Update On Local Anesthetic Pharmacology

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

History and general considerations Na channels, cellular electrophysiology, & local anesthetic actions General characteristics of local anesthesia LA pharmacokinetics LA cardiovascular toxicity See: Summary
http://www1.wfubmc.edu/anesthesiology/ research/faculty_presentations.htm
W A K E F O R E S T U N I V E R S I T Y S C H O O L O F M E D I C I N E
Early history of regional anesthesia

Koller and Gartner report local anesthesia (1884)
Carl Koller 1857 -1944
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Koller and Gartner report local anesthesia (1884) 1884 Halsted injects cocaine directly into mandibular nerve and brachial plexus
William S. Halsted

Koller and Gartner report local anesthesia (1884) 1884 Halsted injects cocaine directly into mandibular nerve and brachial plexus 1904 Einhorn discovers procaine (Novocaine)
Procaine
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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)
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Lidocaine
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Chronology of local anesthetics

Cocaine Benzocaine Procaine Tetracaine Lidocaine Chloroprocaine Mepivacaine Bupivacaine Ropivacaine Niemann Salkowski Einhorn Eisler Lofgren Marks, Rubin Ekenstam Ekenstam Sandberg 1860 1895 1904 1928 1943 1949 1956 1957 1989 Ester Ester Ester Ester Amide Ester Amide Amide Amide
After: Cartwright & Fyhr. Reg Anesth 1988;13:1-12

Local anesthetics: amides vs. esters

Common structure
Aromatic ring Tertiary amine Alkyl chain
Lidocaine
Linking bond
Amide bond (see lidocaine) Ester bond (see procaine)
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Procaine
O F
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History and general considerations Na channels, cellular electrophysiology, & local anesthetic actions General characteristics of local anesthesia LA pharmacokinetics LA cardiovascular toxicity Summary
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 2001;98:7588-92 Viswanathan & Balser. Trends Cardiovasc Med 2004;14:28-35
Structural characteristics of 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 1992;72:S15-S48 Ann Rev Biochem 1995;6:493-531 Biophys J 2000;79:1379-87; J Exp Biol 2002;205:574-84
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4 domains have 6 membranespanning -helical segments (S1-S6) S5-S6 P-loop part of ion-conducting pore
Cytoplasm
Plummer, Meisler. Genomics 1999;57:323-31


4 domains have 6 membranespanning -helical segments (S1-S6) S5-S6 P-loop part of ion-conducting pore
Cytoplasm
Plummer, Meisler. Genomics 1999;57:323-31

Membrane potentials and ionic currents in neurons

Characteristic of living cells (-70 mV) Na-K ATPase and K leak
Potential (in mV)
Resting potential
Squid axon, 16o
Action potential
Time after stimulus (ms)
Na channels open, allow Na flux Within milliseconds, Na channels return to nonconducting inactivated state
Na channel conformations
3 channel forms: resting, open, & inactivated (1952) Na+ ions pass only through open channels Membrane potential (or voltage) determines the conformation
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AL Hodgkin AF Huxley 19171914-1998 Nobel Prize 1963
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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: S4S3 hairpin loop, supports paddle
rhem. Lancet 2004;363:1221-3 Jiang. Nature 2003;423:33-41
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
Use-dependent block of cardiac Na currents by LAs

Control Control
QX222 0.5 mM
QX222
Hanck et al. J Gen Physiol 1994;103:19-43

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
LA binding to D4S6
D4S6 point mutations reduce LA binding to Nav1.2, 1.4 Binding between F1479 & Y1586
Godwin. Biophys Chem 2005;113:1-7 Ragsdale. Science 1994;265:1724-8 Wang. Pflugers Arch 1998;435:293302
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LA binding to D4S6
D4S6 point mutations reduce LA binding to Nav1.2, 1.4 Binding between F1479 & Y1586
Godwin. Biophys Chem 2005;113:1-7 Ragsdale. Science 1994;265:1724-8 Wang. Pflugers Arch 1998;435:293302
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LA binding to D4S6
Increasing hydrophobicity permits better fit in binding cavity for neutral LAs
Godwin. Biophys Chem 2005;113:1-7
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Many classes of compounds bind and inhibit Na channels

Local anesthetics
Lidocaine
Procaine
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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 1980;24:402-6

S C H O O L O F M E D I C I N E

Local anesthetics General anesthetics Ca channel blockers
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% Inhibition of Action Potential
Local anesthetics General anesthetics Ca channel blockers 2 agonists
Fiber types A C
10-5 10-4 10-3 10-2 10-1 Clonidine Concentration (M) Anesth Analg. 1993;76:295-301

Local anesthetics General anesthetics Ca channel blockers 2 agonists Tricyclic antidipressants
Duration of sciatic block in rats (min) A. D. L. 250
200 150 100 Pro Mot Noc 50 0 Bup Ami Imi Des
Sudoh et al. Pain 2003;103:49-55


Local anesthetics % block of action potential General anesthetics 100 Ca channel blockers A. D. L. 2 agonists 50 Tricyclic antidipressants Substance P antagonists
A. SP D. D-Pro2, D-Trp7,9 SP L. Lidocaine Arg5, D-Trp7,9 0
.02
.1 .2 .4 (mM)
Post. Eur J Pharmacol 1985;117:347-54


