Local anesthetics: agents, actions,

1
Local anesthetics agents, actions,
misconceptions

• John Butterworth, MD
• Professor Head
• Section on Cardiothoracic Anesthesiology
• Wake Forest University School of Medicine
• Winston-Salem, North Carolina

2
Local anesthetics agents, actions,
misconceptions

• History and general considerations
• Na channels, cellular electrophysiology, local
  anesthetic actions
• General characteristics of local anesthesia
• LA pharmacokinetics
• LA toxicity
• Summary

3
History of local anesthesia-1

• Cocaine natural product
• Properties well-known to Incas
• Chewed coca dripped on trepanning sites
• 1500s Spaniards seize plantations pay workers
  with coca paste
• Mixed with corn starch, chewed with guano, CaCO3,
  or ash first example of free basing
• Monardes brings coca leaves back to Europe
  (1580) fail to achieve instant popularity of
  tobacco

Erythroxylon coca
4
History of local anesthesia-1

• Cocaine natural product
• Properties well-known to Incas
• Chewed coca dripped on trepanning sites
• 1500s Spaniards seize plantations pay workers
  with coca paste
• Mixed with corn starch, chewed with guano, CaCO3,
  or ash first example of free basing
• Monardes brings coca leaves back to Europe
  (1580) fail to achieve instant popularity of
  tobacco

Chewing coca From cocamuseum.com
5
History of local anesthesia-1

• Cocaine natural product
• Properties well-known to Incas
• Chewed coca dripped on trepanning sites
• 1500s Spaniards seize plantations pay workers
  with coca paste
• Mixed with corn starch, chewed with guano, CaCO3,
  or ash first example of free basing
• Monardes brings coca leaves back to Europe
  (1580) fail to achieve instant popularity of
  tobacco

Trepanning knife
From Renato Sabbatini, PhD
6
History of local anesthesia-1

• Cocaine natural product
• Properties well-known to Incas
• Chewed coca dripped on trepanning sites
• 1500s Spaniards seize plantations pay workers
  with coca paste
• Mixed with corn starch, chewed with guano, CaCO3,
  or ash first example of free basing
• Monardes brings coca leaves back to Europe
  (1580) fail to achieve instant popularity of
  tobacco

Skulls from trepanned patients
www.epub.org.br/cm/n02/ historia/trepan6b.gif
7
History of local anesthesia-1

• Cocaine natural product
• Properties well-known to Incas
• Chewed coca dripped on trepanning sites
• 1500s Spaniards seize plantations pay workers
  with coca paste
• Mixed with corn starch, chewed with guano, CaCO3,
  or ash first example of free basing
• Monardes brings coca leaves back to Europe
  (1580) fail to achieve instant popularity of
  tobacco

Spaniards and Native Slaves
From cocamuseum.com
8
History of local anesthesia-1

• Cocaine natural product
• Properties well-known to Incas
• Chewed coca dripped on trepanning sites
• 1500s Spaniards seize plantations pay workers
  with coca paste
• Mixed with corn starch, chewed with guano, CaCO3,
  or ash first example of free basing
• Monardes brings coca leaves back to Europe
  (1580) fail to achieve instant popularity of
  tobacco

Chewing coca From cocamuseum.com
9
History of local anesthesia-1

• Cocaine natural product
• Properties well-known to Incas
• Chewed coca dripped on trepanning sites
• 1500s Spaniards seize plantations pay workers
  with coca paste
• Mixed with corn starch, chewed with guano, CaCO3,
  or ash first example of free basing
• Monardes brings coca leaves back to Europe
  (1580) fail to achieve instant popularity of
  tobacco

Fresh coca leaves
From Andy Graham of hobotraveler.com
10
History of local anesthesia-2

• Cocaine HCl isolated by Albert Niemann (1860)
• Merck produces 100 g cocaine (1862)
• Koller and Gartner report local anesthesia (1884)
• Merck produces 1450 kg (1884) 72,000 kg (1886)
• Coca-Cola (1886) and many other products contain
  cocaine

