镇静药物中毒 课件

烦恼有何惧怕，既然躲不掉，就调好心态与它共存。心向阳光，何惧风霜。

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(sedative-hypnoticpoisoning)acutesedative-hypnoticpoisoning—coma,respiratorydepressionandshock。drugresistanceanddependencewithdrawalsyndrome病因

(reason)◈苯二氮卓类

(Benzodiazepines,BZD)：

呼吸抑制作用小,不影响肝药酶活性(enzymaticactivity),大剂量无麻醉(anesthetic)作用,耐受性和成瘾性低超短效类：midazolam,temazepam,triazolum,brotizolam短效类：alprazolam,lorazepam,oxazepam,bromasepam,flunitrazepam,estazolam长效类：chlordiazepoxide,clonazepam,diazepam,flurazepam

◈

巴比妥类

(barbiturate)：

作静脉麻醉药、抗惊厥药(anticonvulsant)、脑复苏治疗(resuscitationtherapy)超短效类：methohexital,nembutal,pentothal短效类：secobarbital,pentobarbital,talbutal中效类：amobarbital,allybarbital,aprobarbital,butabarbital长效类：barbital,phenobarbital,methlphenobarbital,primidone◈

非巴比妥非苯二氮卓类(Nonbenzodiazepine,Nonbarbiturate,NBNB)：

pharmacologicaction:pharmacokinetics:toxicreaction:chloralhydrote,glutethimide,meprobamate,methaqualone

药代动力学(pharmacokinetics)liposolubilityabsorption、distribution、protienbinding、metabolismdischarging、starteffecttimeandactiontime易通过血脑屏障(blood-brainbarrier)◈

Benzodiazepines,BZD：口服吸收迅速完全,1h—spikedensity,3h—peak蛋白结合率,分布容积变化在肝脏微粒体氧化系统(microsomaloxidizingsystem)

羟化(hydroxylation)、去甲基化(nor-methylation)和葡萄糖醛酸化(glucuronation)◈

Barbiturate分布容积大,脑、肝、肾和脂肪组织(fattytissue)中浓度高cleaningway:

脂溶性高的巴比妥类:肝脏微粒体酶(microsomeenzyme)→无活性的产物+葡萄糖醛酸(glucuronate)→肾脏脂溶性低的巴比妥类→肾脏◈

Nonbenzodiazepine,Nonbarbiturate,NBNB：大多经肝脏微粒体酶系统(microsomeenzymaticsystem)

代谢

中毒机制

(poisoningmechanisms)◈

Benzodiazepines,BZD：BZD+CNS特异性受体(w1,w2,w3)(toproduceamarkedeffect)W1:(sensorimotorarea),镇静、催眠(hypnosis);w2:(limbicsystem),抗焦虑(antianxiety)、抗惊厥(anticonvulsion)

w3:

notclearfacilitateBZD+receptor→GABA(gamma-aminobutyricacid—neurotransmitter)↓receptor

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Barbiturate↗+GABA受体,氯离子通道复合物→开放t↑→抑制Barbiturate

(chloridechannelcompound)↘chloridechannel→拟GABA广泛抑制CNS◈

Nonbenzodiazepine,Nonbarbiturate,NBNB：

inhibitoryactionforCNS:similartobarbiturate

临床表现

(clinicalsituation)◈

Benzodiazepines,BZD：发音困难(dysarthria)、眼球震颤(nystaxis)记忆力减退、幻觉(illusion)、惊厥、昏睡(hypnody)、昏迷共济失调(incoordination)、反射减退(hypopreflexia)或亢进(hyperreflexia)、肌张力障碍(myodystony)体温降低(hypothermy)、呼吸抑制◈

Barbiturate

★

light、midrangepoisoning:注意力、记忆力、判断力减退、欣快(hyperhedonia)、情绪不稳(emotionalinstability)、言语不清、共济失调、眼球震颤(nystaxis)

★

severepoisoning:昏迷、瞳孔缩小(miosis)、脑干反射消失(areflexia)、肌张力(musculartension)降低、深部腱反射(deeptendonreflex)消失、肠梗阻(intestinalobstruction)、低血压、休克◈