Batrachotoxin
From: www.bio.davidson.edu

Batrachotoxin
From: chemweb.calpoly.edu

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

1.Might these other Local anesthetics compounds be used General anesthetics effectively for regional Ca channel blockers anesthesia or pain 2 agonists management? Tricyclic antidipressants Substance P antagonists Many nerve toxins
Batrachotoxin Grayanotoxin Tetrodotoxin (TTX)

1.Might these other Local anesthetics compounds be used General anesthetics effectively for regional Ca channel blockers anesthesia or pain 2 agonists management? Tricyclic antidipressants 2. Might they be Substance P antagonists betteror safer than conventional local Many nerve toxins anesthetics? Batrachotoxin
Grayanotoxin Tetrodotoxin (TTX)

EC50 LA concentrations (in M) for block of Na and K channels

Xenopus laevis sciatic nerve fibers
Lid
Na K 204
Eti
18
Mep Bup
149 27 92
Pro
60
Tet
0.7
1118 176 2305
6303 946
Observations 1. Potency at Na > 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 1998;87:885-9 Olschewski et al Anesthesiology 1998:88:172-9

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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
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pKa and speed of onset: the facts vs. the textbooks of anesthesiology
Strichartz. Anesth Analg 1990;71:158-70
Temp (oC)
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pKa O O L S C H
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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 LAsensitive than larger (A fibers more LAsensitive than A fibers) Selective Nav inhibitors in future?
Bupivacaine produces differential onset of block; mepivacaine does not
Br J Anaesth 1998;81:515-21
Genomics of human Nav channels

Only 1 or 2 Nav channel genes in invertebrates 9 distinct Nav channel -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 2001;98:7588-92

Chromosomes, distribution of neuronal Nav channels

Nav1.1 Nav1.2 2 2 Nav1.3 2 Nav1.6 15 Nav1.7 2 Nav1.8 9 Nav1.9 9
Adult DRG DRG, DRG, CNS, DRG CNS, (80% (small), motor, CNS DRG, CNS Injured small, hippoc. motor CNS DRG 20% lg) 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 2003;13:291-7 Wu, Pan. Brain Res 2004;1029:251-8

History and general considerations Na channels, cellular electrophysiology, & local anesthetic actions General characteristics of local anesthesia LA pharmacokinetics and dosing LA cardiovascular toxicity Summary
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; 29:564-75
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 1972;37:277
Effects of medical conditions & drugs on LA dosing & kinetics

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

LAs bind and inhibit many differing receptors and channels

Do not assume LA toxic side effects arise from Na channel inhibition!
Anesthesiology 1990; 72:711-34


Na, K, Ca channels G-protein modulation of channels Many enzymes Many receptors
Nicotinic acetylcholine NMDA 2-adrenergic
Adenylyl cyclase Guanylyl cyclase Lipases Anesthesiology 1990; 72:711-34


Na, K, Ca channels G-protein modulation of channels Many enzymes Many receptors
Nicotinic acetylcholine NMDA 2-adrenergic
Adenylyl cyclase Guanylyl cyclase Lipases Anesthesiology 1990; 72:711-34

Important for spinal, epidural, or systemic effects?

Do not assume LA toxic side effects arise from Na channel inhibition!
Anesthesiology 1990; 72:711-34

Cardiovascular toxicity from 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

LA blood concentrations producing cardiac arrest in dogs: similar rank order as for potency
120 100
g/mL
80 60 40 20 0 Bup Levo
U N I V E R S I T Y
Free Total
Rop
S C H O O L
Lid
O F M E D I C I N E
Groban. Anesth Analg 2000;91:1103-11

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Ventricular arrhythmias after supraconvulsant (2x) doses of LAs

6 5 4
N 3
2 1 0 Bup Rop Lido
V arr No V arr
Feldman. Anesth Analg 1989;69:794-801

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
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50 40 30 20 10 0
% of animals
Death EpVF
R LB Li
Groban. Anesth Analg 2000;91:1103; Anesth Analg 2001;92:37; RAPM 2002;27:460

U N I V E R S I T Y S C H O O L O F M E D I C I N E
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!
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
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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 1998;88:1071-5 Weinberg. Reg Anesth Pain Med 2003;28:198-202
Lipid emulsion vs. saline after bupivacaine in rats

CPR BUPI 15 mg/kg CPR CPR
Weinberg. Reg Anesth Pain Med 2002;27:568-75

Lipid emulsion vs. saline after bupivacaine in rats
BUPI 15 mg/kg
LIPID BOLUS
Weinberg. Reg Anesth Pain Med 2002;27:568-75

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 1998;88:1071-5 Weinberg. Reg Anesth Pain Med 2003;28:198-202

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:
W A K E F O R E S T U N I V E R S I T Y S C H O O L O F
http://www1.wfubmc.edu/anesthesiology/ research/faculty_presentations.htm
M E D I C I N E

Update On Local Anesthetic Pharmacology

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Update on local anesthetic pharmacology