第五章中樞神經(jīng)系統(tǒng)藥物ChapterCentralNervoussystemDrugs第一節(jié)鎮(zhèn)靜

第五章中樞神經(jīng)系統(tǒng)藥物

Chapter5CentralNervoussystemDrugs第一節(jié)鎮(zhèn)靜催眠藥Section1sedativehypnotics背景介紹

BackgroundIntroduction中樞神經(jīng)系統(tǒng)藥物對中樞神經(jīng)活動起到抑制或興奮的作用，用于治療相關(guān)的疾病。Thecentralnervoussystemdrugcaninhibitorexcitethecentralnervousactivities,soitcanbeusedtotreatrelateddiseases.

中樞神經(jīng)系統(tǒng)藥物Centralnervoussystemdrugs鎮(zhèn)靜催眠藥Sedativehypnotics抗精神病失常藥Antipsychotics鎮(zhèn)痛藥Analgesics抗老年癡呆及改善腦代謝藥Anti-seniledementiaandbrainmetabolismimprovingdrugs

學(xué)習(xí)目標(biāo)——知識要求

LearningObjectives-Knowledgerequirements掌握Master----------------熟悉Befamiliarwith----------------了解Understand-----------鎮(zhèn)靜催眠藥的結(jié)構(gòu)類型；典型藥物地西泮、苯巴比妥的化學(xué)結(jié)構(gòu)、理化性質(zhì)及臨床用途。Structuraltypesofsedativehypnotics;Chemicalstructures,physicochemicalpropertiesandclinicalusesoftypicaldrugs,suchasdiazepam,phenobarbital.苯二氮?類、巴比妥類藥物的構(gòu)效關(guān)系。Structure-activityrelationshipofbenzodiazepinesandbarbiturates.鎮(zhèn)靜催眠藥的概念；鎮(zhèn)靜催眠藥的發(fā)展；酒石酸唑吡坦的理化性質(zhì)及臨床用途。Theconceptofsedativehypnotics;developmentofsedativehypnotics;Physicochemicalpropertiesandclinicalusesofzolpidemtartrate.學(xué)習(xí)目標(biāo)——技能要求

