药剂学第12章镇静药

Chapter12:Sedative-HypnoticDrugs

Thesedative-hypnoticdrugindicatesthatitsmajortherapeuticuseistocausesedationortoencouragesleep.Anxietystatesandsleepdisordersarecommonproblems,andsedative-hypnoticsareamongthemostwidelyprescribeddrugsworldwide.Aneffectivesedative(anxiolytic)agentshouldreduceanxietyandexertacalmingeffectwithlittleornoeffectonmotorormentalfunctions.Ahypnoticdrugshouldproducedrowsinessandencouragetheonsetandmaintenanceofastateofsleepthatasfaraspossibleresemblesthenaturalsleepstate.Hypnoticeffectscanbeachievedwithmostsedativedrugssimplybyincreasingthedose.Atstillhigherdoses,sedative-hypnoticsmaydepressrespiratoryandvasomotorcentersinthemedulla,leadingtocomaanddeath.I.CHEMICALCLASSIFICATION

Thebenzodiazepinesarethemostimportantsedative-hypnotics.Thebarbituratesaresomeolderandlesscommonlyusedsedative-hypnotics.“Nonbarbituratesedative-hypnotics”includechloralhydrateandmeprobamate(甲丙氨酯).

II.

BENZODIAZEPINES

A.Pharmacokinetics1.Absorption:Theratesoforalabsorptionofbenzodiazepinesdifferdependingonanumberoffactors,includinglipophilicity.2.Distribution:

Lipidsolubilityplaysamajorroleindeterminingtherateatwhichaparticularsedative-hypnoticentersthecentralnervoussystem.Allsedative-hypnoticscrosstheplacentalbarrierduringpregnancy.Benzodiazepinesbindextensivelytoplasmaproteins,rangesfrom60%toover95%.3.Biotransformation:Mostbenzodiazepinesundergomicrosomaloxidation(phaseIreactions).Themetabolitesaresubsequentlyconjugated(phaseIIreactions)byglucuronosyltransferasestoformglucuronidesthatareexcretedintheurine.However,manyphaseImetabolitesofbenzodiazepinesareactive,withhalf-livesgreaterthantheparentdrugs.4.Excretion:

Thewater-solublemetabolitesofbenzodiazepinesareexcretedmainlyviathekidney.Inmostcases,changesinrenalfunctiondonothaveamarkedeffectontheeliminationofparentdrugs.5.FactorsAffectingBiodisposition:Thebiodispositionofsedative-hypnoticscanbeinfluencedbyseveralfactors,particularlyalterationsinhepaticfunctionresultingfromdisease,oldage,ordrug-inducedincreasesordecreasesinmicrosomalenzymeactivities.B.Pharmacodynamics1.MolecularMechanismsThebenzodiazepines,thebarbiturates,andtheimidazopyridines(咪唑吡啶)bindtomolecularcomponentsoftheGABAA

receptorpresentinneuronalmembranesinthecentralnervoussystem.Thisionotropicreceptor,atransmembraneheteroligomericproteinthatfunctionsasachlorideionchannel,isactivatedbytheinhibitoryneurotransmitterGABA.MolecularcloningtechniquesshowtheGABAAreceptorchlorideionchannelmacromolecularcomplextohaveapentamericstructureassembledfromfivesubunits.ReconstitutionoftheGABAAreceptorchlorideionchannelcomplexhasrevealedthatcombinationsofthethreemajorsubunits-alpha,beta,andgamma－areessentialfornormalphysiologicandpharmacologicfunctions.AmodelofthehypotheticalGABA-BZreceptor-chlorideionchannelmacromolecularcomplexisshowninFigure11-5.Gamma-aminobutyricacid(GABA)isthemajorinhibitoryneurotransmitterinthecentralnervoussystem.ElectrophysiologicstudieshaveshownthatbenzodiazepinespotentiateGABAergicinhibitionatalllevelsoftheneuraxis(脑脊髓),includingthespinalcord,hypothalamus,hippocampus,substantianigra,cerebellarcortex,andcerebralcortex.BenzodiazepinesappeartoincreasetheefficiencyofGABAergicsynapticinhibition(viamembranehyperpolarization),whichleadstoadecreaseinthefiringrateofcriticalneuronsinmanyregionsofthebrain.ThebenzodiazepinesdonotsubstituteforGABAbutappeartoenhanceGABA’seffectswithoutdirectlyactivatingGABAreceptorsoropeningtheassociatedchloridechannels.TheenhancementinchlorideionconductanceinducedbytheinteractionofbenzodiazepineswithGABAtakestheformofanincreaseinthefrequencyofchannel-openingevents.ThiseffectmaybedueinparttoenhancedreceptoraffinityforGABA.2.OrganLevelEffectsandApplications(1)SedationandAntianxiety

