local anesthetics / Medicinal Chemistry

Local anesthetics-Medicinal Chemistry
Dr.Narmin Hamaamin Hussen

1. Local Anesthetics
Medicinal Chemistry III/ 4th stage / 1
st
semester
Lecture 5
Dr.Narmin HamaaminHussen
University of Sulaimani
College of Pharmacy

2. Local anesthetics
•Localanesthetics(LA)aredrugsthatareusedtopreventor
relievepaininspecificregionsofthebodywithoutlossof
consciousness.Theyactbyreversiblyblockingnerve
conduction.
•Regionalanesthesianumbsoneregionofyourbody.The
anesthesiamaybegivenaroundnervesorintoveinsinyour
arms,neck,orlegs(nerveblockorBierblock).
•Oritmaybesentintothespinalfluid(spinalanesthesia)
orintothespacejustoutsidethespinalfluid(epidural
anesthesia).Youmayalsobegivensedativestohelpyou
relax.
•Localanesthesianumbsjustasmallareaoftissuewherea
minorprocedureistobedone.

3. Mechanism of action of local anesthetics:
▪Localanestheticsactprimarilybyinhibitingthevoltage-gatedsodiumchannelsontheneuronal
membraneandthusblockperipheralnerveconduction.
▪Whenthelocalanestheticbinds,itblockssodiumionpassageintothecellandthusblocksthe
formationandpropagationoftheactionpotential.
▪Thisblocksthetransmittanceofthemessageof“pain”oreven“touch”fromgettingtothebrain.

4. ➢The ability of a local anesthetic to block action potentials depends on the ability of the drug to penetrate the tissue
surrounding the targeted nerve as well as the ability of the drug to access the binding site on the sodium channel.
➢Ionization of the drug affects its transportation across the lipid plasma membrane. The ionized form (water-soluble but
lipid insoluble) of a local anesthetic is important as it is the most active at the receptor site (lipidic plasma
membrane/axon)
Ionized (cation) and unionized forms of LA

5. Classificationoflocalanestheticsdrugsaccordingtochemistry
Ester GroupAmide Group
Cocaine Lidocaine
Procaine Etidocaine
Choroprocaine Bupivacaine
Tetracaine Dibucaine
Benzocaine Prilocaine
Ropivacaine
Mepivacaine
Ether GroupKetone Group
Pramoxine Dyclonine
Ether Ketone

6. Classificationaccordingtodurationofaction
Soluble:Cocaine,Lidocaine
andTetracaine
Insoluble: Benzocaine and
Oxenthazaine

7. Classification according to clinical uses
I.Surface Anesthesia
Lignocaine , Procaine ,Bupivacaine , Tetracaine
II. Infiltration Anesthesia & Field Block Anesthesia
Lignocaine ,Cocaine, Benzocaine
III. Nerve Block Anesthesia
Procaine , Lignocaine ,Bupivacaine , Tetracaine ,Ropivacaine
IV. Spinal Anesthesia
Lignocaine ,Tetracaine , Bupivacaine
V. Epidural Anesthesia
Lignocaine ,Bupivacaine
VI. Anesthetic Used In Ophthalmology
Proparacaine

8. SARsof Local Anesthetics
Basic Structure

9. 1. The Aromatic Ring(Lipophilic group)
▪Thearomaticringaddslipophilicitytotheanesthetic
andhelpsthemoleculepenetratethroughbiological
membranes.
▪Substituentsonthearomaticringmayincreasethe
lipophilicnatureofthearomaticring.
▪AnSARstudyofparasubstitutedestertypelocal
anestheticsshowedthatlipophilicsubstituentsand
electron-donatingsubstituentsintheparaposition
increasedanestheticactivity.
▪Presenceofelectronwithdrawinggroupinorthoorpara
(notmeta)positiondecreasesLipophilicitybutstill
increasesactivityforonlyestergroup.