LearningObjectives-Skillrequirements熟練掌握Master----------------學(xué)會分析Learntoanalyze----------------典型藥物的化學(xué)鑒別方法。Chemicalidentificationmethodfortypicaldrugs.典型藥物的結(jié)構(gòu)特征；會應(yīng)用藥物的理化性質(zhì)解決藥物在合理用藥、制劑、分析檢驗(yàn)、儲存養(yǎng)護(hù)、使用等方面的問題。Structuralcharacteristicsoftypicaldrugs;solvetheproblemsofrationaldruguse,preparation,analysisandtesting,storageandmaintenance,anduseofdrugsbyapplyingthephysicochemicalpropertiesofdrugs.鎮(zhèn)靜催眠藥SedativeHypnotics鎮(zhèn)靜藥可使人處于安靜或思睡狀態(tài)，催眠藥可引起類似正常的睡眠，兩者并沒有明顯界限，常因劑量不同而產(chǎn)生不同效果，通常小劑量時鎮(zhèn)靜，較大劑量時催眠，大劑量時則產(chǎn)生麻醉、抗驚厥作用，統(tǒng)稱鎮(zhèn)靜催眠藥。Sedativescanmakepeopleinaquietorsleepystate,whilehypnoticscancausesimilarnormalsleep,thereisnoclearboundarybetweenthetwodrugs,andtheyhavedifferenteffectsduetodifferentdoses,usuallyasmalldosecanachievethesedativeeffect,alargerdosecanachievethehypnoticeffect,thelargedosemaygenerateanestheticandanticonvulsanteffects,soitiscollectivelyreferredtoassedativehypnotics.鎮(zhèn)靜催眠藥Sedativehypnotics苯二氮?類Benzodiazepines巴比妥類Barbiturates其他類Others鎮(zhèn)靜催眠藥SedativeHypnotics鎮(zhèn)靜催眠藥長期應(yīng)用，幾乎都可產(chǎn)生耐受性和依賴性，突然停藥時可引起戒斷綜合征，多數(shù)屬于國家特殊管理的第二類精神藥品，因此鎮(zhèn)靜催眠藥的處方、使用、保管必須嚴(yán)加管理，臨床應(yīng)用時要嚴(yán)格控制藥量，避免長期應(yīng)用。Afterbeingusedforalongtime,thesedativehypnoticscanalmostalwayscausetoleranceanddependence,andsuddendiscontinuationcancauseabstinencesyndrome.Mostofthembelongtothesecondcategoryofpsychotropicdrugsunderspecialnationalmanagement,sotheprescription,useandstorageofthesedativehypnoticsmustbestrictlymanaged,andthedoseshallbestrictlycontrolledinclinicaluse,andthenlong-termuseshallbeavoided.苯二氮?類Benzodiazepines20世紀(jì)60年代初發(fā)展起來的鎮(zhèn)靜催眠藥，由于此類藥物具有較好的抗焦慮和鎮(zhèn)靜催眠作用，毒副作用較小，安全范圍大，臨床上已成為鎮(zhèn)靜、催眠、抗焦慮的首選藥物。Thesedativehypnoticsdevelopedintheearly1960shavebecomethefirstchoiceforsedation,hypnosisandanti-anxietyinclinicaluseduetothegoodanti-anxietyandsedative-hypnoticeffects,lesstoxicsideeffectsandawiderangeofsafety.臨床上常用的苯二氮卓類藥物有地西泮、氯硝西泮、奧沙西泮、艾司唑侖、阿普唑侖、三唑侖等。Commonlyusedbenzodiazepinesincludediazepam,clonazepam,oxazepam,estazolam,alprazolamandtriazolam.氯氮?Chlordiazepoxide苯二氮卓類藥物Benzodiazepines并入雜環(huán)生物活性明顯提高Thebiologicalactivityoftheincorporatedheterocyclicringissignificantlyimproved.并入雜環(huán)生物活性明顯提高Thebiologicalactivityoftheincorporatedheterocyclicringissignificantlyimproved.構(gòu)效關(guān)系Structure-activityrelationship活性必需結(jié)構(gòu)Activityessentialstructure在7位引入吸電子基團(tuán)，活性增強(qiáng)，吸電子越強(qiáng)，作用越強(qiáng)，其次序?yàn)椋璑O2﹥－Br﹥－CF3﹥－Cl。Theelectron-withdrawinggroupisintroducedat7thposition.whentheactivityisincreased,theelectron-withdrawingisstronger,andtheeffectisstronger.Theorderis-NO2﹥-Br﹥-CF3﹥-Cl.NitrazepamClonazepamFlurazepam1,2位并入三唑環(huán)不僅增加了苯二氮?藥物的化學(xué)穩(wěn)定性，還增加了藥物與受體的親和力，從而增加了藥物的生理活性。Theincorporationofthetriazoleringatthe1and2positionsnotonlyincreasesthechemicalstabilityofthebenzodiazepinedrug,butalsoincreasestheaffinityofthedrugandthereceptor,therebyincreasingthephysiologicalactivityofthedrug.EstazolamAlprazolamTriazolam地西泮Diazepam（安定）典型藥物Typicaldrug有機(jī)氯原子Organochlorineatom苯環(huán)取代Benzeneringsubstitution甲基取代Methylsubstitution水解開環(huán)Hydrolysisringopening苯并七元雜環(huán)（苯二氮卓）Benzoheptabasicheterocycle(benzodiazepine)地西泮（安定）Diazepam理化性質(zhì)Physicochemicalproperties:白色結(jié)晶性粉末Whitecrystallinepowder;在酸或堿性溶液中，受熱易水解，水解開環(huán)發(fā)生在1,2位或4,5位，兩過程平行進(jìn)行，4,5位開環(huán)為可逆性水解。Inacidoralkalinesolution,itiseasytobehydrolyzedwhenheated,thehydrolysisringopeningoccursatthe1,2or4,5positions,thetwoprocessesarecarriedoutinparallel,andthe4,5ringopeningisreversiblehydrolysis;溶于硫酸，在紫外光燈(365nm)下檢視，顯黃綠色熒光。Dissolvedinsulfuricacid,inspectedunderultravioletlight(365nm),itshowedyellow-greenfluorescence.溶于稀鹽酸，加碘化鉍鉀試劑，即產(chǎn)生橙紅色沉淀，放置顏色加深。Dissolvedindilutehydrochloricacid,generateanorange-redprecipitatewhenaddingpotassiumbismuthiodidereagent,andwhenthecolorisdarkwhenitisplaced.地西泮（安定）Diazepam臨床應(yīng)用Clinicaluse:治療焦慮癥以及失眠；Treatanxietyandinsomnia;是治療癲癇持續(xù)發(fā)作的首選藥物。Itistheprioritydrugfortreatingpersistentseizures.苯二氮卓類藥物Benzodiazepines奧沙西泮oxazepam