Nonbenzodiazepine,Nonbarbiturate,NBNB：

轻者嗜睡(drowsiness)、共济失调,重者昏迷水合氯醛(chloralhydrate):心律失常(arhythmia),肝肾衰竭格鲁米特(glutethimide):抗胆碱(luridine)能综合症甲丙氨酯(meprobamat):CNS抑制,严重低血压甲喹酮(methaqualone):锥体系征(pyramidalsystem):肌阵挛(myoclonus)、张力增强、腱反射亢进(tendonhyperreflexia)

实验室检查

(laboratoryexamination)concentrationmeasurement:

blood、urine、gastricfluidbloodgasanalysis:

PaCO2↑bloodbiochemistrydetect：

bloodglucose、ureanitrogen、creatinine、electrolyte

诊断

(diagnosis)historysingsandsymptomsconcentrationmeasurement

鉴别诊断

(differentialdiagnosis)cerebralvascularaccident:diabeticketoacidosis:uremiccoma:urinecreatinine、ureanitrogenpoisoning:alcohol◈

Firstaidcoma:glucose,vitaminB1,naloxonerespiratoryfailure:airtube,oxygen,tracheacannula,mechanicalventilationshock:

hypovolemia◈Togetridofpoison：gastriclavage：2hactivatedcarbonadsorption:

消化道透析diuresis：血液净化(bloodpurification)：血液透析(hemodialysis):prolongedactionbarbiturates,BZD(no)

血液灌流(hemoperfusion):nonwater-solubility、highproteinbindingbarbituratesandothers◈

ToxicideBarbiturates:no

BZD:

flumazenil—BZDreceptor竞争性拮抗药(competitiveantagonist)

三环抗抑郁药(tricyclicantidepressants)过量、长期应用BZD、

BZD(irritability)—to

prohibitsideeffect:

convulsion、arrhythmia、intracranialpressure↑◈Totreatcomplicationpneumonia:antibioticsarrhythmia:electrocardio-monitoringacuterenalfailure:shockwater、electrolyte、acid-basebalance有机磷杀虫药中毒(organophosphorusinsecticidespoisoning)◈

Effect:

inhibitinternal乙酰胆碱酯酶(acetylcholinesterase):↗Msample

acetylcholineacumulation→烟碱(nicotine,N)samplesymptom↘CNS→respiratoryfailure

→death.◈

Characteristics:

★难溶于水(indissolvable)

★不易溶于多种有机剂(organism)

★挥发性(volatility),大蒜味(garlic)

★碱性(alkalinity)条件下易分解(resolve)失效.

分类(classification)rankpoisonedspecies:LD50<10mg/kg,甲拌磷(3911)、内吸磷(1059)、对硫磷(1605).highpoisonedspecies:LD5010-100mg/kg,甲基对硫磷(metacide)、甲胺磷(tamaron)、氧乐果(omethoate)、敌敌畏.Midrangepoisonedspecies:LD50100-1000mg/kg,乐果(rogor)、乙硫磷(ethion)、敌百虫(Danex)等.lowpoisonedspecies:LD501000-5000mg/kg,马拉硫磷(malathion)等.

病因(reason)acutepoisoning:

livingpoisoningchronicpoisonging:

occupational

poisoningabsorption—skin、gastrointestinalandrespiratorytractmembranes.

发病机制(poisoningmechanisms)◈

Metabolism:

livercellsmicrosomaloxidizingenzymesystem: oxidize→virulence↑hydrolysis→virulence↓distribution:liver>kidney、lungandspleen>muscle、briantissure★

products→urine(24h)→lungtoexcrete(small),noaccumulation.

