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LocalAnesthetics
Medicinal Chemistry III/ 4th stage / 1st semester
Lecture 7
Dr.Narmin Hamaamin Hussen
2023-2024
1
Localanesthetics
• Local anesthetics (LAs) 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.
• Local anesthesia numbs just a small area of tissue where a minor procedure is to be
done.
• 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.
2
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.
3
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
4
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
5
Basic Structure of Local anesthetics
Hydrophilic group
Lipophilic group
Ester LA
Amide LA
6
7
1. The Aromatic Ring(Lipophilic group)
▪ The aromatic ring adds lipophilicity to the anesthetic and helps the molecule penetrate through biological
membranes.
SARs of Local Anesthetics
8
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 .
▪ 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.
▪ They attack atoms with positive charges. More positive the atom, the better the attack.
10
Exceptional with thiophene ring
➢Articaine
▪ It is the only local anaesthetic to contain a thiophene ring, meaning it can be described as
'thiophenic'; this conveys lipid solubility.
▪ 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
11
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
Procaine
Chloroprocaine
Tetracaine
Lidocaine
Etidocaine
Prilocaine
Mepivacaine
Bupivacaine
Levobuvicane
Ropivacaine
12
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
13
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
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
▪ Tokeep 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.
14
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
▪ Its nonionized base under normal physiologic conditions
Benzocaine has no amine but is still effective LA
15
Differences between Ester and Amide group
1. Acid Dissociation constant (pKa)
2. Onset of action
3. Chemical stability
4. Hypersensitivity
16
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
p
pH= 7.4
Nearer to pH
p
Easily absorbed
17
pH and pKa Relationship
Local anesthetics Weak base
Henderson–Hasselbalch equation
pH ≈ pKa pH < pKa
[ base ] ≈ [ salt ] [ base ] < [ salt ]
50% ionization More ionization
18
Ester LA pH= 7.4 Amide LA
8.5-9.0 PKa 7.6-8.1
More ionization 50% ionization
Less lipophilic More lipophilic
19
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
20
Chemical stability
Ester Amide
Plasma
esterases
Less stable
Liver
More stable
Stable in heat
Stable in light
X
X
X
21
Hypersensitivity
Immunogenic
Hypersensitivity
Sulfonamides
Allergic reaction
22
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 believedto be responsible for
the allergic reactions.
▪ Although the amide type local anesthetics are not metabolized to PABA
▪ 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
23
▪ 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
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.
24
Esters Local Anesthetics
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.
▪ 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
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
Tetracaine
▪ 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
▪ Severe toxic reactions following tetracaine overdose
include convulsions and respiratory arrest
28
Amide Local Anesthetics
Lidocaine:
▪ Lidocaine was the first amino amide synthesized in 1948 and has become the most widely used
local anesthetic.
▪ 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
29
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 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.
30
31
Mepivacaine (Carbocaine), 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.
▪ 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
▪ Literature reports of cardiovascular toxicity, including severe hypotension and bradycardia.
▪ 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.
32
Change methyl to butyl ---- increase lipophilicity---potency ----duration of action
➢ Levobupivacaine
▪ 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.
33
Ropivacaine:
▪ 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.
34
35

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Local anesthetics 2024/ Medicinal Chemistry pdf

  • 1. LocalAnesthetics Medicinal Chemistry III/ 4th stage / 1st semester Lecture 7 Dr.Narmin Hamaamin Hussen 2023-2024 1
  • 2. Localanesthetics • Local anesthetics (LAs) 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. • Local anesthesia numbs just a small area of tissue where a minor procedure is to be done. • 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. 2
  • 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. 3
  • 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 4
  • 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 5
  • 6. Basic Structure of Local anesthetics Hydrophilic group Lipophilic group Ester LA Amide LA 6
  • 7. 7
  • 8. 1. The Aromatic Ring(Lipophilic group) ▪ The aromatic ring adds lipophilicity to the anesthetic and helps the molecule penetrate through biological membranes. SARs of Local Anesthetics 8
  • 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 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. ▪ They attack atoms with positive charges. More positive the atom, the better the attack. 10
  • 11. Exceptional with thiophene ring ➢Articaine ▪ It is the only local anaesthetic to contain a thiophene ring, meaning it can be described as 'thiophenic'; this conveys lipid solubility. ▪ 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 11
  • 12. 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 Procaine Chloroprocaine Tetracaine Lidocaine Etidocaine Prilocaine Mepivacaine Bupivacaine Levobuvicane Ropivacaine 12
  • 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 body enzymes 13 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 ion channels. • Procaine believed to bind to it’s receptor when the amine group is positively charge quaternary form ▪ Tokeep 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. 14
  • 15. 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 ▪ Its nonionized base under normal physiologic conditions Benzocaine has no amine but is still effective LA 15
  • 16. Differences between Ester and Amide group 1. Acid Dissociation constant (pKa) 2. Onset of action 3. Chemical stability 4. Hypersensitivity 16
  • 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 p pH= 7.4 Nearer to pH p Easily absorbed 17
  • 18. pH and pKa Relationship Local anesthetics Weak base Henderson–Hasselbalch equation pH ≈ pKa pH < pKa [ base ] ≈ [ salt ] [ base ] < [ salt ] 50% ionization More ionization 18
  • 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 19
  • 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 20
  • 21. Chemical stability Ester Amide Plasma esterases Less stable Liver More stable Stable in heat Stable in light X X X 21
  • 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 believedto be responsible for the allergic reactions. ▪ Although the amide type local anesthetics are not metabolized to PABA ▪ 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 23
  • 24. ▪ 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 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. 24 Esters Local Anesthetics
  • 25. 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. ▪ 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 25
  • 26. 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
  • 27. Treatment is an intravenous infusion of a 1% methylene blue solution, 1 mg/kg body weight, over 5 minutes 27
  • 28. Tetracaine ▪ 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 ▪ Severe toxic reactions following tetracaine overdose include convulsions and respiratory arrest 28
  • 29. Amide Local Anesthetics Lidocaine: ▪ Lidocaine was the first amino amide synthesized in 1948 and has become the most widely used local anesthetic. ▪ 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 29
  • 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 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. 30
  • 31. 31
  • 32. Mepivacaine (Carbocaine), 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. ▪ 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 ▪ Literature reports of cardiovascular toxicity, including severe hypotension and bradycardia. ▪ 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. 32 Change methyl to butyl ---- increase lipophilicity---potency ----duration of action
  • 33. ➢ Levobupivacaine ▪ 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. 33
  • 34. Ropivacaine: ▪ 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. 34
  • 35. 35