Title: Local anesthetic clinical pharmacology: do the new ones make any difference
1Local 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
2Local 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
3Benjamin 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
4History 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
5History 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
6History 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
7History 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)
8Chronology of local anesthetics
After Cartwright Fyhr. Reg Anesth 1988131-12
9Local anestheticsamides vs. esters
- Common structure
- Aromatic ring
- Tertiary amine
- Alkyl chain
- Linking bond
- Amide bond (see lidocaine)
- Ester bond (see procaine)
Lidocaine
Procaine
10Local 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
11Membrane 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)
12Structural 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
13From 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
14Na 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
15Na 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
16Use-dependent block of cardiac Na channels by LAs
Control
Control
QX222 0.5 mM
QX222
Hanck et al. J Gen Physiol 199410319-43
17Many 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
19TTX 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
20Local 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
21Why my appreciation for LAs increased after 1
July 2002
22General characteristics of local anesthesia
- LA potency
- LA speed of onset
- LA duration of action
- Tendency of LA to produce differential block
23Local 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
24Protein binding increases with increasing lipid
solubility
25pKa and speed of onset the facts vs. the
textbooks of anesthesiology Strichartz. Anesth
Analg 199071158-70
Temp (oC)
pKa
26Characteristics 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
27Factors 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
28Pregnancy 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
29Differential 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)
30Bupivacaine produces differential onset of block
mepivacaine does not
Br J Anaesth 199881515-21
31Local 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
32Levobupivacaine and ropivacaine
- Less toxic than bupivacaine?
- As potent as bupivacaine?
- Should we replace bupivacaine?
33LA doses and blood concentrations with
convulsions in sheep (?45 kg)
Rutten. Anesth Analg 198969291-9
34Local anesthetic concentrations and cardiac
arrest in dogs
µg/mL
Groban et al Anesth Analg 2000911103-11
35Bupivacaine 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
36Relative 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
37Should 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?
38Local 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
39Summary
- 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
40Local 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
41Bicarbonate 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)
42Alkaline pH increases procaine potency in frog
sciatic axons
pH
inhibition
mM
Butterworth. Anesthesiology 198868501-6
43LA-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