Local anesthetic clinical pharmacology: do the new ones make any difference

1
Local anesthetic clinical pharmacology do the
new ones make any difference?

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

2
Local anesthetic clinical pharmacology do the
new ones make any difference?

• History and general considerations
• Na channels, cellular electrophysiology, local
  anesthetic actions
• General characteristics of local anesthesia
• Levobupivacaine and ropivacaine
• Summary

3
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
• A founder of ASRAPM
• Editor in Chief Regional Anesthesia

4
History of local anesthesia-1

• Indigenous plant in South America
• Available only to Incan aristocracy
• 1500s Spaniards seize plantations pay workers
  with coca paste
• Coca mixed with corn starch or guano, chewed with
  lime or ash first example of free basing
• Chewed coca dripped on trephination sites
• Monardes brings coca leaves back to Europe
  (1580) fails to achieve instant popularity of
  tobacco

Erythroxylon coca
5
History of local anesthesia-2

• Cocaine HCl isolated by Albert Niemann (1860)
• Merck produces 0.25 lbs cocaine (1862)
• Koller and Gartner report local anesthesia (1884)
• Merck produces 3179 lbs (1884) 158,362 lbs
  (1886)
• Pemberton introduces Coca-Cola (1886)

Cocaine HCl powder
6
History of local anesthesia-2

• Cocaine HCl isolated by Albert Niemann (1860)
• Merck produces 0.25 lbs cocaine (1862)
• Koller and Gartner report local anesthesia (1884)
• Merck produces 3179 lbs (1884) 158,362 lbs
  (1886)
• Pemberton introduces Coca-Cola (1886)

Cocaine HCl powder
Carl Koller 1857 -1944
7
History of local anesthesia-2

• Cocaine HCl isolated by Albert Niemann (1860)
• Merck produces 0.25 lbs cocaine (1862)
• Koller and Gartner report local anesthesia (1884)
• Merck produces 3179 lbs (1884) 158,362 lbs
  (1886)
• Pemberton introduces Coca-Cola (1886)

8
Chronology of local anesthetics
After Cartwright Fyhr. Reg Anesth 1988131-12
9
Local anestheticsamides vs. esters

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

Lidocaine
Procaine
10
Local anesthetic clinical pharmacology do the
new ones make any difference?

• History and general considerations
• Na channels, cellular electrophysiology, local
  anesthetic actions
• General characteristics of local anesthesia
• Levobupivacaine and ropivacaine
• Summary

11
Membrane potentials andionic currents in neurons

• Resting potential
• Characteristic of living
• cells (-70 mV) arises
• from Na-K ATPase
• and K leak
• Action potential
• With sufficient depolarization Na channels
  activate, open, allow Na flux
• Within milliseconds, Na channels inactivate,
  return to nonconducting state

Potential (in mV)
Squid axon, 16o
Time after stimulus (ms)
12
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

Physiol Rev 199272S15-S48 Ann Rev Biochem
19956493-531 Biophys J 2000791379-87
13
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
14
Na channel conformations

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

AL Hodgkin 1914-1998
AF Huxley 1917-
Shared Nobel Prize in 1963
15
Na channel conformations

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

GR Strichartz Brigham and Womens
Hospital Harvard Medical School
16
Use-dependent block of cardiac Na channels by LAs
Control
Control
QX222 0.5 mM
QX222
Hanck et al. J Gen Physiol 199410319-43
17
Many classes of compounds bind and inhibit Na
channels

• Local anesthetics
• General anesthetics
• Ca channel blockers verapamil
• ?2 agonists
• Antidipressants amitriptyline
• Substance P antagonists
• Toxins
• TTX, STX
• Batrachotoxin, grayanotoxin

Inhibition of Action Potential
Fiber types ? Aa ? C
10-5 10-4 10-3 10-2 10-1 Clonidine
Concentration (M)
18

• Tetrodotoxin (TTX)
• Fugu (puffer fish) sushi a delicacy, but contains
  TTX
• Chefs undergo a long apprenticeship to reduce
  fatalities
• Nevertheless, 5-10 Japanese die each year from
  TTX after eating fugu

19
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 for Na
  channels than LAs

(A) Time (ms)
0
5
10
I(nA)
10
0
Control
-10
(B)
300 nM TTX
20
Local anesthetic clinical pharmacology do the
new ones make any difference?

