藥理學 Chapter 8 局部麻醉劑

Chapter8

LocalAnaesthetics

SARandclassificationActionandmechanismApplicationModesADRCommonanaestheticsLocalanaesthetics

--reversiblyblockimpulseconductionalongnerveaxonsandotherexcitablemembranes,canbeclinicallyusedtoblockpainsensation.--Patientsareconscious,showanalgesisoflocaltissueinordertodolocaloperation.Cocaine

--thefirstagent,wasisolatedfromcocaleavesin1860.Part1.StructureandclassificationElementarystructure

lipophilicgroup:aromaticringorheterocycle

hydrophilicaminesubstituents

intermediatechainClassification

esterbond:aromaticesters

procaine

amidelinkage:amides

lidocaineLocalanestheticincludesestersandamidesprocainetetracainelidocainebupivacaine

Structure-ActivityRelationship

Lipidsolubility:duetoaromaticring,facilitatetocrosscellmembranetoexertlocalanaesthesia.esterswithhighlipidsolubilityusuallyhaveashorterdurationofaction.

Hydrophilicalkylamine:Localanestheticsareweakbases.Fortherapeuticapplication,theyareusuallymadeavailableassaltsforsolubilityandstability.Structure-ActivityRelationship

Esters:hydrolysisbylipaseinplasma.

Amides:degradationbyamidaseinliver.comparedtwotypes,amideshasquickonset,broaddiffusion,longerdurationandstablization.Part2.Actionandmechanism

[PharmacologicalActions]1.Localanaesthesia↑excitingthreshold,↓actionpotential,↓conductionrate

Theactiondegreeisrelatedthefiberstype.Smallerfibersareblockedfirst.Terminal,ganglion,synapsishavehighsensitivity.Nervefiberswithoutmyelinsheatharemoresensitivethanthosewithmyelinsheath.Anaesthesiainorderofpainfibers>othersensations>motorfunction痛覺＞溫覺＞觸、壓覺＞中樞抑制性神經元＞中樞興奮性神經元＞自主神經＞運動神經＞心?。狙芷交。疚改c平滑?。咀訉m平滑?。竟趋兰PharmacologicalActions]2.Anti-arrhythmiaLidocaine:commonusedinventriculartachycardia,suchasVT,VF,etc.3.GeneralreactionExertadversereactionbyabsorption.cellmembranestabilizingaction

(膜穩(wěn)定作用)---blockadeofvoltage-gatedsodiumchannels

（鈉通道阻滯作用）

→inhibittogenerateanactionpotential→blockadeoftheproduceandconductionofnerveimpulse[MechanismofAction]1)Twomolecularstatesofanaesthetics:

--un-ionizedform(B)--cationicform(ionizedform,BH+)TherelativeproportionsoftwoformsisregulatedbytheirpKaandthe

pHofbodyfluids.Bformcouldpenetrateintocells,thenchangedtoBH+form.Thecationicform(BH+)bindstophosphategroup(negativecharge)ofNa+channeltoblocktheopenofchannel→↓Na+influx.

Reason:sincethepKaofmostlocalanestheticsisintherangeof8.0-9.0,intracellularpHis7.08.2)Lipidsolubility,dissociationrateanddegreeofdrugsarerelatedtotime-activityoflocalanaesthesia.Thecationicformisthoughttobethemostactiveformatthereceptorsite,buttheunionizedformisveryimportantforrapidpenetrationofbiologicmembranes.MechanismofactionBlockingvoltage-gatedsodiumchannelsbycationicforminsidethecellPart3.Modesoflocalanesthesia

1.surfaceanaesthesia(ortopical

anaesthesia,表面麻醉)2.infiltrationanaesthesia(浸潤麻醉)3.conductionanaesthesia(傳導麻醉)

---blockanaesthesia

(阻滯麻醉)4.subarachnoidalanaesthesia(蛛網膜下腔麻醉)---spinalanaesthesiaorlumbaranaesthesia5.epiduralanaesthesia(硬脊膜外麻醉)

---將穿透力強的局麻藥噴或涂于粘膜表面，使粘膜下神經末梢麻醉。---適用于口腔、鼻、咽喉、眼睛、尿道等粘膜部位的淺表手術。

tetracaine

surfaceanaesthesia（表面麻醉）---將局麻藥注入手術野皮下或手術區(qū)各層組織里，使局部的神經末梢麻醉。---常用于淺表小手術。lidocaine,procaine

infiltrationanaesthesia（浸潤麻醉）

----是將局麻藥注射到神經干附近，阻止神經沖動傳導，使其支配的區(qū)域產生麻醉。----常用于四肢及口腔手術。lidocaine,bupivacaine,ropivacaineconductionanaesthesia（傳導麻醉，阻滯麻醉）---也叫脊麻、腰麻。將局麻藥液經腰椎間隙注入蛛網膜下腔，以阻滯該部位的神經根，使神經根所支配的部位產生麻醉，麻醉范圍較廣。---適用于下腹部及下肢的手術。

bupivacaine,lidocaine,procaine

subarachnoidanaesthesia（蛛網膜下腔麻醉）

---將局麻藥液注入硬脊膜外腔，使通過此腔穿出椎間孔的神經根麻醉。---可用于頸部到下肢的手術，尤其適用于上腹部手術。

lidocaine,bupivacaine,ropivacaine

epiduralanaesthesia（硬脊膜外麻醉）Section4.AbsorptionandAdverseReaction

Localanestheticagentsareabsorbedfromthesiteofadministration----absorptiveaction:A.CentralNervousSystemB.CardiovascularSystemC.HypersensitiveReactionsD.AllergicReactionsA.CentralNervousSystem:

Atlowdoses,sedation,headache,dizziness,hypesthesia,cloudingofconsciousness.(inhibition)Athigherdoses,insanity,andmusculartwitching,evenconvulsion.(excitation)Finally,inhibitionofbothinhibitiveandexcitedneurons→overallinhibitionofCNS→coma,cardiacarrest,respiratoryparalysis,andevendeath.B.CardiovascularSystem:

Na+channelblockade→heartinhibition→myocardialcontractility↓,conduction↓,prolongERP;Vasodilation

→BP↓,evenshockGenerally,CNStoxicitypriortoCVStoxicity;

Bupivacaine(conversely),severeCVStoxicity,includingarrhythmiaandlethalVF.

C.HypersusceptibilityReaction:

Somepatientstreatmentwith<1/3highdose,showtoxiceffects,suchasfaint,respiratorydepression,circulatoryfailure.Duetoindividualdifference.Note:Foroneperson,thesensitivitytodrugsmaychangedobviouslyatdifferentphysiologicalorpathologicalstatus.D.AllergicReactions(Anaphylaxis):

Theestertypelocalanaestheticsaremetabolizedtop-aminobenzoicacid(PABA)derivatives.Thesemetabolitesareresponsibleforallergicreactionsinasmallpercentageofthepopulation.Symptom:Urticaria(蕁麻疹),bronchospasm,dyspnea,hypotensionandangioedema.Esters>amidesSection5.CommonLocalanaesthetics1.Procaine(普魯卡因)instabilityofaqueoussolution，lesstoxicityinfiltrationanaesthesia;conductionanaesthesiasubarachnoidalandepiduralanaesthesia（needauxiliarysolvent）badpenetratingpower,

notusedinsurfaceanaesthesia

2.Lidocaine

(利多卡因)

strongpenetratingability

quickandstrongaction

surfaceanaesthesia,

infiltrationanaesthesia,