Cocaine HCl powder
11
History of local anesthesia-2

• Cocaine HCl isolated by Albert Niemann (1860)
• Merck produces 100 g cocaine (1862)
• Koller and Gartner report local anesthesia (1884)
• Merck produces 1450 kg (1884) 72,000 kg (1886)
• Coca-Cola (1886) and many other products contain
  cocaine

Cocaine HCl powder
Carl Koller 1857 -1944
12
History of local anesthesia-2

• Cocaine HCl isolated by Albert Niemann (1860)
• Merck produces 100 g cocaine (1862)
• Koller and Gartner report local anesthesia (1884)
• Merck produces 1450 kg (1884) 72,000 kg (1886)
• Coca-Cola (1886) and many other products contain
  cocaine

13
History of local anesthesia-2

• Cocaine HCl isolated by Albert Niemann (1860)
• Merck produces 100 g cocaine (1862)
• Koller and Gartner report local anesthesia (1884)
• Merck produces 1450 kg (1884) 72,000 kg (1886)
• Coca-Cola (1886) and many other products contain
  cocaine

http//wings.buffalo.edu/aru/preprohibition.htm
14
History of local anesthesia-2

• Cocaine HCl isolated by Albert Niemann (1860)
• Merck produces 100 g cocaine (1862)
• Koller and Gartner report local anesthesia (1884)
• Merck produces 1450 kg (1884) 72,000 kg (1886)
• Coca-Cola (1886) and many other products contain
  cocaine

http//wings.buffalo.edu/aru/preprohibition.htm
15
Early history of spinal anesthesia

• 1891 Quincke describes lumbar puncture
• 1898 Bier undergoes spinal (has headache
  incorrectly diagnosed as hangover)
• 1899 Bier reports 6 surgeries with spinal
• 1899 Tuffier relieves cancer pain with spinal

Professor August Bier 1861-1949
16
Early history of spinal anesthesia

• 1891 Quincke describes lumbar puncture
• 1898 Bier undergoes spinal (has headache
  incorrectly diagnosed as hangover)
• 1899 Bier reports 6 surgeries with spinal
• 1899 Tuffier relieves cancer pain with spinal

Professor August Bier 1861-1949
17
History of epidural anesthesia

• 1885 Cocaine injected near spinal blood
  vessels, producing probable epidural
• 1901 Sicard and Cathelin popularize caudal
  epidural anesthesia
• 1921 Pages popularizes lumbar epidural
  anesthesia

J. L. Corning
18
Chronology of local anesthetics
After Cartwright Fyhr. Reg Anesth 1988131-12
19
Benjamin G. Covino, PhD, MD 12 Sep1930 6 Apr
1991

• Astra Pharmaceuticals
• 1962-1977
• Professor, Vice
• Chairman, U Mass
• Anesthesiology
• Department, 1977-1979
• Professor Chairman,
• Brigham Womens
• Hospital Anesthesia Department, 1979-1991
• Editor-in-Chief Regional Anesthesia

20
Local anesthetics agents, actions,
misconceptions

• History and general considerations
• Na channels, cellular electrophysiology, local
  anesthetic actions
• General characteristics of local anesthesia
• LA pharmacokinetics
• LA toxicity
• Summary

21
Membrane potentials andionic currents in neurons

• Resting potential
• Characteristic of
• living cells (-70 mV)
• Na-K ATPase and
• K leak
• Action potential
• Na channels open, allow Na flux
• Within milliseconds, Na channels return to
  nonconducting inactivated state

Potential (in mV)
Squid axon, 16o
Time after stimulus (ms)
22
Na channel conformations

• 3 channel forms resting,
• open, inactivated (1952)
• Na ions pass only through
• open channels
• No Na current through
• channels bound by LA
• LA binding favored by
• Depolarization
• Open or inactivated Na channels
• Frequent impulses (use-dependence)

AL Hodgkin 1914-1998
AF Huxley 1917-
Shared Nobel Prize in 1963
23
Na channel conformations