• History and general considerations
• Na channels, cellular electrophysiology, local
  anesthetic actions
• General characteristics of local anesthesia
• Levobupivacaine and ropivacaine
• Summary

21
Why my appreciation for LAs increased after 1
July 2002
22
General characteristics of local anesthesia

• LA potency
• LA speed of onset
• LA duration of action
• Tendency of LA to produce differential block

23
Local anesthetic potency correlates with 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
24
Protein binding increases with increasing lipid
solubility
25
pKa and speed of onset the facts vs. the
textbooks of anesthesiology Strichartz. Anesth
Analg 199071158-70
Temp (oC)
pKa
26
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

27
Factors influencing LA activity

• Increasing dose ?latency of onset ?duration,
  ?block success, ?LA
• Vasoconstrictors ?duration, block success ?LA
• Site of injection influences dose, onset,
  duration, success rate, LA
• Alkalinization (NaHCO3) ?latency of onset
  ?potency
• Pregnancy ?dermatomal spread, ?LA potency, ?free
  blood LA

28
Pregnancy and local anesthesia

• Increased spread of neuraxial blocks in pregnancy
  (probably due to CSF volume)
• Progesterone increases bupivacaine potency in
  animals
• Lidocaine more potent at median nerve block in
  pregnant women

inhibition
Elapsed time (min)
Butterworth. Anesthesiology 199072962-5
29
Differential block

• Goal analgesia without motor block
• Successful for postop and labor analgesia
• Differential sensory block during onset of
  bupivacaine (contrast mepivacaine)
• No intraoperative differential block at steady
  state when the block fully set up
• Smaller fibers of a given type are more
  LA-sensitive than larger (A? fibers more
  LA-sensitive than A? or C fibers)

30
Bupivacaine produces differential onset of block
mepivacaine does not
Br J Anaesth 199881515-21
31
Local anesthetic clinical pharmacology do the
new ones make any difference?

• History and general considerations
• Na channels, cellular electrophysiology, local
  anesthetic actions
• General characteristics of local anesthesia
• Levobupivacaine and ropivacaine
• Summary

32
Levobupivacaine and ropivacaine

• Less toxic than bupivacaine?
• As potent as bupivacaine?
• Should we replace bupivacaine?

33
LA doses and blood concentrations with
convulsions in sheep (?45 kg)
Rutten. Anesth Analg 198969291-9
34
Local anesthetic concentrations and cardiac
arrest in dogs
µg/mL
Groban et al Anesth Analg 2000911103-11
35
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
36
Relative potency of ropivacaine, levobupivacaine,
and bupivacaine

• No local anesthetic equivalent of mean alveolar
  concentration (MAC)
• Available data are confusing studies poorly
  designed
• Supramaximal concentrations used in clinic
• Opioids and other additives
• Onset time and motor block are NOT substitutes
  for potency
• Potency ratios remain unknown

37
Should we replace bupivacaine?

• Not needed
• Small doses (spinal, ankle, wrist)
• Reduced concentration (cervical plexus)
• Reasonable
• Large doses (sciatic femoral)
• Multiples blocks
• How much are you willing to spend?

38
Local anesthetic clinical pharmacology do the
new ones make any difference?

• History and general considerations
• Na channels, cellular electrophysiology, local
  anesthetic actions
• General characteristics of local anesthesia
• Levobupivacaine and ropivacaine
• Summary

39
Summary

• LAs and Na channels voltage-, state-, and
  use-dependent block
• Potency, lipid solubility, protein binding, onset
  time, duration, CV toxicity tend to sort together
• No direct mechanistic action of pKa on onset or
  protein binding on duration of action
• Pharmacodynamic effects of dose, pH,
  vasoconstrictors, pregnancy
• Differential block
• Ropivacaine and levobupivacaine vs bupivacaine

40
Local anesthetic clinical pharmacology do the
new ones make any difference?

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

41
Bicarbonate reduces fractionof protonated LA
speeds onset

• Protonated 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)

42
Alkaline pH increases procaine potency in frog
sciatic axons
pH
inhibition
mM
Butterworth. Anesthesiology 198868501-6
43
LA-induced arrhythmias, LV depression,
mortality in dogs

• LA infusion more inducible arrhythmias with B,
  LB than R,L
• When MAPlt45 mmHg, ACLS epi used to restore
  MAPgt55
• Continued epi more often needed for Li (86)
  than others
• More epi-induced VF (EpVF) death with B than R
  or Li

of animals
Groban. Anesth Analg 2000911103 Anesth Analg
20019237 RAPM 200227460