在研究地西泮的代謝過程中發(fā)現(xiàn)的新藥。Anewdrugdiscoveredduringthestudyofthemetabolismofdiazepam.艾司唑侖（舒樂安定）estazolam亞胺Imine三氮唑Triazole苯二氮卓類藥物Benzodiazepines學(xué)以致用Practicewhatyoulearnt作用特點(diǎn)Functionandcharacteristics:苯二氮卓類藥物具有使用安全、起效快、耐受性良好的特點(diǎn)?？煽s短入睡時間、減少覺醒時間和次數(shù)、增加總睡眠時間。Benzodiazepineshavethecharacteristicsofsafeuse,rapidonsetandgoodtolerance,soitcanshortenthetimetofallasleep,reducethetimeandfrequencyofawakening,andincreasethetotalsleeptime.副作用Sideeffect:

殘留效應(yīng)、遺忘效應(yīng)、停藥效應(yīng)、成癮性。Residualeffects,amnesticeffects,effectsofdrugwithdrawal,addiction.服用注意事項(xiàng)Notesfortaking:避免長期用藥，不宜超過4周；Avoidlong-termmedication,notmorethan4weeks;以最小有效劑量、短期間斷性使用。Useattheminimumeffectivedoseandintermittentlyforashortperiodoftime.苯二氮卓類藥物Benzodiazepines學(xué)習(xí)小結(jié)Learningsummary掌握重點(diǎn)藥物Masterkeydrugs地西泮Diazepam熟悉構(gòu)效關(guān)系和作用特點(diǎn)Befamiliarwithstructure-activityrelationshipandactioncharacteristics了解體內(nèi)代謝Learnaboutmetabolism巴比妥類藥物Barbiturates分類Classification巴比妥類藥物Barbiturates長時效Longvalidtime超短時效Ultra-shortvalidtime短時效Shortvalidtime中時效Mediumvalidtime巴比妥類藥物Barbiturates

基本結(jié)構(gòu)Basicstructure巴比妥酸（丙二酰脲）5位亞（次）甲基上的兩個氫原子被烴基取代的衍生物。Aderivativeofwhichtwohydrogenatomsonthe(meth)methylenegroupatthe5thpositionofbarbituricacid(malonylurea)isreplacedbyahydrocarbylgroup.理化性質(zhì)Physicochemicalproperties與金屬離子反應(yīng)，成銀鹽、吡啶銅鹽Reactwithmetalionstoformsilversalt,copperpyridinesalt水解性內(nèi)酰脲結(jié)構(gòu)Hydrolyzabilityglydantstructure弱酸性存在互變異構(gòu)現(xiàn)象WeakacidTautomerism巴比妥類藥物一般為白色結(jié)晶或結(jié)晶性粉末，加熱多能升華，不溶于水，易溶于乙醇及有機(jī)溶劑。Barbituratesaregenerallywhitecrystalsorcrystallinepowder,whichcanbepleuripotentandsublimatedbyheating,insolubleinwater,andeasilysolubleinethanolandorganicsolvents.內(nèi)酰脲結(jié)構(gòu)使其具有水解性，隨溫度和pH的升高，水解速度加快。其鈉鹽水溶液室溫放置即可水解，鈉鹽在吸濕的情況下也能水解成無效的物質(zhì)。因此巴比妥類藥物鈉鹽注射液須制成粉針劑，臨用時配制。Theglydantstructuremakesithydrolyzable,andthehydrolysisspeedincreaseswiththeincreasedtemperatureandpH.Itssodiumsaltaqueoussolutioncanbehydrolyzedatroomtemperature,andthesodiumsaltcanalsobehydrolyzedintoineffectivesubstancesundertheconditionofhygroscopicity,therefore,thebarbituratessodiumsaltinjectionmustbemadeintopowderinjectionandpreparedwhenbeingused.水解性Hydrolyzability結(jié)構(gòu)存在互變異構(gòu)現(xiàn)象，即丙二酰脲的內(nèi)酰胺（酮式）和內(nèi)酰亞胺醇（烯醇式）互變異構(gòu)。可與堿金屬形成可溶性的鹽類，如鈉鹽可供配制注射液使用，也可利用此性質(zhì)，用酸堿滴定法測定其含量。酸性比碳酸酸性弱，其鈉鹽水溶液不穩(wěn)定，易吸收空氣中二氧化碳而析出藥物，使溶液呈現(xiàn)渾濁。Thereistautomerisminthestructure,namelytautomerismbetweenthelactam(ketoform)andlactimol(enolform)ofmalonylurea.Thesolublesaltswithalkalimetals,suchassodiumsalt,canbeusedforpreparinginjection,anditscontentcanalsobedeterminedbyacid-basetitrationbytakingadvantageofthisproperty.Acidityisweakerthancarbonicacid,anditssodiumsaltsolutionisunstable,andeasytoabsorbcarbondioxideintheairandprecipitatedrugs,makingthesolutionturbid.弱酸性Weakacid可用丙二酰脲類藥物的一般鑒別試驗(yàn)進(jìn)行鑒別。Itcanbeidentifiedbythegeneralidentificationtestformalonureaureas.①與硝酸銀作用，生成白色可溶性的一銀鹽，加入過量的硝酸銀試液，可生成白色不溶性二銀鹽沉淀。①Whenreactingwithsilvernitrate,thewhitesolublesilversaltisgenerated,andthenexcesssilvernitratetestsolutionisaddedtogeneratewhiteinsolubledisilversaltprecipitation.②與吡啶-硫酸銅試液作用，生成吡啶銅鹽，顯紫色或生成紫色沉淀，含硫巴比妥顯綠色。②Whenreactingwithpyridine-coppersulfatetestsolution,thecopperpyridinesaltgenerates,todeveloppurpleorpurpleprecipitate,anditcontainsgreenthiobarbital.與金屬離子反應(yīng)Reactwithmetalions巴比妥類藥物Barbiturates苯巴比妥（鈉）phenobarbital魯米那

