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 use dated to 2000 BC
• Incas believed coca a gift from the Sun god Manco
  Capac available only to 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
• Coca use described by explorer Amerigo Vespucci
  (1505)
• Monardes brings coca leaves back to Europe
  (1580) fails to achieve popularity of tobacco

Erythroxylon coca
4
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)
• Procaine (1905?)
• Dibucaine (1929)
• Lidocaine (1944)
• Bupivacaine (1963)

Carl Koller
5
Local anestheticsamides vs. esters

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

Lidocaine
Procaine
6
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

7
Membrane potentials andionic currents in nerve

• Resting potential
• Characteristic of living cells (-70 mV) arises
  from NaK-ATPase and K leak
• Action potential
• Na currents elicited by depolarization
• Rapidly terminated by Na channel inactivation (K
  channels unneeded for repolarization)

Frog muscle
(A) FROG MUSCLE 5C
EM
70
INa
2 mA/cm2
2 ms
-10
(B) FROG NODE 5C
70
10 nA
2 ms
-30
8
Structural characteristicsof Na channels

• 1 larger ? subunit (260 kD) (has ion conducting
  path)
• 1 or 2 smaller ? subunits (35 kD)
• All subunits are heavily glycosylated

Physiol Rev 199272S15-S48 Ann Rev Biochem
19956493-531 Biophys J 2000791379-87
9
Inactivation gating in D3-D4 link LA binding in
D1-S6 and D4-S6. From Catterall Mackie Ch 15,
p334. Goodman Gilman 9th Edition, 1996
? subunit has 4 domains, each with 6 membrane
spanning ?-helixes (S1-S6)
10
Na channels, local anesthetics, and local
anesthesia
Na channels in Ranvier node

• Local anesthesia
• occurs when LAs
• bind sufficient Na
• channels to prevent
• impulse conduction
• Na channel distribution, impulse conduction, and
  local anesthesia differ for myelinated vs.
  unmyelinated nerves

Black et al. Proc R Soc Lond B 198923839-51
11
Na channel conformations

• 3 Na channel forms resting, open, inactivated
  (deduced by Hodgkin Huxley in 1952!)
• Na currents arise when Na ions pass through open
  Na channels
• LA binding favored by
• Depolarizing potentials (voltage-dependence)
• Open or inactivated forms of Na channels
• More frequent depolarizations (use- or
  frequency-dependence)

12
Use-dependent block of cardiac Na channels by LAs
Control
Control
QX222 0.5 mM
QX222
Hanck et al. J Gen Physiol 199410319-43
13
Tetrodotoxin (TTX) binds Na channels selectively

• Squid axons have both Na currents (early, inward)
  and K currents (later, outward)
• TTX inhibits only Na (early, inward) currents
• 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
14

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

15
Adaptation to TTX a coevolutionary arms race
with toxic newts

• Garter snakes (Thamnophis sirtalis) have a taste
  for newts (Taricha granulosa)
• T. granulosa skin contains TTX bad for most
  snakes!
• Some T. sirtalis species are resistant to TTX
• Evolution to a future of risk free fugu sashimi?

T. sirtalis
T. Granulosa
Geffeney. Science 20022971336-9
16
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

17
Why my appreciation for LAs increased on 2 July
2002
18
General characteristics of local anesthesia

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

19
Potency vs. lipid solubility of procaine,
lidocaine, and etidocaine

• More potent (Pot) LAs tend to be more lipid
  soluble (Sol)
• Greater octanol-water partition coefficients also
  correlate with longer onset delay and greater
  protein binding (Bdg)

Relative to procaine 1
20
If pKa determines speed of onset, why do
chloroprocaine and etidocaine have a faster onset
than mepivacaine? Strichartz. Anesth Analg
199071158-70
Temp (oC)
pKa
21
What does binding to serum proteins have to do
with binding to the Na channel? Nothing!
22
Pharmacodynamic characteristics of LAs

