Local Anesthetics

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Local Anesthetics

• By
• Joanne Van Nostrand SRNA
• Anesthesiology Nursing Program
• Florida International University

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Local Anesthetics

• Local Anesthetics are drugs that produce
  reversible conduction blockade of impulses along
  central and peripheral nerve pathways after
  regional anesthesia this produces transient loss
  of sensory, motor, and autonomic function.

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A Little History

• Cocaine was first local anesthetic
• 1860- Isolated in the pure alkaloid form by
  German Chemist, Dr. Albert Neimann
• 1884- Introduced clinically in Austria by Dr.
  Carl Koller for use topically in opthalmology
• 1884- American surgeon William Halstead employed
  cocaine to produce the first nerve block by local
  injection
• 1898- Employed as spinal anesthetic by German
  surgeon, Dr. August Bier

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A Little History

• 1905- 1st synthetic anesthetic, procaine,
  introduced by German Researcher, Alfred Einhorn
• 1943- Lidocaine synthesized by Swedish Scientist,
  Nils Lofgren present-day prototype local
  anesthetic with which all other such drugs are
  compared

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Mechanism of Action

• Local Anesthetics produce conduction blockade of
  neural impulses by preventing passage of sodium
  ions through ion selective channels in nerve
  membranes
• Interfere with flux of sodium ions either by
• Binding to open state of ion channels, blocking
  it
• or
• Binding to closed state of the ion channels,
  preventing its opening

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Mechanism of Action
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Mechanism of Action
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Efficacy and Potency

• Several chemical properties of local anesthetics
  affect efficacy and potency
• They can exist as
• Lipid-soluble, neutral form
• or
• Charged, hydrophilic form
• Combination of pH of the environment and pKa, or
  dissociation constant, of local anesthetic
  determines how much of the compound exits in each
  form
• Henderson-Hasselbach equation
• Log _Cationic form_ pKa pH
• Uncharged form

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Efficacy and Potency

• Hydrophilic and Hydrophobic Agents
• Hydrophilic (water-loving dissolves in water)
  bind through the extracellular space
• Hydrophobic (water-fearing does not dissolve in
  water) pass through the cell membrane prior to
  binding
• It is much easier for non-polar molecules to pass
  through non-polar compounds and polar to pass
  through polar
• LIKE DISSOLVES LIKE !

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Efficacy and Potency

• Lipo - Fat
• Hydro - Water

• Philic- Loving
• Phobic- Afraid of

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Efficacy and Potency

• Since the pKa of most local anesthetics is in the
  range of 8.0-9.0 (weak bases), the larger
  fraction in the body fluids at physiologic pH
  will be the charged cationic form.
• Therefore, local anesthetics with pKa closer to
  physiologic pH will have higher concentration of
  nonionized base that can be pass through the
  nerve cell membrane, and onset will be more rapid.

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Efficacy and Potency

• The cationic form is thought to be the most
  active form at the receptor site.
• The primary site of action of local anesthetics
  appears to exist on the intracellular side of the
  sodium channel, and the charged form appears to
  be predominantly active form.
• The uncharged form is very important for rapid
  penetration of cell membranes (local anesthetic
  receptor is not accessible from the external side
  of the cell membrane).
• Once inside the cell, the nonionized base will
  reach an equilibrium with its ionized form. Only
  the charged cation binds to the receptor within
  the sodium channel.

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Efficacy and Potency

• Both forms can affect function of the sodium
  channel
• The neutral form can cause membrane expansion and
  closure of the sodium channel
• The protonated, charged form will directly
  inhibit the sodium channel by binding with a
  local anesthetic receptor

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Efficacy and Potency
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Efficacy and Potency

• Potency correlates with lipid solubility it
  depends on the ability of the local anesthetic to
  penetrate a hydrophobic environment.
• In general, potency and hydrophobicity increase
  with an increase in the total number of carbon
  atoms in the molecule

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Efficacy and Potency

• Duration of action is associated with plasma
  protein binding
• It is assumed that the degree of plasma protein
  binding of local anesthetics correlates with the
  degree of binding to the receptor site in the ion
  channels

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Efficacy and Potency

• Stereoisomers of local anesthetics appear to have
  potentially different effects on anesthetic
  potency, pharmacokinetics, and systemic toxicity
• Stereoisomers Isomers that have the same
  molecular and structural formulas, but different
  spatial arrangements of their atoms

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Efficacy and Potency

• Chiral Having right or left handedness able to
  have two different mirror-image forms
• Chiral carbon atom A carbon atom bonded to four
  different groups

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Chiral
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Chiral Carbon Atom
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Efficacy and Potency

• Enantiomers The two image-mirror forms of a
  chiral molecule same formula but different
  arrangement of their atoms
• A type of stereoisomer (Other examples, cis-trans
  isomers)

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Efficacy and Potency

• Mepivacaine, Bupivacaine, Ropivacaine
• Are chiral drugs because their molecules possess
  an asymmetric carbon atom
• These drugs may have left- (S) or right (R)
  handed configuration.

