Local anesthetics 2024/ Medicinal Chemistry pdf

Medicinal Chemistry

1. LocalAnesthetics
Medicinal Chemistry III/ 4
th
stage / 1
st semester
Lecture7
Dr.Narmin HamaaminHussen
2023-2024
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2. Localanesthetics
•Localanesthetics(LAs)aredrugsthatareusedtopreventorrelievepaininspecific
regionsofthebodywithoutlossofconsciousness.Theyactbyreversiblyblocking
nerveconduction.
• Local anesthesia numbs just a small area of tissue where a minor procedure is to be
done.
•Regionalanesthesianumbsoneregionofyourbody.Theanesthesiamaybegiven
aroundnervesorintoveinsinyourarms,neck,orlegs(nerveblockorBierblock).
•Oritmaybesentintothespinalfluid(spinalanesthesia)orintothespacejustoutside
thespinalfluid(epiduralanesthesia).Youmayalsobegivensedativestohelpyourelax.
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3. Mechanism of action of localanesthetics:
▪Local anesthetics act primarily by inhibiting the voltage-gated sodium channels on the neuronal
membrane and thus block peripheral nerveconduction.
▪Whenthelocalanestheticbinds,itblockssodiumionpassageintothecellandthusblocksthe
formation and propagation of the actionpotential.
▪This blocks the transmittance of the message of “pain” or even “touch” from getting to thebrain.
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4. Mechanism of action
To be effective, LAs need to:
1. Diffuse from site of administration, across the nerve cell membrane to the intracellular side
2. Bind to the LA target site
Their ability to do this is related to their chemical structure
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5. Classification of local anesthetics drugs according tochemistry
EsterGroupAmideGroup
Cocaine Lidocaine
Procaine Etidocaine
Choroprocaine Bupivacaine
Tetracaine Dibucaine
Benzocaine Prilocaine
Ropivacaine
Mepivacaine
EtherGroupKetoneGroup
Pramoxine Dyclonine
Ether Ketone
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6. BasicStructure of Local anesthetics
Hydrophilic group Lipophilic group
Ester LA
Amide LA
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8. 1.TheAromaticRing(Lipophilicgroup)
▪Thearomaticringaddslipophilicitytotheanestheticandhelpsthemoleculepenetratethroughbiological
membranes.
SARs of LocalAnesthetics
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9. 9
▪Substituents on the aromatic ring may increase the lipophilic nature of the aromatic ring.
▪ An SAR study of para substituted ester type local anesthetics showed that lipophilic substituents and
electron-donating substituents in the para position increased anesthetic activity.
▪Presence of electron withdrawing group in ortho or para (not meta) position decreases Lipophilicity but still
increases activity for only ester group .

10. ▪Presence of e-withdrawing halogens in ortho position only can decrease duration of action by
making the ester more Likely for a nucleophilicattack
▪Chlorine in ortho group makes the carbonyl carbon more positive and more likely to be attacked by
nucleophiles that causes breakdown of compound.
▪They attack atoms with positive charges. More positive the atom, the better theattack.
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11. Exceptional with thiophenering
➢Articaine
▪It is the only local anaesthetic to contain a thiophene ring, meaning it can be describedas
'thiophenic'; this conveys lipidsolubility.
▪Articaine has a thiophene ring, which confers greater lipid solubility than aromatic ring
▪Articaine is lipid soluble has a dissociation constant (pKa) of 7.8
▪Articaine is an intermediate-potency, short-acting amide local anesthetic with a fast
metabolism due to an ester group in its structure
▪Its thiophene ring contains a sulfur atom, which has no immunogenic property, and an ester
side chain that renders the compound inactive after hydrolysis
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12. 2. TheLinker
▪Thelinkerisusuallyanesteroranamidegroupalongwith
ahydrophobicchainofvariouslengths.
▪Ingeneral,whenthenumberofcarbonatomsinthelinker
isincreased,thelipidsolubility,proteinbinding,duration
ofactionandtoxicityincreases.
▪Estersandaminoamidesdifferinmetabolism,stability
andadverseeffects
Procaine
Chloroprocaine
Tetracaine
Lidocaine
Etidocaine
Prilocaine
Mepivacaine
Bupivacaine
Levobuvicane
Ropivacaine
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13. 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 bodyenzymes
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CH3 groups make it difficult to hydrolyze, thus it is Stable in water and blood
Sufficient duration of action
No protection against hydrolysis by disubstituted group. Thus unstable in water and blood .
Not enough duration of action