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

23
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

24
Effects of pH on LA action

• ?pH increases fraction of free base (neutral) LA
• Free base LA has greater membrane permeability
  than protonated LA
• Generally faster onset of anesthesia if
  bicarbonate added (esp. LA epi compounded at
  factory)
• But protonated LA more potent at inhibiting Na
  channels inside cell

25
Alkaline pH increases procaine potency in frog
sciatic axons
pH
inhibition
mM
Butterworth. Anesthesiology 198868501-6
26
Influence of pregnancy on local anesthetic
activity

• Increased spread of neuraxial blocks in pregnancy
  (probably due to CSF volume)
• Progesterone increases bupivacaine potency in
  rabbits
• Increased lidocaine potency at median nerve in
  pregnant women

inhibition
Elapsed time (min)
From Butterworth. Anesthesiology 199072962-5
27
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
• Myelinated A? fibers more LA-sensitive than A?
  or C fibers (smaller fibers of a given type are
  more LA-sensitive)

28
Bupivacaine produces differential onset of block
mepivacaine does not
Br J Anaesth 199881515-21
29
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

30
Local anesthetic pharmacokinetics

• Differences between LAs and other drugs
• Sites of injection and LA concentrations in blood
• Protein binding
• Metabolism
• Disease states and pregnancy

31
LAs are differentfrom other drugs

• LAs lack efficacy when not administered on or
  near site of action
• CNS and CV toxicity arise from absorption and
  systemic distribution
• Appropriate local or regional doses produce
  marked toxicity if given at another site or into
  a blood vessel

32
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
33
Protein binding of LAs

• Erroneously over-emphasized in relation to
  mechanism of LA duration of action
• All LAs are lipid soluble, so all are
  protein-bound to some extent
• ?1-acid glycoprotein
• albumin
• A greater fraction of more potent LAs is protein
  bound (than less potent LAs)
• Protein binding declines during pregnancy (but
  not by much!)

34
Protein binding of lidocaine (2 ?g/ml) decreases
during pregnancyFragneto et al. Anesth Analg
199479295-7

Trimester
35
LA metabolism

• Esters (half-lives in seconds to minutes)
• Hydolyzed 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 metabolites (prilocaine ? o-toluidine)

36
Effects of pregnancy, drugs, and organ failure on
LA kinetics

• Renal failure increases Vd accumulation of
  metabolic products
• Hepatic failure increases amide Vd, decreases
  clearance
• Cardiac failure decreases amide clearance
• Cholinesterase deficiency or inhibition decrease
  ester clearance
• Pregnancy increases amide clearance
• ? and H2 blockers decrease amide clearance

37
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

38
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

• CV toxicity requires greater LA doses and
  concentrations than CNS toxicity
• Convulsive LA dose inversely related to LA
  potency
• Acidosis, hypercarbia ? convulsive dose

39
LA doses and blood concentrations producing
convulsions in sheep similar rank order as for
potency
Rutten. Anesth Analg 198969291-9
40
Acidosis and hypercarbia reduce the convulsive
dose of lidocaine in cats Englesson Grevsten.
Acta Anaesthesiol Scand 1974 1888-103
41
Cardiovascular toxicity from LAs

• Bupivacaine vs. lidocaine more avid binding,
  delayed unbinding from cardiac Na channels
• S- isomers (levo-bupivacaine and ropivacaine)
  less potent at CV toxicity than R isomers or
  racemic mixes
• LAs inhibit conduction system, contractility,
  cAMP formation, multiple enzyme systems
• LAs vasoconstrict (low dose) dilate (high dose)
• Mechanism of LA-induced cardiac death
• Arrhythmias?
• Left-ventricular depression?
• Resuscitation drug failure?

42
(No Transcript)
43
Mortality, arrhythmias and LV depression in
anesthetized dogs

• 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
• Epi-induced VF (EpVF), death more common with B
  than R or Li

of animals
Groban. Anesth Analg 2000911103 Anesth Analg
20019237 RAPM 2002 (in press)
44
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!