10. ▪Presence of e-withdrawing halogens in ortho position only can decrease duration of action by
making the ester more Likely for a nucleophilic attack
▪Chlorineinorthogroupmakesthecarbonylcarbonmorepositiveandmorelikelytobeattackedby
nucleophilesthatcausesbreakdownofcompound.Nucleophilescontainalonepairofelectron.
▪Theyattackatomswithpositivecharges.Morepositivetheatom,thebettertheattack.

11. Exceptional with thiophene ring
➢Articaine
▪Articaine is a dental amide-type local anesthetic.
▪It is the most widely used local anesthetic in a number of European countries and is available in
many countries.
▪It is the only local anaesthetic to contain a thiophene ring, meaning it can be described as
'thiophenic'; this conveys lipid solubility.
▪It was approved by the FDA in April 2000, and became available in the United States of America
two months later under the brand name Septocaine, an anesthetic/vasoconstrictor combination
with Epinephrine 1:100,000.

12. Articaine metabolism
❖Articaineisquicklymetabolizedviahydrolysisintoits
inactivemetabolitearticainicacid,whichispartly
metabolizedinthekidneyintoarticainicacid
glucuronide

13. 2. The Linker
▪Thelinkerisusuallyanesteroranamidegroupalongwitha
hydrophobicchainofvariouslengths.
▪Ingeneral,whenthenumberofcarbonatomsinthelinkeris
increased,thelipidsolubility,proteinbinding,durationofactionand
toxicityincreases.
▪Estersandaminoamidesdifferinmetabolism,stabilityandadverse
effects:
Estergroup:
➢Metabolizedintheserumbyesterases
➢Haveahigherriskofcausingallergicreactionsorsystemictoxicity
Amidegroup
➢Metabolizedintheliver
➢Saferthantheesteragents
➢Shouldbeusedwhenpatientsareallergictoesters
➢Amidesaremorestablethanestersandthushavelongerhalf-lives
thanesters.
Procaine
Chloroprocaine
Tetracaine
Lidocaine
Etidocaine
Prilocaine
Mepivacaine
Bupivacaine
Levobuvicane
Ropivacaine

14. For Amide group only :
▪Presence of di-ortho substituted group prevent breakdown of amide and thus increase its stability in
both liquid formulation and the body enzymes

15. 3. The Nitrogen( Hydrophilic)
▪UsefulLAhaveasecondaryortertiaryaminegroup.
▪Thisisimportantbecauseitisbelievedthatwhentheyenterthecell,theywillacceptaprotonand
formpositivelychargedquaternaryformwhichisneededforbindingtovoltagegatedionchannels.
•Procainebelievedtobindtoit’sreceptorwhentheaminegroupispositivelychargequaternary
form
▪Tokeeptheanestheticsolubleincommercialsolutions,mostpreparationsareacidified.
▪Inanattempttodecreasepainoninjectionandtoincreasetheonsetofaction,somepractitioners
advocateaddingsodiumbicarbonatetothecommercialpreparation.
▪Byaddingsodiumbicarbonate,thesolutionwillbecomelessacidicandmoreofthedrugwillbe
foundintheneutralform.

16. Exceptionalwithbenzocaine
▪However,benzocainehasnoamineportionbutisstillaneffectivetopicalLA.
▪ThustheuseofAminepartcouldonlybeforproperwatersolubilityandnotdirectlyrelatedto
properbinding
Benzocaine has no amine but is still effective LA

17. Local Anesthetic Monographs, Individual Products:
A-The Ester Local Anesthetics
Esters of Benzoic acid:
1-Cocaine:
▪Cocainewasthefirstagentusedfortopicalanesthesia.
▪In1884,aGermansurgeondemonstratedthesuccessfuluseofcocaineto
anesthetizethecorneaduringeyesurgery.
▪Today,cocaineisusedfortopicalanesthesiaofmucousmembranesusinga4%to
10%solution.Ifthesolutionremainsonthemembranefor5minutes,anesthesia
andvasoconstrictionoftheareawilloccur.
▪Toxicmanifestationsincludeexcitation,dysphoria,tremor,seizureactivity,
hypertension,tachycardia,myocardialischemia,andinfarction.
▪Whencocainewascomparedwithlidocaine/phenylephrinefornasalintubations,
theresultswerethesamewithlesstoxicityinthelidocaine/phenylephrinegroup.

