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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

Update on local anesthetic pharmacology:

Update on local anesthetic pharmacology History and general considerations Na channels, cellular electrophysiology, & local anesthetic actions General characteristics of local anesthesia LA pharmacokinetics LA cardiovascular toxicity Summary See: http://www1.wfubmc.edu/anesthesiology/research/faculty_presentations.htm

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Early history of regional anesthesia Koller and Gartner report local anesthesia (1884) Carl Koller 1857 -1944

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Early history of regional anesthesia Koller and Gartner report local anesthesia (1884) 1884 Halsted injects cocaine directly into mandibular nerve and brachial plexus William S. Halsted

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Early history of regional anesthesia 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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Early history of regional anesthesia 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) Lidocaine

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

Local anesthetics: amides vs. esters:

Local anesthetics: amides vs. esters Common structure Aromatic ring Tertiary amine Alkyl chain Linking bond Amide bond ( see lidocaine ) Ester bond ( see procaine ) Lidocaine Procaine

Update on local anesthetic pharmacology:

Update on local anesthetic pharmacology 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:

Voltage-gated Na (Na v ) 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:

Structural characteristics of Na v 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

Structural characteristics of Nav channels:

Structural characteristics of Na v 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

Structural characteristics of Nav channels:

Structural characteristics of Na v 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

Structural characteristics of Nav channels:

Structural characteristics of Na v channels 4 domains have 6 membrane- spanning α -helical segments (S1-S6) S5-S6 P-loop part of ion-conducting pore Plummer, Meisler. Genomics 1999;57:323-31 Cytoplasm

Structural characteristics of Nav channels:

Structural characteristics of Na v channels 4 domains have 6 membrane- spanning α -helical segments (S1-S6) S5-S6 P-loop part of ion-conducting pore Plummer, Meisler. Genomics 1999;57:323-31 Cytoplasm

Membrane potentials and ionic currents in neurons:

Membrane potentials and ionic currents in neurons Resting potential Characteristic of living cells (-70 mV) Na-K ATPase and K “leak” Action potential Na channels open , allow Na flux Within milliseconds, Na channels return to nonconducting inactivated state Potential (in mV) Squid axon, 16 o Time after stimulus (ms)

Na channel conformations:

Na channel conformations 3 channel forms: resting , open , & inactivated (1952) Na + ions pass only through open channels Membrane potential (or voltage) determines the conformation AL Hodgkin 1914-1998 AF Huxley 1917- Nobel Prize 1963

Latest model for voltage-gating of ion channels:

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: S4-S3 hairpin loop, supports “paddle” Århem. Lancet 2004;363:1221-3 Jiang. Nature 2003;423:33-41

How LAs inhibit Na currents:

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 Na v 1.2a channels

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Use-dependent block of cardiac Na currents by LAs Hanck et al. J Gen Physiol 1994;103:19-43 Control Control QX222 0.5 mM QX222

How LAs inhibit Na currents:

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 Na v 1.2a channels

LA binding to D4S6:

LA binding to D4S6 D4S6 point mutations reduce LA binding to Na v 1.2, 1.4 Binding between F1479 & Y1586 Godwin. Biophys Chem 2005;113:1-7 Ragsdale. Science 1994;265:1724-8 Wang. Pflugers Arch 1998;435:293-302

LA binding to D4S6:

LA binding to D4S6 D4S6 point mutations reduce LA binding to Na v 1.2, 1.4 Binding between F1479 & Y1586 Godwin. Biophys Chem 2005;113:1-7 Ragsdale. Science 1994;265:1724-8 Wang. Pflugers Arch 1998;435:293-302

LA binding to D4S6:

LA binding to D4S6 Increasing hydrophobicity permits better “fit” in binding cavity for neutral LAs Godwin. Biophys Chem 2005;113:1-7

Many classes of compounds bind and inhibit Na channels:

Many classes of compounds bind and inhibit Na channels Local anesthetics Lidocaine Procaine

Many classes of compounds bind and inhibit Na channels:

Many classes of compounds bind and inhibit Na channels Local anesthetics General anesthetics Ca channel blockers  2 agonists Tricyclic antidipressants Substance P antagonists Many nerve toxins Tetrodotoxin Batrachotoxin Grayanotoxin Strichartz. Acta Anaesth Scand 1980;24:402-6 Use-dependent block of frog sciatic axons by halothane 1%

Many classes of compounds bind and inhibit Na channels:

Many classes of compounds bind and inhibit Na channels Local anesthetics General anesthetics Ca channel blockers

Many classes of compounds bind and inhibit Na channels:

Many classes of compounds bind and inhibit Na channels Local anesthetics General anesthetics Ca channel blockers  2 agonists % Inhibition of Action Potential 10 -5 10 -4 10 -3 10 -2 10 -1 Clonidine Concentration (M) Fiber types ○ A α ● C Anesth Analg. 1993;76:295-301

Many classes of compounds bind and inhibit Na channels:

Many classes of compounds bind and inhibit Na channels Local anesthetics General anesthetics Ca channel blockers  2 agonists Tricyclic antidipressants L. D. A. Sudoh et al. Pain 2003;103:49-55 Duration of sciatic block in rats (min)

Many classes of compounds bind and inhibit Na channels:

Many classes of compounds bind and inhibit Na channels Local anesthetics General anesthetics Ca channel blockers  2 agonists Tricyclic antidipressants Substance P antagonists % block of action potential 100 50 .02 .1 .2 .4 1 2 (mM) L. Arg 5 , D-Trp 7,9 SP D. D-Pro 2 , D-Trp 7,9 SP L. Lidocaine D. A. Post. Eur J Pharmacol 1985;117:347-54 0

Many classes of compounds bind and inhibit Na channels:

Many classes of compounds bind and inhibit Na channels Local anesthetics General anesthetics Ca channel blockers  2 agonists Tricyclic antidipressants Substance P antagonists Many nerve toxins Batrachotoxin From: www.bio.davidson.edu

Many classes of compounds bind and inhibit Na channels:

Many classes of compounds bind and inhibit Na channels Local anesthetics General anesthetics Ca channel blockers  2 agonists Tricyclic antidipressants Substance P antagonists Many nerve toxins Batrachotoxin From: chemweb.calpoly.edu

Many classes of compounds bind and inhibit Na channels:

Many classes of compounds bind and inhibit Na channels Local anesthetics General anesthetics Ca channel blockers  2 agonists Tricyclic antidipressants Substance P antagonists Many nerve toxins Batrachotoxin Grayanotoxin From: www.currieecology.org.uk & vm.cfsan.fda.gov

Many classes of compounds bind and inhibit Na channels:

Many classes of compounds bind and inhibit Na channels Local anesthetics General anesthetics Ca channel blockers  2 agonists Tricyclic antidipressants Substance P antagonists Many nerve toxins Batrachotoxin Grayanotoxin Tetrodotoxin (TTX)

Many classes of compounds bind and inhibit Na channels:

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

Many classes of compounds bind and inhibit Na channels:

Many classes of compounds bind and inhibit Na channels Local anesthetics General anesthetics Ca channel blockers  2 agonists Tricyclic antidipressants Substance P antagonists Many nerve toxins Batrachotoxin Grayanotoxin Tetrodotoxin (TTX) 1.Might these other compounds be used effectively for regional anesthesia or pain management? 2. Might they be “better”or safer than conventional local anesthetics?

Update on local anesthetic pharmacology:

Update on local anesthetic pharmacology History and general considerations Na channels, cellular electrophysiology, & local anesthetic actions General characteristics of local anesthesia LA pharmacokinetics LA cardiovascular toxicity Summary

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

EC 50 LA concentrations (in  M) for block of Na and K channels Lid Eti Mep Bup Pro Tet Na 204 18 149 27 60 0.7 K 1118 176 2305 92 6303 946 Brau et al. Anesth Analg 1998;87:885-9 Olschewski et al Anesthesiology 1998:88:172-9 Xenopus laevis sciatic nerve fibers 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

LA characteristics that sort together: bupivacaine vs. mepivacaine:

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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pK a and speed of onset: the facts vs. the textbooks of anesthesiology Strichartz. Anesth Analg 1990;71:158-70 Temp ( o C) pK a

Differential block:

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 LA-sensitive than larger (A  fibers more LA-sensitive than A  fibers) Selective Na v inhibitors in future?