14. 3. The Nitrogen(Hydrophilic)
▪Useful LA have a secondary or tertiary amine group.
▪This is important because it is believed that when they enter the cell, they will accept a proton and
form positively charged quaternary form which is needed for binding to voltage gated ionchannels.
•Procaine believed to bind to it’s receptor when the amine group is positively charge quaternary form
▪To keep the anesthetic soluble in commercial solutions, most preparations areacidified.
▪In an attempt to decrease pain on injection and to increase the onset of action, some practitioners
advocate adding sodium bicarbonate to the commercialpreparation.
▪By adding sodium bicarbonate, the solution will become less acidic and more of the drug will be
found in the neutralform.
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15. Exceptional withbenzocaine
▪However, benzocaine has no amine portion but is still an effective topical LA.
▪Thus the use of Amine part could only be for proper water solubility and not directly related to
properbinding
▪Its nonionized base under normal physiologic conditions
Benzocaine has no amine but is still effectiveLA
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16. Differences between Ester and Amide group
1.Acid Dissociation constant (pKa)
2.Onset of action
3.Chemical stability
4.Hypersensitivity
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17. Acid Dissociation constant (pKa)
Ester LA 8.5-9.0 Tetracaine = 8.5, Chlorprocaine = 9.0
Amide LA 7.6-8.1 Mepivacaine = 7.6, Ropivacaine = 8.1
ppH= 7.4
Nearer to pH
pEasily absorbed
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18. pH and pKaRelationship
Local anesthetics Weak base
Henderson–Hasselbalch equation
pH ≈pKa pH < pKa
[ base ] ≈[ salt ] [ base ] < [ salt ]
50% ionization More ionization
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19. Ester LA pH= 7.4 Amide LA
8.5-9.0 PKa 7.6-8.1
More ionization 50% ionization
Less lipophilic More lipophilic
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20. Onset of action
Onset of action
Drug transport across the membrane
Depends on pKa
BH+
B
X
B
Ester Amide
Less lipophilic More lipophilic
More ionization Less ionization

Fast onset action
Slow onset action
Ester LA Fast Amide LA
Tetracaine 8.5 Mepivacaine 7.6
Cocaine 8.7 Lidocaine 7.8
Procaine 8.9 Prilocaine 7.9
Chlorprocaine 9.0 Ropivacaine 8.1
Slow Bupivacaine 8.1
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21. Chemical stability
Ester Amide
Plasma
esterases
Less stable
Liver
More stable
Stable in heat
Stable in light
X
X
X
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22. Hypersensitivity
Immunogenic
Hypersensitivity
Sulfonamides
Allergic reaction
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23. Allergic reactions to PABA metabolism (Para aminobenzoic Acid)
▪Allergies to the ester anesthetics are more common than allergies to the amide anesthetics. As
discussed, the ester anesthetics may be metabolized to PABA, which is believed to be responsible for
the allergicreactions.
▪Although the amide type local anesthetics are not metabolized to PABA
▪PABAalsoblocksthemechanismofactionofthesulfonamideantibiotics.Sulfonamideantibioticsbindtoand
inhibittheactionofthedihydropteroatesynthetaseenzyme,theenzymebacteriausedtoconvertPABAto
folate.Thus,thereisatleastatheoreticalreasonnottouseaPABAforminganestheticinapatientbeing
treatedwithasulfonamideantibiotic
▪Tetracaineishydrolyzedtheslowestwhichmakesit16timesmoretoxicthanChloroprocainewhichis
hydrolyzedthefastest.
▪SlowerHydrolyzation=Toxicity
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24. ▪The 2-chloro-4-aminobenzoic acid metabolite precludes this from being used in patients allergic toPABA.
▪The very short duration of action means that this drug can be used in large doses for conduction block
Chloroprocaine:
▪The 2 chloride substitution on the aromatic ring of chloroprocaine is an electron withdrawing functionalgroup.
▪Thus, it pulls the electron density from the carbonyl carbon into the ring. The carbonyl carbon is now a stronger
electrophile and more susceptible to esterhydrolysis.
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Esters Local Anesthetics