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Efficacy and Potency

• Mepivacaine and Bupivacaine
• Available for clinical use as racemic mixtures
  (5050 mixture) of the enantiomers.
• The administration of a racemic drug mixture is,
  in reality, the administration of two different
  drugs
• The S enantiomers of bupivacaine and mepivacaine
  appear to be less toxic than the commercially
  available racemic mixtures of these local
  anesthetics.

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Efficacy and Potency
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Efficacy and Potency

• Ropivacaine
• Developed as a pure S enantiomer

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Efficacy and Potency

• All other local anesthetics are racemic mixtures
  except for lidocaine which is achiral
• Achiral The opposite of chiral having no
  right- or left- handedness and no superimposible
  mirror images.

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Additives

• Addition of Epinephrine
• Prolongation of block
• Increased intensity of block
• Decrease systemic absorption

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Additives

• Alkalinization of Local Anesthetics
• Local anesthetics are commercially prepared as
  water-soluble hydrochloride salts with pH ranges
  of 6-7 especially acidic if pre-packaged with
  epinephrine at pH ranges of 4-5 since epinephrine
  is unstable in alkaline environments
• Slower onset of action to accelerate onset,
  sodium bicarbonate is added

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pH
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Foundations

• Amides and esters, by themselves, are derivatives
  of carboxylic acids
• Carboxylic acids are easily converted to esters
  and amides, and the esters and amides are easily
  converted back to carboxylic acids

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Foundations

• Carbonyl Carbon
• A carbon atom doubly bonded to an oxygen atom.
  O
• Amide C
• A carbonyl carbon linked directly to nitrogen
  atom.
• Ester
• A carbonyl carbon linked to an oxygen atom (R
  being a metallic ion or carbon atom)

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Foundations
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Basic Structure of Local Anesthetics

• Local Anesthetics are classified as amides and
  esters depending on the linkage that connects the
  lipophilic (hydrophobic) and the hydrophilic
  group.
• Composed of three parts
• Lipophilic Group - Amide or Ester Linkage -
  Hydrophilic Group

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Basic Structure of Local Anesthetics

• 
  R
• 
  
• 
  N
• 
  
• Amide or Ester Link
  R
• Aromatic Group
  Amine
• (Lipophilic Group)
  (Hydrophilic Group)

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Basic Structure of Local Anesthetics

• The type of linkage separates them into
• Amides, which are metabolized in the liver
• and
• Esters, which are metabolized by plasma
  cholinesterases

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Amide or EsterHow Do You Know?

• When deciding whether the local anesthetic
  chemical structure is an amide or an ester
• Look for the carbonyl carbon 1st
• 
  O Carbon atom double bonded
  to oxygen
• C
• 
  
• 
  
• Then look to the right or left of it to determine
  link
• O
  O
• Amide
  Ester
• C N
  C O
  

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Which is the Amide? Which is the Ester?

• Amide
• (Etidocaine)

• Ester
• (Cocaine)

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Esters

• Cocaine
• Cocaine Hydrochloride
• 3-benzoyloxy-8-methyl-8-azabicyclo3.2.1octane-4
  -carboxylic acid methyl ester
• C17H21N04

• Minimally used as a topical anesthetic
• pKa 8.7

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Esters

• Benzocaine
• Anbesol
• Ethyl p-aminobenzoate
• C9H11NO2

• Used only in topical solutions or in lozenges

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Esters

• Procaine
• Novocaine
• 2-Diethylaminoethyl 4-aminobenzoate hydrochloride
  
• C13H20N2O2HCl

• Used for
• Spinal
• Infiltration
• Peripheral nerve block
• pKa 8.9
• Toxicity can arise from procaine in the blood
  stream, leading to allergic reactions and
  sensitivity.

