Local anesthetics-Medicinal Chemistry Dr.Narmin Hamaamin Hussen

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

2. Local anesthetics
• Local anesthetics (LA) are drugs that are used to prevent or
relieve pain in specific regions of the body without loss of
consciousness. They act by reversibly blocking nerve
conduction.
• Regional anesthesia numbs one region of your body. The
anesthesia may be given around nerves or into veins in your
arms, neck, or legs (nerve block or Bier block).
• Or it may be sent into the spinal fluid (spinal anesthesia)
or into the space just outside the spinal fluid (epidural
anesthesia). You may also be given sedatives to help you
relax.
• Local anesthesia numbs just a small area of tissue where a
minor procedure is to be done.

3. Mechanism of action of local anesthetics:
▪ Local anesthetics act primarily by inhibiting the voltage-gated sodium channels on the neuronal
membrane and thus block peripheral nerve conduction.
▪ When the local anesthetic binds, it blocks sodium ion passage into the cell and thus blocks the
formation and propagation of the action potential.
▪ This blocks the transmittance of the message of “pain” or even “touch” from getting to the brain.

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. Classification of local anesthetics drugs according to chemistry
Ester Group Amide Group
Cocaine Lidocaine
Procaine Etidocaine
Choroprocaine Bupivacaine
Tetracaine Dibucaine
Benzocaine Prilocaine
Ropivacaine
Mepivacaine
Ether Group Ketone Group
Pramoxine Dyclonine
Ether Ketone

6. Classification according to duration of action
Soluble:Cocaine,Lidocaine
and Tetracaine
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. SARs of Local Anesthetics
Basic Structure

9. 1. The Aromatic Ring(Lipophilic group)
▪ The aromatic ring adds lipophilicity to the anesthetic
and helps the molecule penetrate through biological
membranes.
▪ 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 nucleophilic attack
▪ Chlorine in ortho group makes the carbonyl carbon more positive and more likely to be attacked by
nucleophiles that causes breakdown of compound. Nucleophiles contain a lone pair of electron.
▪ They attack atoms with positive charges. More positive the atom, the better the attack.

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
❖ Articaine is quickly metabolized via hydrolysis into its
inactive metabolite articainic acid, which is partly
metabolized in the kidney into articainic acid
glucuronide

13. 2. The Linker
▪ The linker is usually an ester or an amide group along with a
hydrophobic chain of various lengths.
▪ In general, when the number of carbon atoms in the linker is
increased, the lipid solubility, protein binding, duration of action and
toxicity increases.
▪ Esters and amino amides differ in metabolism, stability and adverse
effects :
Ester group:
➢ Metabolized in the serum by esterases
➢ Have a higher risk of causing allergic reactions or systemic toxicity
Amide group
➢ Metabolized in the liver
➢ Safer than the ester agents
➢ Should be used when patients are allergic to esters
➢ Amides are more stable than esters and thus have longer half-lives
than esters.
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)
▪ 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 ion channels.
• 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 are acidified.
▪ In an attempt to decrease pain on injection and to increase the onset of action, some practitioners
advocate adding sodium bicarbonate to the commercial preparation.
▪ By adding sodium bicarbonate, the solution will become less acidic and more of the drug will be
found in the neutral form.

16. Exceptional with benzocaine
▪ 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
proper binding
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:
▪ Cocaine was the first agent used for topical anesthesia.
▪ In 1884, a German surgeon demonstrated the successful use of cocaine to
anesthetize the cornea during eye surgery.
▪ Today, cocaine is used for topical anesthesia of mucous membranes using a 4% to
10% solution. If the solution remains on the membrane for 5 minutes, anesthesia
and vasoconstriction of the area will occur.
▪ Toxic manifestations include excitation, dysphoria, tremor, seizure activity,
hypertension, tachycardia, myocardial ischemia, and infarction.
▪ When cocaine was compared with lidocaine/phenylephrine for nasal intubations,
the results were the same with less toxicity in the lidocaine/phenylephrine group.