－Thesebehavioralchangesoccuratthelowesteffectivedosesofthecommonlyusedsedative-hypnotics,anditisnotyetclearwhethersuchantianxietyactionsseenclinicallyareequivalenttoordifferentfromsedativeeffects.(2)Hypnosis－Bydefinition,allofthesedative-hypnoticswillinducesleepifhighenoughdosesaregiven.Normalsleepconsistsofdistinctstages.Twomajorcategoriescanbedistinguished:non-rapideyemovement(NREM)sleep,whichrepresentsapproximately70-75%oftotalsleep;andrapideyemovement(REM)sleep.REMandNREMsleepoccurcyclicallyoveranintervalofabout90minutes.TheREMsleepstageisthatinwhichmostrecallabledreamsoccur.Theeffectsofsedative-hypnoticsonpatternsofnormalsleepareasfollows:(1)thelatencyofsleeponsetisdecreased(timetofallasleep);(2)thedurationofstage2NREMsleepisincreased;(3)thedurationofREMsleepisdecreased.Asimilarpatternof"REMrebound"canbedetectedfollowingcessationofdrugtreatmentwithmostsedative-hypnotics.Theuseofsedative-hypnoticsformorethan1-2weeksleadstosometolerancetotheireffectsonsleeppatterns.(3)Anesthesia－benzodiazepinesgiveninlargedosesasadjunctstogeneralanestheticsmaycontributetoapersistentpostanestheticrespiratorydepression.Thisisprobablyrelatedtotheirrelativelylonghalf-livesandtheformationofactivemetabolites.

(4)Anticonvulsanteffects－Mostofthesedative-hypnoticsarecapableofinhibitingthedevelopmentandspreadofepileptiformactivityinthecentralnervoussystem.Severalbenzodiazepineshaveselectiveactionsthatareclinicallyusefulinthemanagementofseizurestates.(5)Musclerelaxation－Somebenzodiazepinesexertinhibitoryeffectsonpolysynapticreflexesandinternuncial(联络性)transmissionandathighdosesmayalsodepresstransmissionattheskeletalneuromuscularjunction.Usefulnessforrelaxingcontractedvoluntarymuscleinjointdiseaseormusclespasm.(6)Effectsonrespirationandcardiovascularfunction－Sedative-hypnoticsevenattherapeuticdosescanproducesignificantrespiratorydepressioninpatients-withpulmonarydisease.Effectsonrespirationaredose-related,anddepressionofthemedullaryrespiratorycenteristheusualcauseofdeathduetooverdoseofsedative-hypnotics.C.AdverseReaction1.Tolerance－decreasedresponsivenesstoadrugfollowingrepeatedexposure-isacommonfeatureofsedative-hypnoticuse.Itmayresultinanincreaseinthedoseneededtomaintainsymptomaticimprovementortopromotesleep.Inthecaseofbenzodiazepines,thedevelopmentoftoleranceinanimalsisassociatedwithdown-regulationofbrainbenzodiazepinereceptors.2.Dependences－Theperceived(看见)desirablepropertiesofreliefofanxiety,euphoria,disinhibition,andpromotionofsleephaveledtothecompulsivemisuseofvirtuallyallsedative-hypnotics.Theconsequencesofabuseoftheseagentscanbedefinedinbothpsychologicandphysiologicterms.Thepsychologicdependencemayinitiallyparallelsimpleneuroticbehaviorpatternsdifficulttodifferentiatefromthoseoftheinveterate(长期形成的)coffeedrinkerorcigarettesmoker.Physiologicdependencecanbedescribedasanalteredphysiologicstatethatrequirescontinuousdrugadministrationtopreventtheappearanceofanabstinenceorwithdrawalsyndrome.Thissyndromeischaracterizedbystatesofincreasedanxiety,insomnia,andcentralnervoussystemexcitabilitythatmayprogresstoconvulsions.Mostbenzodiazepinesarecapableofcausingphysiologicdependencewhenusedonachronicbasis.theseverityofwithdrawalsymptomsdiffersbetweenindividualdrugsanddependsalsoonthemagnitudeofthedoseusedimmediatelypriortocessationofuse.3.DirectToxicActions:thecommonadverseeffectsarethoseresultingfromdose-relateddepressionofcentralnervoussystemfunctions,includingdrowsiness,impairedjudgment,anddiminishedmotorskills,sometimeswithasignificantimpactondrivingability,jobperformance,andpersonalrelationships.Itcanexacerbatebreathingproblemsinpatientswithchronicpulmonarydiseaseandinthosewithsymptomaticsleepapnea(呼吸暂停,窒息).