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Esters

• Tetracaine
• Amethocaine hydrochloride
• 2-dimethylaminoethyl 4-n-butylaminobenzoate
  hydrochloride
• C15H24N2O2HCl

• Used for
• Spinal
• Topical
• pKa 8.2

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Esters

• Chloroprocaine
• Nesacaine hydrochloride

• Used for
• Epidural, caudal
• Infiltration
• Peripheral nerve block
• pKa 9.0
• Has rapid onset of action despite pKa and is
  short acting

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Amides

• Lidocaine
• Xylocaine
• 2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide
  monohydrochloride

• Used for..
• Epidural, caudal, spinal
• Infiltration
• Peripheral nerve block
• Topical
• pKa 7.8
• Toxicity initially manifests as drowsiness,
  tinnitus, and dizziness.
• More toxic than procaine

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Amides

• Dibucaine
• Nupercaine
• 2-Butyloxy-N-(2-diethylaminoethyl)-4-quinolinecarb
  oxamide monohydrochloride
• C20H29N3O2

• Used for..
• Spinal
• Topical
• pKa 8.8

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Amides

• Mepivacaine
• Carbocaine Hydrochloride
• N-(2,6-Dimethylphenyl)-1-methyl-2-piperidinecarbox
  amide monohydrochloride
• C15H23ClN2O

• Used for
• Epidural, caudal
• Infiltration
• Peripheral nerve bloc
• pKa 7.6
• Not used in obstetrics due to toxicity to
  neonates because of reduced metabolism

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Amides

• Etidocaine
• Duranest
• N-(2,6-dimethylphenyl)-2-(ethylpropylamine)
• C17H28N20

• Used for
• Epidural, caudal
• Infiltration
• Peripheral nerve block
• pKa 7.7

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Amides

• Bupivacaine
• Marcaine
• 1-Butyl-n-(2,6-Dimethylphenyl)-2-Piperidine
  Carboxamide
• C18H28N2OHCl

• Used for
• Epidural, caudal, spinal
• Infiltration
• Peripheral nerve block
• pKa 8.1
• More toxic to cardiovascular system than lidicaine

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Amides

• Prilocaine
• Citanest
• N-(2-methylphenyl)-2-(propylamino)
• C13H20N20

• Used for
• Epidural, caudal
• Infiltration
• Peripheral nerve block
• pKa 7.8
• Limited use in obstetrics causes blood
  dyscrasias (blood abnormalities)

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Amides

• Ropivacaine
• Naropin
• S-(-)-1-propyl-2,6-pipecoloxylidide
  hydrochloride monohydrate
• C17H26N20HClH20

• Used for
• Epidural, caudal, spinal
• Infiltration
• Peripheral nerve block
• pKa 8.1
• S- enantiomer is less toxic than R- enantiomer

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Local Anesthetics

• Esters
• Cocaine
• Benzocaine
• Procaine
• Tetracaine
• Chloroprocaine

• Amides
• Lidocaine
• Dibucaine
• Mepivacaine
• Etidocaine
• Bupivacaine
• Prilocaine
• Ropivacaine

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Metabolism of Local Anesthetics

• Local Anesthetics can be metabolized by one or
  multiple methods, depending on the functional
  group present and how vulnerable the group is to
  the chemical reaction.
• Esters
• Ester Hydrolysis
• Amides
• N-dealkylation
• Amide Hydrolysis
• Aromatic Hydroxylation

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Metabolism of Ester Local Anesthetics

• Esters
• Objective is to replace the OR group with an OH
  (Hydroxyl group) and form carboxylic acid
• O
  O
• C OR C
  OH
• Ester Hydrolysis
• Enzyme (plasma cholinesterase) breaks down H2O
  into one H and an OH
• Then uses OH to replace the OR group in the ester

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Ester Hydrolysis
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Metabolism of Amide Local Anesthetics

• Amides
• R R
  
• N
  N R or N
• R
  R R
• N-dealkylation
• An enzyme detaches one or more carbon atoms from
  the amine group, making it either a 2 or 1
  amine.
• Target is the amine group of the local anesthetic.

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N-dealkylation
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Metabolism of Amide Local Anesthetics

• Amides (continued)
• Objective is to replace the N-group with an OH
  (Hydroxyl group) and form carboxylic acid.
• O R
  O
• C N R
  C OH
• R
• Amide
  Hydrolysis
• Enzyme breaks down H2O into one H and an OH
• Then uses OH to replace the N group in the amide

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Amide Hydrolysis
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Metabolism of Amide Local Anesthetics

• Amides (continued)
• 
  OH
• OH
• Aromatic Hydroxylation
• Introduction of the OH (Hydroxyl group) to the
  benzene ring
• Target is lipophilic group (aromatic group)

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Aromatic Hydroxylation
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Allergic Reactions

• Esters-
• Due to metabolite p-aminobenzoic acid
• Amide-
• Methylparaben preservative in amide agents

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Highlights

• Explain the mode of action of local anesthetics.
• What are the three component parts of a local
  anesthetic structure?
• Identify an amide or ester local anesthetic by
  looking at the structure.
• What is chirality?
• What is an enantiomer?
• Explain and identify ester hydrolysis.
• Explain and identify amide hydrolysis.
• Explain and identify N-dealkylation.
• Explain and identify aromatic hydroxylation.

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References

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