18. 2-Procaine:
▪ The pKa of procaine is 8.9; it has low lipid solubility and the ester group is unstable in basic solutions.
▪ Procaine is available in concentrations ranging from 0.25% to 10% with pHs adjusted to 5.5 to 6.0 for
chemical stability.
▪ Procaine is also included in some formulations of penicillin G to decrease the pain of intramuscular
injection.
▪ Procaine is not used topically because of its inability to pass through lipid membranes and finds use as an
infiltration agent for cutaneous or mucous membranes, for short procedures.
▪ Procaine is also used for peripheral nerve block and as an epidural agent to diagnose pain syndromes
Esters of Para amino benzoic acid:

19. Metabolism:
▪ Procaine is very quickly metabolized in the plasma by cholinesterase and in the liver via ester hydrolysis by a
pseudocholinesterase.
▪ The paraaminobenzoic acid (PABA) metabolite, common to the ester class of drugs, is believed to be
responsible for the allergic reactions some patients have experienced with local anesthetics.

20. Synthesis of Procaine HCl
❖ The direct reaction of the 4-
aminobenzoic acid ethyl ester
with 2-diethylaminoethanol in
the presence of sulfuric acid.

21. Allergic reactions to PABA Metabolism (ParaAminoBenzoic Acid)
Ester Local Anesthetics
▪ 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 allergic reactions.
▪ Although the amide type local anesthetics are not metabolized to PABA they may contain a paraben
preservative that can be metabolized to PABA like compounds.
▪ Parabens are methyl, ethyl, propyl, and butyl aliphatic esters of PABA. In addition to parabens,
anesthetics may be preserved with metabisulfites that are also known to cause allergic reactions in
sensitive patients, especially patients with asthma. Thus, patients that are allergic to ester type local
anesthetics should receive a preservative free amide type anesthetic.
▪ PABA also blocks the mechanism of action of the sulfonamide antibiotics. Sulfonamide antibiotics bind
to and inhibit the action of the dihydropteroate synthetase enzyme, the enzyme bacteria used to
convert PABA to folate. Thus, there is at least a theoretical reason not to use a PABA forming anesthetic
in a patient being treated with a sulfonamide antibiotic
▪ Tetracaine is hydrolyzed the slowest which makes it 16 times more toxic than Chloroprocaine which is
hydrolyzed the fastest Slower Hydrolyzation = Toxicity

22. 3-Chloroprocaine:
▪ The 2 chloride substitution on the aromatic ring of chloroprocaine is an electron withdrawing functional group.
▪ 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 ester hydrolysis.
▪ The in vitro plasma half-life is approximately 25 seconds. The 2-chloro-4- aminobenzoic acid metabolite
precludes this from being used in patients allergic to PABA.
▪ The very short duration of action means that this drug can be used in large doses for conduction block (with
rapid onset and short duration of action.).
▪ As with procaine, a decrease in the plasma cholinesterase activity will prolong the half-life.
▪ Chloroprocaine is formulated with a pH between 2.5 and 4.0 using hydrochloric acid. The acidic pH of the
formulation is responsible for considerable irritation and pain on injection.
▪ Chloroprocaine is used for cutaneous or mucous membrane infiltration for surgical procedures, epidural
anesthesia (without preservatives) and for peripheral conduction block.
Esters of Para amino benzoic acid:

23. Synthesis of Chloroprocaine
▪ The hydrochloride salt of 4-amino-2-chlorobenzoyl chloride is made by the reaction of 2-chloro-4-
aminobenzoic acid with thionyl chloride.
▪ Synthesis of this drug is then accomplished by directly reacting the product of the last step with the
hydrochloride salt of 2-diethylaminoethanol.
4-amino-2-chlorobenzoyl chloride