发病机制(poisoningmechanisms)◈

Poisoningmechanisms:

真性胆碱酯酶(truecholinesterase乙酰-):foracetylcholine特异性高,水解作用(hydrol)强

假性胆碱酯酶(pesudocholinesterase丁酰-):

foracetylcholine特异性低,严重肝损时活力降低

发病机制(poisoningmechanisms)organophosphorusinsecticides+cholinesterase酯解部位(esteraticsite)丝氨酸(serine)羟基(hydroxy)

↓

难以水解的磷酰化胆碱酯酶(organophosphate-cholinesterase)→cholinesterasecantresolve乙酰胆碱(acetylcholine)

↓

acetylcholineaccumulation→cholinergicnerve传导功能障碍→toxicsymptom

direct

organophosphorusinsecticides

→acetylcholinereceptor

临床特点(clinicalsituation)

◈

Acutepoisoning

★

oraladministration:

tofallin(10min-2h)

inhaler:

tofallin(30min)

skinabsorption:

tofallin(2-6h)

★

light:

Msymptom,cholinesteraseactivity＜50%midrange:M+Nsymptom,cholinesteraseactivity10%-20%severe:M+N+CNSsymptom,cholinesteraseactivity＜10%Msamplesymptom:

parasympatheticnerveendingexcite→smoothmusclespasm,外分泌腺分泌(exocrineglandsecretion)enhanceNsamplesymptom:alloverthebodypresshard,vencricularfibrillation,强直性痉挛(toniccramp)→muscleforcedecrease,瘫痪(tobeparalyzed)CNSsymptom:

dizzy、headache、restlessness、谵妄(acuteconfusionalstate)、incoordination、convulsionorcoma◈

Delayedneuropathysymptomdisappeared2-3w,toinvolvemotornervefibre→thelowerlimbstobeparalyzed,fourlimbsmuscle

萎缩(atrophy)—沃勒变性(Walleriandegeneration)progression:

periphsensoryneuropathy,lowerextremities→upperextremities→thelowerlimbsdeeptendonreflexdisappearheavy→迟缓性瘫痪(flaccidparalysis)stablephase:

sensorydisturbance3-12month,incompleteparalysiscatabasis:

6-18month,motorfunction→recover◈

中间综合症(intermediatesyndrome)

☆

recover1-4d,4-18drelieve

☆

颈屈肌(flexor)、脑神经支配的(innerv)肌肉、肢体近侧(proximum)肌、呼吸肌瘫痪

☆脂溶性(liposolubility)多见

☆

reason:

organophosphorusinsecticidestobedelayeddischarging、redistributionorantidotenotenough

实验室检查(laboratoryexamination)◈

cholinesteraseenergometry:

specificityindex—reflectpoisoneddegree、therapeuticefficacy、prognosisrepeattodeterminestoppyraloxime:todetermine/d,continous3d◈

metabolicproduct:determination:

urine

antinitrophenol-most;ethapon-danex

others:electromyogram;nerveconductedfunction

诊断(diagnosis)

history,garlicflavor,musclebundleventricularfibrillation具胆碱(choline)能症状

contactinsecticide12hbloodplasmaandredbloodcellcholinesteraseactivityloss>50%post-treatmentatropine:Msamplesymptomrelieve

鉴别诊断(differentialdiagnosis)

heatstrokeacutegastroenteritis:diarrheacerebritis:stiff-neck;lumbarpunctureothers治疗(treatment)◈

Firstaid:respiratorydepressionpulmonaryedemaasystolecerebraledemacoma:mannitol◈

Togetridofpoison：

gastriclavage:clearwater,normalsodium,2%bakingsoda

(danextobeprohibited),1:5000kalium

permanganicum(parathiontobeprohibited)◈

Toxicide

胆碱酯酶复活药(cholinesterasereactivators)碘解磷定(pyraloximeiodide),氯磷定(pyraloximemethylcholride),

双复磷(obidoximechloride),双解磷(trimedoxime)resolvephosphoryl_cholinesterase,recovercholinesteraseactivityTherapeuticeffect:forNsamplesymptom抗胆碱药(anticholine)atropine—blockacetylcholineeffectforparasympatheticandCNSMreceptor,relieveM,exciterespiratorycenternouse—N,cholinesteraseactivity,advancedstagerespiratorymuscularparalysisprinciple:early、fulldose、repeatmild:cholinesterasereactivatorssevere:atropine+pyraloximeiodideAtropinization:dilatedpupil(lightreactionexist)、heartrate↑、faceflash、