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Bupivacaine produces differential onset of block; mepivacaine does not Br J Anaesth 1998;81:515-21

Genomics of human Nav channels:

Genomics of human Na v channels Only 1 or 2 Na v channel genes in invertebrates 9 distinct Na v channel α -subunit genes in mammals (10 th homologous gene doesn’t code for functional channel) Cell-specific expression and localization of Na v channel gene products Lopreato. Proc Natl Acad Sci 2001;98:7588-92

Chromosomes, distribution of neuronal Nav channels:

Chromosomes, distribution of neuronal Na v channels Na v 1.1 Na v 1.2 Na v 1.3 Na v 1.6 Na v 1.7 Na v 1.8 Na v 1.9 2 2 2 15 2 9 9 CNS, DRG, motor CNS Adult CNS, Injured DRG DRG, motor, CNS DRG, CNS DRG (80% small, 20% lg) DRG (small), hippoc . Lai et al. Curr Opin Neurobiol 2003;13:291-7 Wu, Pan. Brain Res 2004;1029:251-8 1. Na v 1.8, Na v 1.9 relatively TTX insensitive: related to neuropathic pain? 2. Na v 1.3 TTX sensitive: related to ectopic discharges after axotomy? 3. Na v 1.4 skeletal muscle, 1.5 cardiac muscle

Update on local anesthetic pharmacology:

Update on local anesthetic pharmacology 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?:

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:

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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Effects of medical conditions & drugs on LA dosing & kinetics Renal failure : ↑ Vd; ↑ accumulation of metabolic products Hepatic failure : ↑ amide Vd, ↓ amide clearance Cardiac failure; β and H2 blockers : ↓ hepatic blood flow and ↓ amide clearance Cholinesterase deficiency or inhibition : ↓ ester clearance Pregnancy : ↑ hepatic blood flow; ↑ amide clearance; ↓ protein binding

Update on local anesthetic pharmacology:

Update on local anesthetic pharmacology History and general considerations Na channels, cellular electrophysiology, & local anesthetic actions General characteristics of local anesthesia LA pharmacokinetics LA cardiovascular toxicity Summary

LAs bind and inhibit many differing receptors and channels:

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

LAs bind and inhibit many differing receptors and channels:

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

LAs bind and inhibit many differing receptors and channels:

LAs bind and inhibit many differing receptors and channels Na, K, Ca channels G-protein modulation of channels Many enzymes Adenylyl cyclase Guanylyl cyclase Lipases Many receptors Nicotinic acetylcholine NMDA β 2 -adrenergic Important for spinal, epidural, or systemic effects? Anesthesiology 1990; 72:711-34

LAs bind and inhibit many differing receptors and channels:

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

Cardiovascular toxicity from local anesthetics:

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:

LA blood concentrations producing cardiac arrest in dogs: similar rank order as for potency Groban. Anesth Analg 2000;91:1103-11 μ g/mL

Ventricular arrhythmias after supraconvulsant (2x) doses of LAs:

Ventricular arrhythmias after supraconvulsant (2x) doses of LAs N Feldman. Anesth Analg 1989;69:794-801

LA infusions, cardiac arrest & resuscitation in dogs:

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 Groban. Anesth Analg 2000;91:1103; Anesth Analg 2001;92:37; RAPM 2002;27:460 % of animals

Is there one common mechanism for LA-induced cardiac death?:

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!

PowerPoint Presentation:

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

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

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

PowerPoint Presentation:

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

Update on local anesthetic pharmacology:

Update on local anesthetic pharmacology History and general considerations Na channels, cellular electrophysiology, & local anesthetic actions General characteristics of local anesthesia LA pharmacokinetics LA cardiovascular toxicity Summary

Summary:

Summary LAs bind and inhibit Na v channels Other drugs that inhibit Na v channels Pharmacodynamic effects of medical conditions, additives Differential block and specific Na v channel types Toxicity: CNS vs. CV; neurotoxicity; allergy Resuscitation See: http://www1.wfubmc.edu/anesthesiology/research/faculty_presentations.htm

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