2+ CNrhodanaseSCNSO3 2+u 优点 破坏毒剂，抗毒彻底，故临床上常与NaNO2伍用，取长补短。u 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9.4 Cobalt compoundsDicobalt EDTA (Co2EDTA, Kelocyanor, 依地酸钴)Hydroxycobalamin (vitamin B12a, 羟钴胺)u优点直接破坏

26、毒剂，抗毒彻底。u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u Should administration of oxygen be applied as a treatment measure for cyanide poisoning? Why? Question: 71ppt课件uAlthough in theory oxygen should not help, in both experimental studies and in actual patient management normobaric oxygen has pro

27、vided some benefit.uAdministration of oxygen has been one of the most useful initial treatments for cyanide poisoning. uThe mechanism is not yet clear. 9.5 Others: O2 72ppt课件 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10. Medical management and pretreatment7

28、4ppt课件u器材防护为主，药物预防为辅u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timeMHb (%)1h152h (max)206h5*Can prevent i.v. HCN 2 LD, inhalation of HCN 4LD50. (dog) 76ppt课件戴面具脱离毒区，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 305

29、0ml 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Isoamyl nitrite inhalant (亚硝酸异戊酯吸入剂) 78ppt课件Auto-injector for cyanide 79ppt课件time MHb (%) 510min 8 30min (max) 28 19 19 MHb formation after 10%4-DMAP 2ml i.m.*Can resc

30、ue (dog) poisoning i.v. HCN 2 LD, inhalation of HCN 4LD50. 80ppt课件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 comme

31、nt81ppt课件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Management of acute cyanide poisoning (USA): 1.Termination of exposure 2.Supportive care 3.Antidotal treatment 83ppt课件1. Termination of

32、exposure: uFor inhalation exposure, removal of victim from site of exposure, using appropriate personal protective equipment uFor exposure by ingestion, gastric lavage and activated charcoal unless contraindicated uFor dermal exposure, decontamination of skin with soap and water 84ppt课件2.Supportive

33、care :uBasic Life Support 100% oxygen Cardiopulmonary support or resuscitation uAdvanced 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3.Antidotal treatment :uCyanide Antidote Kit (amyl nitrite + sodiu

34、m nitrite + thiosulfate) (* not generally recommended in smoke-inhalation victims) uHydroxocobalamin (proposed antidote in the United States; can be used regardless of suspected cyanide source, including fire smoke) 86ppt课件最近进展u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.u3-mercaptopyruvate/cyanide sulfurtransferase (3-MPST)的新底物做为抗毒药物的研究. HSH2CCCOOHOCCOOROCOCH3NHCOOHEtOOCHSCOOROHROOCOHH3CCOSHHerbert T. Nagasawa et al. J. Med. Chem. 2007, 50, 6462646487ppt课件88ppt课件