18. 2-Procaine:
▪ThepKaofprocaineis8.9;ithaslowlipidsolubilityandtheestergroupisunstableinbasicsolutions.
▪Procaineisavailableinconcentrationsrangingfrom0.25%to10%withpHsadjustedto5.5to6.0for
chemicalstability.
▪ProcaineisalsoincludedinsomeformulationsofpenicillinGtodecreasethepainofintramuscular
injection.
▪Procaineisnotusedtopicallybecauseofitsinabilitytopassthroughlipidmembranesandfindsuseasan
infiltrationagentforcutaneousormucousmembranes,forshortprocedures.
▪Procaineisalsousedforperipheralnerveblockandasanepiduralagenttodiagnosepainsyndromes
Esters of Para amino benzoic acid:

19. Metabolism:
▪Procaineisveryquicklymetabolizedintheplasmabycholinesteraseandintheliverviaesterhydrolysisbya
pseudocholinesterase.
▪Theparaaminobenzoicacid(PABA)metabolite,commontotheesterclassofdrugs,isbelievedtobe
responsiblefortheallergicreactionssomepatientshaveexperiencedwithlocalanesthetics.

20. Synthesis of Procaine HCl
❖Thedirectreactionofthe4-
aminobenzoicacidethylester
with2-diethylaminoethanolin
thepresenceofsulfuricacid.

21. Allergic reactions to PABA Metabolism (ParaAminoBenzoicAcid)
EsterLocalAnesthetics
▪Allergiestotheesteranestheticsaremorecommonthanallergiestotheamideanesthetics.As
discussed,theesteranestheticsmaybemetabolizedtoPABA,whichisbelievedtoberesponsiblefor
theallergicreactions.
▪AlthoughtheamidetypelocalanestheticsarenotmetabolizedtoPABAtheymaycontainaparaben
preservativethatcanbemetabolizedtoPABAlikecompounds.
▪Parabensaremethyl,ethyl,propyl,andbutylaliphaticestersofPABA.Inadditiontoparabens,
anestheticsmaybepreservedwithmetabisulfitesthatarealsoknowntocauseallergicreactionsin
sensitivepatients,especiallypatientswithasthma.Thus,patientsthatareallergictoestertypelocal
anestheticsshouldreceiveapreservativefreeamidetypeanesthetic.
▪PABAalsoblocksthemechanismofactionofthesulfonamideantibiotics.Sulfonamideantibioticsbind
toandinhibittheactionofthedihydropteroatesynthetaseenzyme,theenzymebacteriausedto
convertPABAtofolate.Thus,thereisatleastatheoreticalreasonnottouseaPABAforminganesthetic
inapatientbeingtreatedwithasulfonamideantibiotic
▪Tetracaineishydrolyzedtheslowestwhichmakesit16timesmoretoxicthanChloroprocainewhichis
hydrolyzedthefastestSlowerHydrolyzation=Toxicity

