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John Butterworth, MD Professor & Section-Head Section on Cardiothoracic Anesthesiology Wake Forest University School of Medicine Winston-Salem, North Carolina
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William S. Halsted
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
Procaine
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Lidocaine
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Linking bond
Amide bond (see lidocaine) Ester bond (see procaine)
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Procaine
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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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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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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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Cytoplasm
Cytoplasm
Resting potential
Action potential
Na channels open, allow Na flux Within milliseconds, Na channels return to nonconducting inactivated state
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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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Ragsdale (1994) shows point mutations to D4S6 alter LA block of Nav1.2a channels
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QX222 0.5 mM
QX222
Ragsdale (1994) shows point mutations to D4S6 alter LA block of Nav1.2a channels
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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
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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Lidocaine
Procaine
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Fiber types A C
10-5 10-4 10-3 10-2 10-1 Clonidine Concentration (M) Anesth Analg. 1993;76:295-301
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.02
.1 .2 .4 (mM)
From: www.bio.davidson.edu
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Lid
Na K 204
Eti
18
Mep Bup
149 27 92
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60
Tet
0.7
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
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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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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?
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Br J Anaesth 1998;81:515-21
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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
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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
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LA blood concentrations producing cardiac arrest in dogs: similar rank order as for potency
120 100
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80 60 40 20 0 Bup Levo
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Free Total
Rop
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N 3
2 1 0 Bup Rop Lido
V arr No V arr
50 40 30 20 10 0
% of animals
Death EpVF
R LB Li
Treatment of LA CV toxicity
Follow ACLS guidelines
Substitute amiodarone for lidocaine Substitute vasopressin for epinephrine
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BUPI 15 mg/kg
LIPID BOLUS
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:
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http://www1.wfubmc.edu/anesthesiology/ research/faculty_presentations.htm
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