24. 4-Benzocaine:
▪ Benzocaine is a unique local anesthetic because it does not contain a tertiary amine.
▪ The pKa of the aromatic amine is 3.5 ensuring that benzocaine is uncharged at physiological pH.
Because it is uncharged, it is not water soluble.
▪ The onset of action is within 30 seconds and the duration of drug action is 10 to 15 minutes.
▪ Benzocaine was first used for local anesthesia in dentistry.
▪ Benzocaine is used for endoscopy, bronchoscopy, and topical anesthesia.
▪ Toxicity to benzocaine can occur when the topical dose exceeds 200 to 300 mg resulting in
methemoglobinemia.
▪ Infants and children are more susceptible to this and methemoglobinemia has been reported after
benzocaine lubrication of endotracheal tubes and after topical administration to treat a painful diaper
rash.

25. Methemoglobinemia:
▪ Cyanosis as a result of the formation of methemoglobinemia
may occur after the administration of the local anesthetics
lidocaine, prilocaine, and benzocaine.
▪ When normal hemoglobin is oxidized by a drug or drug
metabolite, it forms methemoglobin.
▪ Methemoglobin contains the oxidized form of iron, ferric iron
(Fe3+) rather than the reduced ferrous iron (Fe2+) that
hemoglobin contains. The oxidized iron cannot bind to oxygen
and methemoglobinemia results when the methemoglobin
concentration in the blood reaches 10 to20 g/L (6%–12% of
the normal hemoglobin concentration).
▪ Patients with increased risk factors for developing drug-
induced methemoglobinemia include children younger than 2
years, anemic patients, those with a genetic deficiency of
glucose-6-phosphate dehydrogenase or nicotinamide adenine
dinucleotide methemoglobin reductase or those exposed to
excessive doses of the causative local anesthetic.
Mechanisms suggested to underlie prilocaine-and lidocaine-induced Met-Hb formation. Two
metabolic pathways are proposed: the hydrolysis pathway, which is mediated by CES and CYP2E1,
and the nonhydrolysis pathway, which is mediated by CYP3A4.

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

27. ▪ Compound A serves as a prodrug for the analgesic benzocaine. (A prodrug is a pharmacologically inactive
compound that is converted in the body to an active drug, usually by a metabolic transformation.)
▪ The enzyme amidase catalyzes the hydrolysis of compound A into benzocaine
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:
▪ Lidocaine was the first amino amide synthesized in 1948 and has become the most widely used
local anesthetic. The tertiary amine has a pKa of 7.8 and it is formulated as the hydrochloride
salt with a pH between 5.0 and 5.5.
▪ When lidocaine is formulated premixed with epinephrine the pH of the solution is adjusted to
between 2.0 and 2.5 to prevent the hydrolysis of the epinephrine.

30. Lidocaine HCl synthesis

31. ▪ The metabolism of lidocaine is typical of the amino
amide. The liver is responsible for most of the
metabolism of lidocaine and any decrease in liver
function will decrease metabolism.
▪ Lidocaine is primarily metabolized by de-ethylation of
the tertiary nitrogen to form monoethylglycinexylid-
ide (MEGX).
▪ Toxicity increases in patients with liver disease and
those with acidosis, which decreases plasma protein
binding of lidocaine.
▪ CNS toxicity is low with seizure activity reported with
high doses.
▪ The cardiac toxicity of lidocaine is manifested by
bradycardia, hypotension, and cardiovascular
collapse, which may lead to cardiac arrest and death.
▪ Cimetidine reduces lidocaine clearance, and can thus
increase its toxicity.
Lidocaine Metabolism

32. 2-Etidocaine:
▪ 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.
▪ 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:
▪ Prilocaine hydrochloride is a water-soluble salt available as a solution for nerve block or infiltration in dental
procedures.
▪ 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 possible carcinogen.
▪ Many aromatic amines, including o-toluidine have been shown to be mutagenic, and metabolites of o-
toluidine have been shown to form DNA adducts. Metabolites of o-toluidine are also believed to be
responsible for the methemoglobinemia observed with prilocaine use.