22. 3-Chloroprocaine:
▪The2chloridesubstitutiononthearomaticringofchloroprocaineisanelectronwithdrawingfunctionalgroup.
▪Thus,itpullstheelectrondensityfromthecarbonylcarbonintothering.Thecarbonylcarbonisnowastronger
electrophileandmoresusceptibletoesterhydrolysis.
▪Theinvitroplasmahalf-lifeisapproximately25seconds.The2-chloro-4-aminobenzoicacidmetabolite
precludesthisfrombeingusedinpatientsallergictoPABA.
▪Theveryshortdurationofactionmeansthatthisdrugcanbeusedinlargedosesforconductionblock(with
rapidonsetandshortdurationofaction.).
▪Aswithprocaine,adecreaseintheplasmacholinesteraseactivitywillprolongthehalf-life.
▪ChloroprocaineisformulatedwithapHbetween2.5and4.0usinghydrochloricacid.TheacidicpHofthe
formulationisresponsibleforconsiderableirritationandpainoninjection.
▪Chloroprocaineisusedforcutaneousormucousmembraneinfiltrationforsurgicalprocedures,epidural
anesthesia(withoutpreservatives)andforperipheralconductionblock.
Esters of Para amino benzoic acid:

23. Synthesis of Chloroprocaine
▪Thehydrochloridesaltof4-amino-2-chlorobenzoylchlorideismadebythereactionof2-chloro-4-
aminobenzoicacidwiththionylchloride.
▪Synthesisofthisdrugisthenaccomplishedbydirectlyreactingtheproductofthelaststepwiththe
hydrochloridesaltof2-diethylaminoethanol.
4-amino-2-chlorobenzoyl chloride

24. 4-Benzocaine:
▪Benzocaineisauniquelocalanestheticbecauseitdoesnotcontainatertiaryamine.
▪ThepKaofthearomaticamineis3.5ensuringthatbenzocaineisunchargedatphysiologicalpH.
Becauseitisuncharged,itisnotwatersoluble.
▪Theonsetofactioniswithin30secondsandthedurationofdrugactionis10to15minutes.
▪Benzocainewasfirstusedforlocalanesthesiaindentistry.
▪Benzocaineisusedforendoscopy,bronchoscopy,andtopicalanesthesia.
▪Toxicitytobenzocainecanoccurwhenthetopicaldoseexceeds200to300mgresultingin
methemoglobinemia.
▪Infantsandchildrenaremoresusceptibletothisandmethemoglobinemiahasbeenreportedafter
benzocainelubricationofendotrachealtubesandaftertopicaladministrationtotreatapainfuldiaper
rash.

25. Methemoglobinemia:
▪Cyanosisasaresultoftheformationofmethemoglobinemia
mayoccuraftertheadministrationofthelocalanesthetics
lidocaine,prilocaine,andbenzocaine.
▪Whennormalhemoglobinisoxidizedbyadrugordrug
metabolite,itformsmethemoglobin.
▪Methemoglobincontainstheoxidizedformofiron,ferriciron
(Fe3+)ratherthanthereducedferrousiron(Fe2+)that
hemoglobincontains.Theoxidizedironcannotbindtooxygen
andmethemoglobinemiaresultswhenthemethemoglobin
concentrationinthebloodreaches10to20g/L(6%–12%of
thenormalhemoglobinconcentration).
▪Patientswithincreasedriskfactorsfordevelopingdrug-
inducedmethemoglobinemiaincludechildrenyoungerthan2
years,anemicpatients,thosewithageneticdeficiencyof
glucose-6-phosphatedehydrogenaseornicotinamideadenine
dinucleotidemethemoglobinreductaseorthoseexposedto
excessivedosesofthecausativelocalanesthetic.
Mechanismssuggestedtounderlieprilocaine-andlidocaine-inducedMet-Hbformation.Two
metabolicpathwaysareproposed:thehydrolysispathway,whichismediatedbyCESandCYP2E1,
andthenonhydrolysispathway,whichismediatedbyCYP3A4.