典型藥物Typicaldrug丙二酰脲結(jié)構(gòu)Malonureastructure5,5-二取代5,5-disubstituted巴比妥類藥物Barbiturates苯巴比妥Phenobarbital理化性質(zhì)Physicochemicalproperties:白色結(jié)晶性粉末。Whitecrystallinepowder。顯弱酸性，在氫氧化鈉或碳酸鈉溶液中溶解。Itisweaklyacidicanddissolvesinsodiumhydroxideorsodiumcarbonatesolution。

鈉鹽水溶液放置易水解。Theplacedsodiumsaltsolutioniseasytobehydrolyzed。與硝酸銀作用。Reactingwithsilvernitrate。與銅吡啶試液作用。Reactingwithcopperpyridinetestsolution。苯環(huán)+亞硝酸鈉-硫酸試液→顯橙黃色→橙紅色。Benzenering+sodiumnitrite-sulfuricacidtestsolution→orange-yellow→orange-red。苯環(huán)+甲醛-硫酸→接界面玫瑰紅色。Benzenering+formaldehyde-sulfuricacid→interfacerosered巴比妥類藥物Barbiturates苯巴比妥Phenobarbital臨床用途Clinicaluse:主要副作用為用藥后有頭暈和困倦等后遺效應(yīng)，久用可產(chǎn)生耐受性和依賴性，多次連用可出現(xiàn)蓄積中毒以及呼吸抑制等。Themainsideeffectsaredizziness,drowsinessandotherresidualeffectsaftertakingthedrug.Long-termusecanleadtotoleranceanddependence,andrepeatedusecanleadtoaccumulativeintoxicationandrespiratorydepression.具有鎮(zhèn)靜催眠和抗驚厥作用。臨床上用于治療焦慮、失眠，也可治療驚厥及癲癇大發(fā)作。Withsedativehypnoticandanticonvulsanteffects,itisclinicallyusedtotreatanxiety,insomnia,convulsionsandgrandmal.巴比妥類藥物Barbiturates苯巴比妥鈉注射液放置過程可吸收空氣中的二氧化碳，析出苯巴比妥沉淀，使溶液呈現(xiàn)渾濁，因此要現(xiàn)用現(xiàn)配。Phenobarbitalsodiuminjectioncanabsorbcarbondioxideintheairduringtheplacementprocess,andprecipitatephenobarbitalprecipitation,thesolutionisturbid,soitshallbepreparedwhenbeingused.苯巴比妥鈉注射液與酸性藥物配伍時，可析出苯巴比妥沉淀，使溶液呈現(xiàn)渾濁，因此不能與酸性藥物配伍使用。Whenphenobarbitalsodiuminjectioniscompatiblewithacidicdrugs,phenobarbitalprecipitationcanbeprecipitated,makingthesolutionturbid,soitcannotbeusedincombinationwithacidicdrugs.苯巴比妥鈉注射液為什么要現(xiàn)用現(xiàn)配？Whyshouldphenobarbitalsodiuminjectionbepreparedwhenus