Update on local anesthetic pharmacology

1
Update on local anesthetic pharmacology

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

2
Update on local anesthetic pharmacology

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

See http//www1.wfubmc.edu/anesthesiology/researc
h/faculty_presentations.htm
3
Early history of regional anesthesia

• Koller and Gartner report local anesthesia (1884)

Carl Koller 1857 -1944
4
Early history of regional anesthesia

• Koller and Gartner report local anesthesia (1884)
• 1884 Halsted injects cocaine directly into
  mandibular nerve and brachial plexus

William S. Halsted
5
Early history of regional anesthesia

• Koller and Gartner report local anesthesia (1884)
• 1884 Halsted injects cocaine directly into
  mandibular nerve and brachial plexus
• 1904 Einhorn discovers procaine (Novocaine)

Procaine
6
Early history of regional anesthesia

• Koller and Gartner report local anesthesia (1884)
• 1884 Halsted injects cocaine directly into
  mandibular nerve and brachial plexus
• 1904 Einhorn discovers procaine (Novocaine)
• 1943 Lofgren discovers lidocaine (Xylocaine)

Lidocaine
7
Chronology of local anesthetics
After Cartwright Fyhr. Reg Anesth 1988131-12
8
Local anestheticsamides vs. esters

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

Lidocaine
Procaine
9
Update on local anesthetic pharmacology

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

10
Voltage-gated Na (Nav) channels

• Propagate action potentials in nerve and muscle
• Shape, filter synaptic inputs
• Initiate, maintain cellular oscillations (sinus
  node) and burst generation (brain cells)
• Mutations lead to muscle, cardiac, neural
  diseases and stillbirth
• Bind local anesthetics to produce regional
  anesthesia, necessitating ASRAPM meeting!

Lopreato. Proc Natl Acad Sci 2001987588-92 Viswa
nathan Balser. Trends Cardiovasc Med
20041428-35
11
Structural characteristicsof Nav channels

• 1 larger ? subunit (260 kD) (has ion conducting
  path)
• 1 or 2 smaller ? subunits (30 kD)
• All subunits heavily glycosylated

From Physiol Rev 199272S15-S48 Ann Rev Biochem
19956493-531 Biophys J 2000791379-87 J Exp
Biol 2002205574-84
12
Structural characteristicsof Nav channels

• 1 larger ? subunit (260 kD) (has ion conducting
  path)
• 1 or 2 smaller ? subunits (30 kD)
• All subunits heavily glycosylated

From Physiol Rev 199272S15-S48 Ann Rev Biochem
19956493-531 Biophys J 2000791379-87 J Exp
Biol 2002205574-84
13
Structural characteristicsof Nav channels

• 1 larger ? subunit (260 kD) (has ion conducting
  path)
• 1 or 2 smaller ? subunits (30 kD)
• All subunits heavily glycosylated

From Physiol Rev 199272S15-S48 Ann Rev Biochem
19956493-531 Biophys J 2000791379-87 J Exp
Biol 2002205574-84
14
Structural characteristicsof Nav channels

• 4 domains
• have 6
• membrane-
• spanning
• a-helical
• segments
• (S1-S6)
• S5-S6 P-loop part of ion-conducting pore

Cytoplasm
Plummer, Meisler. Genomics 199957323-31
15
Structural characteristicsof Nav channels

• 4 domains
• have 6
• membrane-
• spanning
• a-helical
• segments
• (S1-S6)
• S5-S6 P-loop part of ion-conducting pore

Cytoplasm
Plummer, Meisler. Genomics 199957323-31
16
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)
17
Na channel conformations

• 3 channel forms resting, open, inactivated
  (1952)
• Na ions pass only through open channels
• Membrane potential (or voltage) determines the
  conformation

AL Hodgkin 1914-1998
AF Huxley 1917-
Nobel Prize 1963
18
Latest model for voltage-gating of ion channels

• S1-S4 segments form voltage sensor
• Conventional models assume S4 moves in and out
  of lipid membrane
• Xray diffraction S4-S3 hairpin loop, supports
  paddle

Århem. Lancet 20043631221-3 Jiang. Nature
200342333-41
19
How LAs inhibit Na currents