• 3 channel forms resting,
• open, inactivated (1952)
• Na ions pass only through
• open channels
• No Na current through
• channels bound by LA
• LA binding favored by
• Depolarization
• Open or inactivated Na channels
• Frequent impulses (use-dependence)

GR Strichartz Brigham and Womens
Hospital Harvard Medical School
24
Use-dependent block of cardiac Na channels by LAs
Control
Control
QX222 0.5 mM
QX222
Hanck et al. J Gen Physiol 199410319-43
25
Structural characteristicsof Na channels

• 1 larger ? subunit (230-270 kD) (has ion
  conducting path)
• 1 or 2 smaller ? subunits (37-39 kD)
• All subunits are heavily glycosylated
• 4 domains with 6 membrane spanning regions

From Physiol Rev 199272S15-S48 Ann Rev Biochem
19956493-531 Biophys J 2000791379-87
26
From Catterall Mackie Ch 15, p334. Goodman
Gilman 9th Edition, 1996 Wang. Mol Pharm
2001591100-7 Nau. Mol Pharm 199956404-13
a-subunit has 4 domains, each has 6 membrane
spanning a-helical segments (S1-S6). LA binding
in D1-S6, D3-S6 and D4-S6, but not D2-S6
27
LAs bind and inhibit many differing receptors and
channels

• Channels
• Na
• Ca (multiple types)
• K
• Enzymes
• Adenylyl cyclase
• Guanylyl cyclase
• Lipases

• Receptors
• Nicotinic acetylcholine
• NMDA
• ß2-adrenergic
• Important for spinal, epidural, or systemic
  effects?

Anesthesiology 1990 72711-34
28
Many classes of compounds bind and inhibit Na
channels

• Local anesthetics
• General anesthetics
• Ca channel blockers
• ?2 agonists
• Tricyclic antidipressants
• Substance P antagonists
• Many nerve toxins
• Tetrodotoxin
• Batrachotoxin
• Grayanotoxin

Inhibition of Action Potential
Fiber types ? Aa ? C
10-5 10-4 10-3 10-2 10-1 Clonidine
Concentration (M)
Anesth Analg. 199376295-301
29
Tetrodotoxin (TTX)

• Fugu (puffer fish) sushi a delicacy
• Fugu liver contains TTX illegal to sell
• Chefs undergo long apprenticeship
• Annually, 5-10 Japanese die from TTX after eating
  fugu

30
TTX binds Na channels selectively with high
affinity

• Squid axons have both Na currents (early, inward)
  and K currents (later, outward)
• TTX inhibits only Na (early, downward) current
• TTX has greater affinity and selectivity than LAs

(A) Time (ms)
0
5
10
I(nA)
10
0
Control
-10
(B)
300 nM TTX
Hille. Nature. 19662101220-2
31
Local anesthetics agents, actions,
misconceptions

• History and general considerations
• Na channels, cellular electrophysiology, local
  anesthetic actions
• General characteristics of local anesthesia
• LA pharmacokinetics
• LA toxicity
• Summary

32
Local anestheticsamides vs. esters

• Common structure
• Aromatic ring
• Tertiary amine
• Alkyl chain
• Linking bond
• Amide bond (see lidocaine)
• Ester bond (see procaine)

Lidocaine
Procaine
33
General characteristics of local anesthesia

• Potency
• Speed of onset
• Duration of action
• Tendency to produce differential block
• Modifiers of local anesthetic activity

34
Potency and protein binding increase with
increasing lipid solubility

• Potency etidocaine gt lidocaine gt procaine
• More potent (Pot) LAs tend to be more lipid
  soluble (Sol)
• Greater lipid solubility also results in greater
  protein binding (Bdg)

Relative to procaine 1
35
pKa and speed of onset the facts vs. the
textbooks of anesthesiology Strichartz. Anesth
Analg 199071158-70
Temp (oC)
pKa
36
Characteristics of LAs