34. 4-Mepivacaine:
▪ Mepivacaine hydrochloride is available in 1% to 3% solutions and is indicated for infiltration
anesthesia, dental procedures, peripheral nerve block, or epidural block.
▪ The onset of anesthesia is rapid, ranging from about 3 to 20 minutes for sensory block.
▪ Mepivacaine is rapidly metabolized in the liver with 50% of the administered dose excreted
into the bile as metabolites.
▪ The primary metabolic products are the N-demethylated metabolite and the 3 and 4 phenolic
metabolites excreted as their glucuronide conjugates.
Mepivacaine Metabolism

35. 5-Bupivacaine (Marcaine ) and Levobuvacaine:
▪ When the methyl on the cyclic amine of mepivacaine is exchanged for a butyl group the lipophilicity,
potency and the duration of action all increase. Literature reports of cardiovascular toxicity, including severe
hypotension and bradycardia.
▪ It is a medication used to decrease feeling in a specific area.
▪ In nerve blocks, it is injected around a nerve that supplies the area, or into the spinal canal's epidural space.
It is available mixed with a small amount of epinephrine to increase the duration of its action.
▪ It typically begins working within 15 minutes and lasts for 2 to 8 hours
▪ The cardiotoxicity of bupivacaine is a result of its affinity to cardiac tissues and its ability to depress electrical
conduction and predispose the heart to reentry types of arrhythmias.

36. ▪ Levobupivacaine is the pure “S” enantiomer of bupivacaine and in vivo and in vitro studies confirm that
it does not undergo metabolic inversion to R(+) bupivacaine.
▪ Levobupivacaine has lower CNS and cardiotoxicity than bupivacaine although unintended intravenous
injection when performing nerve blocks may result in toxicity.
▪ Racemic bupivacaine is metabolized extensively with no unchanged drug found in the urine or feces.
Liver enzymes including the CYP3A4 and CYP1A2 isoforms are responsible for N-dealkylation and 3-
hydroxylation of levobupivacaine followed by glucuronidation or sulfation.
➢ Levobupivacaine

37. 6-Ropivacaine:
▪ Ropivacaine is a long-acting amide-type local anesthetic with inherent vasoconstrictor activities.
▪ The recognized increase in cardiotoxicity of one bupivacaine isomer led to the stereospecific production
of ropivacaine as the single “S” (-) enantiomer.
▪ Ropivacaine is the propyl analog of mepivacaine (methyl) and bupivacaine (butyl). The pKa of the tertiary
nitrogen is 8.1.
▪ The shortened alkyl chain gives it approximately one third of the lipid solubility of bupivacaine.
▪ Animal studies have shown that ropivacaine dissociates from cardiac sodium channels more rapidly than
bupivacaine. This decreases the sodium channel block in the heart and may be responsible for the
reduced cardiotoxicity of ropivacaine.

38. ▪ Dibucaine is a quinoline derivative and amino amide with anesthetic activity.
▪ Among the most potent and toxic of the long-acting local anesthetics, current use of cinchocaine is
generally restricted to spinal and topical anesthesia.
▪ Dibucaine topical (for the skin) is used to treat minor pain and itching caused by minor cuts or burns, insect
bites or stings, sunburn, or other skin irritations.
7- Dibucaine(Cinchocaine)

39. C – The Ether Local Anesthetics :
➢ Pramoxine
▪ Pramoxine is a topical anesthetic used on the skin to relieve minor pain, itching, and discomfort(used as an
antipruritic).
▪ Pramoxine is used to temporarily relieve pain and itching from insect bites and poison ivy

40. D- The Ketone Local Anesthetics:
➢ Dyclonine
▪ Dyclonine HCl Topical Solution, USP is indicated for anesthetizing accessible mucous membranes (e.g., the
mouth, pharynx, larynx, trachea, esophagus, and urethra) prior to various endoscopic procedures
▪ It is also found in some varieties of the Cepacol sore throat spray.
▪ It is a local anesthetic, used topically as the hydrochloride salt

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