4.DrugInteractions:

Themostfrequentdruginteractionsareinteractionswithothercentralnervoussystemdepressantdrugs,leadingtoadditiveeffects.Theseinteractionshavesometherapeuticutilitywithrespecttotheuseofthesedrugsaspremedicantsoranestheticadjuvants.However,ifnotanticipated,theycanleadtoseriousconsequences.D.BenzodiazepineAntagonists

Flumazenilistheonlybenzodiazepinereceptorantagonistavailableforclinicaluseatpresent.Itblocksmanyoftheactionsofbenzodiazepines(andimidazopyridines)butdoesnotantagonizethecentralnervoussystemeffectsofothersedative-hypnotics,ethanol,opioids,orgeneralanesthetics.Flumazenilisapprovedforuseinreversingthecentralnervoussystemdepressanteffectsofbenzodiazepineoverdoseandtohastenrecoveryfollowinguseofthesedrugsinanestheticanddiagnosticprocedures.III.

BARBITURATES

A.

Pharmacokinetics1.Absorption:

Thebarbituratesareusuallyabsorbedveryrapidlyintothebloodfollowingoraladministration.

2.Distribution:

Thethiobarbiturates(eg,thiopental),inwhichtheoxygenonC2isreplacedbysulfur,areverylipid-soluble,andahighrateofentryintothecentralnervoussystemcontributestotherapidonsetoftheircentraleffects.thethiobarbiturateshaveshownthattheyarerapidlyredistributedfromthebrain,firsttohighlyperfusedtissuessuchasskeletalmuscleandsubsequentlytopoorlyperfusedadiposetissue.Theseprocessescontributetotheterminationoftheirmajorcentralnervoussystemeffects.3.Biotransformation:ThemajormetabolicpathwaysinvolveoxidationbyhepaticenzymesofchemicalgroupsattachedtoC5,whicharedifferentfortheindividualbarbiturates.Thealcohols,acids,andketonesformedappearintheurineasglucuronideconjugates.Withveryfewexceptions,themetabolitesofthebarbiturateslackpharmacologicactivity.4.Excretion:

Phenobarbitalisexcretedunchangedintheurinetoacertainextent(20-30%ithumans),anditseliminationratecanbeincreasedsignificantlybyalkalinizationoftheurine.ThisispartlyduetoincreasedionizationatalkalinepH,sincephenobarbitalisaweakacidwithapKaof7.4.5.FactorsAffectingBiodisposition:phenobarbitalismostlikelytocausetheenzymeinductionandresultinanincreaseintheirownhepaticmetabolismaswellasthatofcertainotherdrugs.Self-inductionofmetabolismcontributestothedevelopmentoftolerancetosedative-hypnotics.Increasedbiotransformationofotherpharmacologicagentsasaresultofenzymeinductionbybarbituratesisapotentialmechanismunderlyingdruginteractions.B.PharmacodynamicsofBarbiturates