• Physical and chemical
• Increasing lipid solubility
• Increased protein binding
• Pharmacological toxicological
• Increasing potency
• Prolonged onset time
• Prolonged duration of action
• Increasing tendency to produce severe
  cardiovascular toxicity
• In general, all tend to sort together

37
Differential block

• Goal analgesia without motor block
• Success in postoperative, labor analgesia
• Differential onset of block with bupivacaine
  (versus mepivacaine)
• No consistent differential block when the block
  fully set up
• Smaller fibers of a given type more LA-sensitive
  than larger (A? fibers more LA-sensitive than A?
  fibers)

38
Bupivacaine produces differential onset of block
mepivacaine does not
Br J Anaesth 199881515-21
39
Additives and modifiersof LA activity

• Increasing dose ?latency of onset ?duration,
  ?block success, ?LA
• Vasoconstrictors ?duration, ?block success,
  ?LA
• a2 agonists ?duration,?LA
• Opioids ?duration permit ?LA dose
• Alkalinization (usually NaHCO3) ?latency of
  onset, ?potency
• Pregnancy ?dermatomal spread, ?LA potency, ?free
  blood LA

40
Bicarbonate reduces fractionof protonated LA
speeds onset

• Charged LA
• less membrane
• permeable than
• uncharged LA
• Generally faster
• onset of block
• with bicarbonate
• Particularly with
• LAs formulated with epinephrine by
  manufacturer (acidity promotes long shelf-life)

41
Alkaline pH increases procaine potency in frog
sciatic axons
pH
inhibition
mM
Butterworth. Anesthesiology 198868501-6
42
Pregnancy and local anesthesia

• ?spread of epidural spinal in pregnancy
  (probably due to ?CSF volume)
• Progesterone ?bupivacaine potency
• ?lidocaine potency at median nerve block in
  pregnant women

inhibition
Elapsed time (min)
Butterworth. Anesthesiology 199072962-5
43
Local anesthetics agents, actions,
misconceptions

• History and general considerations
• Na channels, cellular electrophysiology, local
  anesthetic actions
• General characteristics of local anesthesia
• LA pharmacokinetics
• LA toxicity
• Summary

44
Mepivacaine concentrations in blood after
injection of the same dose in different sites

• Greatest to Least
• Intercostal
• Caudal
• Lumbar epidural
• Brachial plexus
• Sciatic-femoral

Anesthesiology 197237277
45
Protein binding of LAs

• All LAs are lipid soluble, so all are
  protein-bound to some extent
• ?1-acid glycoprotein
• albumin
• Greater fraction of more potent LAs protein bound
  than less potent LAs
• Protein binding declines during pregnancy (but
  not by much!)

46
Protein binding of lidocaine (2 ?g/ml) decreases
during pregnancyFragneto et al. Anesth Analg
199479295-7

Trimester
47
LA metabolism

• Esters (half-lives in seconds to minutes)
• Hydrolyzed by nonspecific esterases
• Clearance independent of liver flow function
• Active metabolites (p-aminobenzoic acid (PABA)
  and allergy with procaine or benzocaine)
• Amides (half-lives in hours)
• N-dealkylation or hydroxylation (CYP450)
• Clearance depends on liver blood flow, function
• Active metabolite (prilocaine ? o-toluidine and
  methemoglobinemia)

48
Effects of pregnancy, drugs, and organ failure on
LA kinetics

• Renal failure ?Vd ?accumulation of metabolic
  products
• Hepatic failure ?amide Vd, ?amide clearance
• Cardiac failure ß and H2 blockers ?hepatic
  blood flow and ?amide clearance
• Cholinesterase deficiency or inhibition ?ester
  clearance
• Pregnancy ?hepatic blood flow ?amide clearance
  ?protein binding

49
Local anesthetics agents, actions,
misconceptions

• History and general considerations
• Na channels, cellular electrophysiology, local
  anesthetic actions
• General characteristics of local anesthesia
• LA pharmacokinetics
• LA toxicity
• Summary

