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Local Anesthetics

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Title: Local Anesthetics


1
Local Anesthetics
  • By
  • Joanne Van Nostrand SRNA
  • Anesthesiology Nursing Program
  • Florida International University

2
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.

3
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

4
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5
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

6
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

7
Mechanism of Action
8
Mechanism of Action
9
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

10
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 !

11
Efficacy and Potency
  • Lipo - Fat
  • Hydro - Water
  • Philic- Loving
  • Phobic- Afraid of

12
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.

13
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.

14
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

15
Efficacy and Potency
16
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

17
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

18
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

19
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

20
Chiral
21
Chiral Carbon Atom
22
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23
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)

24
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.

25
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.

26
Efficacy and Potency
27
Efficacy and Potency
  • Ropivacaine
  • Developed as a pure S enantiomer

28
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.

29
Additives
  • Addition of Epinephrine
  • Prolongation of block
  • Increased intensity of block
  • Decrease systemic absorption

30
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

31
pH
32
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

33
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)

34
Foundations
35
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

36
Basic Structure of Local Anesthetics

  • R


  • N

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

37
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

38
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

39
Which is the Amide? Which is the Ester?
  • Amide
  • (Etidocaine)
  • Ester
  • (Cocaine)

40
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41
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42
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

43
Esters
  • Benzocaine
  • Anbesol
  • Ethyl p-aminobenzoate
  • C9H11NO2
  • Used only in topical solutions or in lozenges

44
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.

45
Esters
  • Tetracaine
  • Amethocaine hydrochloride
  • 2-dimethylaminoethyl 4-n-butylaminobenzoate
    hydrochloride
  • C15H24N2O2HCl
  • Used for
  • Spinal
  • Topical
  • pKa 8.2

46
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

47
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

48
Amides
  • Dibucaine
  • Nupercaine
  • 2-Butyloxy-N-(2-diethylaminoethyl)-4-quinolinecarb
    oxamide monohydrochloride
  • C20H29N3O2
  • Used for..
  • Spinal
  • Topical
  • pKa 8.8

49
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

50
Amides
  • Etidocaine
  • Duranest
  • N-(2,6-dimethylphenyl)-2-(ethylpropylamine)
  • C17H28N20
  • Used for
  • Epidural, caudal
  • Infiltration
  • Peripheral nerve block
  • pKa 7.7

51
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

52
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)

53
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

54
Local Anesthetics
  • Esters
  • Cocaine
  • Benzocaine
  • Procaine
  • Tetracaine
  • Chloroprocaine
  • Amides
  • Lidocaine
  • Dibucaine
  • Mepivacaine
  • Etidocaine
  • Bupivacaine
  • Prilocaine
  • Ropivacaine

55
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

56
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

57
Ester Hydrolysis
58
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.

59
N-dealkylation
60
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

61
Amide Hydrolysis
62
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)

63
Aromatic Hydroxylation
64
Allergic Reactions
  • Esters-
  • Due to metabolite p-aminobenzoic acid
  • Amide-
  • Methylparaben preservative in amide agents

65
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.

66
References
  • Barash, P. G. (2005). Clinical anesthesia (5th
    ed.). Philadelphia, PA Lippincott Williams
    Wilkins.
  • Barash, P. G., Cullen, B. F., Stoelting, R. K.
    (2001). Clinical Anesthesia (4th ed.).
    Philadelphia, PA Lippincott Williams Wilkins .
  • Brown, D. L. (1999). Atlas of regional anesthesia
    (2nd ed.). Philadelphia, PA Saunders.
  • Katzung, B. G. (2001). Basic clinical
    pharmacology (8th ed.). New York Lange Medical
    Books/McGraw-Hill.
  • Kier, L. B., Dowd, C. S. (2004). The chemistry
    of drugs for nurse anesthetists. Park Ridge, IL
    AANA Publishing.
  • McMurry, J., Castellion, M. E. (2003).
    Fundamentals of general, organic, and biological
    chemistry (4th ed.). Upper Saddle River, NJ
    Prentice Hall.
  • Morgan, G. E., Jr., Mikhail, M. S., Murray, M.
    J., Larson, C. P.Jr. (2002). Clinical
    anesthesiology (3rd ed.). New York Lange Medical
    Books/McGraw-Hill.
  • Stoelting, R. K. (1999). Pharmacology
    physiology in anesthetic practice (3rd ed.).
    Philadelphia, PA Lippincott Williams Wilkins.
  • Stoelting, R. K., Miller, R. D. (2000). Basics
    of anesthesia (4th ed.). Philadelphia, PA
    Churchill Livingstone.
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