26. Treatmentis an intravenous infusion of a 1% methylene blue solution, 1 mg/kg body weight, over 5 minutes

27. ▪CompoundAservesasaprodrugfortheanalgesicbenzocaine.(Aprodrugisapharmacologicallyinactive
compoundthatisconvertedinthebodytoanactivedrug,usuallybyametabolictransformation.)
▪TheenzymeamidasecatalyzesthehydrolysisofcompoundAintobenzocaine
Benzocaine with amino acid ( Prodrug)
▪Prodrugs increase water solubility
Amino acid

28. 5-Tetracaine
▪Tetracaine, also known as amethocaine, is a local anesthetic used to numb the eyes, nose, or
throat. It may also be applied to the skin before starting an intravenous to decrease pain from the
procedure.
▪Tetracaine is an ester local anesthetic currently available in combination with lidocaine as a
cream and patch.
❖Tetracaine is hydrolyzed the slowest which makes it 16
times more toxic than Chloroprocaine which is
hydrolyzed the fastest Slower Hydrolyzation = Toxicity

29. B-The Amino Amide Local Anesthetics
1-Lidocaine:
▪Lidocainewasthefirstaminoamidesynthesizedin1948andhasbecomethemostwidelyused
localanesthetic.ThetertiaryaminehasapKaof7.8anditisformulatedasthehydrochloride
saltwithapHbetween5.0and5.5.
▪WhenlidocaineisformulatedpremixedwithepinephrinethepHofthesolutionisadjustedto
between2.0and2.5topreventthehydrolysisoftheepinephrine.

30. Lidocaine HCl synthesis

31. ▪Themetabolismoflidocaineistypicaloftheamino
amide.Theliverisresponsibleformostofthe
metabolismoflidocaineandanydecreaseinliver
functionwilldecreasemetabolism.
▪Lidocaineisprimarilymetabolizedbyde-ethylationof
thetertiarynitrogentoformmonoethylglycinexylid-
ide(MEGX).
▪Toxicityincreasesinpatientswithliverdiseaseand
thosewithacidosis,whichdecreasesplasmaprotein
bindingoflidocaine.
▪CNStoxicityislowwithseizureactivityreportedwith
highdoses.
▪Thecardiactoxicityoflidocaineismanifestedby
bradycardia,hypotension,andcardiovascular
collapse,whichmayleadtocardiacarrestanddeath.
▪Cimetidinereduceslidocaineclearance,andcanthus
increaseitstoxicity.
Lidocaine Metabolism

32. 2-Etidocaine:
▪Etidocainediffersfromlidocainebytheadditionofanalkylchainandtheextensionofoneethylgroupon
thetertiaryaminetoabutylgroup.
▪Theadditionallipophilicitygivesetidocaineaquickeronset,longerhalf-life,andanincreasedpotency
comparedwithlidocaine.
▪Etidocaine is metabolized rapidly by the liver, and metabolites and unchanged drug are excreted by the kidney.
▪Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation.
▪To date, approximately 20 metabolites of etidocaine have been found in the urine

33. 3-Prilocaine:
▪Prilocainehydrochlorideisawater-solublesaltavailableasasolutionfornerveblockorinfiltrationindental
procedures.
▪PrilocaineisusedforintravenousregionalanesthesiatheriskofCNStoxicityislowbecauseofthequick
metabolism.
▪Themetabolismofprilocaineintheliveryieldso-toluidine,whichisapossiblecarcinogen.
▪Manyaromaticamines,includingo-toluidinehavebeenshowntobemutagenic,andmetabolitesofo-
toluidinehavebeenshowntoformDNAadducts.Metabolitesofo-toluidinearealsobelievedtobe
responsibleforthemethemoglobinemiaobservedwithprilocaineuse.

34. 4-Mepivacaine:
▪Mepivacainehydrochlorideisavailablein1%to3%solutionsandisindicatedforinfiltration
anesthesia,dentalprocedures,peripheralnerveblock,orepiduralblock.
▪Theonsetofanesthesiaisrapid,rangingfromabout3to20minutesforsensoryblock.
▪Mepivacaineisrapidlymetabolizedintheliverwith50%oftheadministereddoseexcreted
intothebileasmetabolites.
▪TheprimarymetabolicproductsaretheN-demethylatedmetaboliteandthe3and4phenolic
metabolitesexcretedastheirglucuronideconjugates.
Mepivacaine Metabolism