• 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

45
Allergy to LAs

• Frequently a misdiagnosis of toxic reactions to
  LAs or epinephrine
• Cross reaction between PABA and methylparaben (a
  preservative sometimes included with amide LAs)
• True allergy (including anaphylaxis) more common
  with esters (particularly those related to PABA)
  than amides

46
(No Transcript)
47
Evaluation of 90 patients referred for LA
hypersensitivity

• 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
48
Treatment of LA toxicity

• Depends on severity
• Allow minor reactions to IV LAs to dissipate
  spontaneously
• Seizures maintain airway provide O2
• May terminate sz with thiopental or midazolam
• May need to intubate (succinylcholine?)
• Cardiac toxicity follow ACLS guidelines (note
  use of amiodarone for arrhythmias and
  epinephrine/vasopressin)
• Allergy steroids, H1 blockers, epinephrine
  (depending on severity)

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
Summary

• LAs bind and inhibit Na channels voltage-,
  state-, and frequency-dependence (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
• Pharmacokinetics esters vs. amides
• Toxicity CNS vs. CV neurotoxicity allergy

51
Local anesthetics agents, actions,
misconceptions

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

52
Effects of pH on LA action

• With ?pH, ?fraction of LA in free base (neutral)
  form
• Free base has greater membrane permeability than
  protonated LA
• Generally faster onset of anesthesia if
  bicarbonate added (esp. LAepi)
• Faster onset lt ?free base LA
• But protonated LA more potent at inhibiting Na
  channels inside cell

53
Effects of pH on LA action

• With ?pH, ?fraction of LA in free base (no
  positive charge) form
• Free base has greater membrane permeability than
  protonated LA
• Generally faster onset of clinical anesthesia
  when bicarbonate added (esp. LAepi)
• Faster onset lt ?free base LA
• Protonated LA more potent at inhibiting Na
  channels inside cell

54
Two ways that LAs inhibitNa currents

• Tonic (infrequent depolarizations)
• Phasic, use-dependent, or frequency-dependent
  (greater inhibition during trains of
  depolarizations gt0.5 Hz)
• With frequent depolarizations Na channels spend
  more time open or inactivated
• With each succeeding impulse additional LA-free
  Na channels open and bind LAs

55
Pregnancy increases 1 lidocaine inhibition of
human median nerve sensory fibers
inhibition
Elapsed time (min)
Butterworth. Anesthesiology 199072962-5
56
History of cocaine anesthesia-1

• South America and the Incas
• Coca a gift from the Sun god Manco Capac
• Available only to religious aristocracy in Incan
  society
• Spaniards pay lower classes and slaves with coca
  paste to increase output
• Coca mixed with corn starch or guano, chewed with
  lime or ash, first example of free basing
• Chewed coca dripped on trephination sites

57
Effects of pH on LA action

• ?pH reduces fraction of free base (neutral) LA
• Free base LA has greater membrane permeability
  than protonated LA
• Generally faster onset of anesthesia if
  bicarbonate added (esp. LA epi compounded at
  factory)
• But protonated LA more potent at inhibiting Na
  channels inside cell

58
Membrane potentials andionic currents in nerve

• Resting potential Characteristic of living cells
  (-70 mV) arises from NaK-ATPase and K leak
• Action potential Na currents elicited by
  depolarization
• Rapidly terminated by Na channel inactivation (K
  channels not necessary for repolarization in
  mammals)
• Na channels and currents similar amongst
  differing species

Frog muscle
(A) FROG MUSCLE 5C
EM
70
INa
2 mA/cm2
2 ms
-10
(B) FROG NODE 5C
70
10 nA
2 ms
-30
59
Membrane potentials andionic currents in nerve

• Resting potential
• Characteristic of living cells (-70 mV) arises
  from NaK-ATPase and K leak
• Action potential
• Na currents elicited by depolarization
• Rapidly terminated by Na channel inactivation (K
  channels unneeded for repolarization)

60
Many classes of compounds bind and inhibit Na
channels

• Local anesthetics
• General anesthetics
• Dihydropyridine Ca channel blockers
• ?2 agonists
• Toxins
• Tetrodotoxin (puffer fish, amphibians), saxitoxin
  (red tide)
• Batrachotoxin (frog), grayanotoxin
  (rhodedendron), scorpion toxins, etc.