• Weidman (1955) shows that LAs reduce Na flux
  during impulses in Purkinje cells
• Taylor (1959) shows that procaine inhibits Na
  currents in squid axons
• No effect on resting membrane potential
• No effect on Na equilibrium potential
• Strichartz (1973) reports use-dependent block
• Blocking and unblocking need open channels
• Drug approaches binding site from inside cell
• Ragsdale (1994) shows point mutations to D4S6
  alter LA block of Nav1.2a channels

20
Use-dependent block of cardiac Na currents by LAs
Control
Control
QX222 0.5 mM
QX222
Hanck et al. J Gen Physiol 199410319-43
21
How LAs inhibit Na currents

• Weidman (1955) shows that LAs reduce Na flux
  during impulses in Purkinje cells
• Taylor (1958) shows that procaine inhibits Na
  currents in squid axons
• No effect on resting membrane potential
• No effect on Na equilibrium potential
• Strichartz (1973) reports use-dependent block
• Blocking and unblocking need open channels
• Drug approaches binding site from inside cell
• Ragsdale (1994) shows point mutations to D4S6
  alter LA block of Nav1.2a channels

22
LA binding to D4S6

• D4S6 point mutations reduce LA binding to Nav1.2,
  1.4
• Binding between F1479 Y1586

Godwin. Biophys Chem 20051131-7 Ragsdale.
Science 19942651724-8 Wang. Pflugers Arch
1998435293-302
23
LA binding to D4S6

• D4S6 point mutations reduce LA binding to Nav1.2,
  1.4
• Binding between F1479 Y1586

Godwin. Biophys Chem 20051131-7 Ragsdale.
Science 19942651724-8 Wang. Pflugers Arch
1998435293-302
24
LA binding to D4S6

• Increasing hydrophobicity permits better fit in
  binding cavity for neutral LAs

Godwin. Biophys Chem 20051131-7
25
Many classes of compounds bind and inhibit Na
channels

• Local anesthetics

Lidocaine
Procaine
26
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

Use-dependent block of frog sciatic axons by
halothane 1
Strichartz. Acta Anaesth Scand 198024402-6
27
Many classes of compounds bind and inhibit Na
channels

• Local anesthetics
• General anesthetics
• Ca channel blockers

28
Many classes of compounds bind and inhibit Na
channels

• Local anesthetics
• General anesthetics
• Ca channel blockers
• ?2 agonists

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
Many classes of compounds bind and inhibit Na
channels

• Local anesthetics
• General anesthetics
• Ca channel blockers
• ?2 agonists
• Tricyclic antidipressants

Duration of sciatic block in rats (min)
A.
L.
D.
Sudoh et al. Pain 200310349-55
30
Many classes of compounds bind and inhibit Na
channels

• Local anesthetics
• General anesthetics
• Ca channel blockers
• ?2 agonists
• Tricyclic antidipressants
• Substance P antagonists

block of action potential
100
A.
L.
D.
50
0

• Arg5, D-Trp7,9 SP
• D. D-Pro2, D-Trp7,9 SP
• L. Lidocaine

.02 .1 .2 .4 1 2
(mM)
Post. Eur J Pharmacol 1985117347-54
31
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
• Batrachotoxin

From www.bio.davidson.edu
32
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
• Batrachotoxin

From chemweb.calpoly.edu
33
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
• Batrachotoxin
• Grayanotoxin

From www.currieecology.org.uk vm.cfsan.fda.gov
34
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
• Batrachotoxin
• Grayanotoxin
• Tetrodotoxin (TTX)

35
Many classes of compounds bind and inhibit Na
channels

• 1.Might these other compounds be used effectively
  for regional anesthesia or pain management?

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

36
Many classes of compounds bind and inhibit Na
channels

• 1.Might these other compounds be used effectively
  for regional anesthesia or pain management?
• 2. Might they be betteror safer than
  conventional local anesthetics?