1.MechanismofactionBarbituratesalsofacilitatetheactionsofGABAatmultiplesitesinthecentralnervoussystem,but－incontrasttobenzodiazepines－theyappeartoincreasethedurationoftheGABA-gatedchannelopenings.Athighconcentrations,thebarbituratesmayalsobeGABA-mimetic,directlyactivatingchloridechannels.Barbituratesarelessselectiveintheiractionsthanbenzodiazepines,sincetheyalsodepresstheactionsofexcitatoryneurotransmittersandexertnonsynapticmembraneeffectsinparallelwiththeireffectsonGABAneurotransmission.Thismultiplicityofsitesofactionofbarbituratesmaybethebasisfortheirabilitytoinducefullsurgicalanesthesiaandfortheirmorepronouncedcentraldepressanteffects(whichresultintheirlowmarginofsafety)comparedtobenzodiazepines.2.PharmacologicActionsandclinicalApplicationsThedegreeofcentralnervoussystemdepressionisadose-responserelationship.(1)SedationandHypnosis:

thedurationofREMsleepisobviouslydecreased."REMrebound"canbedetectedfollowingcessationofdrug.(2)AnticonvulsantandAntiepilepticeffects:

Ofthebarbiturates,phenobarbitalandmetharbital(甲基巴比妥,convertedtophenobarbitalinthebody)areeffectiveinthetreatmentofgeneralizedtonic-clonicseizures.

(3)Anesthesia:

Amongthebarbiturates,thiopentalandmethohexital(甲己炔巴比妥)areverylipid-soluble,penetratingbraintissuerapidlyfollowingintravenousadministration.Rapidtissueredistributionaccountsfortheshortdurationofactionofthesedrugs,whicharethereforeusefulinanesthesiapractice(inductionofanesthesia).(4)Potentiatetheeffectsofothercentralnervousdepressantagents:Alcohol,Anesthetics,AntipsychoticAgents,Analgesics,

Anti-histaminedrugs,Antipyretic-AnalgesicandAnti-inflammatoryDrugs,etc.3.AdverseReaction(1)aftereffect(residualeffect):(2)Tolerance－Analterationintherateofmetabolicinactivationwithchronicadministrationmaybepartlyresponsible(metabolictolerance)inthecaseofbarbiturates,butchangesinresponsivenessofthecentralnervoussystem(pharmacodynamictolerance)areofgreaterimportanceformostsedative-hypnotics.(3)Dependences－Psychologic&PhysiologicDependence.(4)Becausebarbituratesenhanceporphyrinsynthesis,theyareabsolutelycontraindicatedinpatientswithahistoryofacuteintermittentporphyria,variegate(杂色,多样性)porphyria,hereditarycoproporphyria,orsymptomaticporphyria.4.AcuteIntoxicationandTreatmentTheeliminationrateofbarbituratescanbeincreasedsignificantlybyalkalinization(NaHCO3,iv.)oftheurine.Promotetheexcretionofbarbiturates.IV.OTHERSEDATIVE-HYPNOTICS

1.Chloralhydrate:Trichloroethanolisthepharmacologicallyactivemetaboliteofchloralhydrateandhasahalf-lifeof6-10hours.However,itstoxicmetabolite,trichloroaceticacid,isclearedveryslowlyandcanaccumulatewiththenightlyadministrationofchloralhydrate.2.Buspirone(丁螺环酮):relievesanxietywithoutcausingmarkedsedativeoreuphoriceffects.Unlikebenzodiazepines,thedrughasnohypnotic,anticonvulsant,ormusclerelaxantproperties.Buspironed