Download Lipid solubility Degree of vascularity of the tissue

PARTONE
Sodiumishighextracellularlyandlowintracellularly
Potassiumislowextracellularlyandhighintracellularly
ConductioniscausedbyasuddenshiftinNaandKionsacrossthecellmembrane
Na/K/ATPPumpmechanismkeepsthisgradientinarestingnerve
Inarestingstate,themembraneismorepermeabletopotassium
Becauseofthisshiftofpositiveionsoutofthecentre,thecentreisnownegative
Thereisa60-70mVpotentialacrossthecellmembraneduetotheseions
Stimulilikeasurgeon’scutareconvertedintominusculeelectriccurrents-
makingtheareaaroundreceptorsitesLESSnegative
Ifthesecurrentscausethethresholdpotentialtobemet,willcauseanactionpotentialto
bepropagateddownthenerve
Thisworksviathecellmembranesuddenlybecomingmorepermeabletopositive
sodiumions,thatfloodintoa-vearea(itbeingapositiveion)
Thisgeneratesacurrentthatsequentiallydepolarizestheadjacentsegmentofthenerve,
thus"activating"thenerveandsendingawaveofsequentialpolarizationdownthenerve
membrane.
BecausetherapidinfluxofNa+ionsoccursinresponsetoachangeinthetransmembrane
potential,Na+channelsinthenervearecharacterizedas"voltagegated"-large,three
subunitproteinstructuresthatcrossthemembranelayerconnectingtheexteriorofthecell
totheaxoplasm(interior).
LA’sbindtothealphapartofthissubunitandblocksodiumfromgoingbackin
Ifsodiumcan’tflowbackin,thenthewaveofdepolarisation/transmissionisblocked
ArestingnerveislesssensitivetoaLAthananervethatisrepeatedlystimulated
Ahigherfrequencyofstimulationandamorepositivemembranepotentialcausea
greaterdegreeoftransmissionblock
Themoreanareaaroundthenerveisdepolarised,themorelikelythatanLAwill
findanopen/activatedsodiumsubunit!
THEGREATERTHELIPIDSOLUBILITY,THE
GREATERTHEDURATIONOFACTION.
THEMORELIPIDSOLUBLEANLA,THE
MORETOXICITCANBEATLARGERDOSES
LA’shaveahydrophilicandahydrophobicsection.
Ester&AmideLA’s-basicallydescribingthemoleculethat
connectsthehydrophilic/phobicsections.
Ester-linkedLAsaremetabolizedinplasmaby
pseudocholinesterase
Amide-linkeddrugsundergometabolismintheliver.
Themorelipidsoluble,thelargerthepotencyand
durationofaction-(moredissolvableatlipidmembranes)
Greaterlipidsolubilityalsoincreasestoxicity,decreasingthe
therapeuticindexformorehydrophobicdrugs.
Blockdurationisnotrelatedtoproteinbinding!
THREEDEPENDANTFACTORSTHATAFFECTBLOCKLENGTH
Lipidsolubility
Degreeofvascularityofthetissue
Presenceofvasoconstrictorsthatpreventvascularuptake
ThepKagenerallycorrelateswiththespeedofonsetofactionofmostamideLAdrugs(lignocaine)
ThecloserthepKatothebodypH,thefastertheonset
ThepKaisthepHatwhich50%ofthedrugisionizedand50%ispresentasbase
pKaoftheLAisrelatedtopHandtheconcentrationsofthecationicandbaseformsbythe
Henderson-Hasselbalchequation:pH=pKa+log([base]/[cation]).
ThepKagenerallycorrelateswiththespeedofonsetofactionofmostamideLAdrugs;thecloserthe
pKatothebodypH,thefastertheonset.
Thecoexistenceofthetwoformsofthedrug-thechargedcationandtheunchargedbase-isimportant
becausedrugpenetrationofthenervemembranebytheLArequiresthebase(unionized)formtopass
throughthenervelipidmembrane
Onceintheaxoplasm(centre)ofthenerve,thebaseformcanacceptahydrogenionandequilibrate
intothecationicform.
ThecationicformispredominantandproducesablockadeoftheNa+channel.
Theamountofbaseformthatcanbeinsolutionislimitedbyitsaqueoussolubility.
Itisgenerallyacceptedtheclosestyoucaninfiltratetothenerveitself,thequickeritsonset-dueto
distance.
Directinjectionintothenerveisnotrecommended-itcancauseinjury.
http://www.nysora.com/regional-anesthesia/foundations-of-ra/3492-local-anesthetics-clinical-pharmacology-and-rational-selection.html