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

37
Update on local anesthetic pharmacology

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

38
EC50 LA concentrations (in ?M) for block of Na
and K channels
Xenopus laevis sciatic nerve fibers
Observations 1. Potency at Na gt K channel 2. Rank
order the same as for clinical regional
anesthesia 3. Larger, more lipid soluble agents
are more potent
Brau et al. Anesth Analg 199887885-9
Olschewski et al Anesthesiology 199888172-9
39
LA characteristics that sort together
bupivacaine vs. mepivacaine

• Physical and chemical
• ?lipid solubility
• ?protein binding

• Pharmacological toxicological
• ?potency
• ?onset time
• ?duration of action
• ?tendency to produce severe CV toxicity

40
pKa and speed of onset the facts vs. the
textbooks of anesthesiology Strichartz. Anesth
Analg 199071158-70
Temp (oC)
pKa
41
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)
• Selective Nav inhibitors in future?

42
Bupivacaine produces differential onset of block
mepivacaine does not
Br J Anaesth 199881515-21
43
Genomics of human Nav channels

• Only 1 or 2 Nav channel genes in invertebrates
• 9 distinct Nav channel a-subunit genes in mammals
  (10th homologous gene doesnt code for functional
  channel)
• Cell-specific expression and localization of Nav
  channel gene products

Lopreato. Proc Natl Acad Sci 2001987588-92
44
Chromosomes, distribution of neuronal Nav channels
1. Nav1.8, Nav1.9 relatively TTX insensitive
related to neuropathic pain? 2. Nav1.3 TTX
sensitive related to ectopic discharges after
axotomy? 3. Nav1.4 skeletal muscle, 1.5 cardiac
muscle
Lai et al. Curr Opin Neurobiol 200313291-7 Wu,
Pan. Brain Res 20041029251-8
45
Update on local anesthetic pharmacology

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

46
Why do books and chapter persist in defining a
maximal drug dose?

• Depends on site of administration
• Altered by additives
• Depends on patient characteristics
• Altered by diseases
• Tolerable dose is small when given into the
  vertebral artery or into a vein!
• Illogical to speak of one maximal safe dose of
  local anesthetic

Rosenberg. Reg Anesth Pain Med 2004 29564-75
47
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
48
Effects of medical conditions drugs on LA
dosing 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
Update on local anesthetic pharmacology

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

50
LAs bind and inhibit many differing receptors and
channels

• Do not assume LA toxic side effects arise from Na
  channel inhibition!

Anesthesiology 1990 72711-34
51
LAs bind and inhibit many differing receptors and
channels

• Na, K, Ca channels
• G-protein modulation of channels
• Many enzymes
• Adenylyl cyclase
• Guanylyl cyclase
• Lipases

• Many receptors
• Nicotinic acetylcholine
• NMDA
• ß2-adrenergic

Anesthesiology 1990 72711-34
52
LAs bind and inhibit many differing receptors and
channels

• Na, K, Ca channels
• G-protein modulation of channels
• Many enzymes
• Adenylyl cyclase
• Guanylyl cyclase
• Lipases

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

Anesthesiology 1990 72711-34
53
LAs bind and inhibit many differing receptors and
channels

• Do not assume LA toxic side effects arise from Na
  channel inhibition!

Anesthesiology 1990 72711-34
54
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
• Biochemical, electrophysiologic, negative
  inotropic, vascular actions

55
LA blood concentrations producing cardiac arrest
in dogs similar rank order as for potency
µg/mL
Groban. Anesth Analg 2000911103-11
56
Ventricular arrhythmias after supraconvulsant
(2x) doses of LAs
N
Feldman. Anesth Analg 198969794-801
57
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
58
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!

59
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

60
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
61
Lipid emulsion vs. saline after bupivacaine in
rats
CPR
BUPI 15 mg/kg
CPR
CPR
Weinberg. Reg Anesth Pain Med 200227568-75
62
Lipid emulsion vs. saline after bupivacaine in
rats
BUPI 15 mg/kg
LIPID BOLUS
Weinberg. Reg Anesth Pain Med 200227568-75
63
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
64
Update on local anesthetic pharmacology

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

65
Summary

• LAs bind and inhibit Nav channels
• Other drugs that inhibit Nav channels
• Pharmacodynamic effects of medical conditions,
  additives
• Differential block and specific Nav channel types
• Toxicity CNS vs. CV neurotoxicity allergy
• Resuscitation

See http//www1.wfubmc.edu/anesthesiology/researc
h/faculty_presentations.htm