25. Benzocaine:
▪Benzocaine is a unique local anesthetic because it does not contain a tertiaryamine.
▪The pKaof the aromatic amine is 3.5 ensuring that benzocaine is uncharged at physiologicalpH.
Because it is uncharged, it is not watersoluble.
▪Toxicitytobenzocainecanoccurwhenthetopicaldoseexceeds200to300mgresultingin
methemoglobinemia.
▪Infantsandchildrenaremoresusceptibletothisandmethemoglobinemiahasbeenreportedafter
benzocainelubricationofendotrachealtubesandaftertopicaladministration
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26. 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

27. Treatment is an intravenous infusion of a 1% methylene blue solution, 1 mg/kg body weight, over 5minutes
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28. Tetracaine
▪Tetracaine is an ester local anesthetic currently available in combination with lidocaine as a
cream andpatch.
▪Tetracaine is hydrolyzed the slowest which makes it 16
times more toxic than Chloroprocaine which is
hydrolyzed the fastest
▪Slower Hydrolyzation =Toxicity
▪Severe toxic reactions following tetracaine overdose
include convulsions and respiratory arrest
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29. Amide LocalAnesthetics
Lidocaine:
▪Lidocainewasthefirstaminoamidesynthesizedin1948andhasbecomethemostwidelyused
localanesthetic.
▪Etidocaine differs from lidocaine by the addition of an alkyl chain and the extension of one ethyl group on
the tertiary amine to a butyl group.
▪The additional lipophilicity gives etidocaine a quicker onset, longer half-life, and an increased potency
compared with lidocaine
▪ PKa of etidocaine is 7.74
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30. Prilocaine:
▪Prilocaine is used for intravenous regional anesthesia the risk of CNS toxicity is low because of the quick
metabolism.
▪The metabolism of prilocaine in the liver yields o-toluidine, which is a possiblecarcinogen.
▪Manyaromaticamines,includingo-toluidinehavebeenshowntobemutagenic,andmetabolitesofo-
toluidinehavebeenshowntoformDNAadducts.
▪Metabolitesofo-toluidinearealsobelievedtoberesponsibleforthemethemoglobinemiaobservedwith
prilocaineuse.
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32. Mepivacaine (Carbocaine), Bupivacaine(Marcaine)andLevobuvacaine:
▪Whenthemethylonthecyclicamineofmepivacaineisexchangedforabutylgroupthelipophilicity,potency
andthedurationofactionallincrease.
▪Innerveblocks,itisinjectedaroundanervethatsuppliesthearea,orintothespinalcanal'sepiduralspace.
Itisavailablemixedwithasmallamountofepinephrinetoincreasethedurationofitsaction.
▪Ittypicallybeginsworkingwithin15minutesandlastsfor2to8hours
▪Literature reports of cardiovascular toxicity, including severe hypotension and bradycardia.
▪Thecardiotoxicityofbupivacaineisaresultofitsaffinitytocardiactissuesanditsabilitytodepresselectrical
conductionandpredisposethehearttoreentrytypesofarrhythmias.
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Change methyl to butyl ---- increase lipophilicity---potency ----duration of action

33. ➢Levobupivacaine
▪Levobupivacaineisthepure“S”enantiomerofbupivacaineandinvivoandinvitrostudiesconfirmthat
itdoesnotundergometabolicinversiontoR(+)bupivacaine.
▪LevobupivacainehaslowerCNSandcardiotoxicitythanbupivacainealthoughunintendedintravenous
injectionwhenperformingnerveblocksmayresultintoxicity.
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34. Ropivacaine:
▪Ropivacaine is the propyl analog of mepivacaine (methyl) and bupivacaine (butyl). The pKaof the tertiary
nitrogen is8.1.
▪The shortened alkyl chain gives it approximately one third of the lipid solubility ofbupivacaine.
▪Animalstudieshaveshownthatropivacainedissociatesfromcardiacsodiumchannelsmorerapidlythan
bupivacaine.Thisdecreasesthesodiumchannelblockintheheartandmayberesponsibleforthereduced
cardiotoxicityofropivacaine.
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