50
CNS toxicity from LAs

• Progression of signs symptoms with ?LA
• Vertigo
• Tinnitus
• Ominous feelings
• Circumoral numbness
• Garrulousness
• Tremors
• Myoclonic jerks
• Convulsions
• CNS depression
• CV depression

• Convulsive LA dose inversely related to LA
  potency
• Acidosis, hypercarbia ? convulsive dose
• Pregnancy lowers dose but not concentration
  producing convulsions
• CV toxicity requires greater LA doses and
  concentrations than CNS toxicity

51
CNS toxicity from LAs

• Progression of signs symptoms with ?LA
• Vertigo
• Tinnitus
• Ominous feelings
• Circumoral numbness
• Garrulousness
• Tremors
• Myoclonic jerks
• Convulsions
• CNS depression
• CV depression

• Convulsive LA dose inversely related to LA
  potency
• Acidosis, hypercarbia ? convulsive dose
• Pregnancy lowers dose but not concentration
  producing convulsions
• CV toxicity requires greater LA doses and
  concentrations than CNS toxicity

52
Lethal vs. convulsive LA doses in anesthetized
dogs Liu et al Reg Anesth 1982714-9 Anesth
Analg 198261317-22
53
Cardiovascular toxicityfrom local anesthetics

• Predisposition to cardiac arrest with bupivacaine
  etidocaine (Albright, 1979)
• S- isomers (levo-bupivacaine and ropivacaine)
  less potent at CV toxicity than R isomers or
  racemic mixes
• Which is most important?
• Increasing potency (increasing LA size)
• R stereoisomer

54
Multiple LA actions on the cardiovascular system

• Biochemical
• Inhibit cAMP formation
• Inhibit multiple enzyme systems
• Electrophysiologic
• Bupivacaine vs. lidocaine faster binding,
  delayed unbinding from cardiac Na channels
• Inhibit conduction system
• Negative inotropic (Ca interactions)
• Vascular
• Vasoconstrict (low concentrations)
• Vasodilate (high concentrations)

55
Is there one common mechanism for LA-induced
cardiac death?

• Arrhythmias (bupivacaine)?
• Left-ventricular depression (lidocaine)?
• Resuscitation drug failure (bupivacaine)?
• Mechanism probably depends on specific drug!

56
LA blood concentrations producing cardiac arrest
in dogs similar rank order as for potency
µg/mL
Groban et al Anesth Analg 2000911103-11
57
Bupivacaine more toxic thanlevo or ropivacane in
rats

• Rats infused LA at 2 mg/kg/min
• Asystole treated with epi .01 mg/kg CPR
• Resuscitation success SAP gt100 mmHg
• B more potent than LB or R at sz, arr, asystole
• Less epi needed for ropiv than bup or levo

Cumulative dose mg/kg
Ohmura. Anesth Analg 200193743-8
58
LA infusions, cardiac arrest resuscitation in
dogs

• More inducible arrhythmias with B, LB than R, Li
• More epi-induced VF (EpVF) death with B than R
  or Li
• Continued epi often needed for Li (86) after
  arrest rarely with B

of animals
Groban. Anesth Analg 2000911103 Anesth Analg
20019237 RAPM 200227460
59
Levobupivacaine and ropivacaine

• Less toxic than bupivacaine
• Are they as potent as bupivacaine?
• Confusing data supramaximal doses opioids,
  other additives
• Onset time, motor block NOT substitutes for
  potency
• Thus, potency ratios remain unknown

60
Should we replace bupivacaine?

• Not needed
• Small doses (spinal, ankle, wrist)
• Reduced concentration (cervical plexus)
• Reasonable
• Large doses (sciatic femoral)
• Multiple blocks
• Unclear
• Epidural
• Brachial plexus

61
Neurotoxic effects of LAs

• 2-chloroprocaine
• Large doses injected accidentally in CSF produce
  cauda equina syndrome
• Metabisulfite, low pH
• Toxicity disappeared when 2-CP reformulated
• Toxicity returns when generic manufacturers use
  old formulation!
• 2-CP used for spinals