35. 5-Bupivacaine (Marcaine ) and Levobuvacaine:
▪Whenthemethylonthecyclicamineofmepivacaineisexchangedforabutylgroupthelipophilicity,
potencyandthedurationofactionallincrease.Literaturereportsofcardiovasculartoxicity,includingsevere
hypotensionandbradycardia.
▪Itisamedicationusedtodecreasefeelinginaspecificarea.
▪Innerveblocks,itisinjectedaroundanervethatsuppliesthearea,orintothespinalcanal'sepiduralspace.
Itisavailablemixedwithasmallamountofepinephrinetoincreasethedurationofitsaction.
▪Ittypicallybeginsworkingwithin15minutesandlastsfor2to8hours
▪Thecardiotoxicityofbupivacaineisaresultofitsaffinitytocardiactissuesanditsabilitytodepresselectrical
conductionandpredisposethehearttoreentrytypesofarrhythmias.

36. ▪Levobupivacaineisthepure“S”enantiomerofbupivacaineandinvivoandinvitrostudiesconfirmthat
itdoesnotundergometabolicinversiontoR(+)bupivacaine.
▪LevobupivacainehaslowerCNSandcardiotoxicitythanbupivacainealthoughunintendedintravenous
injectionwhenperformingnerveblocksmayresultintoxicity.
▪Racemicbupivacaineismetabolizedextensivelywithnounchangeddrugfoundintheurineorfeces.
LiverenzymesincludingtheCYP3A4andCYP1A2isoformsareresponsibleforN-dealkylationand3-
hydroxylationoflevobupivacainefollowedbyglucuronidationorsulfation.
➢Levobupivacaine

37. 6-Ropivacaine:
▪Ropivacaineisalong-actingamide-typelocalanestheticwithinherentvasoconstrictoractivities.
▪Therecognizedincreaseincardiotoxicityofonebupivacaineisomerledtothestereospecificproduction
ofropivacaineasthesingle“S”(-)enantiomer.
▪Ropivacaineisthepropylanalogofmepivacaine(methyl)andbupivacaine(butyl).ThepKaofthetertiary
nitrogenis8.1.
▪Theshortenedalkylchaingivesitapproximatelyonethirdofthelipidsolubilityofbupivacaine.
▪Animalstudieshaveshownthatropivacainedissociatesfromcardiacsodiumchannelsmorerapidlythan
bupivacaine.Thisdecreasesthesodiumchannelblockintheheartandmayberesponsibleforthe
reducedcardiotoxicityofropivacaine.

38. ▪Dibucaineisaquinolinederivativeandaminoamidewithanestheticactivity.
▪Amongthemostpotentandtoxicofthelong-actinglocalanesthetics,currentuseofcinchocaineis
generallyrestrictedtospinalandtopicalanesthesia.
▪Dibucainetopical(fortheskin)isusedtotreatminorpainanditchingcausedbyminorcutsorburns,insect
bitesorstings,sunburn,orotherskinirritations.
7-Dibucaine(Cinchocaine)

39. C –The Ether Local Anesthetics :
➢Pramoxine
▪Pramoxineisatopicalanestheticusedontheskintorelieveminorpain,itching,anddiscomfort(usedasan
antipruritic).
▪Pramoxineisusedtotemporarilyrelievepainanditchingfrominsectbitesandpoisonivy

40. D-The Ketone Local Anesthetics:
➢Dyclonine
▪DyclonineHClTopicalSolution,USPisindicatedforanesthetizingaccessiblemucousmembranes(e.g.,the
mouth,pharynx,larynx,trachea,esophagus,andurethra)priortovariousendoscopicprocedures
▪ItisalsofoundinsomevarietiesoftheCepacolsorethroatspray.
▪Itisalocalanesthetic,usedtopicallyasthehydrochloridesalt

41. ✓What is the advantage of bicarbonate added to lidocaine?