• Spinal lidocaine
• Deficits first linked to microcatheters later
  reported after single-shot spinal anesthetics
• 5 lidocaine (not other spinal LAs) in vitro
  produces irreversible nerve block
• Transient neurologic symptoms linked with
  arthroscopy, lithotomy position, and lidocaine
  spinal anesthesia

62
Neurotoxic effects of LAs

• 2-chloroprocaine
• Large doses injected accidentally in CSF produce
  cauda equina syndrome
• Metabisulfite, low pH
• Toxicity disappeared when 2-CP reformulated
• Toxicity returns when generic manufacturers use
  old formulation!
• 2-CP used for spinals

• Spinal lidocaine
• Deficits first linked to microcatheters later
  reported after single-shot spinal anesthetics
• 5 lidocaine (not other spinal LAs) in vitro
  produces irreversible nerve block
• Transient neurologic symptoms linked with
  arthroscopy, lithotomy position, and lidocaine
  spinal anesthesia

63
Allergy to LAs

• Common misdiagnosis after accidental IV
  injections
• True allergy more common with esters
  (particularly those related to PABA) than amides
• Avoid PABA in sunscreens
• Cross reactions between PABA and methylparaben
  (preservative sometimes added to amide LAs)

64
None of 90 patients referred for LA reactions
have allergy!

• 0 of 90 reacted to 1100 LA dilutions!
• Few respond to undiluted LA even among 14
  referred after anaphylactoid reactions
• Thus, almost no patients had real LA allergy

1100 Undiluted
deShazo. J All Clin Immunol 197963387-94
65
Treatment of local anesthetic toxicity

• Apparent allergy
• Steroids
• Histamine (H1) blockers
• With severe reactions
• Intravenous fluid
• Epinephrine

• CNS toxicity
• Dont treat minor reactions
• Seizures maintain airway, provide O2
• Terminate seizure with thiopental, midazolam, or
  propofol
• Intubate patients with full stomachs

66
Treatment of local anesthetic toxicity

• Apparent allergy
• Steroids
• Histamine (H1) blockers
• With severe reactions
• Intravenous fluid
• Epinephrine

• CNS toxicity
• Dont treat minor reactions
• Seizures maintain airway, provide O2
• Terminate seizure with thiopental, midazolam, or
  propofol
• Intubate patients with full stomachs

67
Treatment of LA CV toxicity

• Follow ACLS guidelines
• Substitute amiodarone for lidocaine
• Substitute vasopressin for epinephrine
• Consider cardiopulmonary bypass or lipid infusion
  if standard drugs fail

68
Lipid emulsion counteracts bupivacaine cardiac
toxicity

• Lipid pretreatment with increases toxic dose of
  bupivacaine
• Animals not resuscitated using ACLS recovered
  when given lipid emulsion
• Lipid may draw bupivacaine into plasma from
  binding site(s) in the heart
• No human data

Weinberg. Anesthesiology 1998881071-5 Weinberg.
Reg Anesth Pain Med 200328198-202
69
Local anesthetics agents, actions,
misconceptions

• History and general considerations
• Na channels, cellular electrophysiology, local
  anesthetic actions
• General characteristics of local anesthesia
• LA pharmacokinetics
• LA toxicity
• Summary

70
Summary

• LAs bind and inhibit Na channels voltage-,
  state-, and use-dependent block
• Potency, lipid solubility, protein binding, onset
  time, duration, CV toxicity tend to sort together
• Pharmacodynamic effects of dose, additives,
  pregnancy
• Differential block
• Pharmacokinetics esters vs. amides
• Toxicity CNS vs. CV neurotoxicity allergy

71
Local anesthetics agents, actions,
misconceptions

• John Butterworth, MD
• Professor Head
• Section on Cardiothoracic Anesthesiology
• Wake Forest University School of Medicine
• Winston-Salem, North Carolina